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This study was conducted to investigate possible differences in the interactions of some selected steroids based on their distribution coefficients with cholesterol- or ergosterol-rich liposomes. Structurally cholesterol and ergosterol have very close resemblance to each other and generally it is thought that they behave in a similar manner. In this work we will show that this is not the case. Liposome electrokinetic chromatography (LEKC) was selected as the methodology for estimating the interactions between the steroids and the liposomes and for calculating the distribution coefficients. Apart from the distribution coefficients, the interactions were also studied with a response surface methodology and exploratory regression analysis. Both graphical and statistical analysis confirmed that there is an obvious difference in the interactions between the studies steroids and the cholesterol- or ergosterol-rich liposomes, and even a minute change in the sterol content had a significant impact on the interactions. The study demonstrates the flexibility and efficacy of LEKC for studying analyte-lipid membrane interactions, and for investigating taylor-made liposome systems., 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 © 2025. Published by Elsevier B.V.)

Purpose: To report the normative dimensions of the frontal nerve (FN) on fat-suppressed suppressed gadolinium (fs-gad) enhanced magnetic resonance imaging (MRI)., Method: A retrospective cohort study of patients who underwent coronal fs-gad T1-weighted MRI. Orbits were excluded if there was unilateral or bilateral pathology of the FN or optic nerve sheath (ONS), incomplete MRI sequences, poor image quality or indiscernible FN on radiological assessment. The maximum diameter of the FN and ONS was measured., Results: The mean age of participants was 58 ± 16 years and 50% were females (n = 42). The mean normative measurements (mean ± standard deviation) on coronal T1-weighted imaging: optic nerve sheath, 5.08 ± 0.67mm. On coronal fs-gad T1-weighted imaging: frontal nerve, 0.74 ± 0.18mm. No significant differences were found between male or female participants in both the frontal nerve (p = 0.913) or optic nerve sheath (p = 0.646). There was no significant correlation between age and mean diameter of the frontal nerve (r = 0.14, p = 0.067) or optic nerve sheath (r = 0.075, p = 0.336). Additionally, no significant difference was identified between the mean diameter of the frontal nerve (p = 0.075) and optic nerve sheath (p = 0.120) across age groups. The mean frontal nerve to optic nerve sheath ratio was 0.15 ± 0.04., Conclusion: Normative dimensions of the FN may provide quantitative cut-offs that can aid the diagnosis of FN enlargement seen in instances such as IgG4-related ophthalmic disease (IgG4-ROD) and neoplastic perineural spread., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Context: Obesity is prevalent in type 1 diabetes (T1D) and is problematic with higher risk for diabetes complications. It is unknown to what extent gut microbiome changes are associated with obesity and T1D., Objective: This work aimed to describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized statistically significant gut microbial and metabolite differences in lean T1D youth (body mass index [BMI]: 5%-<85%) vs those with obesity (BMI: ≥95%)., Methods: We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) differences in lean (n = 27) and obese (n = 21) T1D youth in a pilot study. The mean ± SD age was 15.3 ± 2.2 years, glycated hemoglobin A1c 7.8 ± 1.3%, diabetes duration 5.1 ± 4.4 years, 42.0% female, and 94.0% were White., Results: Bacterial community composition showed between sample diversity differences (β-diversity) by BMI group (P = .013). There was a higher ratio of Prevotella to Bacteroides in the obese group (P = .0058). There was a differential distribution of significantly abundant taxa in either the lean or obese groups, including increased relative abundance of Prevotella copri, among other taxa in the obese group. Functional profiling showed an upregulation of branched-chain amino acid (BCAA) biosynthesis in the obese group and upregulation of BCAA degradation, tyrosine metabolism, and secondary bile acid biosynthesis in the lean group. Stool SCFAs were higher in the obese vs the lean group (P < .05 for all)., Conclusion: Our findings identify a gut microbiome and microbial metabolite signature associated with obesity in T1D. These findings could help identify gut microbiome-targeted therapies to manage obesity in T1D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

A 73-year-old man presented with acute coronary syndrome secondary to stent failure. Intravascular imaging identified a recurrent protruding calcific nodule as the mechanism, which was effectively treated with low-speed rotablation, resulting in ablation of the nodule allowing the application of a drug-coated balloon., Competing Interests: Dr Ezad is supported by a British Heart Foundation Clinical Research Training Fellowship (FS/CRTF/21/24118). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2025 The Authors.)

Objectives: This study introduces Smart Imitator (SI), a 2-phase reinforcement learning (RL) solution enhancing personalized treatment policies in healthcare, addressing challenges from imperfect clinician data and complex environments., Materials and Methods: Smart Imitator's first phase uses adversarial cooperative imitation learning with a novel sample selection schema to categorize clinician policies from optimal to nonoptimal. The second phase creates a parameterized reward function to guide the learning of superior treatment policies through RL. Smart Imitator's effectiveness was validated on 2 datasets: a sepsis dataset with 19 711 patient trajectories and a diabetes dataset with 7234 trajectories., Results: Extensive quantitative and qualitative experiments showed that SI significantly outperformed state-of-the-art baselines in both datasets. For sepsis, SI reduced estimated mortality rates by 19.6% compared to the best baseline. For diabetes, SI reduced HbA1c-High rates by 12.2%. The learned policies aligned closely with successful clinical decisions and deviated strategically when necessary. These deviations aligned with recent clinical findings, suggesting improved outcomes., Discussion: Smart Imitator advances RL applications by addressing challenges such as imperfect data and environmental complexities, demonstrating effectiveness within the tested conditions of sepsis and diabetes. Further validation across diverse conditions and exploration of additional RL algorithms are needed to enhance precision and generalizability., Conclusion: This study shows potential in advancing personalized healthcare learning from clinician behaviors to improve treatment outcomes. Its methodology offers a robust approach for adaptive, personalized strategies in various complex and uncertain environments., (© The Author(s) 2025. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Transcriptome-wide association studies (TWAS) have been successful in identifying disease susceptibility genes by integrating cis-variants predicted gene expression with genome-wide association studies (GWAS) data. However, trans-variants for predicting gene expression remain largely unexplored. Here, we introduce transTF-TWAS, which incorporates transcription factor (TF)-linked trans-variants to enhance model building for TF downstream target genes. Using data from the Genotype-Tissue Expression project, we predict gene expression and alternative splicing and applied these prediction models to large GWAS datasets for breast, prostate, lung cancers and other diseases. We demonstrate that transTF-TWAS outperforms other existing TWAS approaches in both constructing gene expression prediction models and identifying disease-associated genes, as shown by simulations and real data analysis. Our transTF-TWAS approach significantly contributes to the discovery of disease risk genes. Findings from this study shed new light on several genetically driven key TF regulators and their associated TF-gene regulatory networks underlying disease susceptibility., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: The application of the transorbital (TO) approach for vascular lesions has been scarcely explored. In this anatomic study, we examine the carotid and middle cerebral arteries from the TO perspective and investigate the feasibility of vascular clipping in a pseudovascularized model., Methods: Three fixed human cadaveric specimens (6 sides) were used for dissection. The sequential TO approach comprised 1) conventional lateral orbital craniectomy; 2) lateral orbital rim removal; and 3) anterior clinoidectomy. The clinoidal, ophthalmic, and communicating carotid segments, branches, related cranial nerves, and dural attachments were examined. Comparison among the 3 variations of bone removal determined the minimal necessary steps for each vascular segment. An additional fresh pseudovascularized specimen (2 sides) was used to test the surgical feasibility of clipping., Results: The TO approach allowed exposure of the carotid C4 to bifurcation. Clinoidectomy and dural ring opening exposed lateral and dorsal aspects of C5/C6 and the ophthalmic, but not medial or ventral aspects, nor the superior hypophyseal artery or the carotid cave. The posterior communicating artery could be followed from origin to end. The anterior choroidal origin was seen but disappeared behind the uncus. The carotid bifurcation was visible, M1 could be followed to its bifurcation, but A1 lay deep within the field. The corridor permitted arachnoidal dissection, vessel manipulation, and clipping of exposed segments., Conclusions: The TO approach provides anatomic access to the lateral and dorsal carotid siphon, complete posterior communicating artery, and proximal middle cerebral artery. This preliminary study suggests potential application in the elective treatment of paraclinoid and posterior communicating aneurysms., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hard-to-cook (HTC) beans are characterised by extended cooking times. Although the changes in cell walls limiting hydration in HTC beans are widely investigated, the role of macro-molecules (starch and protein, which constitute >80 % of beans) are almost overlooked. This study investigates the structural changes in starch associated with the HTC quality in faba and adzuki beans stored at contrasting temperature and humidity regimes. Beans were stored at 4 °C (control) and 40 °C with relative humidity (RH) levels of 60 % and 80 %. Significant changes in starch properties were observed, particularly in beans stored at 40 °C and 80 % RH, with swelling power decreasing by 7 % and 12 % for faba and adzuki beans, respectively. Additionally, gelatinisation behaviour was negatively affected, with peak temperatures increasing for adzuki beans (from 66.64 °C to 68.46 °C) and enthalpy rising for faba beans (from 9.25 J/g to 10.64 J/g) along with an increase in relative crystallinity. Overall findings indicate that storage at elevated temperature (40 °C) under both moderate and high humidity conditions (60 % and 80 %) primarily or partially leads to developing HTC beans due to molecular rearrangement of starch at helical and crystalline levels., 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 © 2024. Published by Elsevier Ltd.)

