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Competing Interests: None declared.

Mucinous ovarian carcinoma (MOC) is a subtype of ovarian cancer that is distinct from all other ovarian cancer subtypes and currently has no targeted therapies. To identify novel therapeutic targets, we developed and applied a new method of differential network analysis comparing MOC to benign mucinous tumours (in the absence of a known normal tissue of origin). This method mapped the protein-protein network in MOC and then utilised structural bioinformatics to prioritise the proteins identified as upregulated in the MOC network for their likelihood of being successfully drugged. Using this protein-protein interaction modelling, we identified the strongest 5 candidates, CDK1, CDC20, PRC1, CCNA2 and TRIP13, as structurally tractable to therapeutic targeting by small molecules. siRNA knockdown of these candidates performed in MOC and control normal fibroblast cell lines identified CDK1, CCNA2, PRC1 and CDC20, as potential drug targets in MOC. Three targets (TRIP13, CDC20, CDK1) were validated using known small molecule inhibitors. Our findings demonstrate the utility of our pipeline for identifying new targets and highlight potential new therapeutic options for MOC patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Background: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%., Methods: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction., Results: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo., Conclusions: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology., Clinical Trials Registration: NCT04510194., Competing Interests: Potential conflicts of interest. J. B. B. reports contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support by NIH, PCORI, Bayer, Boehringer-Ingelheim, Carmot, Corcept, Dexcom, Eli Lilly, Insulet, MannKind, Novo Nordisk, and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, Aqua Medical Inc, AstraZeneca, Boehringer-Ingelheim, CeQur, Corcept Therapeutics, Eli Lilly, embecta, GentiBio, Glyscend, Insulet, Mellitus Health, Metsera, Moderna, Novo Nordisk, Pendulum Therapeutics, Praetego, Stability Health, Tandem, Terns Inc, and Vertex.; personal compensation for expert testimony from Medtronic MiniMed; participation on advisory boards for Altimmune, AstraZeneca, and Insulet; a leadership role for the Association of Clinical and Translational Science; and stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, Praetego, and Stability Health. M. A. P. receives consulting fees from Opticyte and Cytovale. A. B. K. has served as an external consultant for Roche Diagnostics; received speaker honoraria from Siemens Healthcare Diagnostics, the American Kidney Fund, the National Kidney Foundation, the American Society of Nephrology, and Yale University Department of Laboratory Medicine; research support unrelated to this work from Siemens Healthcare Diagnostics, Kyowa Kirin Pharmaceutical Development, the Juvenile Diabetes Research Foundation, and the NIH; support for travel from College of American Pathologists Point-Of-Care Testing Committee; participation on an advisory board for the Minnesota Newborn Screening Advisory Committee; grants from NIH and JDRF for multiple unrelated clinical research projects and Kyowa Kirin Pharmaceutical Development and Siemens Healthcare Diagnostics for unrelated clinical research studies; and leadership roles for the American Board of Clinical Chemistry, Association for Diagnostics and Laboratory Medicine (ADLM) Evidence-Based Laboratory Medicine Subcommittee, and ADLM Academy Test Utilization Committee. M. R. R. reports consulting fees from 20/20 Gene Systems for coronavirus disease 2019 testing. D. B. R. reports grants from the NIH NCATS ACTIV-6 Steering Committee Chair. K. C. reports stock or stock options for United Health Group. C. T. B. reports consulting fees from NCATS/DCRI and the ACTIV-6 Executive Committee and support for travel from Academic Medical Education. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The Myocyte enhancer factor-2 (MEF2) transcription factor plays a vital role in orchestrating muscle differentiation. While MEF2 cannot effectively induce myogenesis in naïve cells, it can potently accelerate myogenesis in mesodermal cells. This includes in Drosophila melanogaster imaginal disc myoblasts, where triggering premature muscle gene expression in these adult muscle progenitors has become a paradigm for understanding the regulation of the myogenic program. Here, we investigated the global consequences of MEF2 overexpression in the imaginal wing disc myoblasts, by combining RNA-sequencing with RT-qPCR and immunofluorescence. We observed the formation of sarcomere-like structures that contained both muscle and cytoplasmic myosin, and significant upregulation of muscle gene expression, especially genes essential for myofibril formation and function. These transcripts were functional since numerous myofibrillar proteins were detected in discs using immunofluorescence. Interestingly, muscle genes whose expression is restricted to the adult stages were not activated in these adult myoblasts. These studies confirm a broad activation of the myogenic program in response to MEF2 expression and suggest that additional regulatory factors are required for promoting the adult muscle-specific program. Our findings contribute to understanding the regulatory mechanisms governing muscle development and highlight the multifaceted role of MEF2 in orchestrating this intricate process., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Coronary artery disease (CAD) and severe aortic valve stenosis (AS) frequently coexist. While pre-transcatheter aortic valve replacement (TAVR) computed tomography angiography (CTA) allows to rule out obstructive CAD, interpreting hemodynamic significance of intermediate stenoses is challenging. This study investigates the incremental value of CT-derived fractional flow reserve (CT-FFR), quantitative coronary plaque characteristics (e.g., stenosis degree, plaque volume, and composition), and peri-coronary adipose tissue (PCAT) density to detect hemodynamically significant lesions among those with AS and CAD., Materials and Methods: We included patients with severe AS and intermediate coronary lesions (20-80% diameter stenosis) who underwent pre-TAVR CTA and invasive coronary angiogram (ICA) with resting full-cycle ratio (RFR) assessment between 08/16 and 04/22. CTA image analysis included assessment of CT-FFR, quantitative coronary plaque analysis, and PCAT density. Coronary lesions with RFR ≤ 0.89 indicated hemodynamic significance as reference standard., Results: Overall, 87 patients (age 77.9 ± 7.4 years, 38% female) with 95 intermediate coronary artery lesions were included. CT-FFR showed good discriminatory capacity (area under receiver operator curve (AUC) = 0.89, 95% confidence interval (CI) 0.81-0.96, p < 0.001) to identify hemodynamically significant lesions, superior to anatomical assessment, plaque morphology, and PCAT density. Plaque composition and PCAT density did not differ between lesions with and without hemodynamic significance. Univariable and multivariable analyses revealed CT-FFR as the only predictor for functionally significant lesions (odds ratio 1.28 (95% CI 1.17-1.43), p < 0.001). Overall, CT-FFR ≤ 0.80 showed diagnostic accuracy, sensitivity, and specificity of 88.4% (95%CI 80.2-94.1), 78.5% (95%CI 63.2-89.7), and 96.2% (95%CI 87.0-99.5), respectively., Conclusion: CT-FFR was superior to CT anatomical, plaque morphology, and PCAT assessment to detect functionally significant stenoses in patients with severe AS., Clinical Relevance Statement: CT-derived fractional flow reserve in patients with severe aortic valve stenosis may be a useful tool for non-invasive hemodynamic assessment of intermediate coronary lesions, while CT anatomical, plaque morphology, and peri-coronary adipose tissue assessment have no incremental or additional benefit. These findings might help to reduce pre-transcatheter aortic valve replacement invasive coronary angiogram., Key Points: • Interpreting the hemodynamic significance of intermediate coronary stenoses is challenging in pre-transcatheter aortic valve replacement CT. • CT-derived fractional flow reserve (CT-FFR) has a good discriminatory capacity in the identification of hemodynamically significant coronary lesions. • CT-derived anatomical, plaque morphology, and peri-coronary adipose tissue assessment did not improve the diagnostic capability of CT-FFR in the hemodynamic assessment of intermediate coronary stenoses., (© 2024. The Author(s).)

