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Aims: Acute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti-inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF)., Methods and Results: We present the rationale and design of the ARCHER Trial, an international multicentre, double-blind, randomized, placebo-controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow-up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs-troponin, NT-proBNP, markers of inflammation and endothelial function during the 12-week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper., Conclusions: The ongoing ARCHER Trial is an international, multicentre, double-blind, randomized, placebo-controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Gallium-based liquid metals (LMs) are widely used for stretchable and reconfigurable electronics thanks to their fluidic nature and excellent conductivity. These LMs possess attractive optical properties for photonics applications as well. However, due to the high surface tension of the LMs, it is challenging to form LM nanostructures with arbitrary shapes using conventional nanofabrication techniques. As a result, LM-based nanophotonics has not been extensively explored. Here, a simple yet effective technique is demonstrated to deterministically fabricate LM nanopatterns with high yield over a large area. This technique demonstrates for the first time the capability to fabricate LM nanophotonic structures of various precisely defined shapes and sizes using two different LMs, that is, liquid gallium and liquid eutectic gallium-indium alloy. High-density arrays of LM nanopatterns with critical feature sizes down to ≈100 nm and inter-pattern spacings down to ≈100 nm are achieved, corresponding to the highest resolution of any LM fabrication technique developed to date. Additionally, the LM nanopatterns demonstrate excellent long-term stability under ambient conditions. This work paves the way toward further development of a wide range of LM nanophotonics technologies and applications., (© 2024 Wiley‐VCH GmbH.)

Technological advances have led to a modern-day lighting and smartphone revolution, with artificial light exposure at night increasing to levels never before seen in the evolutionary history of living systems on Earth. Light as a pollutant, however, remains largely unrecognized, and the reproductive effects of light pollution are mostly if not entirely unconsidered. This is despite the reproductive system being intricately linked to metabolism and the circadian system, both of which can be disturbed even by low levels of light. Here, we aim to change this perspective by reviewing the physiological and pathophysiological mechanisms by which light exposure alters the intricate hormonal, metabolic and reproductive networks that are relevant to reproductive toxicology. Nascent human studies have recently identified the photoreceptors responsible for the light dose relationship with melatonin suppression and circadian re-entrainment, directly shown the association between the alignment of light-dark cycles with activity-rest cycles on metabolic health and provided proof-of-principle that properly timed blue light-enriched and blue light-depleted delivery can accelerate circadian re-entrainment. With these advances, there is now a need to consider testicular effects of light pollution., Competing Interests: The author declares 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 Liu.)

Background: Excessive daytime sleepiness (EDS) is a complex sleep problem that affects approximately 33% of the United States population. Although EDS usually occurs in conjunction with insufficient sleep, and other sleep and circadian disorders, recent studies have shown unique genetic markers and metabolic pathways underlying EDS. Here, we aimed to further elucidate the biological profile of EDS using large scale single- and pathway-level metabolomics analyses., Methods: Metabolomics data were available for 877 metabolites in 6,071 individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and EDS was assessed using the Epworth Sleepiness Scale (ESS) questionnaire. We performed linear regression for each metabolite on continuous ESS, adjusting for demographic, lifestyle, and physiological confounders, and in sex specific groups. Subsequently, gaussian graphical modelling was performed coupled with pathway and enrichment analyses to generate a holistic interactive network of the metabolomic profile of EDS associations., Findings: We identified seven metabolites belonging to steroids, sphingomyelin, and long chain fatty acids sub-pathways in the primary model associated with EDS, and an additional three metabolites in the male-specific analysis. The identified metabolites particularly played a role in steroid hormone biosynthesis., Interpretation: Our findings indicate that an EDS metabolomic profile is characterized by endogenous and dietary metabolites within the steroid hormone biosynthesis pathway, with some pathways that differ by sex. Our findings identify potential pathways to target for addressing the causes or consequences of EDS and related sleep disorders., Funding: Details regarding funding supporting this work and all studies involved are provided in the acknowledgments section., Competing Interests: Declaration of Interests Dr. Redline discloses consulting relationships with Eli Lilly Inc, Jazz Pharma, and Apnimed Inc. Additionally, Dr. Redline serves as an unpaid board member for the Alliance for Sleep Apnoea Partners and has received loaned equipment for a multi-site study: oxygen concentrators from Philips Respironics and polysomnography equipment from Nox Medical.

Aims: Results from randomized trials suggest benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitor initiation in clinically stable acute heart failure. We aim to examine the real-world effectiveness of early versus delayed post-discharge SGLT2 inhibitor initiation in people with acute heart failure and type 2 diabetes., Methods and Results: Using linkable administrative databases in Ontario, Canada, individuals aged 66 years or older with type 2 diabetes who were discharged to the community from acute care hospitals for heart failure between 1 July 2016 and 31 March 2020 were included in this retrospective, population-based cohort study. The primary outcome was hospitalization for heart failure (HHF) or cardiovascular mortality as a composite. Follow-up started from discharge for maximum 1 year. We compared outcomes between post-discharge SGLT2 inhibitor initiation within 3 days, 4-90 days, or 91-180 days, versus delayed initiation for at least 180 days. The 'clone-censor-weight' approach with a target trial emulation framework was used to address time-related biases. There were 9641 eligible individuals. After cloning and artificial censoring, there were 38 564 clones, 12 439 person-years, and 7584 events. Compared to delayed initiation for at least 180 days, initiation within 3 days post-discharge was associated with a lower 1-year risk of HHF or cardiovascular mortality (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.45-0.83), while initiation 4-90 days (RR 0.83, 95% CI 0.72-0.93) or 91-180 days (RR 0.89, 95% CI 0.79-0.97) showed smaller risk reduction., Conclusion: Real-world evidence supports early SGLT2 inhibitor initiation to reduce HHF or cardiovascular mortality in acute heart failure and type 2 diabetes., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Laparoscopic liver surgery is a newly developed minimally invasive technique and represents an inevitable trend in the future development of surgical methods. By using augmented reality (AR) technology to overlay preoperative CT models with intraoperative laparoscopic videos, surgeons can accurately locate blood vessels and tumors, significantly enhancing the safety and precision of surgeries. Point cloud registration technology is key to achieving this effect. However, there are two major challenges in registering the CT model with the point cloud surface reconstructed from intraoperative laparoscopy. First, the surface features of the organ are not prominent. Second, due to the limited field of view of the laparoscope, the reconstructed surface typically represents only a very small portion of the entire organ. To address these issues, this paper proposes the keypoint correspondence registration network (KCR-Net). This network first uses the neighborhood feature fusion module (NFFM) to aggregate and interact features from different regions and structures within a pair of point clouds to obtain comprehensive feature representations. Then, through correspondence generation, it directly generates keypoints and their corresponding weights, with keypoints located in the common structures of the point clouds to be registered, and corresponding weights learned automatically by the network. This approach enables accurate point cloud registration even under conditions of extremely low overlap. Experiments conducted on the ModelNet40, 3Dircadb, DePoLL demonstrate that our method achieves excellent registration accuracy and is capable of meeting the requirements of real-world scenarios.

