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OBJECTIVE: The factor structure of the Children's Eating Attitudes Test (ChEAT) and the predictors of problem eating were examined in young boys and girls. METHODS: Two hundred and twenty eight children from Grades 2 and 4 completed questionnaires which examined problem eating attitudes and behaviors, body image, and self-concepts. RESULTS: Four factors were found for girls and boys. The girls' four factors, Dieting, Food Preoccupation, Social Pressure to Eat, and Restricting and Purging, corresponded closely to previous studies with older girls and women. Four different factors were found for the boys, Global Problems, Dieting versus Purging, Dieting and Food Preoccupation, and Emotional Eating. However, dieting behaviors in both girls and boys were predicted by poorer body image and in boys emotional concerns about eating were predicted by poorer body image and lower self-concepts. DISCUSSION: There is still relatively little research that has examined problem eating attitudes and behaviors of boys and men. As boys tend to report infrequent dieting, we may need to focus more on the emotional concerns about eating and becoming overweight as a potential indicator of eating problems in boys. [ABSTRACT FROM AUTHOR]

Foot-and-mouth disease vaccination using inactivated virus is suboptimal, as the icosahedral viral capsids often disassemble into antigenically distinct pentameric units during long-term storage, or exposure to elevated temperature or lowered pH, and thus raise a response that is no longer protective. Furthermore, as foot-and-mouth disease virus (FMDV)'s seven serotypes are antigenically diverse, cross-protection from a single serotype vaccine is limited, and most existing mouse and bovine antibodies and camelid single-domain heavy chain-only antibodies are serotype-specific. For quality control purposes, there is a real need for pan-serotype antibodies that clearly distinguish between pentamer (12S) and protective intact FMDV capsid. To date, few cross-serotype bovine-derived antibodies have been reported in the literature. We identify a bovine antibody with an ultralong CDR-H3, Ab117, whose structural analysis reveals that it binds to a deep, hydrophobic pocket on the interior surface of the capsid via the CDR-H3. Main-chain and hydrophobic interactions provide broad serotype specificity. ELISA analysis confirms that Ab117 is a novel pan-serotype and conformational epitope-specific 12S reagent, suitable for assessing capsid integrity.

Microcystin-LR (MCLR) exposure has been associated with development of hepatocellular carcinoma (HCC). Many of the carcinogenic mechanisms for MCLR have been attributed to the induction of cell survival and proliferation through altered protein phosphorylation pathways by inhibition of protein phosphatases 1 (PP1) and PP2A. The current study determined MCLR effects on the phosphoproteome in human HepaRG cells. Differentiated HepaRG cells were treated with either vehicle or MCLR followed by phosphoproteomic analysis and Western blotting of MAPK-activated proteins. MCLR decreased cell viability at 24 h at doses as low as 0.03 μM. MCLR also caused a dose-dependent increase in phosphorylation of signaling and stress kinases. The number of decreased phosphosites by 0.1 μM MCLR was similar between the 2 h (212) and 24 h (154) timepoints. In contrast, a greater number of phosphosites were increased at 24 h (567) versus the 2 h timepoint (136), indicating the hyperphosphorylation state caused by MCLR-mediated inhibition of PPs is time-dependent. A kinase perturbation analysis predicted that MCLR exposure at both 2 h and 24 h increased the function of aurora kinase B (AURKB), checkpoint kinase 1 (CHEK1), and serum and glucocorticoid-regulated kinase 1 (SGK1). STRING database analysis of the phosphosites altered by MCLR exposure revealed pathways associated with cell proliferation and survival, including ribosomal protein S6 kinase (RSK), and vascular endothelial growth factor receptor (VEGFR2)-mediated vascular permeability. In addition, several cancer-related KEGG pathways were enriched at both 2 h and 24 h timepoints, and multiple cancer-related disease-gene associations were identified at the 24 h timepoint. Many of the kinases and pathways described above play crucial roles in the development of HCC by affecting processes such as invasion and metastasis. Overall, our data indicate that MCLR-mediated changes in protein phosphorylation involve biological pathways related to carcinogenesis that may contribute to the development of HCC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: John Clarke reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Transverse (t)-tubules drive the rapid and synchronous Ca 2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca 2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca 2+ ., Methods: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca 2+ , and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure., Results: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca 2+ release in the cell interior. Systolic Ca 2+ , I Ca-L , sarcoplasmic reticulum Ca 2+ content, and sarcoendoplasmic reticulum Ca 2+ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca 2+ transient, the rate of Ca 2+ removal, and the peak L-type Ca 2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria., Conclusions: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of I Ca-L , sarcoplasmic reticulum Ca 2+ content, and systolic Ca 2+ . We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy., Competing Interests: None.

The growing co-consumption of botanical natural products with conventional medications has intensified the need to understand potential effects on drug safety and efficacy. This review delves into the intricacies of intestinal pharmacokinetic interactions between botanical natural products and drugs, such as alterations in drug solubility, permeability, transporter activity, and enzyme-mediated metabolism. It emphasizes the importance of understanding how drug solubility, dissolution, and osmolality interplay with botanical constituents in the gastrointestinal tract, potentially altering drug absorption and systemic exposure. Unlike reviews that focus primarily on enzyme and transporter mechanisms, this article highlights the lesser known but equally important mechanisms of interaction. Applying the Biopharmaceutics Drug Disposition Classification System (BDDCS) can serve as a framework for predicting and understanding these interactions. Through a comprehensive examination of specific botanical natural products such as byakkokaninjinto, green tea catechins, goldenseal, spinach extract, and quercetin, we illustrate the diversity of these interactions and their dependence on the physicochemical properties of the drug and the botanical constituents involved. This understanding is vital for healthcare professionals to effectively anticipate and manage potential natural product-drug interactions, ensuring optimal patient therapeutic outcomes. By exploring these emerging mechanisms, we aim to broaden the scope of natural product-drug interaction research and encourage comprehensive studies to better elucidate complex mechanisms.