Purpose: To investigate associations between statin use and glaucoma in the 2017-2022 All of Us (AoU) Research Program., Design: Cross-sectional, population-based., Participants: 79,742 adult participants aged ≥ 40 years with hyperlipidemia and with electronic health record (EHR) data in the AoU database., Methods: Hyperlipidemia, glaucoma status, and statin use were defined by diagnoses and medication information in EHR data collected by AoU. Logistic regression analysis was performed to evaluate the association between statin use and glaucoma likelihood. Logistic regression modeling was used to examine associations between glaucoma and all covariates included in adjusted analysis. Serum low-density lipoprotein cholesterol (LDL-C) was used to assess hyperlipidemia severity. Analyses stratified by LDL-C level and age were performed., Main Outcome Measures: Any glaucoma as defined by International Classification of Diseases (ICD) codes found in EHR data., Results: Of 79,742 individuals with hyperlipidemia in AoU, there were 6,365 (8.0%) statin users. Statin use was associated with increased glaucoma prevalence when compared with statin non-use (adjusted odds ratio [aOR]: 1.13, 95% confidence interval [CI]: 1.01-1.26). Higher serum levels of LDL-C were associated with increased odds of glaucoma (aOR: 1.003, 95% CI: 1.003, 1.004). Statin users had significantly higher LDL-C levels compared to nonusers (144.9 mg/dL versus 136.3 mg/dL, p-value < 0.001). Analysis stratified by LDL-C identified positive associations between statin use and prevalence of glaucoma among those with optimal (aOR = 1.39, 95% CI = 1.05-1.82) and high (aOR = 1.37, 95% CI = 1.09-1.70) LDL-C levels. Age-stratified analysis showed a positive association between statin use and prevalence of glaucoma in individuals aged 60-69 years (aOR = 1.28, 95% CI = 1.05-1.56)., Conclusions: Statin use was associated with increased glaucoma likelihood in the overall adult AoU population with hyperlipidemia, in individuals with optimal or high LDL-C levels, and in individuals 60-69 years old. Findings suggest that statin use may be an independent risk factor for glaucoma, which may furthermore be affected by one's lipid profile and age., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Alcohol consumption is a strong risk factor for both cirrhosis and esophageal squamous cell carcinoma (ESCC). Few studies have been conducted on the treatment of ESCC in patients with cirrhosis. This study aimed to analyze the clinical outcomes of ESCC in patients with cirrhosis., Materials and Methods: Medical records of patients with esophageal cancer between January 2009 and December 2023 were retrospectively reviewed. A total of 479 patients with ESCC were included and divided into cirrhotic (n = 69) and non-cirrhotic (n = 410) groups. Clinical outcomes and survival according to treatment were compared between these groups., Results: The cirrhotic group was younger (median age 64 years vs. 69 years, p  = 0.022) and had a higher proportion of male (97.1 % vs. 88.3 %, p  = 0.042) than the non-cirrhotic group. Patients with cirrhosis were less likely to undergo surgery (31.9 % vs. 47.8 %, p  = 0.015) and were more likely to receive no active cancer treatment (26.1 % vs. 13.7 %, p  = 0.010). Overall survival was lower in the cirrhotic group (hazard ratio [HR], 1.41; 95 % confidence interval [CI], 1.01-1.99; p  = 0.045), however, no difference was found between Child-Pugh class A patients and those in the non-cirrhotic group (HR, 1.04 [95 % CI, 0.69-1.56]; p  = 0.864). Postoperative mortality was significantly higher in cirrhotic group (27.3 % vs. 8.7 %, p  = 0.011). Upon performing concurrent chemoradiotherapy (CRT), the clinical complete response rate (84.2 % vs. 43.3 %, p  = 0.004) was better in the cirrhotic group. CRT yielded better overall survival for patients with cancer in the resectable stages in the cirrhotic group compared to surgery (HR, 0.19 [95 % CI, 0.42-0.84]; p  = 0.029]., Conclusions: In patient with ESCC and cirrhosis, chemoradiotherapy may be a better treatment option than surgery., Competing Interests: 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., (© 2024 The Author(s).)

Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6-7 months, and ∼12 months of age, malin-deficient mice ("KO") and wild-type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age-dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home-cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse., (© 2024 Wiley Periodicals LLC.)

Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (C max ) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for C max ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Targeting ribosomal frameshifting has emerged as a potential therapeutic intervention strategy against Covid-19. During ribosomal translation, a fraction of elongating ribosomes slips by one base in the 5' direction and enters a new reading frame for viral protein synthesis. Any interference with this process profoundly affects viral replication and propagation. For Covid-19, two RNA sites associated with ribosomal frameshifting for SARS-CoV-2 are positioned on the 5' and 3' of the frameshifting residues. Although much attention has been on the 3' frameshift element (FSE), the 5' stem-loop (attenuator hairpin, AH) can play a role. The formation of AH has been suggested to occur as refolding of the 3' RNA structure is triggered by ribosomal unwinding. However, the attenuation activity and the relationship between the two regions are unknown. To gain more insight into these two related viral RNAs and to further enrich our understanding of ribosomal frameshifting for SARS-CoV-2, we explore the RNA folding of both 5' and 3' regions associated with frameshifting. Using our graph-theory-based modeling tools to represent RNA secondary structures, "RAG" (RNA- As-Graphs), and conformational landscapes to analyze length-dependent conformational distributions, we show that AH coexists with the 3-stem pseudoknot of the 3' FSE (graph 3&#95;6 in our dual graph notation) and alternative pseudoknot (graph 3&#95;3) but less likely with other 3' FSE alternative folds (such as 3-way junction 3&#95;5). This is because an alternative length-dependent Stem 1 (AS1) can disrupt the FSE pseudoknots and trigger other folds. In addition, we design four mutants for long lengths that stabilize or disrupt AH, AS1 or FSE pseudoknot to illustrate the deduced AH/AS1 roles and favor the 3&#95;5, 3&#95;6 or stem-loop. These mutants further show how a strengthened pseudoknot can result from a weakened AS1, while a dominant stem-loop occurs with a strengthened AS1. These structural and mutational insights into both ends of the FSE in SARS-CoV-2 advance our understanding of the SARS-CoV-2 frameshifting mechanism by suggesting a sequence of length-dependent folds, which in turn define potential therapeutic intervention techniques involving both elements. Our work also highlights the complexity of viral landscapes with length-dependent folds, and challenges in analyzing these multiple conformations., Competing Interests: Competing interests No competing interest is declared.