Introduction: DNA methylation (DNAm) predictors of high sensitivity C-reactive protein (CRP) offer a stable and accurate means of assessing chronic inflammation, bypassing the CRP protein fluctuations secondary to acute illness. Poor sleep health is associated with elevated inflammation (including elevated blood CRP levels) which may explain associations of sleep insufficiency with metabolic, cardiovascular and neurological diseases. Our study aims to characterize the relationships among sleep health phenotypes and CRP markers -blood, genetic, and epigenetic indicators-within the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)., Methods: In HCHS/SOL, methylation risk scores (MRS)-CRP and polygenetic risk score (PRS)-CRP were constructed separately as weighted sums of methylation beta values or allele counts, respectively, for each individual. Sleep health phenotypes were measured using self-reported questionnaires and objective measurements. Survey-weighted linear regression established the association between the multiple sleep phenotypes (obstructive sleep apnea (OSA), sleep duration, insomnia and excessive sleepiness symptom), cognitive assessments, diabetes and hypertension with CRP markers while adjusting for age, sex, BMI, study center, and the first five principal components of genetic ancestry in HCHS/SOL., Results: We included 2221 HCHS/SOL participants (age range 37-76 yrs, 65.7% female) in the analysis. Both the MRS-CRP (95% confidence interval (CI): 0.32-0.42, p = 3.3 × 10 -38 ) and the PRS-CRP (95% CI: 0.15-0.25, p = 1 × 10 -14 ) were associated with blood CRP level. Moreover, MRS-CRP was associated with sleep health phenotypes (OSA, long sleep duration) and related conditions (diabetes and hypertension), while PRS-CRP markers were not associated with these traits. Circulating CRP level was associated with sleep duration and diabetes. Associations between OSA traits and metabolic comorbidities weakened after adjusting for MRS-CRP, most strongly for diabetes, and least for hypertension., Conclusions: MRS-CRP is a promising estimate for systemic and chronic inflammation as reflected by circulating CRP levels, which either mediates or serves as a common cause of the association between sleep phenotypes and related comorbidities, especially in the presence of diabetes.

Advances in upstream production of biologics-particularly intensified fed-batch processes beyond 10% cell solids-have severely strained harvest operations, especially depth filtration. Bioreactors containing high amounts of cell debris (more than 40% particles <10 µm in diameter) are increasingly common and drive the need for more robust depth filtration processes, while accelerated timelines emphasize the need for predictive tools to accelerate development. Both needs are constrained by the current limited mechanistic understanding of the harvest filter-feedstream system. Historically, process development relied on screening scale-down depth filter devices and conditions to define throughput before fouling, indicated by increasing differential pressure and/or particle breakthrough (measured via turbidity). This approach is straightforward, but resource-intensive, and its results are inherently limited by the variability of the feedstream. Semi-empirical models have been developed from first principles to describe various mechanisms of filter fouling, that is, pore constriction, pore blocking, and/or surface deposit. Fitting these models to experimental data can assist in identifying the dominant fouling mechanism. Still, this approach sees limited application to guide process development, as it is descriptive, not predictive. To address this gap, we developed a hybrid modeling approach. Leveraging historical bench scale filtration process data, we built a partial least squares regression model to predict particle breakthrough from filter and feedstream attributes, and leveraged the model to demonstrate prediction of filter performance a priori. The fouling models are used to interpret and provide physical meaning to these computational models. This hybrid approach-combining the mechanistic insights of fouling models and the predictive capability of computational models-was used to establish a robust platform strategy for depth filtration of Chinese hamster ovary cell cultures. As new data continues to teach the computational models, in silico tools will become an essential part of harvest process development by enabling prospective experimental design, reducing total experimental load, and accelerating development under strict timelines., (© 2024 Wiley Periodicals LLC.)

People with long COVID are those who still have symptoms, signs, and conditions after the initial phase of infection of SARS-CoV-2. The incidence of long COVID varies among regions-31% in North America, 44% in Europe, and 51% in Asia, which is challenging the healthcare system, but there is limited guidelines for its treatment. With more and more nationwide projects funded by the government such as the RECOVER initiative in the United States and National Institute for Health Research funding in the United Kingdom, an increasing number of ongoing clinical trials are investigating the efficacy of diverse therapies on reversing long COVID. After searching the World Health Organization International Clinical Trial Registry Platform, 587 clinical studies are identified as long COVID studies. Among these, 312 studies (53.2%) are testing potential therapies. Most of the long COVID trials were conducted in the United States (58 trials [18.6%]), followed by India (55 trials [17.6%]), and Spain (20 trials [6.4%]). Interventions in these clinical trials include physical exercise, rehabilitation therapy, behavioral therapy, and pharmacological therapies including herbs, paxlovid, and fluvoxamine. These trials are aiming to deal with these long COVID symptoms and signs including fatigue, decreased pulmonary function, reduced cognitive function, and others. To date, only 11 of these 312 studies have published their results that were not confirmative, unfortunately. Future studies should be designed to address sleep disorders which were seldomly included in registered clinical studies. Moreover, interventions aimed at treating the underlying pathophysiology of long COVID are also necessary but currently lacking., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Bipolar hemostasis electrocoagulation is a fundamental procedure in neurosurgery. A precise electrocoagulation model is essential to enable realistic visual feedback in virtual neurosurgical simulation. However, existing models lack an accurate description of the heat damage and irreversible tissue deformation caused by electrocoagulation, thus diminishing the visual realism. This work focuses on the electrocoagulation model for neurosurgery simulation., Method: In this paper, a position-based dynamics (PBD) model with a bioheat transfer and damage prediction (BHTDP) method is developed for simulating the deformation of brain tissue caused by electrocoagulation. The presented BTHDP method uses the Arrhenius equation to predict thermal damage of brain tissue. A deformation model with energy and thermal damage constraints is developed to characterize soft tissue deformation during heat absorption before and after thermal injury. Visual effect of damaged brain tissue is re-rendered., Result: To evaluate the accuracy of the proposed method, numerical simulations were conducted and compared with commercial finite element software. The maximum normalized error of the proposed model for predicting midpoint temperature is 10.3 % and the maximum error for predicting the thermal damage is 5.4 %. The contraction effects of heat-exposed anisotropic tissues are also simulated. The results indicate that the presented electrocoagulation model provides stable and realistic visual effects, making it applicable for simulating the electrocoagulation process in virtual neurosurgery., 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 Elsevier B.V. All rights reserved.)