The third complementary-determining regions of the heavy-chain (CDR3H) variable regions (VH) of some cattle antibodies are highly extended, consisting of 48 or more residues. These `ultralong' CDR3Hs form β-ribbon stalks that protrude from the surface of the antibody with a disulfide cross-linked knob region at their apex that dominates antigen interactions over the other CDR loops. The structure of the Fab fragment of a naturally paired bovine ultralong antibody (D08), identified by single B-cell sequencing, has been determined to 1.6 Å resolution. By swapping the D08 native light chain with that of an unrelated antigen-unknown ultralong antibody, it is shown that interactions between the CDR3s of the variable domains potentially affect the fine positioning of the ultralong CDR3H; however, comparison with other crystallographic structures shows that crystalline packing is also a major contributor. It is concluded that, on balance, the exact positioning of ultralong CDR3H loops is most likely to be due to the constraints of crystal packing., (open access.)

Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCO gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1b gene cluster knockout and human SLCO1B1 and SLCO1B3 gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [ Silybum marianum ]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC 0-24h only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC 50 values for the relevant OATPs/Oatps. Silymarin increased the C max of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter ( SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathologic and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1 and SLCO1B3. Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1 expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multifactorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55-fold from the diet alone and the 1.88-fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multifactorial pharmacokinetic interactions. SIGNIFICANCE STATEMENT: Advanced stages of NAFLD cause decreased hepatic OATP1B abundance and increase systemic exposure to OATP substrates in human patients. The humanized OATP1B mouse strain may provide a clinically relevant model to recapitulate these observations and predict pharmacokinetic interactions in NAFLD. This research characterized three diet-induced and one drug-induced NAFLD model in a humanized OATP1B mouse model. Additionally, a multifactorial pharmacokinetic interaction was observed between silymarin and NAFLD., (Copyright © 2024 by The Author(s).)

Purpose: Green tea is a widely consumed beverage. A recent clinical study reported green tea decreased systemic exposure of raloxifene and its glucuronide metabolites by 34-43%. However, the underlying mechanism(s) remains unknown. This study investigated a change in raloxifene's solubility as the responsible mechanism., Methods: The effects of green tea extract, (-)-epigallocatechin gallate (EGCG), and (-)-epigallocatechin (EGC) on raloxifene's solubility were assessed in fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluids (FeSSIF). EGCG and EGC represent green tea's main bioactive constituents, flavan-3-gallate and flavan-3-ol catechins respectively, and the tested concentrations (mM) match the µg/mg of each compound in the extract. Our mouse study (n = 5/time point) evaluated the effect of green tea extract and EGCG on the systemic exposure of raloxifene., Results: EGCG (1 mM) and EGC (1.27 mM) decreased raloxifene's solubility in FaSSIF by 78% and 13%, respectively. Micelle size in FaSSIF increased with increasing EGCG concentrations (> 1000% at 1 mM), whereas EGC (1.27 mM) did not change micelle size. We observed 3.4-fold higher raloxifene solubility in FeSSIF compared to FaSSIF, and neither green tea extract nor EGCG significantly affected raloxifene solubility or micelle size in FeSSIF. The mice study showed that green tea extract significantly decreased raloxifene C max by 44%, whereas EGCG had no effect. Green tea extract and EGCG did not affect the AUC 0-24 h of raloxifene or the metabolite-to-parent AUC ratio., Conclusions: This study demonstrated flavan-3-gallate catechins may decrease solubility of poorly water-soluble drugs such as raloxifene, particularly in the fasted state., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin C max and area under the blood concentration versus time curve (AUC) by 27% and 23%, respectively, but half-life and renal clearance were unchanged. These observations suggested goldenseal altered processes involved in metformin absorption. The underlying mechanism(s) remain(s) unknown. One mechanism for the decreased metformin systemic exposure is inhibition by goldenseal of intestinal uptake transporters involved in metformin absorption. Goldenseal extract and three goldenseal alkaloids (berberine, (-)- β -hydrastine, hydrastinine) were tested as inhibitors of organic cation transporter (OCT) 3, plasma membrane monoamine transporter (PMAT), and thiamine transporter (THTR) 2 using human embryonic kidney 293 cells overexpressing each transporter. The goldenseal extract, normalized to berberine content, was the strongest inhibitor of each transporter (IC 50 : 4.9, 13.1, and 5.8 μ M for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice compared the effects of berberine, (-)- β -hydrastine, goldenseal extract, and imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract and imatinib significantly decreased metformin C max by 31% and 25%, respectively, and had no effect on half-life. Berberine and (-)- β -hydrastine had no effect on metformin pharmacokinetics, indicating neither alkaloid alone precipitated the interaction in vivo. A follow-up murine study involving intravenous metformin and oral inhibitors examined the contributions of basolateral enteric/hepatic uptake transporters to the goldenseal-metformin interaction. Goldenseal extract and imatinib had no effect on metformin AUC and half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake transporters. Results may have implications for patients taking goldenseal with drugs that are substrates for OCT3 and THTR2. SIGNIFICANCE STATEMENT: Goldenseal is used to self-treat respiratory infections and digestive disorders. We investigated potential mechanisms for the clinical pharmacokinetic interaction observed between goldenseal and metformin, specifically inhibition by goldenseal of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters in vitro and decreased metformin systemic exposure in mice. These data may have broader implications for patients co-consuming goldenseal with other drugs that are substrates for these transporters., (Copyright © 2023 by The Author(s).)

Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (K i  ~2 μM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well-characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4'-glucuronide, and raloxifene 6-glucuronide were evaluated in 16 healthy adults via a three-arm crossover, fixed-sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC 0-96h ratio to ~0.60 after both acute and chronic administration, which is below the predefined no-effect range (0.75-1.33). Lack of change in terminal half-life and glucuronide-to-raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC 50 , 0.37-12 μM). Another potential mechanism, interruption by green tea of gut microbe-mediated raloxifene reabsorption, prompted a follow-up exploratory clinical study to evaluate the potential for a green tea-gut microbiota-drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT-mediated drug interactions are needed. Informing patients about the risk of co-consuming green tea with raloxifene may be considered., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Leadless pacemakers (LPs) may mitigate the risk of lead failure and pocket infection related to conventional transvenous pacemakers. Atrial LPs are currently being investigated. However, the optimal and safest implant site is not known., Objectives: We aimed to evaluate the right atrial (RA) anatomy and the adjacent structures using complementary analytic models [gross anatomy, cardiac magnetic resonance imaging (MRI), and computer simulation], to identify the optimal safest location to implant an atrial LP human., Methods and Results: Wall thickness and anatomic relationships of the RA were studied in 45 formalin-preserved human hearts. In vivo RA anatomy was assessed in 100 cardiac MRI scans. Finally, 3D collision modelling was undertaken assessing for mechanical device interaction. Three potential locations for an atrial LP were identified; the right atrial appendage (RAA) base, apex, and RA lateral wall. The RAA base had a wall thickness of 2.7 ± 1.6 mm, with a low incidence of collision in virtual implants. The anteromedial recess of the RAA apex had a wall thickness of only 1.3 ± 0.4 mm and minimal interaction in the collision modelling. The RA lateral wall thickness was 2.6 ± 0.9 mm but is in close proximity to the phrenic nerve and sinoatrial artery., Conclusions: Based on anatomical review and 3D modelling, the best compromise for an atrial LP implantation may be the RAA base (low incidence of collision, relatively thick myocardial tissue, and without proximity to relevant epicardial structures); the anteromedial recess of the RAA apex and lateral wall are alternate sites. The mid-RAA, RA/superior vena cava junction, and septum appear to be sub-optimal fixation locations., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Despite being uncommon, speech-induced atrial tachycardias carry significant morbidity and affect predominantly healthy individuals. Little is known about their mechanism, treatment, and prognosis. In this review, we seek to identify the underlying connections and pathophysiology between speech and arrhythmias while providing an informed approach to evaluation and management., (© 2023 Heart Rhythm Society. Published by Elsevier Inc.)

Microcystin-leucine arginine (MCLR) is one of the most common and toxic microcystin variants, a class of cyanotoxins produced by cyanobacteria. A major molecular mechanism for MCLR-elicited liver toxicity involves the dysregulation of protein phosphorylation through protein phosphatase (PP) inhibition and mitogen-activated protein kinase (MAPK) modulation. In this study, specific pharmacological MAPK inhibitors were used in HepaRG cells to examine the pathways associated with MCLR cytotoxicity. SB203580 (SB), a p38 inhibitor, rescued HepaRG cell viability, whereas treatment with SP600125 (JNK inhibitor), MK2206 (AKT inhibitor), or N-acetylcysteine (reactive oxygen species scavenger) did not. Phosphoproteomic analysis revealed that phosphosites-which were altered by the addition of SB compared to MCLR treatment alone-included proteins involved in RNA processing, cytoskeletal stability, DNA damage response, protein degradation, and cell death. A closer analysis of specific proteins in some of these pathways indicated that SB reversed the MCLR-mediated phosphorylation of the necroptosis-associated proteins, the mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine kinase 1 (RIP1), DNA damage response proteins, ataxia telangiectasia and Rad3-related kinase (ATR), and checkpoint kinase 1 (CHK1). Overall, these data implicate p38/MK2, DNA damage, and necroptosis in MCLR-mediated hepatotoxicity, and suggest these pathways may be targets for prevention prior to, or treatment after, MCLR toxicity.

Context: Research and policy studies alike have enumerated population and community health benefits of system integration between medical, public health, and social entities. The emergence of the COVID-19 pandemic revealed the necessity of a well-trained and adequately staffed public health and medical workforce in order to process SARS-CoV-2 cases and prevent subsequent transmission. Higher education systems, in particular, represented defined populations of exposure and transmission. Opportunities existed for collaboration and task sharing between institutions of higher education and local public health departments to limit spread and impacts., Program: This article describes the Pandemic Response Officer (PRO) program at Cornell University, a team of staff and students created during the intensity of the pandemic to benefit the Tompkins County and Cornell University communities., Implementation: The PRO program was formed in January 2021, with an original team of 8 individuals, working iteratively to investigate and support employee cases and exposures. Implementation was motivated by Cornell University's dual responsibility as a large employer that also possessed SARS-CoV-2 test results of employees. PROs loaded case information into a shared HIPPA-compliant electronic record that collected information for case notification, case investigation, isolation support, contact tracing, contact notification, and quarantine support. Over time, the PROs grew to a team of 25, gaining responsibilities as university and public health systems shared roles to maximize resources., Evaluation: From January 1 to December 31, 2021, PROs managed 773 employee and 2943 student cases. During the Omicron surge (November 28-December 31, 2021), PROs saved the public health department an estimated 2797 hours of effort, equating to more than 10 professionals working full-time, evenings and weekends, to process cases and contacts during this interval., Discussion: By integrating efforts between a university and public health agency, this intervention minimized SARS-CoV-2 transmission via expedient case support and alleviated strain on public health systems by expanding the public health workforce., Competing Interests: No authors report relevant affiliations or conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc.)