Objective: Hydrocephalic macrocephaly can result in poor psychosocial development, positioning difficulties, skin breakdown, and poor cosmesis. Although reduction cranioplasty can address these sequelae, the postoperative outcomes, complications, and mortality risk of reduction cranioplasty are not well understood given the rarity of hydrocephalic macrocephaly. Therefore, the primary objective of this systematic review was to evaluate the surgical outcomes of reduction cranioplasty for the treatment of hydrocephalic macrocephaly., Methods: A systematic review was performed using the PubMed, Scopus, and Web of Science databases while following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent reviewers screened 350 studies; 27 studies reporting surgical outcomes on reduction cranioplasty for hydrocephalic macrocephaly met inclusion criteria. Data on study design, patient demographics, operative details, and surgical outcomes were collected., Results: There were 65 reduction cranioplasties among the 27 included studies. Eighteen (66.7%) studies presented level V evidence, 7 (25.9%) presented level IV evidence, and 2 (7.4%) presented level III evidence. Following reduction cranioplasty, there was improvement in postoperative head positioning in 23 (85.2%) studies, improvement in postoperative cosmesis in 22 (81.5%) studies, and improvement in global postoperative neurological functioning in 20 (74.1%) studies. The median estimated blood loss was 633 mL (range 20-2600 mL). Shunt revisions were the most common complication, reported in 9 (47.4%) of the 19 studies assessing complications. Of the 65 patients, there was a mortality rate of 6.2% (n = 4)., Conclusions: The majority of the included studies reported improvement in head size, head positioning, cranial cosmesis, and global neurological functioning following reduction cranioplasty for hydrocephalic macrocephaly. However, the prevalence of lower-level evidence, risk of blood loss, complications, and mortality indicates the need for a serious discussion of surgical indication, an experienced team, and thorough perioperative planning to perform these complex surgeries.

Conventional passive ankle foot orthoses (AFOs) have not seen substantial advances or functional improvements for decades, failing to meet the demands of many stakeholders, especially the pediatric population with neurological disorders. Our objective is to develop the first comfortable and unobtrusive powered AFO for children with cerebral palsy (CP), the DE-AFO. CP is the most diagnosed neuromotor disorder in the pediatric population. The standard of care for ankle control dysfunction associated with CP, however, is an unmechanized, bulky, and uncomfortable L-shaped conventional AFO. These passive orthoses constrain the ankle's motion and often cause muscle disuse atrophy, skin damage, and adverse neural adaptations. While powered orthoses could enhance natural ankle motion, their reliance on bulky, noisy, and rigid actuators like DC motors limits their acceptability. Our innovation, the DE-AFO, emerged from insights gathered during customer discovery interviews with 185 stakeholders within the AFO ecosystem as part of the NSF I-Corps program. The DE-AFO is a biomimetic robot that employs artificial muscles made from an electro-active polymer called dielectric elastomers (DEs) to assist ankle movements in the sagittal planes. It incorporates a gait phase detection controller to synchronize the artificial muscles with natural gait cycles, mimicking the function of natural ankle muscles. This device is the first of its kind to utilize lightweight, compact, soft, and silent artificial muscles that contract longitudinally, addressing traditional actuated AFOs' limitations by enhancing the orthosis's natural feel, comfort, and acceptability. In this paper, we outline our design approach and describe the three main components of the DE-AFO: the artificial muscle technology, the finite state machine (the gait phase detection system), and its mechanical structure. To verify the feasibility of our design, we theoretically calculated if DE-AFO can provide the necessary ankle moment assistance for children with CP-aligning with moments observed in typically developing children. To this end, we calculated the ankle moment deficit in a child with CP when compared with the normative moment of seven typically developing children. Our results demonstrated that the DE-AFO can provide meaningful ankle moment assistance, providing up to 69% and 100% of the required assistive force during the pre-swing phase and swing period of gait, respectively.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment.

Background/Objectives: Chronic total occlusion (CTO) is a prevalent finding in patients with coronary artery disease and is associated with increased mortality. Prior reports on the efficacy of percutaneous coronary intervention (PCI) compared to optimal medical therapy (OMT) were controversial. Following the emergence of recently published new evidence, a meta-analysis is warranted. The current meta-analysis assessed the effects of PCI compared to OMT in the treatment of CTO. Methods: A structured literature search was performed. Randomized controlled trials (RCTs) and non-randomized controlled studies of interventions were eligible. The primary outcome was an accumulated composite of cardiac mortality, myocardial infarction and target vessel/lesion revascularization events. Results: Thirty-two studies reporting on 11260 patients were included. Of these, 5712 (50.7%) were assigned to the PCI and 5548 (49.3%) were allocated to the OMT group. The primary outcome occurred in 14.6% of the PCI and 20.1% of the OMT group (12 trials, OR 0.66, 95% CI 0.50 to 0.88, p = 0.005, I 2 = 67%). Subgrouping demonstrated a consistent reduction in the primary outcome for the PCI group in RCTs (six trials, OR 0.58, 95% CI 0.33 to 0.99, p = 0.05). The primary outcome reduction was irrespective of the study design, and it was replicable in sensitivity and subgroup analyses. Advantages in other outcomes were rather related to statistical pooling effects and dominated by observational data. Conclusions: CTO-PCI was associated with improved patient-oriented primary outcome compared to OMT in a study-level meta-analysis. This composite outcome effect was mainly driven by target vessel treatment, but a significant reduction in mortality and myocardial infarction was observed, irrespectively. These findings have hypothesis-generating implications. Future RCTs with adequate statistical power are eagerly awaited.

This study describes decentralized recruitment and enrollment for a COVID-19 treatment trial, while comparing 5 primary recruitment methods: search engine ads, paid advertising within a national testing company, paid advertising within a regional testing company, electronic health record messages, and word of mouth. These are compared across patient demographics, efficiency, and cost., Clinical Trials Registration: NCT04510194., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: The authors have no conflicts to report.

Rh complexes of a tridentate PPP ligand bearing 1,2-pyrrolediyl linkers have been prepared, including examples with the central P donor being either a phosphine or a phosphide. Three bimetallic Rh complexes containing the diamandoid Rh 2 P 2 core (P = phosphido) have been structurally and spectroscopically characterized. The Rh-Rh interaction in these three dimers was examined by way of structural comparisons and DFT investigations., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Transcatheter aortic valve replacement (TAVR) has become an established alternative to surgical aortic valve replacement (AVR) for patients with moderate-to-high perioperative risk. Periprocedural TAVR complications decrease with growing expertise of implanters. Nevertheless, TAVR can still be accompanied by life-threatening adverse events such as intraprocedural cardiopulmonary resuscitation (CPR). This study analyzed the role of a reduced left-ventricular ejection fraction (LVEF) in intraprocedural complications during TAVR. Perioperative and postoperative outcomes from patients undergoing TAVR in a high-volume center (600 cases per year) were analyzed retrospectively with regard to their left-ventricular ejection fraction. Patients with a reduced left-ventricular ejection fraction (EF ≤ 40%) faced a significantly higher risk of perioperative adverse events. Within this cohort, patients were significantly more often in need of mechanical ventilation (35% vs. 19%). These patients also underwent CPR (17% vs. 5.8%), defibrillation due to ventricular fibrillation (13% vs. 5.4%), and heart-lung circulatory support (6.1% vs. 2.5%) more often. However, these intraprocedural adverse events showed no significant impact on postoperative outcomes regarding in-hospital mortality, stroke, or in-hospital stay. A reduced preprocedural LVEF is a risk factor for intraprocedural adverse events. With respect to this finding, the identified patient cohort should be treated with more caution to prevent intraprocedural incidents.

