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Abstract Particle geometric is a key parameter that defines the eometric attributes of calcareous sand particles and is intricately related to their mechanical traits, such as compression and shear. The scanning electron microscopy and digital imaging were applied to capture the microscopic properties and geometric projections of calcareous sand. The qualitative analysis, conventional statistical methods and fractal theory were employed to describe the geometric morphology of sand particles. Additionally, we analyzed the structural and physical traits of calcareous sand based on its unique biological genesis. We developed a hypothetical structural-physical model for calcareous sand. Our findings revealed the interwoven reticulation on the surface of calcareous gravel particles, along with an uneven distribution of pores on the external surface. As the particle size increased, the global profile factor decreased and the angularity increased. The critical threshold for the variations in flatness, surface roughness, and circularity was observed at a particle size of 5 mm, with the particle size having a relatively minor effect on these characteristics for particles smaller than 5 mm. The shape of the calcareous sand particles exhibited fractal characteristics, with fractal dimension serving as a measure of surface smoothness, particle breakage, and strength. These experimental results could significantly enhance our understanding of the mechanical behavior of calcareous sand.

Summary: Background: Infectious keratitis (IK) is the leading cause of corneal blindness globally. Deep learning (DL) is an emerging tool for medical diagnosis, though its value in IK is unclear. We aimed to assess the diagnostic accuracy of DL for IK and its comparative accuracy with ophthalmologists. Methods: In this systematic review and meta-analysis, we searched EMBASE, MEDLINE, and clinical registries for studies related to DL for IK published between 1974 and July 16, 2024. We performed meta-analyses using bivariate models to estimate summary sensitivities and specificities. This systematic review was registered with PROSPERO (CRD42022348596). Findings: Of 963 studies identified, 35 studies (136,401 corneal images from >56,011 patients) were included. Most studies had low risk of bias (68.6%) and low applicability concern (91.4%) in all domains of QUADAS-2, except the index test domain. Against the reference standard of expert consensus and/or microbiological results (seven external validation studies; 10,675 images), the summary estimates (95% CI) for sensitivity and specificity of DL for IK were 86.2% (71.6–93.9) and 96.3% (91.5–98.5). From 28 internal validation studies (16,059 images), summary estimates for sensitivity and specificity were 91.6% (86.8–94.8) and 90.7% (84.8–94.5). Based on seven studies (4007 images), DL and ophthalmologists had comparable summary sensitivity [89.2% (82.2–93.6) versus 82.2% (71.5–89.5); P = 0.20] and specificity [(93.2% (85.5–97.0) versus 89.6% (78.8–95.2); P = 0.45]. Interpretation: DL models may have good diagnostic accuracy for IK and comparable performance to ophthalmologists. These findings should be interpreted with caution due to the image-based analysis that did not account for potential correlation within individuals, relatively homogeneous population studies, lack of pre-specification of DL thresholds, and limited external validation. Future studies should improve their reporting, data diversity, external validation, transparency, and explainability to increase the reliability and generalisability of DL models for clinical deployment. Funding: NIH, Wellcome Trust, MRC, Fight for Sight, BHP, and ESCRS.

Abstract Background Recognition of seasonal trends in bacterial infection and drug resistance rates may enhance diagnosis, direct therapeutic strategies, and inform preventive measures. Limited data exist on the seasonal variability of Acinetobacter baumannii. We investigated the seasonality of A. baumannii, the correlation between temperature and meropenem resistance, and the impact of temperature on this bacterium. Results Meropenem resistance rates increased with lower temperatures, peaking in winter/colder months. Nonresistant strain detection exhibited temperature-dependent seasonality, rising in summer/warmer months and declining in winter/colder months. In contrast, resistant strains showed no seasonality. Variations in meropenem-resistant and nonresistant bacterial resilience to temperature changes were observed. Nonresistant strains displayed growth advantages at temperatures ≥ 25 °C, whereas meropenem-resistant A. baumannii with β-lactamase OXA-23 exhibited greater resistance to low-temperature (4 °C) stress. Furthermore, at 4 °C, A. baumannii upregulated carbapenem resistance-related genes (adeJ, oxa-51, and oxa-23) and increased meropenem stress tolerance. Conclusions Meropenem resistance rates in A. baumannii display seasonality and are negatively correlated with local temperature, with rates peaking in winter, possibly linked to the differential adaptation of resistant and nonresistant isolates to temperature fluctuations. Furthermore, due to significant resistance rate variations between quarters, compiling monthly or quarterly reports might enhance comprehension of antibiotic resistance trends. Consequently, this could assist in formulating strategies to control and prevent resistance within healthcare facilities.