The utility of X-ray crystal structures determined under ambient-temperature conditions is becoming increasingly recognized. Such experiments can allow protein dynamics to be characterized and are particularly well suited to challenging protein targets that may form fragile crystals that are difficult to cryo-cool. Room-temperature data collection also enables time-resolved experiments. In contrast to the high-throughput highly automated pipelines for determination of structures at cryogenic temperatures widely available at synchrotron beamlines, room-temperature methodology is less mature. Here, the current status of the fully automated ambient-temperature beamline VMXi at Diamond Light Source is described, and a highly efficient pipeline from protein sample to final multi-crystal data analysis and structure determination is shown. The capability of the pipeline is illustrated using a range of user case studies representing different challenges, and from high and lower symmetry space groups and varied crystal sizes. It is also demonstrated that very rapid structure determination from crystals in situ within crystallization plates is now routine with minimal user intervention., (open access.)

Background: The impact of preprocedure imaging on the safety and effectiveness of left atrial appendage occlusion (LAAO) remains unclear., Objectives: This study sought to determine the rates of use of preprocedure computed tomography (CT)/cardiac magnetic resonance (CMR) and its association with safety and effectiveness of LAAO procedures., Methods: The National Cardiovascular Data Registry LAAO Registry was used to evaluate patients who underwent attempted LAAO with the WATCHMAN and WATCHMAN FLX devices between January 1, 2016, and June 30, 2021. Safety and effectiveness of LAAO procedures was compared by use vs nonuse of preprocedural CT/CMR. Outcomes of interest included implantation success (deployment and release of device), device success (device released with peridevice leak <5 mm), and procedure success (device released with peridevice leak <5 mm and no in-hospital major adverse events [MAE]). Multivariable logistic regression was used to assess the relationship between preprocedure imaging and outcomes., Results: Preprocedure CT/CMR was used for 18.2% (n = 20,851) of the 114,384 procedures in this study. CT/CMR use was more common among government and university hospitals and hospitals in the Midwest and South; it was less common among patients with uncontrolled hypertension, with abnormal renal function, and without prior thromboembolism. Overall rates of implantation success, device success, and procedure success were 93.4%, 91.2%, and 89.4%, respectively. Preprocedure CT/CMR was independently associated with an increased likelihood of implantation success (OR: 1.08; 95% CI: 1.00-1.17), device success (OR: 1.10; 95% CI: 1.04-1.16), and procedural success (OR: 1.07; 95% CI: 1.02-1.13). MAE were uncommon (2.3%) and not associated with use of preprocedure CT/CMR (OR: 1.02; 95% CI: 0.92-1.12)., Conclusions: Preprocedure CT/CMR was associated with an increased likelihood of successful LAAO implantation; however, the magnitude of benefit appears small and it was not associated with MAE., Competing Interests: Funding Support and Author Disclosures Dr Faridi was supported by research funding from the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL161424). Dr Curtis has a contract with the American College of Cardiology for his role as Senior Medical Officer of the National Cardiovascular Disease Registry; and has received salary support from the American College of Cardiology and National Cardiovascular Disease Registry; and holds equity interest in Medtronic. Dr Freeman has received research funding from the National Institutes of Health/National Heart, Lung, and Blood Institute and the American College of Cardiology National Cardiovascular Data Registry; has received consulting/advisory board fees from Medtronic, Boston Scientific, Biosense Webster, and PaceMate; and owns equity in PaceMate. Dr Friedman has received research grants from the American Heart Association, National Cardiovascular Data Registry, Boston Scientific, Abbott, Medtronic, Merit Medical, and Biosense Webster; and consulting fees from Abbott and AtriCure. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The GUIDE-IT trial was, a multicenter, randomized, parallel group, unblinded study that randomized patients to having heart failure therapy titrated to achieve an NT-proBNP <1000 pg/mL or to usual clinical care., Methods and Results: We performed pre-specified subgroup analysis to look for the race and ethnicity-based differences in clinical outcomes of patients who were able to achieve GDMT or target NT-proBNP concentration of ≤1000 pg/mL at 90 days of follow-up. There were 894 patients enrolled in GUIDE-IT study. Of these, 733 participants had available data on 90-day guideline directed triple therapy and 616 on NT-proBNP. 35% of the patients were Black and 6% were Hispanic. Black patients were younger, had more comorbidities, lower EF, and higher NYHA class compared with non-Black. Adjusting for 90-day NT-proBNP and important baseline covariates, Black patients were at a higher risk than non-Black patients for HF hospitalization [HR, 2.19; 95% CI, 1.51-3.17; p < 0.0001], but at a similar risk for mortality [HR, 0.85.; 95% CI, 0.44-1.66; p = 0.64]. Similar results were seen adjusting for 90-day GDMT [HF hospitalization: Black vs non-Black, HR: 1.97; 1.41-2.77, P < 0.0001; mortality: HR: 0.70; 0.39-1.26, p = 0.23]. There were no significant differences between Hispanic and non-Hispanic patients with respect to heart failure hospitalization, cardiovascular or all-cause mortality. Over the study period, Black and Hispanic patients experienced smaller changes in physical function and quality of life as measured by the Kansas City Cardiomyopathy Questionnaire overall score., Conclusion: Compared to non-Black patients, Black patients in GUIDE-IT study had a higher risk of heart failure hospitalization, but a comparable risk of mortality, despite improved use of GDMT and achievement of similar biomarker targets., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Nonalcoholic steatohepatitis (NASH) causes liver extracellular matrix (ECM) remodeling and is a risk factor for fibrosis and hepatocellular carcinoma (HCC). Microcystin-LR (MCLR) is a hepatotoxin produced by fresh-water cyanobacteria that causes a NASH-like phenotype, liver fibrosis, and is also a risk factor for HCC. The focus of the current study was to investigate and compare hepatic recovery after cessation of MCLR exposure in healthy versus NASH animals. Male Sprague-Dawley rats were fed either a control or a high fat/high cholesterol (HFHC) diet for eight weeks. Animals received either vehicle or 30 μg/kg MCLR (i.p: 2 weeks, alternate days). Animals were euthanized at one of three time points: at the completion of the MCLR exposure period and after 2 and 4 weeks of recovery. Histological staining suggested that after four weeks of recovery the MCLR-exposed HFHC group had less steatosis and more fibrosis compared to the vehicle-exposed HFHC group and MCLR-exposed control group. RNA-Seq analysis revealed dysregulation of ECM genes after MCLR exposure in both control and HFHC groups that persisted only in the HFHC groups during recovery. After 4 weeks of recovery, MCLR hepatotoxicity in pre-existing NASH persistently dysregulated genes related to cellular differentiation and HCC. These data demonstrate impaired hepatic recovery and persistent carcinogenic changes after MCLR toxicity in pre-existing NASH., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background Racial and ethnic disparities contribute to differences in access and outcomes for patients undergoing heart transplantation. We evaluated contemporary outcomes for heart transplantation stratified by race and ethnicity as well as the new 2018 allocation system. Methods and Results Adult heart recipients from 2011 to 2020 were identified in the United Network for Organ Sharing database and stratified into 3 groups: Black, Hispanic, and White. We analyzed recipient and donor characteristics, and outcomes. Among 32 353 patients (25% Black, 9% Hispanic, 66% White), Black and Hispanic patients were younger, more likely to be women and have diabetes mellitus or renal disease (all, P <0.05). Over the study period, the proportion of Black and Hispanic patients listed for transplant increased: 21.7% to 28.2% ( P =0.003) and 7.7% to 9.0% ( P =0.002), respectively. Compared with White patients, Black patients were less likely to undergo transplantation (adjusted hazard ratio [aHR], 0.87; CI, 0.84-0.90; P <0.001), but had a higher risk of post-transplant death (aHR, 1.14; CI, 1.04-1.24; P =0.004). There were no differences in transplantation likelihood or post-transplant mortality between Hispanic and White patients. Following the allocation system change, transplantation rates increased for all groups ( P <0.05). However, Black patients still had a lower likelihood of transplantation than White patients (aHR, 0.90; CI, 0.79-0.99; P =0.024). Conclusions Although the proportion of Black and Hispanic patients listed for cardiac transplantation have increased, significant disparities remain. Compared with White patients, Black patients were less likely to be transplanted, even with the new allocation system, and had a higher risk of post-transplantation death.