Some animal species shift their activity towards increased nocturnality in disturbed habitats to avoid predominantly diurnal humans. This may alter diel overlap among species, a precondition to most predation and competition interactions that structure food webs. Here, using camera trap data from 10 tropical forest landscapes, we find that hyperdiverse Southeast Asian wildlife communities shift their peak activity from early mornings in intact habitats towards dawn and dusk in disturbed habitats (increased crepuscularity). Our results indicate that anthropogenic disturbances drive opposing behavioural adaptations based on rarity, size and feeding guild, with more nocturnality among the 59 rarer specialists' species, more diurnality for medium-sized generalists, and less diurnality for larger hunted species. Species turnover also played a role in underpinning community- and guild-level responses, with disturbances associated with markedly more detections of diurnal generalists and their medium-sized diurnal predators. However, overlap among predator-prey or competitor guilds does not vary with disturbance, suggesting that net species interactions may be conserved., (© 2024. The Author(s).)

Functional analysis of high throughput experiments using pathway analysis is now ubiquitous. Though powerful, these methods often produce thousands of redundant results owing to knowledgebase redundancies upstream. This scale of results hinders extensive exploration by biologists and can lead to investigator biases due to previous knowledge and expectations. To address this issue, we present vissE, a flexible network-based analysis and visualisation tool that organises information into semantic categories and provides various visualisation modules to characterise them with respect to the underlying data, thus providing a comprehensive view of the biological system. We demonstrate vissE's versatility by applying it to three different technologies: bulk, single-cell and spatial transcriptomics. Applying vissE to a factor analysis of a breast cancer spatial transcriptomic data, we identified stromal phenotypes that support tumour dissemination. Its adaptability allows vissE to enhance all existing gene-set enrichment and pathway analysis workflows, empowering biologists during molecular discovery., (© 2024. The Author(s).)

Background & Aims: Dysbiosis contributes to alcohol-associated liver disease (ALD); however, the precise mechanisms remain elusive. Given the critical role of the gut microbiota in ammonia production, we herein aim to investigate whether and how gut-derived ammonia contributes to ALD., Methods: Blood samples were collected from human subjects with/without alcohol drinking. Mice were exposed to the Lieber-DeCarli isocaloric control or ethanol-containing diets with and without rifaximin (a nonabsorbable antibiotic clinically used for lowering gut ammonia production) supplementation for five weeks. Both in vitro (NH 4 Cl exposure of AML12 hepatocytes) and in vivo (urease administration for 5 days in mice) hyperammonemia models were employed. RNA sequencing and fecal amplicon sequencing were performed. Ammonia and triglyceride concentrations were measured. The gene and protein expression of enzymes involved in multiple pathways were measured., Results: Chronic alcohol consumption causes hyperammonemia in both mice and human subjects. In healthy livers and hepatocytes, ammonia exposure upregulates the expression of urea cycle genes, elevates hepatic de novo lipogenesis (DNL), and increases fat accumulation. Intriguingly, ammonia promotes ethanol catabolism and acetyl-CoA formation, which, together with ammonia, synergistically facilitates intracellular fat accumulation in hepatocytes. Mechanistic investigations uncovered that ATF4 activation, as a result of ER stress induction and general control nonderepressible 2 activation, plays a central role in ammonia-provoked DNL elevation. Rifaximin ameliorates ALD pathologies in mice, concomitant with blunted hepatic ER stress induction, ATF4 activation, and DNL activation., Conclusions: An overproduction of ammonia by gut microbiota, synergistically interacting with ethanol, is a significant contributor to ALD pathologies., 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 © 2023 Elsevier Inc. All rights reserved.)