Abstract Optical coherence tomography angiography (OCTA) is widely used for non-invasive retinal vascular imaging, but the OCTA methods used to assess retinal perfusion vary. We evaluated the different methods used to assess retinal perfusion between OCTA studies. MEDLINE and Embase were searched from 2014 to August 2021. We included prospective studies including ≥ 50 participants using OCTA to assess retinal perfusion in either global retinal or systemic disorders. Risk of bias was assessed using the National Institute of Health quality assessment tool for observational cohort and cross-sectional studies. Heterogeneity of data was assessed by Q statistics, Chi-square test, and I2 index. Of the 5974 studies identified, 191 studies were included in this evaluation. The selected studies employed seven OCTA devices, six macula volume dimensions, four macula subregions, nine perfusion analyses, and five vessel layer definitions, totalling 197 distinct methods of assessing macula perfusion and over 7000 possible combinations. Meta-analysis was performed on 88 studies reporting vessel density and foveal avascular zone area, showing lower retinal perfusion in patients with diabetes mellitus than in healthy controls, but with high heterogeneity. Heterogeneity was lowest and reported vascular effects strongest in superficial capillary plexus assessments. Systematic review of OCTA studies revealed massive heterogeneity in the methods employed to assess retinal perfusion, supporting calls for standardisation of methodology.

Abstract The particle breakage effect and compression characteristics of calcareous sand are related to the water content in the sand material. However, the effects of water content on the particle breakage and compression characteristics of calcareous sand have rarely been investigated. In this work, 50 sets of confined compression tests were conducted on calcareous sand specimens, and the compression characteristics and particle breakage effects of two single-particle-size groups (particle size ranges of 1–0.5 mm and 0.5–0.25 mm) of calcareous sand were investigated under five different water contents. The test results showed that with the increase in the water content, the final compression deformation of calcareous sand was positively correlated with the water content. The final compression deformation decreased when the water content reached a certain value. The water content corresponding to the peak final compression deformation was related to the gradation of the calcareous sand; the specific values were 10% and 15% for particle size ranges of 1–0.5 mm and 0.5–0.25 mm, respectively. With the increase in the water content, the slope of the loading curve of calcareous sand appeared to increase and then decrease, reaching maximum when the water content was 10%. Moreover, the slope of the loading curve was close to twice that of the loading curve of dry sand, whereas the slope of the unloading curve changed little. Under the same water content, the initial gradation had no effect on the compression and unloading characteristics of the specimens beyond a vertical pressure of 1 MPa. The effects of the variation in the water content on the particle breakage of calcareous sand were mainly reflected in the softening effect of water on the specimen particles, which reduced the Mohr strength of the particles.

Undergraduate medical education in China has shifted from educator-centered learning to self-directed learning (SDL) over the past few decades. Careful design of public engagement activities can enable SDL and empower medical students to pioneer public health and patient safety education. In this study, we aimed to innovate nervous system education by implementing a public engagement model that empowers students to learn about the nervous system by teaching the public. Our goal was to generate greater interest in the nervous system at the undergraduate stage, inspire students’ enthusiasm to pursue a career in neurology, and ultimately, contribute to health promotion. During the nervous system module of the second year of the undergraduate curriculum, students were given the option to participate in the public engagement model. Participants were tasked with the creation of educational videos focusing on knowledge, attitudes, and behaviors associated with the prevention and management of neurological diseases and their complications. The videos were made accessible to the general public through the university’s official channel at the end of the semester. A total of 117 students (67.24% of all students) chose to participate in the public engagement model. Female students and those with higher Grade Point Averages in the present semester were more likely to participate. The model received strong positive feedback from participants, as students found the public engagement task helpful in learning about the nervous system module as well as in enhancing their public engagement skills. Despite the time and effort consumption, participating in the public engagement task did not affect students’ exam scores. The public engagement task is an innovative model in the nervous system curriculum and has the potential to be integrated into a broader range of undergraduate courses. It empowers medical students to pioneer public health and patient safety education.