Study Objectives: Sex differences are related to both biological factors and the gendered environment. We constructed measures to model sex-related differences beyond binary sex., Methods: Data came from the baseline visit of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We applied the least absolute shrinkage and selection operator penalized logistic regression of male versus female sex over sociodemographic, acculturation, and psychological factors jointly. Two "gendered indices," the gendered index of sociodemographic environment (GISE) and gendered index of psychological and sociodemographic environment, summarizing the sociodemographic environment (GISE) and psychosocial and sociodemographic environment (GIPSE) associated with sex, were calculated by summing these variables, weighted by their regression coefficients. We examined the association of these indices with insomnia, a phenotype with strong sex differences, in sex-adjusted and sex-stratified analyses., Results: The distribution of GISE and GIPSE differed by sex with higher values in male individuals. In an association model with insomnia, male sex was associated with a lower likelihood of insomnia (odds ratio [OR] = 0.60, 95% CI [0.53, 0.67]). Including GISE in the model, the association was slightly weaker (OR = 0.63, 95% CI [0.56, 0.70]), and weaker when including instead GIPSE in the association model (OR = 0.78, 95% CI [0.69, 0.88]). Higher values of GISE and of GIPSE, more common in the male sex, were associated with a lower likelihood of insomnia, in analyses adjusted for sex (per 1 standard deviation of the index, GISE OR = 0.92, 95% CI [0.87, 0.99], GIPSE OR = 0.65, 95% CI [0.61, 0.70])., Conclusions: New measures such as GISE and GIPSE capture sex-related differences beyond binary sex and have the potential to better model and inform research studies of sleep health., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Background: Despite the potential of artificial intelligence (AI) in enhancing cardiovascular care, its integration into clinical practice is limited by a lack of evidence on its effectiveness with respect to human experts or gold standard practices in real-world settings., Objectives: The purpose of this study was to identify AI interventions in cardiology that have been prospectively validated against human expert benchmarks or gold standard practices, assessing their effectiveness, and identifying future research areas., Methods: We systematically reviewed Scopus and MEDLINE to identify peer-reviewed publications that involved prospective human validation of AI-based interventions in cardiology from January 2015 to December 2023., Results: Of 2,351 initial records, 64 studies were included. Among these studies, 59 (92.2%) were published after 2020. A total of 11 (17.2%) randomized controlled trials were published. AI interventions in 44 articles (68.75%) reported definite clinical or operational improvements over human experts. These interventions were mostly used in imaging (n = 14, 21.9%), ejection fraction (n = 10, 15.6%), arrhythmia (n = 9, 14.1%), and coronary artery disease (n = 12, 18.8%) application areas. Convolutional neural networks were the most common predictive model (n = 44, 69%), and images were the most used data type (n = 38, 54.3%). Only 22 (34.4%) studies made their models or data accessible., Conclusions: This review identifies the potential of AI in cardiology, with models often performing equally well as human counterparts for specific and clearly scoped tasks suitable for such models. Nonetheless, the limited number of randomized controlled trials emphasizes the need for continued validation, especially in real-world settings that closely examine joint human AI decision-making., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Blood accumulation often occurs during bleeding in surgery. Simulating the blood accumulation in surgical simulation system not only enhances the realism and immersion of surgical training, but also helps researchers better understand the physical properties of blood flow., Methods: To realistically simulate the blood accumulation during the bleeding, this paper proposes a novel kernel function with non-negative second derivatives to improve the SPH method. Meanwhile, a simple form of boundary force equation is constructed to impose the solid boundary condition., Results: We simulate the blood accumulation during liver bleeding and vessel bleeding respectively in the surgical simulation system. The simulation results show that there is no occurrence of blood physically penetrating the boundary., Conclusions: Applying the solid boundary condition to the blood by using the method proposed in this paper is not only convenient but can also eliminate compression instability in the blood accumulation simulation., (© 2024 John Wiley & Sons Ltd.)

This article discusses the complex approach to managing atherosclerotic cardiovascular disease (ASCVD), focusing on person-centred care (PCC) to align treatment strategies with individual patient narratives, values, and preferences. It identifies significant challenges in management of ASCVD, such as the necessity for multidisciplinary strategies and the need for enhanced patient care, particularly given the coexistence of ASCVD with other cardiometabolic risk factors. The paper points out existing practice gaps, including limited patient-provider information sharing and decision making, and considers the role of technology in personalizing care and improving outcomes. Strategies such as electronic health records, telehealth platforms, and motivational interviewing are examined for their potential to boost patient engagement and adherence to treatment. In addition, the article discusses systemic issues such as health care provider burnout and the importance of creating customized care plans for patients with multiple health conditions. The integration of varied approaches, including the involvement of community pharmacists and health coaches, is suggested as important for effective management of ASCVD. This review highlights the need for an innovative, holistic strategy for management of ASCVD and advocates for a transformative shift toward PCC that integrates individual, community, and system-level interventions to enhance patient engagement, therapy adherence, and overall outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Disease spread in the abdomen and pelvis generally occurs in a predictable pattern in relation to anatomic landmarks and fascial planes. Anatomically, the abdominopelvic cavity is subdivided into several smaller spaces or compartments by key ligaments and fascial planes. The abdominal cavity has been traditionally divided into peritoneal, retroperitoneal, and pelvic extraperitoneal spaces. Recently, more clinically relevant classifications have evolved. Many pathologic conditions affect the abdominal cavity, including traumatic, inflammatory, infectious, and neoplastic processes. These abnormalities can extend beyond their sites of origin through various pathways. Identifying the origin of a disease process is the first step in formulating a differential diagnosis and ultimately reaching a final diagnosis. Pathologic conditions differ in terms of pathways of disease spread. For example, simple fluid tracks along fascial planes, respecting anatomic boundaries, while fluid from acute necrotizing pancreatitis can destroy fascial planes, resulting in transfascial spread without regard for anatomic landmarks. Furthermore, neoplastic processes can spread through multiple pathways, with a propensity for spread to noncontiguous sites. When the origin of a disease process is not readily apparent, recognizing the spread pattern can allow the radiologist to work backward and ultimately arrive at the site or source of pathogenesis. As such, a cohesive understanding of the peritoneal anatomy, the typical organ or site of origin for a disease process, and the corresponding pattern of disease spread is critical not only for initial diagnosis but also for establishing a road map for staging, anticipating further disease spread, guiding search patterns and report checklists, determining prognosis, and tailoring appropriate follow-up imaging studies. © RSNA, 2024 Supplemental material is available for this article.