Early detection of cognitive and functional decline is difficult given that current tools are insensitive to subtle changes. The present study evaluated whether cognitive dispersion on neuropsychological testing improved prediction of objectively assessed daily functioning using unobtrusive monitoring technologies. Hierarchical linear regression was used to evaluate whether cognitive dispersion added incremental information beyond mean neuropsychological performance in the prediction of objectively assessed IADLs (i.e., computer use, pillbox use, driving) in a sample of 104 community-dwelling older adults without dementia (M age  = 74.59, 38.5% Female, 90.4% White). Adjusting for age, sex, education, and mean global cognitive performance, cognitive dispersion improved prediction of average daily computer use duration (R 2 Δ = 0.100, F Change, p  = 0.005), computer use duration variability (R 2 Δ = 0.089, F Change p  = 0.009), and average daily duration of nighttime driving (R 2 Δ = 0.072, F Change p  = 0.013). These results suggest cognitive dispersion may improve prediction of objectively assessed functional changes in older adults without dementia., Competing Interests: The authors have no conflicts of interest to disclose. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: As the imbalance in organ demand and supply is getting worse, <1000 patients waiting for organ transplants die each year in South Korea. To enhance positive attitudes to deceased organ-tissue donation through systematic education, we developed an educational program with delivery pathways for premedical and medical students., Methods: Online and offline self-learning educational materials on deceased organ-tissue donation were generated and posted on the Vitallink Academy YouTube site. Thirty-two pre- and 15 posteducation questionnaires were developed using a web-based survey platform, and conducted before and immediately after the education process. The education proceeded in 3 steps: (1) group study sessions on selected topics, (2) poster submissions by each group and the selection of excellent poster by the organizing committee, and (3) excellent poster presentation and questions and answers., Results: A total of 141 students in the first year of premedical classes at the Seoul National University College of Medicine participated in this program. Only 24.2% of responders agreed that anyone who was diagnosed with brain death should donate. The proportion of students with positive attitudes toward organ-tissue donation increased from 74.7% to 97.7% ( P  < 0.001) with our education. Likewise, interest in deceased organ-tissue donation-related issues increased from 33.3% to 84.9% ( P  < 0.001). The expressed willingness for organ-tissue donation also increased from 76.8% to 96.5% ( P  < 0.001). The proportion of accepting brain death as the determination of death increased from 61.6% to 89.5% ( P  < 0.001). Moreover, 81.4% changed their approach and planned to register with an organ donor card., Conclusions: In this study, significant improvements were observed in knowledge, awareness, and attitude toward organ-tissue donation with our newly developed co-participatory education program for premedical students. Hence, target-specific education can be regarded as a valuable approach to enhancing public awareness of deceased organ-tissue donation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Topic: This scoping review summarizes artificial intelligence (AI) reporting in ophthalmology literature in respect to model development and validation. We characterize the state of transparency in reporting of studies prospectively validating models for disease classification., Clinical Relevance: Understanding what elements authors currently describe regarding their AI models may aid in the future standardization of reporting. This review highlights the need for transparency to facilitate the critical appraisal of models prior to clinical implementation, to minimize bias and inappropriate use. Transparent reporting can improve effective and equitable use in clinical settings., Methods: Eligible articles (as of January 2022) from PubMed, Embase, Web of Science, and CINAHL were independently screened by 2 reviewers. All observational and clinical trial studies evaluating the performance of an AI model for disease classification of ophthalmic conditions were included. Studies were evaluated for reporting of parameters derived from reporting guidelines (CONSORT-AI, MI-CLAIM) and our previously published editorial on model cards. The reporting of these factors, which included basic model and dataset details (source, demographics), and prospective validation outcomes, were summarized., Results: Thirty-seven prospective validation studies were included in the scoping review. Eleven additional associated training and/or retrospective validation studies were included if this information could not be determined from the primary articles. These 37 studies validated 27 unique AI models; multiple studies evaluated the same algorithms (EyeArt, IDx-DR, and Medios AI). Details of model development were variably reported; 18 of 27 models described training dataset annotation and 10 of 27 studies reported training data distribution. Demographic information of training data was rarely reported; 7 of the 27 unique models reported age and gender and only 2 reported race and/or ethnicity. At the level of prospective clinical validation, age and gender of populations was more consistently reported (29 and 28 of 37 studies, respectively), but only 9 studies reported race and/or ethnicity data. Scope of use was difficult to discern for the majority of models. Fifteen studies did not state or imply primary users., Conclusion: Our scoping review demonstrates variable reporting of information related to both model development and validation. The intention of our study was not to assess the quality of the factors we examined, but to characterize what information is, and is not, regularly reported. Our results suggest the need for greater transparency in the reporting of information necessary to determine the appropriateness and fairness of these tools prior to clinical use., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Background: The estimated prevalence of hepatitis C virus (HCV) in Canada is approximately 1.0%. However, the number of individuals living with HCV but unaware of it is estimated to be 30%-44%. Increased screening programs that are accessible, effective, and feasible are important to ensure treatment and meet WHO elimination goals. We implemented an HCV point of care test (POCT) program in community pharmacies to examine the effectiveness and feasibility in screening., Methods: Twenty two London Drugs pharmacies in British Columbia and Alberta implemented an HCV POC screening program using OraQuick rapid antibody tests. Consenting patients filled out a 10-question screening questionnaire to examine risk factors. The participants then were tested using the POCT. While waiting for the test (20 minutes), patients were educated on HCV and treatment options., Results: Three hundred seventy-one participants underwent HCV screening. The most common HCV risk factor was being born between 1945 and 1975 (baby boomer) (93% of cohort), while the second most common was having a tattoo or body piercing (22%). Seven people (2%) tested positive; four were HCV-RNA PCR-positive and were treated, whereas the PCR status of three was unknown as they were lost to follow-up or not tested., Conclusions: Pharmacy-based POCT was shown to be effective and feasible in the western Canadian context, especially for baby boomers. Sustainable funding for pharmacy screening programs may be considered nationwide to identify HCV-infected persons and help meet elimination goals., (© Canadian Association for the Study of the Liver, 2023.)

Objectives: Long-term treatment with nucleoside analog (NA) reduces the risks for decompensation and hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with compensated cirrhosis (CC). However, whether antiviral therapy has differential efficacy on the risks for decompensation and HCC is insufficiently elucidated. Therefore, we investigated the disease state transition, focusing on decompensation event-specific HCC risk in NA-treated CHB patients with CC., Methods: We prospectively followed up on 1163 NA-treated CHB patients with CC every six months for up to seven years. The cumulative incidence and risk of HCC were analyzed by the Kaplan-Meier method and competing risk model. The multistate model was used to estimate the transition probabilities to HCC from different disease states., Results: HCC predominated the first liver-related events, with a 5-year cumulative incidence of 9.0%, followed by decompensation (8.3%, including 7.9% nonbleeding decompensation and 2.4% variceal bleeding) and 0.2% death. The decompensation stage had a significantly higher 5-year cumulative HCC incidence than the CC stage (27.6% vs. 9.1%; HR = 2.42, 95% CI: 1.24, 4.71). Furthermore, nonbleeding decompensation events had a higher 5-year transition probability to HCC than bleeding (27.6% vs. 15.8%; HR = 2.69, 95% CI: 1.41, 4.17). Viral suppression modified the on-treatment transition risk to HCC (1-year: HR = 0.45, 95% CI: 0.28, 0.73; 3-year: HR = 0.23, 95% CI: 0.14, 0.38). An online calculator was developed to facilitate HCC risk stratification., Conclusions: In NA-treated CHB patients with compensated cirrhosis, the risk was higher for HCC than for decompensation; more importantly, different decompensation events conferred distinct HCC risks., (© 2023. Asian Pacific Association for the Study of the Liver.)

Background: Guidelines on myocardial infarction (MI) recommend antithrombotic and anticoagulatory treatment at time of diagnosis. MI with ST segment elevation (STEMI) is mostly a certain diagnosis. Acute coronary syndrome without ST segment elevation (NSTE-ACS) has diagnostic uncertainty and remains a working diagnosis in the prehospital setting., Objective: Assessment of prehospital loading with aspirin and heparin depending on ACS subtype and pretreatment with oral anticoagulants., Methods: The PRELOAD survey was a nationwide German study. STEMI/NSTE-ACS scenarios were designed and varied in pretreatment: I) no pretreatment, II) new oral anticoagulants (NOAC), III) vitamin K antagonist (VKA). Loading strategy was assessed and included: a) aspirin (ASA), b) unfractionated heparin (UFH), c) ASA + UFH, d) no loading., Results: A total of 708 emergency physicians were included. In NSTE-ACS without pretreatment, 79% chose loading (p < 0.001). ASA + UFH (71.4%) was the preferred option. In corresponding STEMI scenario, 100% chose loading and 98.6% preferred ASA + UFH (p < 0.001). In NSTE-ACS with NOAC pretreatment, 69.8% favored loading (p < 0.001); in VKA pretreatment the corresponding rate was 72.3% (p < 0.001). In each scenario, ASA was the preferred option. In STEMI with NOAC pretreatment, 97.5% chose loading (p < 0.001); analogous rate was 96.8% in STEMI with VKA pretreatment (p < 0.001). ASA was the preferred option again., Conclusions: Prehospital loading was the preferred treatment strategy despite the diagnostic uncertainty in NSTE-ACS and guidelines recommending loading at time of diagnosis. Pretreatment with oral anticoagulants resulted in a strategy shift to loading with only aspirin. In STEMI patients, this indicates potential undertreatment., (© 2023. The Author(s).)

In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.