Online symptom checkers are increasingly popular health technologies that enable patients to input their symptoms to produce diagnoses and triage advice. However, there is concern regarding the performance and safety of symptom checkers in diagnosing and triaging patients with life-threatening conditions. This retrospective cross-sectional study aimed to evaluate and compare commercially available symptom checkers for performance in diagnosing and triaging myocardial infarctions (MI). Symptoms and biodata of MI patients were inputted into 8 symptom checkers identified through a systematic search. Anonymised clinical data of 100 consecutive MI patients were collected from a tertiary coronary intervention centre between 1st January 2020 to 31st December 2020. Outcomes included (1) diagnostic sensitivity as defined by symptom checkers outputting MI as the primary diagnosis (D1), or one of the top three (D3), or top five diagnoses (D5); and (2) triage sensitivity as defined by symptom checkers outputting urgent treatment recommendations. Overall D1 sensitivity was 48±31% and varied between symptom checkers (range: 6-85%). Overall D3 and D5 sensitivity were 73±20% (34-92%) and 79±14% (63-94%), respectively. Overall triage sensitivity was 83±13% (55-91%). 24±16% of atypical cases had a correct D1 though for female atypical cases D1 sensitivity was only 10%. Atypical MI D3 and D5 sensitivity were 44±21% and 48±24% respectively and were significantly lower than typical MI cases (p

ObjectivesGenetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.MethodsThe analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.ResultsIn our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations.ConclusionOur investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.

BackgroundUpper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus).ResultsAmong the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS.ConclusionUMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.

BackgroundThe reporting of adverse events (AEs) relating to medical devices is a long-standing area of concern, with suboptimal reporting due to a range of factors including a failure to recognize the association of AEs with medical devices, lack of knowledge of how to report AEs, and a general culture of nonreporting. The introduction of artificial intelligence as a medical device (AIaMD) requires a robust safety monitoring environment that recognizes both generic risks of a medical device and some of the increasingly recognized risks of AIaMD (such as algorithmic bias). There is an urgent need to understand the limitations of current AE reporting systems and explore potential mechanisms for how AEs could be detected, attributed, and reported with a view to improving the early detection of safety signals. ObjectiveThe systematic review outlined in this protocol aims to yield insights into the frequency and severity of AEs while characterizing the events using existing regulatory guidance. MethodsPublicly accessible AE databases will be searched to identify AE reports for AIaMD. Scoping searches have identified 3 regulatory territories for which public access to AE reports is provided: the United States, the United Kingdom, and Australia. AEs will be included for analysis if an artificial intelligence (AI) medical device is involved. Software as a medical device without AI is not within the scope of this review. Data extraction will be conducted using a data extraction tool designed for this review and will be done independently by AUK and a second reviewer. Descriptive analysis will be conducted to identify the types of AEs being reported, and their frequency, for different types of AIaMD. AEs will be analyzed and characterized according to existing regulatory guidance. ResultsScoping searches are being conducted with screening to begin in April 2024. Data extraction and synthesis will commence in May 2024, with planned completion by August 2024. The review will highlight the types of AEs being reported for different types of AI medical devices and where the gaps are. It is anticipated that there will be particularly low rates of reporting for indirect harms associated with AIaMD. ConclusionsTo our knowledge, this will be the first systematic review of 3 different regulatory sources reporting AEs associated with AIaMD. The review will focus on real-world evidence, which brings certain limitations, compounded by the opacity of regulatory databases generally. The review will outline the characteristics and frequency of AEs reported for AIaMD and help regulators and policy makers to continue developing robust safety monitoring processes. International Registered Report Identifier (IRRID)PRR1-10.2196/48156