Background: The prognostic value of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) imaging is well-established. However, the direct relationship between image pixels and outcomes remains poorly understood. We hypothesised that leveraging artificial intelligence (AI) to analyse qualitative LGE images based on American Heart Association (AHA) guidelines could elucidate this relationship., Methods: We collected retrospective CMR cases from a stress perfusion database, selecting LGE images comprising three long-axis views and 10 short-axis views. Clinical CMR reports served for annotation. We trained a multi-label convolutional neural network (CNN) to predict each AHA segment. Additionally, we transformed LGE image pixels into features, combined them with clinical data features, and trained a hybrid neural network (HNN) to predict mortality and ventricular arrhythmia. The dataset was divided into training (70%), validation (15%), and test (15%) sets. Evaluation metrics included the area under the curve (AUC)., Results: The total number of cases included was 2,740, with 218 patients experiencing positive mortality events (8%). The total number of cases with at least one AHA segment positive for LGE was 823 (30%), among which 111 (13%) experienced mortality events, and 84 (10%) had ventricular arrhythmia events. When assessing all segments combined, the most common cases were those classified as normal studies, with each AHA segment having a score of 0 (1,661 cases, 60.6%). The multi-label classifier demonstrated fair performance (AUC: 64%), whereas the cluster classifier did not yield any predictions (AUC: 53%, P<0.001). The mortality HNN achieved a satisfactory performance with an AUC of 77%, as did the ventricular arrhythmia HNN with an AUC of 75%., Conclusions: Our study demonstrates the feasibility of generating qualitative AHA LGE maps using AI. Furthermore, the prediction of mortality and ventricular arrhythmia using HNN represents a potent new approach for risk stratification in patients with known or suspected coronary artery disease (CAD)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jmai.amegroups.com/article/view/10.21037/jmai-24-94/coif). The authors have no conflicts of interest to declare.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene ( EDN1 ) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown., Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo., Results: A total of 118 participants (mean±SD; years of age 63.5 [9.2]; 71 [60.2%] females; 25 [21.2%] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95% CI, -19.60 to 11.06] P =0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P <0.001)., Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04097314., Competing Interests: Dr Berry is employed by the University of Glasgow, which holds consultancy and research agreements with Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, Corflow, Coroventis, GlaxoSmithKline, HeartFlow, Menarini, Novartis, Siemens Healthcare, Somalogic, Xylocor and Valo Health. Dr Spyridopoulos receives research grants from Astra Zeneca, Cambridge, UK, and Kancera, Solna, Sweden. Dr Ford is a consultant/speaker/honorarium from Abbott Vascular, Boston Scientific, Boehringer Ingelheim, Biotronik, Bio-Excel, and Novartis. Dr Al-Lamee serves on advisory boards of Janssen Pharmaceuticals, Abbott, and Philips, and has received speaker honoraria from Abbott, Philips, Medtronic, Servier, Omniprex, and Menarini. These companies had no role in the design or conduct of the study or in the data collection or interpretation. Dr Davenport holds research grants from AstraZeneca and is a member of scientific advisory boards of Janssen, ENB Therapeutics, and Pharmazz. Drs Berry, Ford, and Davenport are named on a pending patent for the use of zibotentan for microvascular angina. The University of Glasgow holds the patent. None of the other authors have any relevant disclosures.

Five different millets (foxtail, little, barnyard, kodo and browntop) with and without sprouting were subjected to flaking. Phytic acid and phenolic content tends to decrease significantly, whereas antioxidant activity increased up to 77.32% on flaking of millets. A significant decrease in peak and final viscosity was observed in millet flakes. A-type diffraction pattern was predominant for unsprouted millets whereas the flaked millets showed V-type crystallinity. The protein digestibility significantly increased up to 37.77% in flakes made from sprouted millets. The mineral bioavailability upon flaking of millets increased, especially Ca (88.22% for little), Fe (43.04% for barnyard) and Zn (61.77% for kodo), which is attributed to the reduction in phytic acid. Flaking, however, led to an increase in rapidly and slowly digestible starch with a corresponding decrease in resistant starch. Among the unsprouted and sprouted millet flakes, foxtail received the highest sensory scores for overall acceptability., Competing Interests: Declaration of competing interest The authors state that they have no personal relationships or conflicting financial interests that could have appeared to have an impact on the work discussed in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Modern sequencing instruments bring unprecedented opportunity to study within-host viral evolution in conjunction with viral transmissions between hosts. However, no computational simulators are available to assist the characterization of within-host dynamics. This limits our ability to interpret epidemiological predictions incorporating within-host evolution and to validate computational inference tools. To fill this need we developed Apollo, a GPU-accelerated, out-of-core tool for within-host simulation of viral evolution and infection dynamics across population, tissue, and cellular levels. Apollo is scalable to hundreds of millions of viral genomes and can handle complex demographic and population genetic models. Apollo can replicate real within-host viral evolution; accurately recapturing observed viral sequences from an HIV cohort derived from initial population-genetic configurations. For practical applications, using Apollo-simulated viral genomes and transmission networks, we validated and uncovered the limitations of a widely used viral transmission inference tool.