Background: Immune checkpoint inhibitor (ICI)-based therapy such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab became mainstream first-line systemic treatment in advanced hepatocellular carcinoma (HCC) patients since remarkably superior efficacy of ICI-based therapy compared to tyrosine kinase inhibitors (TKIs) was reported in two recent randomized controlled trials (RCTs) (IMbrave150, HIMALAYA). However, the optimal second-line therapy after treatment failure of first-line ICI-based therapy remains unknown as no RCT has examined this issue., Summary: Therefore, at present, most clinicians are empirically treating patients with TKIs or retrial of ICI or locoregional treatment (LRT) modality such as transarterial therapy, radiofrequency ablation, and radiation therapy in this clinical setting without solid evidence. In this review, we will discuss current optimal strategies for second-line treatment after the failure of first-line ICI-based therapy by reviewing published studies and ongoing prospective trials., Key Messages: Clinicians should consider carefully whether to treat the patients with TKI, other ICI-based therapy, or LRT in this situation by considering several factors including liver function reserve, performance status, adverse events of previous therapy, and presence of lesion that can consider LRT such as oligoprogression and vascular invasion. In the meantime, we await the results of ongoing prospective trials to elucidate the best management options., Competing Interests: Samuel S. Lee has consulted for AbbVie, Gilead, Grifols, Jazz, Novartis, and Oncoustics. The other authors have no disclosures., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The endocytic and secretory pathways of the fungal pathogen Candida albicans are fundamental to various key cellular processes such as cell growth, cell wall integrity, protein secretion, hyphal formation, and pathogenesis. Our previous studies focused on several candidate genes involved in early endocytosis, including ENT2 and END3 , that play crucial roles in such processes. However, much remains to be discovered about other endocytosis-related genes and their contributions toward Candida albicans secretion and virulence. In this study, we examined the functions of the early endocytosis gene PAL1 using a reverse genetics approach based on CRISPR-Cas9-mediated gene deletion. Saccharomyces cerevisiae Pal1 is a protein in the early coat complex involved in clathrin-mediated endocytosis that is later internalized with the coat. The C. albicans pal1 Δ/Δ null mutant demonstrated increased resistance to the antifungal agent caspofungin and the cell wall stressor Congo Red. In contrast, the null mutant was more sensitive to the antifungal drug fluconazole and low concentrations of SDS than the wild type (WT) and the re-integrant (KI). While pal1 Δ/Δ can form hyphae and a biofilm, under some hyphal-inducing conditions, it was less able to demonstrate filamentous growth when compared to the WT and KI. The pal1 Δ/Δ null mutant had no defect in clathrin-mediated endocytosis, and there were no changes in virulence-related processes compared to controls. Our results suggest that PAL1 has a role in susceptibility to antifungal agents, cell wall integrity, and membrane stability related to early endocytosis.

The potential for marine litter being trapped in biodiverse marine habitats such as mangrove forests, seagrass meadows and coral reefs is poorly understood. This study presents the first comprehensive investigation on the status of macro-litter across four marine habitats in Singapore during the two monsoonal seasons. Overall, litter density did not vary considerably between the southwest and the northeast monsoon. The litter density in terms of count was generally lower in seagrass meadows and coral reefs compared to mangroves and beaches. Plastic was the major type of litter found across most habitat types. Notably, many fishing-related items were found on coral reefs, while drinking straws were abundant at the mangrove strandlines during the southwest monsoon. Foam fragments and cigarette butts were common at the beach strandlines. These results suggest that mangroves among other habitats examined here should be prioritised for clean-up efforts in order to restore these critical coastal habitats., 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 © 2023 Elsevier Ltd. All rights reserved.)

Background: SR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive coronary artery atherosclerosis, platelet accumulation in coronary arteries, and myocardial fibrosis. Platelets are involved in atherosclerosis development, and PAR (protease-activated receptor) 4 has a prominent role in platelet function in mice. However, the role of PAR4 on coronary artery disease in mice has not been tested., Methods: We tested the effects of a PAR4 inhibitory pepducin (RAG8) on diet-induced aortic sinus and coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis in SR-B1/LDLR double knockout mice. SR-B1/LDLR double knockout mice were fed a high-fat, high-cholesterol diet containing cholate and injected daily with 20 mg/kg of either the RAG8 pepducin or a control reverse-sequence pepducin (SRQ8) for 20 days., Results: Platelets from the RAG8-treated mice exhibited reduced thrombin and PAR4 agonist peptide-mediated activation compared with those from control SRQ8-treated mice when tested ex vivo. Although aortic sinus atherosclerosis levels did not differ, RAG8-treated mice exhibited reduced coronary artery atherosclerosis, reduced platelet accumulation in atherosclerotic coronary arteries, and reduced myocardial fibrosis. These protective effects were not accompanied by changes in circulating lipids, inflammatory cytokines, or immune cells. However, RAG8-treated mice exhibited reduced VCAM-1 (vascular cell adhesion molecule 1) protein levels in nonatherosclerotic coronary artery cross sections and reduced leukocyte accumulation in atherosclerotic coronary artery cross sections compared with those from SRQ8-treated mice., Conclusions: The PAR4 inhibitory RAG8 pepducin reduced coronary artery atherosclerosis and myocardial fibrosis in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet containing cholate. Furthermore, RAG8 reduced VCAM-1 in nonatherosclerotic coronary arteries and reduced leukocyte and platelet accumulation in atherosclerotic coronary arteries. These findings identify PAR4 as an attractive target in reducing coronary artery disease development, and the use of RAG8 may potentially be beneficial in cardiovascular disease., Competing Interests: Disclosures None.

Background: Pegylated interferon (Peg-IFN) is recommended as first-line therapy for chronic hepatitis B (CHB) but has significant side effects and is rarely used compared to oral nucleos(t)ide analogues (NA). There are limited recent clinical efficacy or economic analysis data comparing approved CHB therapy in North America., Methods: This retrospective study examined clinical outcomes, off-treatment durability, and cost-effectiveness of Peg-IFN versus NA for CHB. Demographic (age, sex, ethnicity), clinical data (i.e., liver tests, hepatitis B virus DNA, serology, transient elastography) and documented side effects were collected by retrospective chart review of patients followed in the University of Calgary Liver Unit who received Peg-IFN therapy from January 2007 to December 2020. The cost-effectiveness of Peg-IFN versus NA therapy was modelled over a 10-year time horizon., Results: Sixty-eight CHB patients were treated with Peg-IFN (median age 45.65, 74% male, 84% Asian); 50/68 (74%) completed 48 weeks of treatment with a median follow-up of 6.54 years (interquartile range 5.07). At the last known follow-up, 23/68 (34%) have not required NA treatment and one had HBsAg loss; 27 have been started on NA. Predictors of obtaining a sustained virological response included being hepatitis B e antigen-negative at treatment end and a quantitative hepatitis B surface antigen <1000 IU/mL. Economic modelling showed that finite Peg-IFN was not cost-effective versus NA at a 10-year time horizon., Conclusions: PEG-IFN remains a potential treatment for CHB although there is a significant intolerance/failure rate. Using PEG-IFN based on patient preference is reasonable and optimal patient selection may improve treatment cost-effectiveness., (© Canadian Association for the Study of the Liver, 2023.)