BackgroundArtificial intelligence (AI) medical devices have the potential to transform existing clinical workflows and ultimately improve patient outcomes. AI medical devices have shown potential for a range of clinical tasks such as diagnostics, prognostics, and therapeutic decision-making such as drug dosing. There is, however, an urgent need to ensure that these technologies remain safe for all populations. Recent literature demonstrates the need for rigorous performance error analysis to identify issues such as algorithmic encoding of spurious correlations (eg, protected characteristics) or specific failure modes that may lead to patient harm. Guidelines for reporting on studies that evaluate AI medical devices require the mention of performance error analysis; however, there is still a lack of understanding around how performance errors should be analyzed in clinical studies, and what harms authors should aim to detect and report. ObjectiveThis systematic review will assess the frequency and severity of AI errors and adverse events (AEs) in randomized controlled trials (RCTs) investigating AI medical devices as interventions in clinical settings. The review will also explore how performance errors are analyzed including whether the analysis includes the investigation of subgroup-level outcomes. MethodsThis systematic review will identify and select RCTs assessing AI medical devices. Search strategies will be deployed in MEDLINE (Ovid), Embase (Ovid), Cochrane CENTRAL, and clinical trial registries to identify relevant papers. RCTs identified in bibliographic databases will be cross-referenced with clinical trial registries. The primary outcomes of interest are the frequency and severity of AI errors, patient harms, and reported AEs. Quality assessment of RCTs will be based on version 2 of the Cochrane risk-of-bias tool (RoB2). Data analysis will include a comparison of error rates and patient harms between study arms, and a meta-analysis of the rates of patient harm in control versus intervention arms will be conducted if appropriate. ResultsThe project was registered on PROSPERO in February 2023. Preliminary searches have been completed and the search strategy has been designed in consultation with an information specialist and methodologist. Title and abstract screening started in September 2023. Full-text screening is ongoing and data collection and analysis began in April 2024. ConclusionsEvaluations of AI medical devices have shown promising results; however, reporting of studies has been variable. Detection, analysis, and reporting of performance errors and patient harms is vital to robustly assess the safety of AI medical devices in RCTs. Scoping searches have illustrated that the reporting of harms is variable, often with no mention of AEs. The findings of this systematic review will identify the frequency and severity of AI performance errors and patient harms and generate insights into how errors should be analyzed to account for both overall and subgroup performance. Trial RegistrationPROSPERO CRD42023387747; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=387747 International Registered Report Identifier (IRRID)PRR1-10.2196/51614

Abstract The Consolidated Standards of Reporting Trials extension for Artificial Intelligence interventions (CONSORT-AI) was published in September 2020. Since its publication, several randomised controlled trials (RCTs) of AI interventions have been published but their completeness and transparency of reporting is unknown. This systematic review assesses the completeness of reporting of AI RCTs following publication of CONSORT-AI and provides a comprehensive summary of RCTs published in recent years. 65 RCTs were identified, mostly conducted in China (37%) and USA (18%). Median concordance with CONSORT-AI reporting was 90% (IQR 77–94%), although only 10 RCTs explicitly reported its use. Several items were consistently under-reported, including algorithm version, accessibility of the AI intervention or code, and references to a study protocol. Only 3 of 52 included journals explicitly endorsed or mandated CONSORT-AI. Despite a generally high concordance amongst recent AI RCTs, some AI-specific considerations remain systematically poorly reported. Further encouragement of CONSORT-AI adoption by journals and funders may enable more complete adoption of the full CONSORT-AI guidelines.

La declaración CONSORT 2010 proporciona unas directrices mínimas para informar sobre los ensayos clínicos aleatorizados. Su uso generalizado ha sido fundamental para garantizar la transparencia en la evaluación de nuevas intervenciones. Más recientemente, se ha reconocido cada vez más que las intervenciones con inteligencia artificial (IA) deben someterse a una evaluación rigurosa y prospectiva para demostrar su impacto en la salud. La extensión CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence) es una nueva pauta de información para los ensayos clínicos que evalúan intervenciones con un componente de IA, esta se desarrolló en paralelo con su declaración complementaria para los protocolos de ensayos clínicos: SPIRIT-AI (Standard Protocol Items – Artificial Intelligence: Recomendaciones para ensayos clínicos de intervención - Inteligencia Artificial). Ambas directrices se desarrollaron a través de un proceso de consenso por etapas que incluía la revisión de la literatura y la consulta a expertos para generar 29 elementos candidatos, que fueron evaluados por un grupo internacional de múltiples partes interesadas en una encuesta Delphi de dos etapas (103 partes interesadas congregados en una reunión de consenso de dos días (31 partes interesadas) y refinados a través de una lista de verificación piloto (34 participantes). La ampliación del CONSORT-AI incluye 14 nuevos elementos que se consideraron lo suficientemente importantes para las intervenciones de IA como para que se informen de forma rutinaria, además de los elementos básicos del CONSORT 2010. CONSORT-AI recomienda que los investigadores proporcionen descripciones claras de la intervención de IA, incluyendo las instrucciones y las habilidades requeridas para su uso, el entorno en el que se integra la intervención de IA, el manejo de los datos de entrada y los datos de salida de la intervención de IA, la interacción entre el ser humano y la IA y la provisión de un análisis de los casos de error. CONSORT-AI ayudará a promover la transparencia y la exhaustividad en los informes de los ensayos clínicos de las intervenciones de AI, también ayudará a los editores y revisores, así como a los lectores en general, a entender, interpretar y valorar críticamente la calidad del diseño del ensayo clínico y el riesgo de sesgo en los resultados comunicados.