Background: Reduced estimated glomerular filtration rate (eGFR) is associated with lower use of invasive management and increased mortality after acute coronary syndrome (ACS). The reasons for this are unclear., Methods: A retrospective clinical cohort study was performed using data from the English National Institute for Health Research Health Informatics Collaborative (2010-2017). Multivariable logistic regression was used to investigate whether eGFR<90 mL/min/1.73 m 2 was associated with conservative ACS management and test whether (a) differences in care could be related to frailty and (b) associations between eGFR and mortality could be related to variation in revascularisation rates., Results: Among 10 205 people with ACS, an eGFR of <60 mL/min/1.73m 2 was found in 25%. Strong inverse linear associations were found between worsening eGFR category and receipt of invasive management, on a relative and absolute scale. People with an eGFR <30 mL compared with ≥90 mL/min/1.73 m 2 were half as likely to receive coronary angiography (OR 0.50, 95% CI 0.40 to 0.64) after non-ST-elevation (NSTE)-ACS and one-third as likely after STEMI (OR 0.30, 95% CI 0.19 to 0.46), resulting in 15 and 17 per 100 fewer procedures, respectively. Following multivariable adjustment, the ORs for receipt of angiography following NSTE-ACS were 1.05 (95% CI 0.88 to 1.27), 0.98 (95% CI 0.77 to 1.26), 0.76 (95% CI 0.57 to 1.01) and 0.58 (95% CI 0.44 to 0.77) in eGFR categories 60-89, 45-59, 30-44 and <30, respectively. After STEMI, the respective ORs were 1.20 (95% CI 0.84 to 1.71), 0.77 (95% CI 0.47 to 1.24), 0.33 (95% CI 0.20 to 0.56) and 0.28 (95% CI 0.16 to 0.48) (p<0.001 for linear trends). ORs were unchanged following adjustment for frailty. A positive association between the worse eGFR category and 30-day mortality was found (test for trend p<0.001), which was unaffected by adjustment for frailty., Conclusions: In people with ACS, lower eGFR was associated with reduced receipt of invasive coronary management and increased mortality. Adjustment for frailty failed to change these observations. Further research is required to explain these disparities and determine whether treatment variation reflects optimal care for people with low eGFR., Trial Registration Number: NCT03507309., Competing Interests: Competing interests: YB-S is partly funded as the Data Science co-lead by the National Institute for Health and Care Research Applied Research Collaboration West (NIHR ARC West) and University of Bristol. RL reports funding unrelated to this work from the Royal Marsden Cancer charity, Cancer Research UK, Innovate UK (co-funded by Roche), RM Partners Cancer Alliance, the NIHR and NHS England and consulting fees from Royal Marsden Private Care for personal private practice and is NHS England Joint National Clinical Lead for the Targeted Lung Health Check Programme and NIHR Clinical Research Network National Specialty Lead for Screening, Prevention and Early Detection., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Epinephrine (EPI) or norepinephrine (NOR) is widely used to treat cardiovascular collapse during lipid emulsion (LE) resuscitation for drug toxicity. However, the effect of LE on the vasoconstriction caused by EPI or NOR remains unknown. The purpose of this study was to examine the effect of an LE (Intralipid) on the vasoconstriction caused by EPI and NOR in isolated rat aorta., Methods: The effect of LE on the vasoconstriction caused by EPI or NOR in isolated rat aorta was examined. Additionally, the effect of LE on the calcium increase caused by EPI or NOR was investigated. The distribution constant (KD: lipid to aqueous phase) of EPI or NOR between a LE (1%) and an aqueous phase was determined., Results: LE (1 and 2%) did not significantly alter vasoconstriction caused by EPI or NOR in isolated endothelium-intact aorta. Moreover, the LE did not significantly alter the increased calcium level caused by EPI or NOR. The log KD of EPI in the LE (1%) was -0.71, -0.99, and -1.00 at 20, 50, and 100 mM ionic strength, respectively. The log KD of NOR in the LE (1%) was -1.22, -1.25, and -0.96 at 20, 50, and 100 mM ionic strength, respectively., Conclusions: Taken together, the Intralipid emulsion did not alter vasoconstriction induced by EPI or NOR that seems to be due to the hydrophilicity of EPI or NOR, leading to sustained hemodynamic support produced by EPI or NOR used during LE resuscitation.

Background: In the REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction) trial, percutaneous coronary intervention (PCI) did not reduce the incidence of death or hospitalization for heart failure (HHF)., Objectives: This prespecified secondary analysis investigated the effect of PCI on health status measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) combined with the primary outcome in a win ratio., Methods: Participants with severe ischemic left ventricular dysfunction were randomized to either PCI in addition to optimal medical therapy (OMT) (PCI) or OMT alone (OMT). The primary outcome was a hierarchical composite of all-cause death, HHF, and KCCQ-Overall Summary Score (OSS) at 24 months analyzed using the unmatched win ratio. The key secondary endpoint was a KCCQ-OSS responder analysis., Results: A total of 347 participants were randomized to PCI and 353 to OMT. Median age was 70.0 years (Q1-Q3: 63.3-76.1 years). Mean left ventricular ejection fraction was 27.0 ± 6.7%. PCI did not improve the primary endpoint (win ratio for PCI vs OMT: 1.05; 95% CI: 0.88-1.26; P = 0.58). PCI resulted in more KCCQ-OSS responders than OMT at 6 months (54.1% vs 40.7%; OR: 1.96; 95% CI: 1.41-2.71; P < 0.001) and fewer deteriorators (25.2% vs 31.4%; OR: 0.69; 95% CI: 0.47-1.00; P = 0.048). PCI did not impact KCCQ-OSS responders or deteriorators at 12 or 24 months., Conclusions: PCI did not improve the hierarchical composite of death, HHF, and health status at 2 years. PCI improved KCCQ-OSS at 6 months, but this benefit was not sustained to 1- or 2-year follow-up. (Revacularization for Ischemic Ventricular Dysfunction [REVIVED-BCIS2]; NCT01920048)., Competing Interests: Funding Support and Author Disclosures All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The REGENERATE-COBRA trial (NCT05711849) will assess the safety and efficacy of an intracoronary infusion of autologous bone marrow-derived mononuclear cells in refractory angina patients with no revascularization options who are symptomatic despite optimal medical and device therapy., Methods: REGENERATE-COBRA is a single site, blinded, randomized, sham-controlled, Phase II clinical trial enrolling 110 refractory angina patients with no revascularization options who are symptomatic despite optimal medical and device therapy. Patients will be randomized to either autologous bone marrow derived-mononuclear cells or a sham procedure. Patients in the cell-treated arm will undergo a bone marrow aspiration and an intracoronary infusion of autologous bone marrow derived-mononuclear cells. Patients in the control arm will undergo a sham bone marrow aspiration and a sham intracoronary infusion. The trial's primary endpoint is an improvement in Canadian Cardiovascular Society (CCS) angina class by 2 classes between baseline and 6 months. Secondary endpoints include change in: CCS class at 12 months, myocardial ischemic burden (as measured by perfusion imaging) at 6 months, quality of life at 6 and 12 months (as measured by EQ-5D-5L, EQ-5D-VAS and Seattle Angina Questionnaire), angina frequency at 6 and 12 months, total exercise time (as measured by a modified Bruce protocol) and major adverse cardiovascular events at 6 and 12 months., Conclusions: This is the first trial to assess the safety and efficacy of an intracoronary infusion of autologous bone marrow-derived unfractionated mononuclear cells in symptomatic refractory angina patients who have exhausted conventional therapeutic options., Competing Interests: Conflict of Interest The authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hand, Foot and Mouth Disease (HFMD), a highly contagious viral disease common among infants and young children, is primarily caused by Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CVA16). Nonetheless, emerging enteroviruses, such as CV-A10 and CV-A6, have also caused widespread outbreaks globally, in part due to the absence of effective antiviral therapies, and the high personto-person transmission rate. Person-to-person transmission is usually through fecal-oral or oral-oral routes, and sometimes via droplets. As the oral cavity is a primary site for early virus infection and replication, controlling oral viral shedding can mitigate the risk of transmission through this route. Povidone-iodine (PVP-I), a widely used antiseptic, has shown broad-spectrum antimicrobial properties but antiviral studies against HFMD-causing enteroviruses are limited, especially for CV-A10 and CVA6. Our study demonstrated that a 1% PVP-I solution (final concentration of 0.5%) exhibited virucidal activity against EV-A71, CV-A16, CV-A10, and CV-A6. All seven EV-A71 isolates and five CV-A16 isolates showed a significant virus titer reduction after a 1-minute incubation, while five CV-A10 isolates and two CV-A6 isolates required a 5-minute incubation to achieve this. The virucidal activity was confirmed through the EN14476:2013+A2:2019 virucidal quantitative suspension test, wherein all four viruses were completely inactivated after a 30-minute incubation with PVP-I at 37°C under both clean and dirty conditions. Western blot analysis suggested that PVP-I could affect the VP1 structural proteins of EV-A71. Our results suggest that PVP-I could serve as a potential virucidal agent to reduce the risk of person-to-person transmission of HFMD.