The left atrial posterior wall has many embryologic, anatomic, and electrophysiologic characteristics, that are important for the initiation and maintenance of persistent atrial fibrillation. The left atrial posterior wall is a potential target for ablation in patients with persistent atrial fibrillation, a population in whom pulmonary vein isolation alone has resulted in unsatisfactory recurrence rates. Published clinical studies report conflicting results on the safety and efficacy of posterior wall isolation. Emerging technologies including optimized use of radiofrequency ablation, pulse field ablation, and combined endocardial/epicardial ablation may optimize approaches to posterior wall isolation and reduce the risk of injury to nearby structures such as the esophagus. Critical evaluation of future and ongoing clinical studies of posterior wall isolation requires careful scrutiny of many characteristics, including intraprocedural definition of posterior wall isolation, concomitant extrapulmonary vein ablation, and study endpoints., (© 2021 Wiley Periodicals LLC.)

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 19 (COVID-19), is a novel human Coronavirus that is responsible for about 300,000 deaths worldwide. To date, there is no confirmed treatment or vaccine prevention strategy against COVID-19. Due to the urgent need for effective treatment, drug repurposing is regarded as the immediate option. Potential drugs can often be identified via in silico drug screening experiments. Consequently, there has been an explosion of in silico experiments to find drug candidates or investigate anecdotal claims. One drug with several anecdotal accounts of benefit is Cefuroxime. The aim of this study was to identify and summarize in silico evidence for possible activity of Cefuroxime against SARS-CoV-2.To this end, we performed a scoping review of literature of in silico drug repurposing experiments for SARS-CoV-2 using PRISMA-ScR. We searched Medline, Embase, Scopus, Web of Knowledge, and Google Scholar for original studies published between 1st Feb, 2020 and 15th May, 2020 that screened drug libraries, and identified Cefuroxime as a top-ranked potential inhibitor drug against SARS-CoV-2 proteins. Six studies were identified. These studies reported Cefuroxime as a potential inhibitor of 3 key SARS-CoV-2 proteins; main protease, RNA dependent RNA polymerase, and ACE2-Spike complex. We provided a summary of the methodology and findings of the identified studies. Our scoping review identified significant in silico evidence that Cefuroxime may be a potential multi-target inhibitor of SARS-CoV-2. Further in vitro and in vivo studies are required to evaluate the potential of Cefuroxime for COVID-19.Communicated by Ramaswamy H. Sarma.

Microcystins are ubiquitous toxins produced by photoautotrophic cyanobacteria. Human exposures to microcystins occur through the consumption of contaminated drinking water, fish and shellfish, vegetables, and algal dietary supplements and through recreational activities. Microcystin-leucine-arginine (MCLR) is the prototypical microcystin because it is reported to be the most common and toxic variant and is the only microcystin with an established tolerable daily intake of 0.04 µg/kg. Microcystin toxicokinetics is characterized by low intestinal absorption, rapid and specific distribution to the liver, moderate metabolism to glutathione and cysteinyl conjugates, and low urinary and fecal excretion. Molecular toxicology involves covalent binding to and inhibition of protein phosphatases, oxidative stress, cell death (autophagy, apoptosis, necrosis), and cytoskeleton disruption. These molecular and cellular effects are interconnected and are commonly observed together. The main target organs for microcystin toxicity are the intestine, liver, and kidney. Preclinical data indicate microcystins may also have nervous, pulmonary, cardiac, and reproductive system toxicities. Recent evidence suggests that exposure to other hepatotoxic insults could potentiate microcystin toxicity and increase the risk for chronic diseases. This review summarizes the current knowledge for microcystin toxicokinetics, molecular toxicology, and pathophysiology in preclinical rodent models and humans. More research is needed to better understand human toxicokinetics and how multifactorial exposures contribute to disease pathogenesis and progression.