La declaración SPIRIT 2013 tiene como objetivo mejorar la exhaustividad de los informes de los protocolos de los ensayos clínicos proporcionando recomendaciones basadas en la evidencia para el conjunto mínimo de elementos que deben abordarse. Esta guía ha sido fundamental para promover la evaluación transparente de nuevas intervenciones. Más recientemente, se ha reconocido cada vez más que las intervenciones con inteligencia artificial (IA) deben someterse a una evaluación rigurosa y prospectiva para demostrar su impacto en los resultados médicos. La extensión SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence, por sus siglas en inglés) es una nueva directriz para el reporte de los protocolos de ensayos clínicos que evalúan intervenciones con un componente de IA. Esta directriz se desarrolló en paralelo con su declaración complementaria para los informes de ensayos clínicos: CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence). Ambas directrices se desarrollaron a través de un proceso de consenso por etapas que incluía la revisión de la literatura y la consulta a expertos para generar 26 ítems candidatos, que fueron consultados por un grupo internacional de múltiples partes interesadas en una encuesta Delphi de dos etapas (103 partes interesadas), acordados en una reunión de consenso (31 partes interesadas) y refinados a través de una lista de verificación piloto (34 participantes). La ampliación de SPIRIT-AI incluye 15 nuevos elementos que se consideraron suficientemente importantes para los protocolos de los ensayos clínicos con intervenciones de IA. Estos nuevos ítems deben ser reportados rutinariamente además de los ítems centrales de SPIRIT 2013. SPIRIT-AI recomienda que los investigadores proporcionen descripciones claras de la intervención de IA, incluyendo las instrucciones y las habilidades necesarias para su uso, el entorno en el que se integrará la intervención de IA, las consideraciones para el manejo de los datos de entrada y salida, la interacción entre el ser humano y la IA y el análisis de los casos de error. SPIRIT-AI ayudará a promover la transparencia y la exhaustividad de los protocolos de los ensayos clínicos de las intervenciones de IA. Su uso ayudará a los editores y revisores, así como a los lectores en general, a comprender, interpretar y valorar críticamente el diseño y el riesgo de sesgo de un futuro ensayo clínico.

Abstract Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia–reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.

Abstract Background Blood brain barrier (BBB) breakdown is one of the key mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Astrocytes interact with endothelial and regulate BBB integrity via paracrine signaling factors. More and more studies reveal astrocyte-derived extracellular vesicles (ADEVs) as an important way of intercellular communication. However, the role of ADEV in BBB integrity after ICH remains unclear. Methods ADEVs were obtained from astrocytes with or without oxygen and glucose deprivation (OGD) pre-stimulation and the role of ADEVs in ICH was investigated using ICH mice model and ICH cell model. The potential regulatory effect of ADEVs on endothelial barrier integrity was identified by TEER, western blot and immunofluorescence in vitro. In vivo, functional evaluation, Evans-blue leakage and tight junction proteins (TJPs) expression were analyzed. MiRNA sequencing revealed that microRNA-27a-3p (miR-27a-3p) was differentially expressed miRNA in the EVs from OGD-pretreated astrocytes compared with normal control. The regulatory mechanism of miR-27a-3p was assessed using Luciferase assay, RT-PCR, western blot and immunofluorescence. Results OGD-activated astrocytes reduced hemin-induced endothelial hyper-permeability through secreting EVs. OGD-activated ADEVs alleviated BBB dysfunction after ICH in vivo and in vitro. MicroRNA microarray analysis indicated that miR-27a-3p is a major component that was highly expressed miRNA in OGD pretreated-ADEVs. OGD-ADEVs mitigated BBB injury through transferring miR-27a-3p into bEnd.3 cells and regulating ARHGAP25/Wnt/β-catenin pathway. Conclusion Taken together, these findings firstly revealed that miR-27a-3p, as one of the main components of OGD-pretreated ADEVs, attenuated BBB destruction and improved neurological deficits following ICH by regulating endothelial ARHGAP25/Wnt/β-catenin axis. OGD-ADEVs might be a novel strategy for the treatment of ICH. this study implicates that EVs from OGD pre-stimulated astrocytes. Graphical Abstract