Purpose of Review: This review summarises the shifting paradigms in the treatment of ischemic left ventricular dysfunction, spotlighting the revascularization for ischemic ventricular dysfunction-British cardiovascular intervention society-2 (REVIVED-BCIS2) trial results and its impact on key therapeutic goals: survival, left ventricular function, arrhythmia prevention, quality of life and viability testing., Recent Findings: The REVIVED-BCIS2 trial, and its subsequent sub studies highlighted that (PCI) does not provide additional benefits to optimal medical therapy in terms of improving survival, left ventricular (LV) function, arrhythmic risk or quality of life. Additionally, viability testing did not differentiate patients who could benefit from PCI, although scar burden was found to be a significant predictor of outcome in these patients., Summary: The outcomes of REVIVED have challenged multiple existing beliefs in the field of ischaemic left ventricular dysfunction management, emphasising the importance of investigating evidence free areas in our practice. Future work, including the STICH3 international consortium of trials, aims to answer some of the remaining unanswered questions., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To report the normative dimensions of the infraorbital nerve on fat-suppressed gadolinium-enhanced MRI and correlate with patient demographics in an Australian cohort., Methods: A retrospective review of patients who underwent coronal fat-suppressed gadolinium T1-weighted MRI from September 2021 to December 2023. One hundred sixty-eight orbits were included. The maximum diameter of the infraorbital nerve and the optic nerve sheath was measured. Orbits were excluded if there was unilateral or bilateral pathology of the infraorbital nerve or optic nerve sheath, incomplete MRI sequences, poor image quality, or indiscernible infraorbital nerve on radiological examination., Results: The mean age of participants was 58 ± 16 years, and 50% were females (n = 42). The mean normative measurements (mean ± standard deviation) on coronal T1-weighted imaging: optic nerve sheath, 5.08 ± 0.67 mm. On coronal fat-suppressed gadolinium T1-weighted imaging: infraorbital nerve, 0.89 ± 0.22mm. No significant differences were found between male or female participants in both the infraorbital nerve (p = 0.757) or optic nerve sheath (p = 0.646). There was no significant correlation between age and mean diameter of the infraorbital nerve (r = 0.077, p = 0.320) or optic nerve sheath (r = 0.075, p = 0.336). Additionally, no significant difference was identified between the mean diameter of the infraorbital nerve (p = 0.079) and optic nerve sheath (p = 0.120) across age groups. The mean infraorbital nerve to optic nerve sheath ratio was 0.18 ± 0.00., Conclusion: Normative dimensions of the infraorbital nerve may be used to identify enlargement in conditions such as IgG4-related ophthalmic disease and reactive lymphoid hyperplasia., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Background: Diffuse coronary artery disease affects the safety and efficacy of percutaneous coronary intervention (PCI). Pathophysiologic coronary artery disease patterns can be quantified using fractional flow reserve (FFR) pullbacks incorporating the pullback pressure gradient (PPG) calculation. This study aimed to establish the capacity of PPG to predict optimal revascularization and procedural outcomes., Methods: This prospective, investigator-initiated, single-arm, multicenter study enrolled patients with at least one epicardial lesion with an FFR ≤0.80 scheduled for PCI. Manual FFR pullbacks were used to calculate PPG. The primary outcome of optimal revascularization was defined as an FFR ≥0.88 after PCI., Results: A total of 993 patients with 1044 vessels were included. The mean FFR was 0.68±0.12, PPG 0.62±0.17, and the post-PCI FFR was 0.87±0.07. PPG was significantly correlated with the change in FFR after PCI (r=0.65 [95% CI, 0.61-0.69]; P <0.001) and demonstrated excellent predictive capacity for optimal revascularization (area under the receiver operating characteristic curve, 0.82 [95% CI, 0.79-0.84]; P <0.001). FFR alone did not predict revascularization outcomes (area under the receiver operating characteristic curve, 0.54 [95% CI, 0.50-0.57]). PPG influenced treatment decisions in 14% of patients, redirecting them from PCI to alternative treatment modalities. Periprocedural myocardial infarction occurred more frequently in patients with low PPG (<0.62) compared with those with focal disease (odds ratio, 1.71 [95% CI, 1.00-2.97])., Conclusions: Pathophysiologic coronary artery disease patterns distinctly affect the safety and effectiveness of PCI. PPG showed an excellent predictive capacity for optimal revascularization and demonstrated added value compared with an FFR measurement., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04789317., Competing Interests: Dr Collet reports receiving research grants from Biosensors, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; consultancy fees from HeartFlow, OpSens Medical, Abbott Vascular, and Philips Volcano; and has patents pending on diagnostic methods for coronary artery disease. Dr Munhoz reports a research grant provided by the CardioPath PhD programme and speaker fees from Abbott Vascular. Dr Mizukami reports receiving research grants from Boston Scientific and speaker fees from Abbott Vascular, CathWorks, and Boston Scientific. Dr Matsuo has received consulting fees from Kaneka and Zeon and speaker’s fees from Abbott Medical Japan, Boston Scientific, Philips, and Amgen. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Biscaglia received research grants provided by Sahajanand Medical Technologies, Medis Medical Imaging, Eukon Srl, Siemens Healthineers, General Electric Healthcare, and Insight Lifetech. Dr Engstrøm reports speaker and advisory board fees from Abbott, Boston Scientific, and Novo Nordisk. Dr Leone reports receiving consultancy fees from Abbott and honoraria for sponsored symposia from Abbott, Medtronic, and Abiomed. Dr Fearon receives institutional research support from Abbott, Boston Scientific, and Medtronic and has consulting relationships with CathWorks and Siemens and stock options from HeartFlow. Dr Christiansen has received consulting fees from Abbott Medical Denmark A/S. Dr Yong has received minor honoraria from Abbott Vascular and research grants from Abbott Vascular and Philips. Dr Escaned is supported by the Intensification of Research Activity project INT22/00088 from the Spanish Instituto de Salud Carlos III and received speaker and advisory board member fees from Abbott and Philips. Dr Storozhenko reports a grant provided by the EAPCI Fellowship Programme. Dr West is an employee of Abbott Vascular. Dr De Potter is a paid consultant for Biosense Webster and receives grant support (institutional) and consultancy fees (institutional) from Abbott. Dr Berry receives research funding from the British Heart Foundation (grants RE/18/6134217, BHF/FS/17/26/32744, and PG/19/28/34310) and is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Coroventis Research, GlaxoSmithKline, HeartFlow, Menarini, Novartis, Servier, Siemens Healthcare, and Valo Health. Dr Collison has received consulting fees from Abbott. Dr Johnson has received consultancy or speaker fees from Abbott Vascular, Boston Scientific, Medtronic, Shockwave, and Terumo, and research grants from Abbott Vascular. Dr Amano reports receiving lecture fees from Astellas Pharma, Astra Zeneca, Bayer, Daiichi Sankyo, and Bristol Myers Squibb. Dr Perera has received research grant support from Abbott Vascular, HeartFlow, and Philips. Dr Jeremias has received consulting fees from Canon Medical, Artrya Medical, and Boston Scientific. Dr Ali reports institutional grant support from Abbott, Abiomed, Acist, Amgen, Boston Scientific, CathWorks, Canon Medical, Conavi, HeartFlow, Inari, Medtronic, the US National Institutes of Health, Nipro, OpSens Medical, Medis, Philips, Shockwave, Siemens, SpectraWAVE, and Teleflex; consulting fees from Abiomed, Astra Zeneca, Boston Scientific, CathWorks, OpSens Medical, Philips, and Shockwave; and equity in Elucid, Lifelink, SpectraWAVE, Shockwave, and VitalConnect. Dr Pijls has received research grants from Abbott and Hexacath; consultancy fees from Abbott, GE, Philips, and HeartFlow; and has equity in General Electric, Philips, and HeartFlow. Dr De Bruyne reports receiving consultancy fees from Boston Scientific and Abbott and research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular. Dr Johnson received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; has received significant institutional research support from St Jude Medical (CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?; URL: https://www.clinicaltrials.gov; Unique identifier: NCT02184117]) and Philips Volcano (DEFINE-FLOW [Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses; URL: https://www.clinicaltrials.gov; Unique identifier: NCT02328820]) for other studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm (now commercialized under 510[k] K191008); and has patents pending on diagnostic methods for quantifying aortic stenosis and TAVI physiology and on methods to correct pressure tracings from fluid-filled catheters.