Silybum marianum (L.) Gaertn. (Asteraceae), commonly known as milk thistle, is a botanical natural product used to self-treat multiple diseases such as Type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH). An extract from milk thistle seeds (achenes), termed silymarin, is comprised primarily of several flavonolignans. Systemic concentrations of these flavonolignans can influence the potential biologic effects of silymarin and the risk for pharmacokinetic silymarin-drug interactions. The aims of this research were to determine the roles of organic anion transporting polypeptides (OATPs/Oatps) in silymarin flavonolignan disposition and in pharmacokinetic silymarin-drug interactions. The seven major flavonolignans from silymarin were determined to be substrates for OATP1B1, OATP1B3, and OATP2B1. Sprague Dawley rats were fed either a control diet or a NASH-inducing diet and administered pitavastatin (OATP/Oatp probe substrate), followed by silymarin via oral gavage. Decreased protein expression of Oatp1b2 and Oatp1a4 in NASH animals increased flavonolignan area under the plasma concentration-time curve (AUC) and maximum plasma concentration. The combination of silymarin inhibition of Oatps and NASH-associated decrease in Oatp expression caused an additive increase in plasma pitavastatin AUC in the animals. These data indicate that OATPs/Oatps contribute to flavonolignan cellular uptake and mediate the interaction between silymarin and NASH on pitavastatin systemic exposure., (© 2021 John Wiley & Sons, Ltd.)

Microcystin-LR (MCLR) is a liver and kidney toxin produced by cyanobacteria. Recently, it was demonstrated that MCLR exposure drives the progression of high fat/high cholesterol (HFHC) induced nonalcoholic fatty liver disease (NAFLD) to a more severe state. NAFLD is also a risk factor for chronic kidney disease (CKD), and the current study investigated MCLR renal toxicity in the context of an HFHC diet. Sprague Dawley rats were fed either a control diet or an HFHC diet for 10 weeks. After 6 weeks of diet, animals were administered either vehicle, 10 μg/kg, or 30 μg/kg MCLR via intraperitoneal injection every other day for 4 weeks. HFHC diet alone increased the renal glomerular change histopathology score, and 30 μg/kg MCLR exposure increased this score in both the control group and the HFHC group. In contrast, 30 μg/kg MCLR caused greater proteinuria and cast formation and decreased protein phosphatase 1 and 2A protein expression in the HFHC group. Urinary excretion of KIM-1 increased, but albumin and tamm-horsfall protein did not change after MCLR exposure. The general concordance between KIM-1, polyuria, proteinuria, and renal casts after MCLR exposure suggests that proximal tubule cell damage contributed to these connected pathologies. The control group adapted to repeated MCLR exposure by increasing the urinary elimination of MCLR and its metabolites, whereas this adaptation was blunted in the HFHC group. These data suggest an HFHC diet may increase the severity of certain MCLR-elicited renal toxicities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The popularity of botanical and other purported medicinal natural products (NPs) continues to grow, especially among patients with chronic illnesses and patients managed on complex prescription drug regimens. With few exceptions, the risk of a given NP to precipitate a clinically significant pharmacokinetic NP-drug interaction (NPDI) remains understudied or unknown. Application of static or dynamic mathematical models to predict and/or simulate NPDIs can provide critical information about the potential clinical significance of these complex interactions. However, methods used to conduct such predictions or simulations are highly variable. Additionally, published reports using mathematical models to interrogate NPDIs are not always sufficiently detailed to ensure reproducibility. Consequently, guidelines are needed to inform the conduct and reporting of these modeling efforts. This recommended approach from the Center of Excellence for Natural Product Drug Interaction Research describes a systematic method for using mathematical models to interpret the interaction risk of NPs as precipitants of potential clinically significant pharmacokinetic NPDIs. A framework for developing and applying pharmacokinetic NPDI models is presented with the aim of promoting accuracy, reproducibility, and generalizability in the literature. SIGNIFICANCE STATEMENT: Many natural products (NPs) contain phytoconstituents that can increase or decrease systemic or tissue exposure to, and potentially the efficacy of, a pharmaceutical drug; however, no regulatory agency guidelines exist to assist in predicting the risk of these complex interactions. This recommended approach from a multi-institutional consortium designated by National Institutes of Health as the Center of Excellence for Natural Product Drug Interaction Research provides a framework for modeling pharmacokinetic NP-drug interactions., Competing Interests: The authors have no financial conflicts of interest to disclose., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: A growing population of patients with end-stage heart failure (HF) with reduced ejection fraction has limited treatment options to improve their quality and quantity of life. Although positive inotropes have failed to show survival benefit, these agents may enhance patient-reported health status, that is, symptoms, functional status, and health-related quality of life. We sought to review the available clinical trial data on positive inotrope use in patients with end-stage HF and to summarize evidence supporting the use of these agents to improve health status of patients with end-stage HF., Methods: A literature review of randomized controlled trials examining the use of positive inotropy in HF with reduced ejection fraction was conducted. We searched MEDLINE, SCOPUS, and Web of Science between January 1980 to December 2018 for randomized controlled trials that used as their main outcome measures the effects of inotrope therapy on (1) morbidity/mortality, (2) symptoms, (3) functional status, or (4) health-related quality of life. Inotropes of interest included adrenergic agents, phosphodiesterase inhibitors, calcium sensitizers, myosin activators, and SERCA2a (sarcoplasmic reticulum Ca 2+ -ATPase) modulators., Results: Twenty-two out of 26 inotrope randomized controlled trials measured the effect of inotropes on at least one patient-reported health status domain. Among the 22 studies with patient-related health status outcomes, 11 (50%) gauged symptom response, 15 (68%) reported functional capacity changes, and 12 (54%) reported health-related quality of life measures. Fourteen (64%) of these trials noted positive outcomes in at least one health status domain measured; 11 (79%) of these positive studies used agents that worked through phosphodiesterase inhibition., Conclusions: There has been a lack of standardization surrounding measurement of patient-centered outcomes in studies of inotropes for end-stage HF with reduced ejection fraction. The degree to which positive inotropes can improve patient-reported health status and the adverse risk they pose remains unknown.