Introduction: High-intensity focused ultrasound (HIFU) is regarded as a promising alternative treatment option for localized prostate cancer (PCa) as it has been proposed to offer similar oncologic control to the standard of care, but with significantly reduced treatment-related side effects. This systematic literature review assesses the available evidence of whole-gland HIFU as primary treatment for localized PCa., Methods: MEDLINE (PubMed) was searched for studies investigating oncological and functional outcomes following whole-gland HIFU as primary treatment for localized PCa. Our primary outcomes for the review were biochemical disease-free survival rates (BDFS), overall and PCa-specific survival rates as well as negative biopsy rates. Our secondary outcomes were functional results and complications of the treatment., Results: A total of 375 articles were identified, of which 35 were included in the present review. All 35 articles were prospective or retrospective case series. Mean/median duration of follow-up across studies was 10.9 to 94 months, and 6618 patients were included in the review. The BDFS rate varied greatly across studies from 21.7% to 89.2% during follow-up. The 10-year PCa-specific survival rate following HIFU was 90%, 99%, and 100% in 3 studies. Negative biopsy rates post-HIFU ranged from 20% to 92.7% across studies. Common side effects to HIFU included urinary incontinence (grade 1: 0%-22.7%), erectile dysfunction (11.6%-77.1%), urinary tract infections (1.5%-47.9%), and bladder outlet obstruction mainly as urethral strictures (7%-41.2%)., Conclusion: Great variation in oncological and functional outcomes was seen across studies. More prospective trials are needed before whole-gland HIFU can be considered as a treatment option for localized PCa., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis., Methods: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes., Results: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05)., Conclusion: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management., Competing Interests: Declarations CONFLICT OF INTEREST C.L.M. has received funding from AstraZeneca not related to the current study. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.C. receives consultancy fees from Roche Diagnostics and Trimedics and speaker fees from Servier. D.A.L. has received support from Medtronic LTD and Roche Diagnostics for biomarker research not related to the current study. The remaining authors declare no competing interests.

Purpose: The purpose of this study was to evaluate the risk of newly diagnosed retinal vein occlusion (RVO) in patients with type 2 diabetes (T2D) using sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared to dipeptidyl peptidase-4 inhibitors (DPP-4i)., Methods: Claims data from the National Health Insurance Research Database of Taiwan were used in this nationwide retrospective cohort study. A target trial emulation framework was applied. Patients with T2D with no prior diagnosis of RVO who had newly commenced treatment with SGLT-2i or DPP-4i between May 1, 2016, and December 31, 2020, were included. Potential systematic differences in baseline characteristics between the paired groups were controlled using stabilized inverse probability of treatment weighting. The outcome of interest was incident RVO. The hazard ratio (HR) for SGLT-2i compared with that of DPP-4i was estimated using a Cox regression model., Results: Data from 123,567 and 578,665 patients receiving SGLT-2i and DPP-4i, respectively, were analyzed. The incidence of RVO was lower in patients newly receiving SGLT-2i (0.59 events per 1000 person-years) compared to those receiving DPP-4i (0.77 events per 1000 person-years) over a mean follow-up of 1.61 years. SGLT-2i users had a significantly lower risk of developing RVO compared with DPP-4i users (HR = 0.76, 95% confidence interval [CI] = 0.59-0.98). In the individual outcome analysis, SGLT-2i use was significantly associated with a lower risk of branch RVO (HR = 0.71, 95% CI = 0.52-0.96), but not central RVO (HR = 0.84, 95% CI = 0.57-1.24)., Conclusions: The risk of developing RVO was lower in patients with T2D receiving SGLT-2i compared with that in those receiving DPP-4i.

Ferritin is a multivalent, self-assembling protein scaffold found in most human cell types, in addition to being present in invertebrates, higher plants, fungi, and bacteria, that offers an attractive alternative to polymer-based drug delivery systems (DDS). In this study, the utility of the ferritin cage as a DDS was demonstrated within the context of T cell agonism for tumor killing. Members of the tumor necrosis factor receptor superfamily (TNFRSF) are attractive targets for the development of anticancer therapeutics. These receptors are endogenously activated by trimeric ligands that occur in transmembrane or soluble forms, and oligomerization and cell-surface anchoring have been shown to be essential aspects of the targeted agonism of this receptor class. Here, we demonstrated that the ferritin cage could be easily tailored for multivalent display of anti-OX40 antibody fragments on its surface and determined that these arrays are capable of pathway activation through cell-surface clustering. Together, these results confirm the utility, versatility, and developability of ferritin as a DDS.

The current thyroid ultrasound relies heavily on the experience and skills of the sonographer and the expertise of the radiologist, and the process is physically and cognitively exhausting. In this paper, we report a fully autonomous robotic ultrasound system, which is able to scan thyroid regions without human assistance and identify malignant nod- ules. In this system, human skeleton point recognition, reinforcement learning, and force feedback are used to deal with the difficulties in locating thyroid targets. The orientation of the ultrasound probe is adjusted dynamically via Bayesian optimization. Experimental results on human participants demonstrated that this system can perform high-quality ultrasound scans, close to manual scans obtained by clinicians. Additionally, it has the potential to detect thyroid nodules and provide data on nodule characteristics for American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) calculation., (© 2024. The Author(s).)

Surface-enhanced Raman scattering (SERS) sensors typically employ nanophotonic structures that support high-field confinement and enhancement in hotspots to increase the Raman scattering from target molecules by orders of magnitude. In general, high field and SERS enhancement can be achieved by reducing the critical dimensions and mode volumes of the hotspots to nanoscale. To this end, a multitude of SERS sensors employing photonic structures with nanometric hotspots have been demonstrated. However, delivering analyte molecules into nanometric hotspots is challenging, and the trade-off between field confinement/enhancement and analyte delivery efficiency is a critical limiting factor for the performance of many nanophotonic SERS sensors. Here, a new type of SERS sensor employing solid-metal nanoparticles and bulk liquid metal is demonstrated to form nanophotonic resonators with a nanoparticle-on-liquid-mirror (NPoLM) architecture, which effectively resolves this trade-off. In particular, this unconventional sensor architecture allows for the convenient formation of nanometric hotspots by introducing liquid metal after analyte molecules are efficiently delivered to the surface of gold nanoparticles. In addition, a cost-effective and reliable process is developed to produce gold nanoparticles on a substrate suitable for forming NPoLM structures. These NPoLM structures achieve two orders of magnitude higher SERS signals than the gold nanoparticles alone., (© 2024 Wiley‐VCH GmbH.)