Background: Complete revascularization of coronary artery disease has been linked to improved outcomes in patients with preserved left ventricular (LV) function., Objectives: This study sought to identify the impact of complete revascularization in patients with severe LV dysfunction., Methods: Patients enrolled in the REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction) trial were eligible if baseline/procedural angiograms and viability studies were available for analysis by independent core laboratories. Anatomical and viability-guided completeness of revascularization were measured by the coronary and myocardial revascularization indices (RI coro and RI myo ), respectively, where RI coro  = (change in British Cardiovascular Intervention Society Jeopardy score [BCIS-JS]) / (baseline BCIS-JS) and RI myo = (number of revascularized viable segments) / (number of viable segments supplied by diseased vessels). The percutaneous coronary intervention (PCI) group was classified as having complete or incomplete revascularization by median RI coro and RI myo . The primary outcome was death or hospitalization for heart failure., Results: Of 700 randomized patients, 670 were included. The baseline BCIS-JS and SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) scores were 8 (Q1-Q3: 6-10) and 22 (Q1-Q3: 15-29), respectively. In those patients assigned to PCI, median RI coro and RI myo values were 67% and 85%, respectively. Compared with the group assigned to optimal medical therapy alone, there was no difference in the likelihood of the primary outcome in those patients receiving complete anatomical or viability-guided revascularization (HR: 0.90; 95% CI: 0.62-1.32; and HR: 0.95; 95% CI: 0.66-1.35, respectively). A sensitivity analysis by residual SYNTAX score showed no association with outcome., Conclusions: In patients with severe LV dysfunction, neither complete anatomical nor viability-guided revascularization was associated with improved event-free survival compared with incomplete revascularization or treatment with medical therapy alone. (Revascularization for Ischemic Ventricular Dysfunction) [REVIVED-BCIS2]; NCT01920048)., Competing Interests: Funding Support and Author Disclosures The trial was funded by the National Institute for Health and Care Research (UK) Health Technology Assessment Program (NIHR 10/57/67); and the present work was supported by the British Heart Foundation (FS/CRTF/21/24118, RE/18/2/34213 and RE/18/6/34217). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The mechanism underlying ischaemic heart disease (IHD) has been primarily attributed to obstructive coronary artery disease (CAD). However, non-obstructive coronary arteries are identified in >50% of patients undergoing elective coronary angiography, recently leading to growing interest in the investigation and management of angina/ischaemia with non-obstructive coronary arteries (ANOCA/INOCA). INOCA is an umbrella term encompassing a multiple spectrum of possible pathogenetic entities, including coronary vasomotor disorders which consist of two major endotypes: coronary microvascular dysfunction (CMD) and vasospastic angina. Both conditions can coexist and be associated with concomitant obstructive CAD. Particularly, CMD refers to myocardial ischaemia due to reduced vasodilatory capacity of coronary microcirculation secondary to structural remodelling or impaired resting microvascular tone (functional) or a combination of both. CMD is not a benign condition and is more prevalent in women presenting with chronic coronary syndrome compared to men. In this setting, an impaired coronary flow reserve has been associated with increased risk of major adverse cardiovascular events. ANOCA/INOCA patients also experience impaired quality of life and associated increased healthcare costs. Therefore, research in this scenario has led to better definition, classification, and prognostic stratification based on the underlying pathophysiological mechanisms. The development and validation of non-invasive imaging modalities, invasive coronary vasomotor function testing and angiography-derived indices provide a comprehensive characterisation of CMD. The present narrative review aims to summarise current data relating to the diagnostic approach to CMD and provides details on the sequence that therapeutic management should follow., 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 Authors.)

Transcriptome-wide association studies (TWAS) have been successful in identifying disease susceptibility genes by integrating cis-variants predicted gene expression with genome-wide association studies (GWAS) data. However, trans-located variants for predicting gene expression remain largely unexplored. Here, we introduce transTF-TWAS, which incorporates transcription factor (TF)-linked trans-located variants to enhance model building. Using data from the Genotype-Tissue Expression project, we predict gene expression and alternative splicing and applied these models to large GWAS datasets for breast, prostate, and lung cancers. We demonstrate that transTF-TWAS outperforms other existing TWAS approaches in both constructing gene prediction models and identifying disease-associated genes, as evidenced by simulations and real data analysis. Our transTF-TWAS approach significantly contributes to the discovery of disease risk genes. Findings from this study have shed new light on several genetically driven key regulators and their associated regulatory networks underlying disease susceptibility.

Background: Cardiac troponin is commonly raised in patients presenting with malignancy. The prognostic significance of raised troponin in these patients is unclear., Objectives: We sought to investigate the relation between troponin and mortality in a large, well characterised cohort of patients with a routinely measured troponin and a primary diagnosis of malignancy., Methods: We used the National Institute for Health Research (NIHR) Health Informatics Collaborative data of 5571 patients, who had troponin levels measured at 5 UK cardiac centres between 2010 and 2017 and had a primary diagnosis of malignancy. Patients were classified into solid tumour or haematological malignancy subgroups. Peak troponin levels were standardised as a multiple of each laboratory's 99th -percentile upper limit of normal (xULN)., Results: 4649 patients were diagnosed with solid tumours and 922 patients with haematological malignancies. Raised troponin was an independent predictor of mortality in all patients (Troponin > 10 vs. <1 adjusted HR 2.01, 95% CI 1.73 to 2.34), in solid tumours (HR 1.84, 95% CI 1.55 to 2.19), and in haematological malignancy (HR 2.72, 95% CI 1.99 to 3.72). There was a significant trend in increasing mortality risk across troponin categories in all three subgroups (p < 0.001)., Conclusion: Raised troponin level is associated with increased mortality in patients with a primary diagnosis of malignancy regardless of cancer subtype. Mortality risk is stable for patients with a troponin level below the ULN but increases as troponin level increases above the ULN in the absence of acute coronary syndrome., (© 2024. The Author(s).)

Background: Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data., Methods: 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups., Results: Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p < 0.001). Phenogroup membership significantly improved survival prediction compared to conventional factors. Phenogroups were not predictive of hospitalisation for HF., Conclusions: Applying unsupervised machine learning to routinely collected electronic health record data identified phenogroups with distinct clinical characteristics and unique survival profiles., (© 2024. The Author(s).)