Alzheimer’s disease (AD) is an intractable and progressive neurodegenerative disease. Amyloid beta (Aβ) aggregation is the hallmark of AD. Aβ induces neurotoxicity through a variety of mechanisms, including interacting with membrane receptors to alter downstream signaling, damaging cellular or organelle membranes, interfering with protein degradation and synthesis, and inducing an excessive immune-inflammatory response, all of which lead to neuronal death and other pathological changes associated with AD. In this study, we extracted gene expression profiles from the GSE5281 and GSE97760 microarray datasets in the GEO (Gene Expression Omnibus) database, as well as from the Human Gene Database. We identified differentially expressed genes in the brain tissues of AD patients and healthy persons. Through GO, KEGG, and ROC analyses, annexin A2 (AnxA2) was identified as a putative target gene. Notably, accumulating evidence suggests that intracellular AnxA2 is a key regulator in various biological processes, including endocytosis, transmembrane transport, neuroinflammation, and apoptosis. Thus, we conducted a series of cell biology experiments to explore the biological function of AnxA2 in AD. The results indicate that AnxA2 gene knockdown primarily affects oxidative phosphorylation, cell cycle, AD, protein processing in the endoplasmic reticulum, SNARE interactions in vesicular transport, and autophagy. In SH-SY5Y cells secreting Aβ42, AnxA2 gene knockdown exacerbated Aβ42-induced cytotoxicity, including cell death, intracellular ROS levels, and neuronal senescence, altered cell cycle, and reduced ATP levels, suggesting its critical role in mitochondrial function maintenance. AnxA2 gene knockdown also exacerbated the inhibitory effect of Aβ42 on cell migration. AnxA2 overexpression reduced the inflammatory response induced by Aβ42, while its absence increased pro-inflammatory and decreased anti-inflammatory responses. Furthermore, AnxA2 gene knockdown facilitated apoptosis and decreased autophagy. These results indicated potential pathophysiological roles of AnxA2 in AD.

This paper proposes a multiplexing multi-scale features network (MMF-Network) for salient target detection to tackle the issue of incomplete detection structures when identifying salient targets across different scales. The network, based on encoder–decoder architecture, integrates a multi-scale aggregation module and a multi-scale visual interaction module. Initially, a multi-scale aggregation module is constructed, which, despite potentially introducing a small amount of noise, significantly enhances the high-level semantic and geometric information of features. Subsequently, SimAM is employed to emphasize feature information, thereby highlighting the significant target. A multi-scale visual interaction module is designed to enable compatibility between low-resolution and high-resolution feature maps, with dilated convolutions utilized to expand the receptive field of high-resolution feature maps. Finally, the proposed MMF-Network is tested on three datasets: DUTS-Te, HUK-IS, and PSCAL-S, achieving scores of 0.887, 0.811, and 0.031 in terms of its F-value SSIM and MA, respectively. The experimental results demonstrate that the MMF-Network exhibits a superior performance in salient target detection.

Zein is the main vegetable protein from maize. In recent years, Zein has been widely used in pharmaceutical, agriculture, food, environmental protection, and other fields because it has excellent biocompatibility and biosafety. However, there is still a lack of systematic review and research on Zein-based nano-delivery systems. This paper systematically reviews preparation and modification methods of Zein-based nano-delivery systems, based on the basic properties of Zein. It discusses the preparation of Zein nanoparticles and the influencing factors in detail, as well as analyzing the advantages and disadvantages of different preparation methods and summarizing modification methods of Zein nanoparticles. This study provides a new idea for the research of Zein-based nano-delivery system and promotes its application.