Purpose: Access-related vascular complications in transfemoral transcatheter aortic valve implantation (TAVI) can be treated endovascularly or surgically. The aim of this study was to evaluate the short- and long-term outcomes of endovascular treatment compared with surgical repair for access-related vascular complications., Methods: This retrospective study was performed from January 1, 2018, to December 31, 2020. All transfemorally treated TAVI patients in whom a surgical or endovascular treatment for an access site complication was needed were included. The primary outcome was the need for any related vascular re-operation., Results: In total, 1219 transfemoral TAVI procedures were conducted during the study period. 19 patients suffered an access complication requiring endovascular treatment, while 54 patients required surgical repair. No differences were seen with regard to re-operations (endovascular 15.8% vs surgical 14.8%; p=0.919), wound infections (endovascular 0% vs surgical. 11.1%; p=0.129), and wound healing disorders (endovascular 15.8% vs surgical 29.6%; p=0.237). Patients undergoing endovascular treatment were discharged earlier (endovascular 11.2 vs surgical 14.9 days; p=0.028). After surgical repair, patients received significantly more blood transfusions than endovascularly treated patients (endovascular 1.00 vs surgical 3.1 red blood cell concentrate bags; p<0.001). No differences were found regarding the new onset of walking pain, rest pain, and ischemic ulcers during follow-up., Conclusion: In this retrospective cohort, endovascular treatment of access-related vascular complications of transfemoral TAVI procedures was safe and feasible. During the hospital stay, endovascularly treated patients received fewer blood transfusions and were discharged faster than surgically treated patients. No differences regarding clinical outcomes and re-intervention rates were seen during the follow-up., Clinical Impact: Given the in this retrospective study demonstrated safety and feasibility of endovascular treatment for major access-related vascular complications, along with the in-hospital benefits and absence of follow-up disadvantages compared to surgical treatment, endovascular treatment should be considered in cases of major access-related vascular complications in transfemoral TAVI patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Machine learning-based gait systems facilitate the real-time control of gait assistive technologies in neurological conditions. Improving such systems needs the identification of kinematic signals from inertial measurement unit wearables (IMUs) that are robust across different walking conditions without extensive data processing. We quantify changes in two kinematic signals, acceleration and angular velocity, from IMUs worn on the frontal plane of bilateral shanks and thighs in 30 adolescents (8-18 years) on a treadmills and outdoor overground walking at three different speeds (self-selected, slow, and fast). Primary curve-based analyses included similarity analyses such as cosine, Euclidean distance, Poincare analysis, and a newly defined bilateral symmetry dissimilarity test (BSDT). Analysis indicated that superior-inferior shank acceleration (SI shank Acc) and medial-lateral shank angular velocity (ML shank AV) demonstrated no differences to the control signal in BSDT, indicating the least variability across the different walking conditions. Both SI shank Acc and ML shank AV were also robust in Poincare analysis. Secondary parameter-based similarity analyses with conventional spatiotemporal gait parameters were also performed. This normative dataset of walking reports raw signal kinematics that demonstrate the least to most variability in switching between treadmill and outdoor walking to help guide future machine learning models to assist gait in pediatric neurological conditions.