Objective: Despite the growing acceptance of neuronavigation in the field of neurosurgery, there is limited comparative research with contradictory results. This study aimed to compare the effectiveness (tumor resection rate and survival) and safety (frequency of neurological complications) of surgery for brain gliomas with or without neuronavigation., Methods: This retrospective cohort study evaluated data obtained from electronic records of patients who underwent surgery for gliomas at Dr. Alejandro Dávila Bolaños Military Hospital and the Clinic Hospital of Barcelona between July 2016 and September 2022. The preoperative and postoperative clinical and radiologic characteristics were analyzed and compared according to the use of neuronavigation., Results: This study included 110 patients, of whom 79 underwent surgery with neuronavigation. Neuronavigation increased gross total resection by 57% in patients in whom it was used; gross total resection was performed in 56% of patients who underwent surgery with neuronavigation as compared with 35.5% in those who underwent surgery without neuronavigation (risk ratio [RR], 1.57; P=0.056). The incidence of postoperative neurologic deficits (transient and permanent) decreased by 79% with the use of neuronavigation, (12% vs. 33.3%; RR, 0.21; P=0.0003). Neuronavigation improved survival in patients with grade IV gliomas (15 months vs. 13.8 months), but it was not statistically significant (odds ratio (OR), 0.19; P=0.13)., Conclusions: Neuronavigation improved the effectiveness (greater gross total resection of tumors) and safety (fewer neurological deficits) of brain glioma surgery. However, neuronavigation does not significantly influence the survival of patients with grade IV gliomas., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Breast density is a strong intermediate endpoint to investigate the association between early-life exposures and breast cancer risk. This study investigates the association between early-life growth and breast density in young adult women measured using Optical Breast Spectroscopy (OBS) and Dual X-ray Absorptiometry (DXA). OBS measurements were obtained for 536 female Raine Cohort Study participants at ages 27-28, with 268 completing DXA measurements. Participants with three or more height and weight measurements from ages 8 to 22 were used to generate linear growth curves for height, weight and body mass index (BMI) using SITAR modelling. Three growth parameters (size, velocity and timing) were examined for association with breast density measures, adjusting for potential confounders. Women who reached their peak height rapidly (velocity) and later in adolescence (timing) had lower OBS-breast density. Overall, women who were taller (size) had higher OBS-breast density. For weight, women who grew quickly (velocity) and later in adolescence (timing) had higher absolute DXA-breast density. Overall, weight (size) was also inversely associated with absolute DXA-breast density, as was BMI. These findings provide new evidence that adolescent growth is associated with breast density measures in young adult women, suggesting potential mediation pathways for breast cancer risk in later life.

Purpose: Age and body mass index (BMI) are critical considerations when assessing individual breast cancer risk, particularly for women with dense breasts. However, age- and BMI-standardized estimates of breast density are not available for screen-aged women, and little is known about the distribution of breast density in women aged < 40. This cross-sectional study uses three different modalities: optical breast spectroscopy (OBS), dual-energy X-ray absorptiometry (DXA), and mammography, to describe the distributions of breast density across categories of age and BMI., Methods: Breast density measures were estimated for 1,961 Australian women aged 18-97 years using OBS (%water and %water + %collagen). Of these, 935 women had DXA measures (percent and absolute fibroglandular dense volume, %FGV and FGV, respectively) and 354 had conventional mammographic measures (percent and absolute dense area). The distributions for each breast density measure were described across categories of age and BMI., Results: The mean age was 38 years (standard deviation = 15). Median breast density measures decreased with age and BMI for all three modalities, except for DXA-FGV, which increased with BMI and decreased after age 30. The variation in breast density measures was largest for younger women and decreased with increasing age and BMI., Conclusion: This unique study describes the distribution of breast density measures for women aged 18-97 using alternative and conventional modalities of measurement. While this study is the largest of its kind, larger sample sizes are needed to provide clinically useful age-standardized measures to identify women with high breast density for their age or BMI., (© 2024. The Author(s).)

Objective: The COVID-19 pandemic was associated with a reduction in the incidence of myocardial infarction (MI) diagnosis, in part because patients were less likely to present to hospital. Whether changes in clinical decision making with respect to the investigation and management of patients with suspected MI also contributed to this phenomenon is unknown., Methods: Multicentre retrospective cohort study in three UK centres contributing data to the National Institute for Health Research Health Informatics Collaborative. Patients presenting to the Emergency Department (ED) of these centres between 1st January 2020 and 1st September 2020 were included. Three time epochs within this period were defined based on the course of the first wave of the COVID-19 pandemic: pre-pandemic (epoch 1), lockdown (epoch 2), post-lockdown (epoch 3)., Results: During the study period, 10,670 unique patients attended the ED with chest pain or dyspnoea, of whom 6,928 were admitted. Despite fewer total ED attendances in epoch 2, patient presentations with dyspnoea were increased ( p  < 0.001), with greater likelihood of troponin testing in both chest pain ( p  = 0.001) and dyspnoea ( p  < 0.001). There was a dramatic reduction in elective and emergency cardiac procedures (both p  < 0.001), and greater overall mortality of patients ( p  < 0.001), compared to the pre-pandemic period. Positive COVID-19 and/or troponin test results were associated with increased mortality ( p  < 0.001), though the temporal risk profile differed., Conclusions: The first wave of the COVID-19 pandemic was associated with significant changes not just in presentation, but also the investigation, management, and outcomes of patients presenting with suspected myocardial injury or MI., Competing Interests: 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., (© 2024 Chammas, Yuan, Little, Roadknight, Varnai, Chang, Sze, Davies, Tsui, Salih, Glampson, Papadimitriou, Mulla, Woods, O'Gallagher, Shah, Williams, Asselbergs, Mayer, Lee, Herbert, Johnson, Grant, Curzen, Shah, Perera, Patel, Channon, Kaura, Mayet, Eyre, Squire, Kharbanda, Lewis and Wijesurendra.)

Artificial Intelligence (AI) applications have shown promise in the management of pandemics. In response to the global Monkeypox (Mpox) outbreak, the HeHealth.ai team leveraged an existing tool to screen for sexually transmitted diseases (STD) to develop a digital screening test for symptomatic Mpox using AI. Before the global Mpox outbreak, the team developed a smartphone app (HeHealth) where app users can use a smartphone to photograph their own penises to screen for symptomatic STD. The AI model initially used 5000 cases and a modified convolutional neural network to output prediction scores across visually diagnosable penis pathologies including syphilis, herpes simplex virus, and human papillomavirus. A total of about 22,000 users had downloaded the HeHealth app, and ~21,000 images were analysed using HeHealth AI technology. We then used formative research, stakeholder engagement, rapid consolidation images, a validation study, and implementation of the tool. A total of 1000 Mpox-related images had been used to train the Mpox symptom checker tool. Based on an internal validation, our digital symptom checker tool showed specificity of 87% and sensitivity of 90% for symptomatic Mpox. Several hurdles identified included issues of data privacy and security for app users, initial lack of data to train the AI tool, and the potential generalisability of input data. We offer several suggestions to help others get started on similar projects in emergency situations, including engaging a wide range of stakeholders, having a multidisciplinary team, prioritising pragmatism, as well as the concept that 'big data' in fact is made up of 'small data'.

Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution., Competing Interests: Declaration of interests A.R.V. is a member of Cell’s advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Systems for disease vector control should be effective, efficient, and flexible to be able to tackle contemporary challenges and threats in the control and elimination of vector-borne diseases. As a priority activity towards the strengthening of vector control systems, it has been advocated that countries conduct a vector-control needs assessment. A review was carried out of the perceived needs for disease vector control programs among eleven countries and subnational states in South Asia and the Middle East. In each country or state, independent teams conducted vector control needs assessment with engagement of stakeholders. Important weaknesses were described for malaria, dengue and leishmaniases regarding vector surveillance, insecticide susceptibility testing, monitoring and evaluation of operations, entomological capacity and laboratory infrastructure. In addition, community mobilization and intersectoral collaboration showed important gaps. Countries and states expressed concern about insecticide resistance that could reduce the continued effectiveness of interventions, which demands improved monitoring. Moreover, attainment of disease elimination necessitates enhanced vector surveillance. Vector control needs assessment provided a useful planning tool for systematic strengthening of vector control systems. A limitation in conducting the vector control needs assessment was that it is time- and resource-intensive. To increase the feasibility and utility of national assessments, an abridged version of the guidance should focus on operationally relevant topics of the assessment. Similar reviews are needed in other regions with different contextual conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 World Health Organization. Licensee Public Library of Science. This is an open access article distributed under the Creative Commons Attribution IGO License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited: https://creativecommons.org/licenses/by/3.0/igo/. In any use of this article, there should be no suggestion that WHO endorses any specific organization, products or services.)