BackgroundDiabetic eye screening (DES) represents a significant opportunity for the application of machine learning (ML) technologies, which may improve clinical and service outcomes. However, successful integration of ML into DES requires careful product development, evaluation, and implementation. Target product profiles (TPPs) summarize the requirements necessary for successful implementation so these can guide product development and evaluation. ObjectiveThis study aims to produce a TPP for an ML-automated retinal imaging analysis software (ML-ARIAS) system for use in DES in England. MethodsThis work will consist of 3 phases. Phase 1 will establish the characteristics to be addressed in the TPP. A list of candidate characteristics will be generated from the following sources: an overview of systematic reviews of diagnostic test TPPs; a systematic review of digital health TPPs; and the National Institute for Health and Care Excellence’s Evidence Standards Framework for Digital Health Technologies. The list of characteristics will be refined and validated by a study advisory group (SAG) made up of representatives from key stakeholders in DES. This includes people with diabetes; health care professionals; health care managers and leaders; and regulators and policy makers. In phase 2, specifications for these characteristics will be drafted following a series of semistructured interviews with participants from these stakeholder groups. Data collected from these interviews will be analyzed using the shortlist of characteristics as a framework, after which specifications will be drafted to create a draft TPP. Following approval by the SAG, in phase 3, the draft will enter an internet-based Delphi consensus study with participants sought from the groups previously identified, as well as ML-ARIAS developers, to ensure feasibility. Participants will be invited to score characteristic and specification pairs on a scale from “definitely exclude” to “definitely include,” and suggest edits. The document will be iterated between rounds based on participants’ feedback. Feedback on the draft document will be sought from a group of ML-ARIAS developers before its final contents are agreed upon in an in-person consensus meeting. At this meeting, representatives from the stakeholder groups previously identified (minus ML-ARIAS developers, to avoid bias) will be presented with the Delphi results and feedback of the user group and asked to agree on the final contents by vote. ResultsPhase 1 was completed in November 2023. Phase 2 is underway and expected to finish in March 2024. Phase 3 is expected to be complete in July 2024. ConclusionsThe multistakeholder development of a TPP for an ML-ARIAS for use in DES in England will help developers produce tools that serve the needs of patients, health care providers, and their staff. The TPP development process will also provide methods and a template to produce similar documents in other disease areas. International Registered Report Identifier (IRRID)DERR1-10.2196/50568

BackgroundArtificial intelligence as a medical device (AIaMD) has the potential to transform many aspects of ophthalmic care, such as improving accuracy and speed of diagnosis, addressing capacity issues in high-volume areas such as screening, and detecting novel biomarkers of systemic disease in the eye (oculomics). In order to ensure that such tools are safe for the target population and achieve their intended purpose, it is important that these AIaMD have adequate clinical evaluation to support any regulatory decision. Currently, the evidential requirements for regulatory approval are less clear for AIaMD compared to more established interventions such as drugs or medical devices. There is therefore value in understanding the level of evidence that underpins AIaMD currently on the market, as a step toward identifying what the best practices might be in this area. In this systematic scoping review, we will focus on AIaMD that contributes to clinical decision-making (relating to screening, diagnosis, prognosis, and treatment) in the context of ophthalmic imaging. ObjectiveThis study aims to identify regulator-approved AIaMD for ophthalmic imaging in Europe, Australia, and the United States; report the characteristics of these devices and their regulatory approvals; and report the available evidence underpinning these AIaMD. MethodsThe Food and Drug Administration (United States), the Australian Register of Therapeutic Goods (Australia), the Medicines and Healthcare products Regulatory Agency (United Kingdom), and the European Database on Medical Devices (European Union) regulatory databases will be searched for ophthalmic imaging AIaMD through a snowballing approach. PubMed and clinical trial registries will be systematically searched, and manufacturers will be directly contacted for studies investigating the effectiveness of eligible AIaMD. Preliminary regulatory database searches, evidence searches, screening, data extraction, and methodological quality assessment will be undertaken by 2 independent review authors and arbitrated by a third at each stage of the process. ResultsPreliminary searches were conducted in February 2023. Data extraction, data synthesis, and assessment of methodological quality commenced in October 2023. The review is on track to be completed and submitted for peer review by April 2024. ConclusionsThis systematic review will provide greater clarity on ophthalmic imaging AIaMD that have achieved regulatory approval as well as the evidence that underpins them. This should help adopters understand the range of tools available and whether they can be safely incorporated into their clinical workflow, and it should also support developers in navigating regulatory approval more efficiently. International Registered Report Identifier (IRRID)DERR1-10.2196/52602