There is a lack of studies that concurrently differentiate the effect of the holiday season from the weekend effect on mortality risk in patients with acute myocardial infarction (AMI). We evaluated the mortality risk among patients admitted with AMI who underwent percutaneous coronary intervention, using data from the Taiwan National Health Insurance Research Database. Adult AMI patients admitted during January and February between 2013 and 2020 were enrolled and classified into the holiday season (using the Chinese New Year holiday seasons as an indicator) (n = 1729), weekend (n = 4725), and weekday (n = 14,583) groups according to the first day of admission. A multivariable logistic regression model was used to assess the risk. With the weekday group or the weekend group as the reference, the holiday season group did not have increased risks of in-hospital mortality (adjusted odds ratio [aOR] 1.15; 95% confidence intervals [CI] 0.93-1.42 or aOR 1.23; 95% CI 0.96-1.56) and 7-day mortality (aOR 1.20; 95% CI 0.90-1.58 or aOR 1.24; 95% CI 0.90-1.70). Stratified and subgroup analyses showed similar trends. We conclude that holiday season-initiated admissions were not associated with higher mortality risks in AMI admission cases than weekday or weekend admissions., (© 2024. The Author(s).)

Background and Objectives: The impact of off-hours admission (such as weekends, nighttime, and non-working hours) vs. regular hours (weekdays and daytime working hours) on the mortality risk of patients undergoing surgery for type A aortic dissection (TAAD) repair is still uncertain. To address this uncertainty, we undertook a comprehensive systematic review and meta-analysis. We aimed to assess the potential link between off-hours admission and the risk of mortality in patients undergoing TAAD repair surgery., Methods: We conducted a thorough search of the PubMed, Embase, and Cochrane Library databases, covering the period from their inception to May 20, 2023. Our inclusion criteria encompassed all studies that examined the potential relationship between off-hour admission and mortality in individuals who had undergone surgery for TAAD repair. The odds ratios (ORs) were extracted and combined utilizing a random effects model for our synthesis., Results: Nine studies with 16,501 patients undergoing TAAD repair surgery were included in the meta-analysis. Overall, patients who underwent surgery during the weekend had higher in-hospital mortality (pooled OR, 1.41; 95% confidence interval [CI], 1.14-1.75; p=0.002) than those treated on weekdays. However, the mortality risks among patients who underwent TAAD surgery during nighttime and non-working hours were not significantly elevated compared to daytime and working hours admission., Conclusions: Weekend surgery for TAAD was associated with a higher in-hospital mortality risk than weekday surgery. However, further studies are warranted to identify and develop strategies to improve the quality of round-the-clock care for patients with TAAD., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2024. The Korean Society of Cardiology.)

Sleep-disordered breathing (SDB) is a prevalent disorder characterized by recurrent episodic upper airway obstruction. Using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we apply principal component analysis (PCA) to seven SDB-related measures. We estimate the associations of the top two SDB PCs with serum levels of 617 metabolites, in both single-metabolite analysis, and a joint penalized regression analysis. The discovery analysis includes 3299 individuals, with validation in a separate dataset of 1522 individuals. Five metabolite associations with SDB PCs are discovered and replicated. SDB PC1, characterized by frequent respiratory events common in older and male adults, is associated with pregnanolone and progesterone-related sulfated metabolites. SDB PC2, characterized by short respiratory event length and self-reported restless sleep, enriched in young adults, is associated with sphingomyelins. Metabolite risk scores (MRSs), representing metabolite signatures associated with the two SDB PCs, are associated with 6-year incident hypertension and diabetes. These MRSs have the potential to serve as biomarkers for SDB, guiding risk stratification and treatment decisions., (© 2024. The Author(s).)

Importance: Denosumab, a humanized monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL), is a widely used antiresorptive medication for osteoporosis treatment. Recent preclinical studies indicate that inhibition of RANKL signaling improves insulin sensitivity, glucose tolerance, and β-cell proliferation, suggesting that denosumab may improve glucose homeostasis; however, whether denosumab reduces the risk of incident diabetes remains unclear., Objective: To evaluate whether denosumab use is associated with a lower risk of developing diabetes in patients with osteoporosis., Design, Setting, and Participants: This nationwide, propensity score-matched cohort study used administrative data from Taiwan's National Health Insurance Research Database. Adult patients who received denosumab for osteoporosis therapy in Taiwan between 2012 and 2019 were included. To eliminate the inherent bias from confounding by indication, the patients were categorized into a treatment group (34 255 patients who initiated denosumab treatment and adhered to it) and a comparison group (34 255 patients who initiated denosumab treatment but discontinued it after the initial dose) according to the administration status of the second dose of denosumab. Propensity score matching was performed to balance patient characteristics and to control for confounders., Exposure: Treatment with denosumab., Main Outcomes and Measures: The primary outcome was incident diabetes requiring treatment with antidiabetic drugs. A Cox proportional hazards model was used to estimate the hazard ratio (HR) for incident diabetes. Data were analyzed from January 1 to November 30, 2023., Results: After propensity score matching, 68 510 patients were included (mean [SD] age, 77.7 [9.8] years; 57 762 [84.3%] female). During a mean (SD) follow-up of 1.9 (1.6) years, 2016 patients developed diabetes in the treatment group and 3220 developed diabetes in the comparison group (incidence rate, 35.9 vs 43.6 per 1000 person-years). Compared with the comparison group, denosumab treatment was associated with a lower risk of incident diabetes (HR, 0.84; 95% CI, 0.78-0.90). Several sensitivity analyses also demonstrated similar results of lower diabetes risk associated with denosumab treatment., Conclusions and Relevance: The results from this cohort study indicating that denosumab treatment was associated with lower risk of incident diabetes may help physicians choose an appropriate antiosteoporosis medication for patients with osteoporosis while also considering the risk of diabetes.

In this article, the adaptive tracking control problem is considered for high-order stochastic nonlinear time-delay systems in fixed-time. Being different from existing results, an improved Lyapunov-Krasovskii function is designed, which can not only compensate for the time-delay term but also remove the obstacle from the high-order term. Due to the introduction of the Lyapunov-Krasovskii function into the total Lyapunov function, it makes it difficult to stabilize the controlled system within a fixed-time interval. L'Hopital's rule is used to determine the boundedness of the Lyapunov-Krasovskii function, and the fixed-time boundedness of the integral functions can be inferred. By utilizing the fixed-time Lyapunov stability theorem, it is proved that the controlled system is semi-globally practical fixed-time stable (SGPFS), all the closed-loop signals (CLSs) are bounded within the fixed-time interval, and the tracking error converges into a small region around zero. The validity of the designed scheme is substantiated via simulation results.