Introduction: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) improves end-organ perfusion in cardiogenic shock but may increase afterload, which can limit cardiac recovery. Left ventricular (LV) unloading strategies may aid cardiac recovery and prevent complications of increased afterload. However, there is no consensus on when and which unloading strategy should be used., Methods: An online survey was distributed worldwide via the EuroELSO newsletter mailing list to describe contemporary international practice and evaluate heterogeneity in strategies for LV unloading., Results: Of 192 respondents from 43 countries, 53% routinely use mechanical LV unloading, to promote ventricular recovery and/or to prevent complications. Of those that do not routinely unload, 65% cited risk of complications as the reason. The most common indications for unplanned unloading were reduced arterial line pulsatility (68%), pulmonary edema (64%) and LV dilatation (50%). An intra-aortic balloon pump was the most frequently used device for unloading followed by percutaneous left ventricular assist devices. Echocardiography was the most frequently used method to monitor the response to unloading., Conclusions: Significant variation exists with respect to international practice of ventricular unloading. Further research is required that compares the efficacy of different unloading strategies and a randomized comparison of routine mechanical unloading versus unplanned unloading., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Donker reports speaker fees from Getinge-Maquet and Fresenius-Xenios-NovaLung and research cooperation with Getinge-Maquet and FreseniusXenios-NovaLung. Dr Pappalardo reports personal fees from Abiomed unrelated to the submitted work. Dr Kapur has received institutional research support and speaker/consulting honoraria from Abbott, Abiomed, Boston Scientific, Getinge, LivaNova, Medtronic, MDStart, Precardia, and Zoll. Prof. Perera reports receiving speaker fees/honoraria/research grant support from Abiomed, Getinge, Abbott Vascular and Philips.

Background: Coronary microvascular dysfunction (CMD) is the leading cause of ischemia with no obstructive coronary arteries disease (INOCA) disease. Diagnosis of CMD relies on surrogate physiological indices without objective proof of ischemia., Objectives: Intracoronary electrocardiogram (icECG) derived hyperemic indices may accurately and objectively detect CMD and reversible ischemia in related territory., Methods: INOCA patients with proven ischemia by myocardial perfusion scan (MPS) and completely normal coronary arteries underwent simultaneous intracoronary electrophysiological (icECG) and physiological (intracoronary Doppler) assessment in all 3 coronary arteries during rest and under adenosine induced hyperemia., Results: Sixty vessels in 21 patients were included in the final analysis. All patients had at least one vessel with abnormal CFR. 41 vessels had CMD (CFR < 2.5), of which 26 had increased microvascular resistance (structural CMD, HMR > 1.9 mmHg.cm -1 .s) and 15 vessels had CMD (CFR < 2.5) with normal microvascular resistance (functional CMD, HMR <= 1.9 mmHg.cm -1 .s). Only one-third of the patients (n = 7) had impaired CFR < 2.5 in all 3 epicardial arteries. Absolute ST shift between hyperemia and rest (∆ST) has shown the best diagnostic performance for ischemia (cut-off 0.10 mV, sensitivity: 95%, specificity: 72%, accuracy: 80%, AUC: 0.860) outperforming physiological indices (CFR: 0.623 and HMR: 0.653 DeLong's test P = .0002)., Conclusions: In INOCA patients, CMD involves coronary artery territories heterogeneously. icECG can accurately detect CMD causing perfusion abnormalities in patients with INOCA outperforming physiological CMD markers, by demonstrating actual ischemia instead of predicting the likelihood of inducible ischemia based on violated surrogate thresholds of blunted flow reserve or increased minimum microvascular resistance., Condensed Abstract: In 21 INOCA patients with coronary microvascular dysfunction (CMD) and myocardial perfusion scan proved ischemia, hyperemic indices of intracoronary electrocardiogram (icECG) have accurately detected vessel-specific CMD and resulting perfusion abnormalities & ischemia, outperforming invasive hemodynamic indices. Absolute ST shift between hyperemia and rest (∆ST) has shown the best classification performance for ischemia in no Obstructive Coronary Arteries (AUC: 0.860) outperforming Doppler derived CMD indices (CFR: 0.623 and HMR: 0.653 DeLong's test P = .0002).icECG can be used to diagnose CMD causing perfusion defects by demonstrating actual reversible ischemia at vessel-level during the initial CAG session, obviating the need for further costly ischemia tests., Clinicaltrials: GOV: NCT05471739., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Prediction of clinical outcomes in coronary artery disease (CAD) has been conventionally achieved using clinical risk factors. The relationship between imaging features and outcome is still not well understood. This study aims to use artificial intelligence to link image features with mortality outcome., Methods: A retrospective study was performed on patients who had stress perfusion cardiac magnetic resonance (SP-CMR) between 2011 and 2021. The endpoint was all-cause mortality. Convolutional neural network (CNN) was used to extract features from stress perfusion images, and multilayer perceptron (MLP) to extract features from electronic health records (EHRs), both networks were concatenated in a hybrid neural network (HNN) to predict study endpoint. Image CNN was trained to predict study endpoint directly from images. HNN and image CNN were compared with a linear clinical model using area under the curve (AUC), F1 scores, and McNemar's test., Results: Total of 1,286 cases were identified, with 201 death events (16%). The clinical model had good performance (AUC =80%, F1 score =37%). Best Image CNN model showed AUC =72% and F1 score =38%. HNN outperformed the other two models (AUC =82%, F1 score =43%). McNemar's test showed statistical difference between image CNN and both clinical model (P<0.01) and HNN (P<0.01). There was no significant difference between HNN and clinical model (P=0.15)., Conclusions: Death in patients with suspected or known CAD can be predicted directly from stress perfusion images without clinical knowledge. Prediction can be improved by HNN that combines clinical and SP-CMR images., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jmai.amegroups.com/article/view/10.21037/jmai-24-1/coif). The authors have no conflicts of interest to declare.

Heart failure with preserved ejection fraction (HFpEF) is a common condition with few effective therapies and hence represents a major healthcare burden. The clinical syndrome of HFpEF can be caused by varying pathophysiological processes, with coronary microvascular dysfunction (CMD) proposed as one of the aetiologies, although confirming causality has been challenging. CMD is characterised by the inability of the coronary vasculature to augment blood flow in response to a physiological stressor and has been established as the driver of angina in patients with non-obstructed coronaries (ANOCA), and this has subsequently led to efficacious endotype-directed therapies. CMD is also highly prevalent among sufferers of HFpEF and may represent a novel treatment target for this particular endotype of this condition. This review aims to discuss the role of the microcirculation in the healthy heart how it's dysfunction may precipitate HFpEF and explore the current diagnostic tools available. We also discuss the gaps in evidence and where we believe future research should be focussed., 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 Authors.)