Importance: Patient outcomes in heart failure clinical trials are generally better than those observed in real-world settings. This may be related to stricter inclusion and exclusion criteria in clinical trials., Objective: We study sought to characterize the clinical implications of differences between patients in clinical trials and those in a real-world registry of patients receiving left ventricular assist devices (LVADs)., Design, Setting, and Participants: This retrospective cohort study included all patients in INTERMACS (the Interagency Registry for Mechanically Assisted Circulatory Support) who were implanted with an axial flow LVAD from 2010 to 2015 to allow for equivalent comparisons., Main Outcomes and Measures: Differences in patient characteristics and 2-year rates of adverse outcomes with those reported in the ENDURANCE and MOMENTUM 3 clinical trials. Survival analyses were used to assess the relationships between prespecified patient factors and clinical outcomes., Results: Of the 10,937 LVAD recipients identified in INTERMACS between 2010-2015, 44% met at least 1 clinical trial exclusion criterion. The 2-year incidence of stroke and death amongst LVAD recipients in INTERMACS and the landmark clinical trials differed significantly (P<0.04, both). Nevertheless, patients who would have been excluded from the clinical trials did not have dramatically different 2-year mortality outcomes in INTERMACS [2y survival estimate: 66.4%, 95% CI (64.9-67.9%) versus 71.9%, 95% CI (70.6-73.1%)]. Clinical interventions driving a significantly increased risk of death were relatively rare (<5% of implants) and included mechanical ventilation, ECMO, severe thrombocytopenia, and dialysis., Conclusions and Relevance: Most exclusion criteria used in LVAD clinical trials did not afford a substantially greater risk to patients in the real-world setting. In the relatively infrequent cases of end stage renal disease, thrombocytopenia, respiratory failure, and need for ECMO, the risks and benefits of LVAD therapy need careful weighting and further study., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JGR was PI of the Endurance Trial. This study does not alter our adherence to PLOS ONE policies on sharing data and materials.

In the vertebrate central nervous system, groups of functionally related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function., Competing Interests: AK, GD, GW, JC, SG No competing interests declared, (© 2020, Knüfer et al.)

Background: Tricuspid regurgitation (TR) is common in patients with end-stage heart failure receiving left ventricular assist devices (LVADs), but the benefit of concomitant tricuspid valve procedures (TVPs) remains uncertain. This study examined the impact of TVP at the time of LVAD implantation on clinical outcomes and quality of life (QOL) metrics., Methods: We included adult patients in the Interagency Registry for Mechanical Circulatory Support database with various degrees of TR who received continuous-flow LVADs from 2008 to 2017. Patients undergoing concomitant TVP were compared with those without the intervention in a stratified analysis. Descriptive analyses, survival analyses, and Andersen‒Gill hazard models were used as appropriate to examine associations with clinical and patient-centered QOL outcomes., Results: Our analysis included 8,263 (53.1%) mild, 4,252 (33.3%) moderate, and 2,100 (13.5%) severe TR cases. TVP rate increased with severity: 8.6% of mild, 18.0% of moderate, and 43.9% of severe cases. TVP was not associated with survival benefit in cases of mild (adjusted hazard ratio [aHR]: 0.97, 95% CI: 0.79-1.19, p = 0.75), moderate (aHR: 1.03, 95% CI: 0.88-1.20, p = 0.72), or severe (aHR: 1.20, 95% CI: 0.98-1.48, p = 0.08) TR. For patients with combined moderate or severe TR, TVP was associated with increased mortality (log-rank p < 0.01, aHR: 1.13, 95% CI: 1.00-1.27, p = 0.04). After adjusting for TR severity, TVP was associated with increased risk of bleeding, arrhythmia, and stroke (p < 0.01 each) and no improvements in QOL (p > 0.05)., Conclusions: TVP at the time of LVAD implantation was not associated with either improved survival or QOL, and there were associations with increased risk of adverse events among patients with moderate and severe TR., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to escape detection by the immune system. Adenosine signaling through the adenosine 2A receptor (A 2A R) on immune cells elicits a range of immunosuppressive effects which promote tumor growth and limit the efficacy of immune checkpoint inhibitors. Preclinical data with A 2A R inhibitors have demonstrated tumor regressions in mouse models by rescuing T cell function; however, the mechanism and role on other immune cells has not been fully elucidated., Methods: We report here the development of a small molecule A 2A R inhibitor including characterization of binding and inhibition of A 2A R function with varying amounts of a stable version of adenosine. Functional activity was tested in both mouse and human T cells and dendritic cells (DCs) in in vitro assays to understand the intrinsic role on each cell type. The role of adenosine and A 2A R inhibition was tested in DC differentiation assays as well as co-culture assays to access the cross-priming function of DCs. Syngeneic models were used to assess tumor growth alone and in combination with alphaprogrammed death-ligand 1 (αPD-L1). Immunophenotyping by flow cytometry was performed to examine global immune cell changes upon A 2A R inhibition., Results: We provide the first report of AZD4635, a novel small molecule A 2A R antagonist which inhibits downstream signaling and increases T cell function as well as a novel mechanism of enhancing antigen presentation by CD103 + DCs. The role of antigen presentation by DCs, particularly CD103 + DCs, is critical to drive antitumor immunity providing rational to combine a priming agent AZD4635 with check point blockade. We find adenosine impairs the maturation and antigen presentation function of CD103 + DCs. We show in multiple syngeneic mouse tumor models that treatment of AZD4635 alone and in combination with αPD-L1 led to decreased tumor volume correlating with enhanced CD103 + function and T cell response. We extend these studies into human DCs to show that adenosine promotes a tolerogenic phenotype that can be reversed with AZD4635 restoring antigen-specific T cell activation. Our results support the novel role of adenosine signaling as an intrinsic negative regulator of CD103 + DCs maturation and priming. We show that potent inhibition of A 2A R with AZD4635 reduces tumor burden and enhances antitumor immunity. This unique mechanism of action in CD103 + DCs may contribute to clinical responses as AZD4635 is being evaluated in clinical trials with IMFINZI (durvalumab, αPD-L1) in patients with solid malignancies., Conclusion: We provide evidence implicating suppression of adaptive and innate immunity by adenosine as a mechanism for immune evasion by tumors. Inhibition of adenosine signaling through selective small molecule inhibition of A 2A R using AZD4635 restores T cell function via an internal mechanism as well as tumor antigen cross-presentation by CD103 + DCs resulting in antitumor immunity., Competing Interests: Competing interests: A.B., C.M.B., Y.W., N.D., M.Y., J.S., K.S., D.C., L.P., J.D.C., B.L., W.S., R.W., C.R., L.D., S.F., A.G.S. and D.A.M. are employees of AstraZeneca Pharmaceuticals. J.D.C., G.A.B., J.B., M.C., R.K.Y.C., A.S.D., E.H. are employees of Heptares Therapeutics., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Psychiatric comorbidities play a key role in patient selection for left ventricular assist devices (LVADs), but their impact on clinical outcomes is unknown., Objectives: The goal of this study was to examine the clinical impact of psychiatric illness on outcomes in patients receiving LVADs for end-stage heart failure (HF)., Methods: The study identified adults in the Interagency Registry for Mechanically Assisted Circulatory Support with psychiatric comorbidities (history of alcohol abuse, drug use, narcotic dependence, depression, and other major psychiatric diagnoses) receiving continuous-flow LVADs from 2008 to 2017. Demographic characteristics, survival, adverse events, and quality of life scores were compared for patients with and without each psychiatric comorbidity., Results: Over the study period, the prevalence of psychiatric comorbidities was low: alcohol abuse, n = 1,093 (5.5%); drug use, n = 1,077 (5.4%); narcotic dependence, n = 96 (0.5%); depression, n = 401 (2.0%); and other major psychiatric illnesses, n = 265 (1.4%). Narcotic dependence (adjusted hazard ratio: 1.9; 95% confidence interval: 1.2 to 3.0; p = 0.004) and other major psychiatric illnesses (adjusted hazard ratio: 1.4; 95% confidence interval: 1.0 to 1.9; p = 0.02) were associated with increased risk of mortality, whereas alcohol abuse, drug use, and depression were not. All comorbidities except narcotic dependence were associated with increased risk of rehospitalization and device-related infection (both p < 0.05). Kansas City Cardiomyopathy Questionnaire scores were lower from 6 to 24 months' post-implantation among patients with psychiatric comorbidities (p < 0.05)., Conclusions: Despite a low prevalence of psychiatric comorbidities among LVAD recipients, these conditions were associated with mortality risk, adverse events, and poorer quality of life. Further study is needed to understand how specific psychiatric conditions affect outcomes and how to best manage this vulnerable patient population., (Copyright © 2020. Published by Elsevier Inc.)