Aims: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have off-target effects on haemoconcentration and anti-inflammation. The impact of SGLT-2i on the risk of venous thromboembolism (VTE) in patients with diabetes mellitus (DM) remains unclear. This study aimed to evaluate the risk of newly diagnosed VTE in patients with DM using SGLT-2i in comparison to dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA)., Materials and Methods: In this nationwide retrospective cohort study, we used data from Taiwan's National Health Insurance Research Database. Patients with diabetes aged 20 years or older who received SGLT-2i, DPP-4i, or GLP-1RA between 1 May 2016, and 31 December 2020, were included. The risks of VTE in SGLT-2i users were compared with those of DPP-4i and GLP-1RA users. A Cox regression model with stabilised inverse probability of treatment weighting was used to calculate hazard ratio (HR) for VTE risk. Additionally, a meta-analysis of relevant articles published before 23 May 2023, was conducted., Results: Data from 136,530 SGLT-2i, 598,280 DPP-4i, and 5760 GLP-1RA users were analysed. SGLT-2i use was associated with a lower risk of VTE than DPP-4i (HR, 0.70; 95% CI, 0.59-0.84; p < 0·001), but not with GLP-1RA (HR, 1.39; 95% CI, 0.32-5.94; p = 0.66). Our meta-analysis further supported these findings (SGLT-2i vs. DPP-4i: HR, 0.71; 95% CI, 0.62-0.82; p < 0·001; SGLT-2i vs. GLP-1RA: HR, 0.91; 95% CI, 0.73-1.15; p = 0.43), suggesting the robustness of our retrospective analysis., Conclusions: In patients with DM, SGLT-2i was associated with a lower risk of VTE compared to DPP-4i, but not GLP-1RA., (© 2023 John Wiley & Sons Ltd.)

Purpose: To inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening in a primary care setting for hypertension in adults aged 18 years and older. This protocol outlines the scope and methods for a series of systematic reviews and one overview of reviews., Methods: To evaluate the benefits and harms of screening for hypertension, the Task Force will rely on the relevant key questions from the 2021 United States Preventive Services Task Force systematic review. In addition, a series of reviews will be conducted to identify, appraise, and synthesize the evidence on (1) the association of blood pressure measurement methods and future cardiovascular (CVD)-related outcomes, (2) thresholds for discussions of treatment initiation, and (3) patient acceptability of hypertension screening methods. For the review of blood pressure measurement methods and future CVD-related outcomes, we will perform a de novo review and search MEDLINE, Embase, CENTRAL, and APA PsycInfo for randomized controlled trials, prospective or retrospective cohort studies, nested case-control studies, and within-arm analyses of intervention studies. For the thresholds for discussions of treatment initiation review, we will perform an overview of reviews and update results from a relevant 2019 UK NICE review. We will search MEDLINE, Embase, APA PsycInfo, and Epistemonikos for systematic reviews. For the acceptability review, we will perform a de novo systematic review and search MEDLINE, Embase, and APA PsycInfo for randomized controlled trials, controlled clinical trials, and observational studies with comparison groups. Websites of relevant organizations, gray literature sources, and the reference lists of included studies and reviews will be hand-searched. Title and abstract screening will be completed by two independent reviewers. Full-text screening, data extraction, risk-of-bias assessment, and GRADE (Grading of Recommendations Assessment, Development and Evaluation) will be completed independently by two reviewers. Results from included studies will be synthesized narratively and pooled via meta-analysis when appropriate. The GRADE approach will be used to assess the certainty of evidence for outcomes., Discussion: The results of the evidence reviews will be used to inform Canadian recommendations on screening for hypertension in adults aged 18 years and older., Systematic Review Registration: This protocol is registered on PROSPERO and is available on the Open Science Framework (osf.io/8w4tz)., (© 2023. The Author(s).)

Background and Objective: Physiological motions have a significant impact on soft tissue deformation and accuracy of surgical procedures, which is essential for realistic surgical simulation. While existing studies offer accurate simulation of soft tissue deformation, integrating physiological motions into deformation models of soft tissue remains a challenging task., Methods: This paper introduces a novel deformation model, based on complementary dynamics, to animate soft tissue deformation under physiological motion. The finite element method is incorporated to accurately characterize the elastic behavior of the soft tissue. Mathematical models of physiological motion are utilized and the physiological effects are converted into displacements of a predefined set of handles within the soft tissue mesh. Complementary displacements derived from the inherent dynamics of the soft tissue are calculated, enabling the simulation of physiological motions and elastic behaviors in soft tissue deformation., Results: Experiments were conducted to evaluate the performance and effectiveness of the proposed method in simulating soft tissue deformation under physiological motion. The simulation results show that the soft tissues exhibit physiological motion that corresponds to the rhythm of arterial pressure fluctuations, heartbeat or respiratory. Furthermore, the presented method exhibits stable performance compared with existing force-based methods., Conclusions: Both elastic behaviors and physiological motions of soft tissue deformation can be governed by the proposed method. A high degree of realistic visualization is achieved for virtual surgery simulation., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pancreatic surgery is considered one of the most technically challenging surgical procedures, despite the evolution of modern techniques. Neoplasms remain the most common indication for pancreatic surgery, although inflammatory conditions may also prompt surgical evaluation. The choice of surgical procedure depends on the type and location of the pathologic finding because different parts of the pancreas have separate vascular supplies that may be shared by adjacent organs. The surgical approach could be conventional or minimally invasive (laparoscopic, endoscopic, or robotic assisted). Because of the anatomic complexity of the pancreatic bed, perioperative complications may be frequently encountered and commonly involve the pancreatic-biliary, vascular, lymphatic, or bowel systems, irrespective of the surgical technique used. Imaging plays an important role in the assessment of suspected postoperative complications, with CT considered the primary imaging modality, while MRI, digital subtraction angiography, and molecular imaging are considered ancillary diagnostic tools. Accurate diagnosis of postoperative complications requires a solid understanding of pancreatic anatomy, surgical indications, normal postoperative appearance, and expected postsurgical changes. The practicing radiologist should be familiar with the most common perioperative complications, such as anastomotic leak, abscess, and hemorrhage, and be able to differentiate these entities from normal anticipated postoperative changes such as seroma, edema and fat stranding at the surgical site, and perivascular soft-tissue thickening. In addition to evaluation of the primary operative fossa, imaging plays a fundamental role in assessment of the adjacent organ systems secondarily affected after pancreatic surgery, such as vascular, biliary, and enteric complications. Published under a CC BY 4.0 license. Test Your Knowledge questions are available in the supplemental material. See the invited commentary by Winslow in this issue.

This paper studies the exponential synchronization problem for a class of delayed coupled neural networks with delay-compensatory impulsive control. A Razumikhin-type inequality involving some destabilizing delayed impulse gains and a new idea of delay-compensatory that shows two critical roles for system stability are presented, respectively. Based on the constructed inequality and the presented delay-compensatory idea, sufficient stability and synchronization criteria for globally exponential synchronization (GES) of coupled neural networks (CNNs) are presented. Compared with existing results, the uniqueness of the presented results lies in that impulse delays can be fetched and integrated to compensate for instantaneous unstable impulse dynamics caused by destabilizing gains. Moreover, constraints between system delay and impulsive delay are relaxed, and the interval of impulses no longer constrains the system delay. Comparisons and a practical application are given to demonstrate the superior performance of the presented novel control methods., 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 ISA. Published by Elsevier Ltd. All rights reserved.)