Objectives: Cardiac surgery for coronary artery disease was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with disease ordinarily treated with coronary artery bypass grafting (CABG) instead underwent percutaneous coronary intervention (PCI). We sought to describe 12-month outcomes following PCI in patients who would typically have undergone CABG., Methods: Between March 1 and July 31, 2020, patients who received revascularization with PCI when CABG would have been the primary choice of revascularization were enrolled in the prospective, multicenter UK-ReVasc Registry. We evaluated the following major adverse cardiovascular events at 12 months: all-cause mortality, myocardial infarction, repeat revascularization, stroke, major bleeding, and stent thrombosis., Results: A total of 215 patients were enrolled across 45 PCI centers in the United Kingdom. Twelve-month follow up data were obtained for 97% of the cases. There were 9 deaths (4.3%), 5 myocardial infarctions (2.4%), 12 repeat revascularizations (5.7%), 1 stroke (0.5%), 3 major bleeds (1.4%), and no cases of stent thrombosis. No difference in the primary endpoint was observed between patients who received complete vs incomplete revascularization (residual SYNTAX score £ 8 vs > 8) (P = .22)., Conclusions: In patients with patterns of coronary disease in whom CABG would have been the primary therapeutic choice outside of the pandemic, PCI was associated with acceptable outcomes at 12 months of follow-up. Contemporary randomized trials that compare PCI to CABG in such patient cohorts may be warranted.

Introduction: Percutaneous coronary intervention for complex coronary disease is associated with a high risk of cardiogenic shock. This can cause harm and limit the quality of revascularization achieved, especially when left ventricular function is impaired at the outset. Elective percutaneous left ventricular unloading is increasingly used to mitigate adverse events in patients undergoing high-risk percutaneous coronary intervention, but this strategy has fiscal and clinical costs and is not supported by robust evidence., Methods: CHIP-BCIS3 (Controlled Trial of High-Risk Coronary Intervention With Percutaneous Left Ventricular Unloading) is a prospective, multicenter, open-label randomized controlled trial that aims to determine whether a strategy of elective percutaneous left ventricular unloading is superior to standard care (no planned mechanical circulatory support) in patients undergoing nonemergent high-risk percutaneous coronary intervention. Patients are eligible for recruitment if they have severe left ventricular systolic dysfunction, extensive coronary artery disease, and are due to undergo complex percutaneous coronary intervention (to the left main stem with calcium modification or to a chronic total occlusion with a retrograde approach). Cardiogenic shock and acute ST-segment-elevation myocardial infarction are exclusions. The primary outcome is a hierarchical composite of all-cause death, stroke, spontaneous myocardial infarction, cardiovascular hospitalization, and periprocedural myocardial infarction, analyzed using the win ratio. Secondary outcomes include completeness of revascularization, major bleeding, vascular complications, health economic analyses, and health-related quality of life. A sample size of 250 patients will have in excess of 80% power to detect a hazard ratio of 0.62 at a minimum of 12 months, assuming 150 patients experience an event across all follow-up., Conclusions: To date, 169 patients have been recruited from 21 National Health Service hospitals in the United Kingdom, with recruitment expected to complete in 2024., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05003817., Competing Interests: None.

Objective: Conus region lumbosacral lipomas (LSLs) are highly heterogeneous in their morphology, clinical presentation, and outcome, with an incompletely understood natural history and often treacherous surgical anatomy. This systematic review aims to critically evaluate and assess the strength of the current LSL evidence base to guide management strategies., Methods: According to a systematic review following PRISMA guidelines, a search was conducted using the key term "lumbosacral lipoma" across MEDLINE (OVID), Embase, Cochrane Library, and PubMed databases from January 1951 to April 2021. All studies containing ten or more paediatric conus lipomas were included. Data heterogeneity and bias were assessed., Results: A total of 13 studies were included, containing 913 LSLs (predominantly transitional type-58.5%). Two-thirds (67.5%) of all patients (treated and non-treated) remained clinically stable and 17.6% deteriorated. Neuropathic bladder was present in 8.6% at final follow-up. Of patients managed surgically, near-total resection vs. subtotal resection deterioration-free survival rates were 77.2-98.4% and 10-67% respectively. 4.5% (0.0-27.3%) required re-do untethering surgery. Outcomes varied according to lipoma type. Most publications contained heterogeneous populations and used variable terminology. There was a lack of consistency in reported outcomes., Conclusion: Amongst published series, there is wide variability in patient factors such as lipoma type, patient age, and methods of (particularly urological) assessment. Currently, there is insufficient evidence base upon which to make clear recommendations for the management of children with LSL. There is an imperative for neurosurgeons, neuroradiologists, and urologists to collaborate to better standardise the terminology, assessment tools, and surgical interventions for this challenging group of conditions., (© 2023. Crown.)

Objective: The perinatal period presents several opportunities to identify and treat perinatal mental health and substance use disorders by integrating into existing care pathways. We aimed to examine the role of birth doulas in supporting their clients' perinatal mental health., Methods: Thematic content analysis of focus groups with doulas, and interviews with doula clients was used to characterize the doula-client relationship, investigate whether and how doulas provide mental health and substance use support, and identify barriers and recommendations for doulas to support their clients' mental health. Participants were doula clients from communities underserved due to race, income, language and culture., Results: Doulas and clients reported positive relationships, supported by congruence in culture, language, and lived experiences. Doulas varied in their confidence in identifying perinatal mental health problems, though most agreed that doulas could support their clients' mental health to different degrees. Barriers to engaging in perinatal mental health treatments included low perceived need and socio-economic burden., Conclusions: With adequate support and training, doulas can play an important role in supporting their client's emotional well-being., Competing Interests: 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 © 2024 Quiray, Richards, Navarro-Aguirre, Glazer, Adachi, Trujillo, Perera, Garcia and Bhat.)

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations., (© 2024. The Author(s).)

Objective: Peripheral arterial stenoses (PAS) are commonly investigated with duplex ultrasound (DUS) and angiography, but these are not functional tests. Fractional flow reserve (FFR), a pressure based index, functionally assesses the ischaemic potential of coronary stenoses, but its utility in PAS is unknown. FFR in the peripheral vasculature in patients with limb ischaemia was investigated., Methods: Patients scheduled for angioplasty and or stenting of isolated iliac and superficial femoral artery stenoses were recruited. Resting trans-lesional pressure gradient (P d /P a ) and FFR were measured after adenosine provoked hyperaemia using an intra-arterial 0.014 inch flow and pressure sensing wire (ComboWire XT, Philips). Prior to revascularisation, exercise ABPI (eABPI) and DUS derived peak systolic velocity ratio (PSVR) of the index lesion were determined. Calf muscle oxygenation was measured using blood oxygenation level dependent cardiovascular magnetic resonance prior to and after revascularisation., Results: Forty-one patients (32, 78%, male, mean age 65 ± 11 years) with 61 stenoses (iliac 32; femoral 29) were studied. For lesions < 80% stenosis, resting P d /P a was not influenced by the degree of stenosis (p = .074); however, FFR was discriminatory, decreasing as the severity of stenosis increased (p = .019). An FFR of < 0.60 was associated with critical limb threatening ischaemia (area under the curve [AUC] 0.87; 95% CI 0.75 - 0.95), in this study performing better than angiographic % stenosis (0.79; 0.63 - 0.89), eABPI (0.72; 0.57 - 0.83), and PSVR (0.65; 0.51 - 0.78). FFR correlated strongly with calf oxygenation (rho, 0.76; p < .001). A greater increase in FFR signalled resolution of symptoms and signs (ΔFFR 0.25 ± 0.15 vs. 0.13 ± 0.09; p = .009) and a post-angioplasty and stenting FFR of > 0.74 predicted successful revascularisation (combined sensitivity and specificity of 95%; AUC 0.98; 0.91 - 1.00)., Conclusion: This pilot study demonstrates that FFR can objectively measure the functional significance of PAS that compares favourably with visual and DUS based assessments. Its role as a quality control adjunct that confirms optimal vessel patency after angioplasty and or stenting also merits further investigation., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)