Arachnoid cysts vary in their size and location. Large cysts may cause symptoms requiring surgery. It is important to assess whether patients with arachnoid cysts and neurologic symptoms can benefit from such surgical interventions., Competing Interests: There are no conflicts of interest to disclose., (© 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

The downregulation of hepatic uptake transporters, including those of the OATP family, are a well known consequence of nonalcoholic steatohepatitis (NASH). Prior studies have shown that the combination of NASH and Oatp1b2 knockout synergistically reduces the clearance of pravastatin (PRAV) in the methionine and choline deficient (MCD) mouse model of NASH, and the current study therefore aimed to determine the impact of NASH and genetic heterozygosity of Oatp1b2 on PRAV clearance, modeling the overlap between the 24% of the human population who are heterozygous for non-functioning OATP1B1, and the ~15% with NASH, potentially placing these people at higher risk of statin-induced myopathy. Therefore, male C57BL/6 wild-type (WT), Oatp1b2+/- (HET), and Oatp1b2-/- (KO) mice were fed either a control (methionine and choline sufficient) or methionine and choline-deficient (MCD) diet to induce NASH. After six weeks of feeding, pravastatin was administered via the carotid artery. Blood and bile samples were collected throughout 90 min after PRAV administration. The concentration of PRAV in plasma, bile, liver, kidney, and muscle was determined by liquid chromatography-tandem mass spectrometry. MCD diet did not alter the plasma AUC values of PRAV in either WT or HET mice. However, the MCD diet increased plasma AUC by 4.4-fold in KO mice. MCD diet and nonfunctional Oatp1b2 synergistically increased not only plasma AUC but also the extrahepatic tissue concentration of pravastatin, whereas the partially decreased function of Oatp1b2 and NASH together were insufficient in significantly altering PRAV pharmacokinetics. These data suggest that a single copy of fully functional OATP1B1 in NASH patients may be sufficient to avoid the increase of pravastatin toxicity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The evaluation of coronary lesions has evolved in recent years. Physiologic-guided revascularization (particularly with pressure-derived fractional flow reserve (FFR)) has led to superior outcomes compared to traditional angiographic assessment. A greater importance, therefore, has been placed on the functional significance of an epicardial lesion. Despite the improvements in the limitations of angiography, insights into the relationship between hemodynamic significance and plaque morphology at the lesion level has shown that determining the implications of epicardial lesions is rather complex. Investigators have sought greater understanding by correlating ischemia quantified by FFR with plaque characteristics determined on invasive and non-invasive modalities. We review the background of the use of these diagnostic tools in coronary artery disease and discuss the implications of analyzing physiological stenosis severity and plaque characteristics concurrently.