Background: Inflammation is a key mediator in the development and progression of the atherosclerotic disease process as well as its resultant complications, like myocardial infarction (MI), stroke and cardiovascular (CV) death, and is emerging as a novel treatment target. Trials involving anti-inflammatory medications have demonstrated outcome benefit in patients with known CV disease. In this regard, colchicine appears to hold great promise. However, there are potential drawbacks to colchicine use, as some studies have identified an increased risk of infection, and a non-significant trend for increased all-cause mortality. Thus, a more thorough understanding of the underlying mechanism of action of colchicine is needed to enable a better patient selection for this novel CV therapy., Objective: The primary objective of the Canadian Study of Arterial Inflammation in Patients with Diabetes and Recent Vascular Events, Evaluation of Colchicine Effectiveness (CADENCE) trial is to assess the effect of colchicine on vascular inflammation in the carotid arteries and ascending aorta measured with 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with type 2 diabetes mellitus (T2DM) or pre-diabetes who have experienced a recent vascular event (acute coronary syndrome (ACS)/MI, transient ischaemic attack (TIA) or stroke). Secondary objectives include determining colchicine's effect on inflammatory biomarkers (high-sensitivity C reactive protein (hs-CRP) and interleukin-6 (IL-6)). Additionally, we will assess if baseline inflammation imaging or biomarkers are associated with a treatment response to colchicine determined by imaging. Exploratory objectives will look at: (1) the difference in the inflammatory response to colchicine in patients with coronary events compared with patients with cerebral events; (2) the difference in the inflammatory response to colchicine in different vascular beds; (3) the relationship of FDG-PET imaging markers with serum biomarkers and (4) assessment of quality-of-life changes., Methods and Design: CADENCE is a multicentre, prospective, randomised, double-blinded, placebo-controlled study to determine the effect of colchicine on arterial inflammation as assessed with imaging and circulatory biomarkers, specifically carotid arteries and aortic FDG uptake as well as hs-CRP and IL-6 among others. Patients with T2DM or pre-diabetes who have recently experienced a CV event (within 30-120 days after an ACS (ie, ST-elevation MI (STEMI) or non-STEMI)) or TIA/stroke with documented large vessel atherosclerotic disease will be randomised to treatment with either colchicine 0.6 mg oral daily or placebo. Participants will undergo baseline clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan of the ascending aorta and left and right carotid arteries. Patients will undergo treatment for 6 months and have repeat clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan at the conclusion of the study. The primary outcome will be the change in the maximum target to background ratio (TBR max ) in the ascending aorta (or carotid arteries) from baseline to follow-up on FDG PET/CT imaging., Discussion: Colchicine is an exciting potential new therapy for CV risk reduction. However, its use is associated with side effects and greater understanding of its underlying mechanism of action is needed. Importantly, the current study will determine whether its anti-inflammatory action is an indirect systemic effect, or a more local plaque action that decreases inflammation. The results will also help identify patients who will benefit most from such therapy., Trial Registration Number: NCT04181996., Competing Interests: Competing interests: RB receives or has received honoraria from, and leads grants supported by GE Healthcare, Jubilant DraxImage and Lantheus Medical Grants. These are not related to the current work. RdK receives royalties from rubidium-82 PET technologies licensed to Jubilant Radiopharma and to INVIA Medical Solutions. He has also received research funding and honoraria from Jubilant Radiopharma and IONETIX. Otherwise, the authors declare that they have no competing interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The differential diagnosis for left lower quadrant pain is wide and conditions range from the benign and self-limited to life-threatening surgical emergencies. Along with patient history, physical examination, and laboratory tests, imaging is often critical to limit the differential diagnosis and identify life-threatening abnormalities. This document will discuss the guidelines for the appropriate use of imaging in the initial workup for patients who present with left lower quadrant pain, patients with suspected diverticulitis, and patients with suspected complications from diverticulitis. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Aims: Social robots are arriving to the modern healthcare system. Whether patients with heart failure, a prevalent chronic disease with high health and human costs would derive benefit from a social robot intervention has not been investigated empirically. Diverse healthcare provider's perspectives are needed to develop an acceptable and feasible social robot intervention to be adopted for the clinical benefit of patients with heart failure. Using a qualitative research design, this study investigated healthcare providers' perspectives of social robot use in heart failure patient care., Methods and Results: Interdisciplinary healthcare providers from a tertiary care cardiac hospital completed a structured individual interview and a supplemental questionnaire. The framework method was used to analyse the qualitative data. Respondents ( n = 22; saturation was reached with this sample; 77% female; 52% physicians) were open to using social robots to augment their practice, particularly with collecting pertinent data and providing patient and family education and self-management prompts, but with limited responsibility for direct patient care. Prior to implementation, providers required robust evidence of: value-added beyond current remote patient monitoring devices, patient and healthcare provider partnerships, streamlined integration into existing practice, and capability of supporting precision medicine goals. Respondents were concerned that social robots did not address and masked broader systemic issues of healthcare access and equity., Conclusion: The adoption of social robots is a viable option to assist in the care of patients with heart failure, albeit in a restricted capacity. The results inform the development of a social robotic intervention for patients with heart failure, including improving social robot efficiencies and increasing their uptake, while protecting patients' and providers' best interest., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

During the course of biopharmaceutical production, heterologous protein expression in Chinese hamster ovary (CHO) cells imposes a high proteostatic burden that requires cellular adaptation. To mitigate such burden, cells utilize the unfolded protein response (UPR), which increases endoplasmic reticulum (ER) capacity to accommodate elevated rates of protein synthesis and folding. In this study, we show that during production the UPR regulates growth factor signaling to modulate growth and protein synthesis. Specifically, the protein kinase R-like ER kinase (PERK) branch of the UPR is responsible for transcriptional down-regulation of platelet-derived growth factor receptor alpha (PDGFRa) and attenuation of the IRE1-alpha (IRE1a) branch of the UPR. PERK knockout (KO) cell lines displayed reduced growth and viability due to higher rates of apoptosis despite having stabilized PDGFRa levels. Knocking out PERK in an apoptosis impaired (Bax/Bak double KO) antibody-expressing cell line prevented apoptotic cell death and revealed that apoptosis was likely triggered by increased ER stress and reactive oxygen species levels in the PERK KO hosts. Our findings suggest that attenuation of IRE1a and PDGFRa signaling by the PERK branch of the UPR reduces ER protein folding capacity and hence specific productivity of CHO cells in order to mitigate UPR and prevent apoptotic cell death. Last, Bax/Bak/PERK triple KO CHO cell lines displayed 2-3 folds higher specific productivity and titer (up to 8 g/L), suggesting that modulation of PERK signaling during production processes can greatly improve specific productivity in CHO cells., (© 2023 American Institute of Chemical Engineers.)