Topics of diversity, equity, and inclusion (DEI) are an integral component of post-graduate medical education. However, it is currently unclear the extent to which physical medicine and rehabilitation residency programs have incorporated a DEI curriculum into their training programs. Here, a novel, multi-institutional DEI journal club is described. This journal club format can be an important component of the DEI curriculum as it provides non-local perspectives and insights into specific issues and allows for a simple way to introduce DEI training in programs currently without such training. The virtual format also provides further opportunities for discussion and networking., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Cirrhotic cardiomyopathy (CCM) is defined as systolic or diastolic dysfunction in the absence of prior heart disease or another identifiable cause in patients with cirrhosis, in whom it is an important determinant of outcome. Its underlying pathogenic/pathophysiological mechanisms are rooted in two distinct pathways: 1) factors associated with portal hypertension, hyperdynamic circulation, gut bacterial/endotoxin translocation and the resultant inflammatory phenotype; 2) hepatocellular insufficiency with altered synthesis or metabolism of substances such as proteins, lipids, carbohydrates, bile acids and hormones. Different criteria have been proposed to diagnose CCM; the first in 2005 by the World Congress of Gastroenterology, and more recently in 2019 by the Cirrhotic Cardiomyopathy Consortium. These criteria mainly utilised echocardiographic evaluation, with the latter refining the evaluation of diastolic function and integrating global longitudinal strain into the evaluation of systolic function, an important addition since the haemodynamic changes that occur in advanced cirrhosis may lead to overestimation of systolic function by left ventricular ejection fraction. Advances in cardiac imaging, such as cardiac magnetic resonance imaging and the incorporation of an exercise challenge, may help further refine the diagnosis of CCM. Over recent years, CCM has been shown to contribute to increased mortality and morbidity after major interventions, such as liver transplantation and transjugular intrahepatic portosystemic shunt insertion, and to play a pathophysiologic role in the genesis of hepatorenal syndrome. In this review, we discuss the pathogenesis/pathophysiology of CCM, its clinical implications, and the role of cardiac imaging modalities including MRI. We also compare diagnostic criteria and review the potential diagnostic role of electrocardiographic QT prolongation. At present, no definitive medical therapy exists, but some promising potential treatment strategies for CCM are reviewed., Competing Interests: HL: nil to disclose. JAN: nil to disclose. GL: Research grants from: Pfizer, Biotronik, IONIS, Anumana. Consulting for: Boston Scientific, IONIS. Equity: Empallo, HeartScreen Health. SSL: consulting or speaking for: Abbvie, Gilead, Grifols, Intercept, Jazz Pharmaceuticals, Lupin, Oncoustics. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Copy number variants (CNVs) are major contributors to genetic diversity and disease. While standardized methods, such as the genome analysis toolkit (GATK), exist for detecting short variants, technical challenges have confounded uniform large-scale CNV analyses from whole-exome sequencing (WES) data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, we developed GATK-gCNV, a flexible algorithm to discover rare CNVs from sequencing read-depth information, complete with open-source distribution via GATK. We benchmarked GATK-gCNV in 7,962 exomes from individuals in quartet families with matched genome sequencing and microarray data, finding up to 95% recall of rare coding CNVs at a resolution of more than two exons. We used GATK-gCNV to generate a reference catalog of rare coding CNVs in WES data from 197,306 individuals in the UK Biobank, and observed strong correlations between per-gene CNV rates and measures of mutational constraint, as well as rare CNV associations with multiple traits. In summary, GATK-gCNV is a tunable approach for sensitive and specific CNV discovery in WES data, with broad applications., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Sensory deficits in individuals with cerebral palsy (CP) play a critical role in balance control. However, there is a lack of effective interventions that address sensory facilitation to improve walking balance. Stochastic Resonance (SR) stimulation involves delivering sub threshold noise to improve balance in patients with sensory deficits by enhancing the detection of sensory input., Research Question: To investigate the immediate effects of SR on walking balance in individuals with and without CP., Methods: Thirty-four participants (17 CP, 17 age-and sex-matched typically developing controls or TD) between 8 and 24 years of age were recruited. SR stimulation was applied to the muscles and ligaments of ankle and hip joint. An optimal SR intensity during walking was determined for each subject. Participants walked on a self-paced treadmill for three trials of two minutes each using a random order of SR stimulation (SR) and no stimulation (noSR) control conditions. Our primary outcome measure was minimum lateral margin of stability (MOS). Secondary outcome measures include anterior MOS before heelstrike and spatiotemporal gait parameters. We performed two-way mixed ANOVAs with group (CP, TD) as between-subject and condition (noSR, SR) as within subject factors., Results: Compared to walking without SR, there was a small but significant increase in the lateral and anterior MOS with SR stimulation, implying that a larger impulse was needed to become unstable, in turn implying higher stability. Step width and step ength decreased with SR for the CP group with SR stimulation. There were no significant effects for other spatiotemporal variables., Significance: Sub threshold electrical noise can slightly improve walking balance control in individuals with CP. SR stimulation, through enhanced proprioception, may have improved the CP group's awareness of body motion during walking, thus leading them to adopt a more conservative stability strategy to prevent a potential fall., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background & Aims: The combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is recommended for the retreatment of patients with HCV infection in whom previous direct-acting antiviral (DAA) treatment failed. However, whether ribavirin further increases the therapeutic efficacy of SOF/VEL/VOX retreatment remains unclear. We aimed to test this hypothesis in a randomized-controlled trial., Methods: We randomly assigned 315 patients with DAA treatment failure from five Egyptian sites into two groups. Group A (n = 158) received SOF/VEL/VOX for 12 weeks, and group B (n = 157) received SOF/VEL/VOX + weight-based ribavirin for 12 weeks. Therapeutic efficacy was defined as SVR12 (sustained virologic response 12 weeks after treatment end). Safety and tolerability were evaluated by monitoring treatment-related adverse events (AEs) and laboratory abnormalities., Results: Males comprised 53.9% of group A and 57.1% of group B (p = 0.58); mean ages were 51.8 and 47.3 years in group A and B, respectively. Seventeen patients in each group were lost to follow-up. SVR12 rates were 87.3% (138/158) by intention-to-treat analysis and 97.8% (138/141) by per-protocol analysis in group A; and 87.9% (138/157) and 98.5% (138/140), respectively, in group B (p = n.s. for intention-to-treat and per-protocol analyses). Both regimens were well-tolerated, with no deaths and only one serious AE (anemia) in group B, which required ribavirin discontinuation. Fifty-five patients in group A vs. 77 in group B experienced any AE (p = 0.002)., Conclusion: This randomized-controlled trial showed equal, high efficacy of both regimens for the retreatment of previous DAA failures, although ribavirin was associated with more AEs. Therefore SOF/VEL/VOX monotherapy should be the preferred retreatment strategy. CLINCIALTRIALS., Gov Number: NCT04695769., Impact and Implications: HCV treatment guidelines recommend retreatment of direct-acting antiviral (DAA) treatment failures with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) for 12 weeks. However, whether ribavirin exerts an additional/synergistic effect remains unclear. The present study confirmed that SOF/VEL/VOX without ribavirin is the best regimen for retreatment of DAA treatment failures, and thus will help guide clinicians caring for patients who are not cured with a first course of DAA therapy., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Currently, the demand for more reliable drug screening devices has made scientists and researchers develop novel potential approaches to offer an alternative to animal studies. Organ-on-chips are newly emerged platforms for drug screening and disease metabolism investigation. These microfluidic devices attempt to recapitulate the physiological and biological properties of different organs and tissues using human-derived cells. Recently, the synergistic combination of additive manufacturing and microfluidics has shown a promising impact on improving a wide array of biological models. In this review, different methods are classified using bioprinting to achieve the relevant biomimetic models in organ-on-chips, boosting the efficiency of these devices to produce more reliable data for drug investigations. In addition to the tissue models, the influence of additive manufacturing on microfluidic chip fabrication is discussed, and their biomedical applications are reviewed., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Abnormal cardiac function in the setting of cirrhosis and in the absence of a primary cardiac disease is known as cirrhotic cardiomyopathy. The pathogenesis of cirrhotic cardiomyopathy is multifactorial but broadly is comprised of two pathways. The first is due to cirrhosis and synthetic liver failure with abnormal structure and function of many substances, including proteins, lipids, hormones, and carbohydrates such as lectins. The second is due to portal hypertension which invariably accompanies cirrhosis. Portal hypertension leads to a leaky, congested gut with resultant endotoxemia and systemic inflammation. This inflammatory phenotype comprises oxidative stress, cellular apoptosis, and inflammatory cell infiltration. Galectins exert all these pro-inflammatory mechanisms across many different tissues and organs, including the heart. Effective therapies for improving cardiac function in patients with cirrhosis are not available. Conventional strategies for other noncirrhotic heart diseases, including vasodilators, are not feasible because of the significant baseline vasodilation in cirrhotic patients. Therefore, exploring new treatment modalities for cirrhotic cardiomyopathy is of great importance. Galectin-3 inhibitors such as modified citrus pectin, N-acetyllactosamine, TD139 and GB0139 exert anti-apoptotic, anti-oxidative and anti-inflammatory effects and thus have potential therapeutic interest. This review briefly summarizes the physiological and pathophysiological role of galectin and specifically examines its role in cardiac disease processes. We present a more detailed discussion of galectin in cardiovascular complications of cirrhosis, particularly cirrhotic cardiomyopathy. Finally, therapeutic studies of galectin-3 inhibitors in cirrhotic cardiomyopathy are reviewed.

Cirrhotic cardiomyopathy is a syndrome of blunted cardiac systolic and diastolic function in patients with cirrhosis. However, the mechanisms remain incompletely known. Since contractility and relaxation depend on cardiomyocyte calcium transients, any factors that impact cardiac contractile and relaxation functions act eventually through calcium transients. In addition, calcium transients play an important role in cardiac arrhythmias. The present review summarizes the calcium handling system and its role in cardiac function in cirrhotic cardiomyopathy and its mechanisms. The calcium handling system includes calcium channels on the sarcolemmal plasma membrane of cardiomyocytes, the intracellular calcium-regulatory apparatus, and pertinent proteins in the cytosol. L-type calcium channels, the main calcium channel in the plasma membrane of cardiomyocytes, are decreased in the cirrhotic heart, and the calcium current is decreased during the action potential both at baseline and under stimulation of beta-adrenergic receptors, which reduces the signal to calcium-induced calcium release. The study of sarcomere length fluctuations and calcium transients demonstrated that calcium leakage exists in cirrhotic cardiomyocytes, which decreases the amount of calcium storage in the sarcoplasmic reticulum (SR). The decreased storage of calcium in the SR underlies the reduced calcium released from the SR, which results in decreased cardiac contractility. Based on studies of heart failure with non-cirrhotic cardiomyopathy, it is believed that the calcium leakage is due to the destabilization of interdomain interactions (dispersion) of ryanodine receptors (RyRs). A similar dispersion of RyRs may also play an important role in reduced contractility. Multiple defects in calcium handling thus contribute to the pathogenesis of cirrhotic cardiomyopathy.