Background: Outcomes of diabetes screening in contemporary, multi-ethnic populations are unknown. We examined the association of prior outpatient diabetes screening with the risks of cardiovascular events and mortality in Ontario, Canada., Methods: We conducted a population-based cohort study using administrative databases among adults aged ≥ 20 years with incident diabetes diagnosed during 2014-2016. The exposure was outpatient diabetes screening performed within 3 years prior to diabetes diagnosis. The co-primary outcomes were (1) a composite of all-cause mortality and hospitalization for myocardial infarction, stroke, coronary revascularization, and (2) all-cause mortality (followed up until 2018). We calculated standardized rates of each outcome and conducted cause-specific hazard modelling to determine the adjusted hazard ratio (HR) of the outcomes, adjusting for prespecified confounders and accounting for the competing risk of death., Results: We included 178,753 Ontarians with incident diabetes (70.2% previously screened). Individuals receiving prior screening were older (58.3 versus 53.4 years) and more likely to be women (49.6% versus 40.0%) than previously unscreened individuals. Individuals receiving prior screening had relatively lower standardized event rates than those without prior screening across all outcomes (composite: 12.8 versus 18.1, mortality: 8.2 versus 11.1 per 1000 patient-years). After multivariable adjustment, prior screening was associated with 34% and 32% lower risks of the composite (HR 0.66, 0.63-0.69) and mortality (0.68, 0.64-0.72) outcomes. Among those receiving prior screening, a result in the prediabetes range was associated with lower risks of the composite (0.82, 0.77-0.88) and mortality (0.71, 0.66-0.78) outcomes than a result in the normoglycemic range., Conclusions: Previously screened individuals with diabetes had lower risks of cardiovascular events and mortality versus previously unscreened individuals. Better risk assessment tools are needed to support wider and more appropriate uptake of diabetes screening, especially among young adults., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: A watch and wait strategy with the goal of organ preservation is an emerging treatment paradigm for rectal cancer following neoadjuvant treatment. However, the selection of appropriate patients remains a challenge. Most previous efforts to measure the accuracy of MRI in assessing rectal cancer response used a small number of radiologists and did not report variability among them., Methods: Twelve radiologists from 8 institutions assessed baseline and restaging MRI scans of 39 patients. The participating radiologists were asked to assess MRI features and to categorize the overall response as complete or incomplete. The reference standard was pathological complete response or a sustained clinical response for > 2 years., Results: We measured the accuracy and described the interobserver variability of interpretation of rectal cancer response between radiologists at different medical centers. Overall accuracy was 64%, with a sensitivity of 65% for detecting complete response and specificity of 63% for detecting residual tumor. Interpretation of the overall response was more accurate than the interpretation of any individual feature. Variability of interpretation was dependent on the patient and imaging feature investigated. In general, variability and accuracy were inversely correlated., Conclusions: MRI-based evaluation of response at restaging is insufficiently accurate and has substantial variability of interpretation. Although some patients' response to neoadjuvant treatment on MRI may be easily recognizable, as seen by high accuracy and low variability, that is not the case for most patients., Key Points: • The overall accuracy of MRI-based response assessment is low and radiologists differed in their interpretation of key imaging features. • Some patients' scans were interpreted with high accuracy and low variability, suggesting that these patients' pattern of response is easier to interpret. • The most accurate assessments were those of the overall response, which took into consideration both T2W and DWI sequences and the assessment of both the primary tumor and the lymph nodes., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study's primary outcome is the rate of pregnancy in couples during the study's 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. IMPLICATIONS: The development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Evidence regarding the risks of serious hypoglycaemia for patients with atrial fibrillation (AF) and diabetes mellitus (DM) taking antidiabetic medications with concurrent non-vitamin K antagonist oral anticoagulants (NOACs) vs. warfarin is limited. This study aimed to investigate this knowledge gap., Methods and Results: This retrospective cohort study used nationwide data from Taiwan's National Health Insurance Research Database and included a total of 56 774 adult patients treated with antidiabetic medications and oral anticoagulants between 1 January 2012 and 31 December 2020. The incidence rate ratios (IRRs) of serious hypoglycaemia were estimated for patients taking antidiabetic drugs with NOACs vs. warfarin. Poisson regression models with generalized estimating equations accounting for intra-individual correlation across follow-up periods were used. Stabilized inverse probability of treatment weighting was used to create treatment groups with balanced characteristics for comparisons. Compared to concurrent use of antidiabetic drugs with warfarin, those with NOACs showed a significantly lower risk of serious hypoglycaemia (IRR = 0.73, 95% CI: 0.63-0.85, P < 0.001). In the analyses of each NOAC, patients taking dabigatran (IRR = 0.76, 95% CI: 0.63-0.91, P = 0.002), rivaroxaban (IRR = 0.72, 95% CI: 0.61-0.86, P < 0.001), and apixaban (IRR = 0.71, 95% CI: 0.57-0.89, P = 0.003) showed a significantly lower risk of serious hypoglycaemia than those taking warfarin., Conclusion: In patients with AF and DM taking antidiabetic drugs, concurrent use of NOACs was associated with a lower risk of serious hypoglycaemia than concurrent use of warfarin., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Existing driving fatigue detection methods rarely consider how to effectively fuse the advantages of the electroencephalogram (EEG) and electrocardiogram (ECG) signals to enhance detection performance under noise conditions. To address the issues, this article proposes a new type of the deep learning (DL) framework based on EEG and ECG called the product fuzzy convolutional network (PFCN). It should be noted that this article first investigates how to fuse EEG and ECG signals to deal with driving fatigue detection under noise conditions in both simulated and real-field driving environments. Specifically, the PFCN includes three subnetworks. The first uses a fuzzy neural network (FNN) with feedback and a product layer, effectively capturing the particularity and temporal variation of high-dimensional EEG signals and reducing the time-space complexity. The second subnetwork uses a 1-D convolution to convert the ECG data into feature sequences, providing high accuracy and low computational complexity in ECG data classification. The third subnetwork proposes a fusion-separation mechanism to effectively fuse the extracted ECG and EEG features, suppressing the noise interference and ensuring higher detection accuracy. To evaluate the performance of PFCN, a series of experiments has been set up in both simulated and real-field driving environments. The results indicate that the proposed PFCN model has better robustness and detection accuracy compared with several mainstream fatigue detection models.