Abstract Background The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD. Methods The data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk. Results Overall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31–2.20) for all-cause mortality, and 2.00 (1.39–2.89) for cardiovascular mortality (both p trend

Abstract The cGAS-STING signaling pathway has emerged as a promising target for immunotherapy development. Here, we introduce a light-sensitive optogenetic device for control of the cGAS/STING signaling to conditionally modulate innate immunity, called ‘light-inducible SMOC-like repeats’ (LiSmore). We demonstrate that photo-activated LiSmore boosts dendritic cell (DC) maturation and antigen presentation with high spatiotemporal precision. This non-invasive approach photo-sensitizes cytotoxic T lymphocytes to engage tumor antigens, leading to a sustained antitumor immune response. When combined with an immune checkpoint blocker (ICB), LiSmore improves antitumor efficacy in an immunosuppressive lung cancer model that is otherwise unresponsive to conventional ICB treatment. Additionally, LiSmore exhibits an abscopal effect by effectively suppressing tumor growth in a distal site in a bilateral mouse model of melanoma. Collectively, our findings establish the potential of targeted optogenetic activation of the STING signaling pathway for remote immunomodulation in mice.

Small interfering RNA (siRNA) therapeutics, characterized by high specificity, potency, and durability, hold great promise in the treatment of cancer and other diseases. However, the clinic implementation of siRNA therapeutics critically depends on the safe and on–demand delivery of siRNA to the target cells. Here, we reported a family of ferrocenyl amphiphilic dendrimers (Fc-AmDs) for on–demand delivery of siRNA in response to the high ROS content in cancer cells. These dendrimers bear ROS–sensitive ferrocene moieties in the hydrophobic components and positively chargeable poly(amidoamine) dendrons as the hydrophilic entities, possessing favorable safety profiles and ROS responsive properties. One of these ferrocenyl amphiphilic dendrimers, Fc-C8-AmD 8A, outperforms in siRNA delivery, benefiting from its optimal balance of hydrophobicity and hydrophilicity. Its ROS feature facilitates specific and efficient disassembly of its complex with siRNA in ROS–rich cancer cells for effective siRNA delivery and gene silencing. Moreover, Fc-C8-AmD 8A also integrates the features and beneficial properties of both lipid and dendrimer vectors. Therefore, it represents a novel on–demand delivery system for cancer cell–specific siRNA delivery. This work opens new perspectives for designing self–assembly nanosystems for on–demand drug delivery.

Abstract Background Pathophysiological mechanisms underlying sex-based differences in diabetes remain poorly understood. Mitochondrial metabolite methylmalonic acid (MMA) accumulation reflects mitochondrial dysfunction which is involved in sex-specific pathophysiological responses biologically. We aimed to investigate the sex-specific associations between mortality risk and MMA in adults with the presence or absence of type 2 diabetes. Methods This cohort study included 24,164 adults (12,123 females and 12,041 males) from the NHANES study during 1999–2014. Both sexes were separately categorized as those with no diabetes, prediabetes, undiagnosed diabetes, and diagnosed diabetes. Circulating MMA level was measured at baseline by mass-spectrometric detection. Mortality status was ascertained from baseline until December 31, 2015. Results During a median follow-up of 11.1 years, 3375 deaths were documented. Males had a particularly higher mortality than females in adults with diagnosed diabetes compared to differences in those with no diabetes, prediabetes and undiagnosed diabetes (sex differences in mortality rate per 1000 person-years across diabetic status: 0.62, 1.44, 5.78, and 9.77, p

ObjectiveCharcot–Marie–Tooth (CMT) disease is the most common inherited neuromuscular disorder. Multi-echo Dixon MRI technique is a highly sensitive method for quantifying muscle fatty infiltration, which may provide excellent value for the assessment of CMT. Due to the rareness of the disease, its use in CMT disease has been rarely evaluated, especially in subtypes.MethodsThirty-four CMT1 patients, 25 CMT2 patients, and 10 healthy controls were recruited. All of the recruited CMT1 patients are CMT1A with PMP22 duplication. Among CMT2 patients, 7 patients are CMT2A with MFN2 mutation, and 7 patients have SORD mutations. Multi-echo Dixon MRI imaging was performed. The fat fractions (FFs) of 5 muscle compartments of the leg were measured at proximal, middle, and distal levels by two specialized musculoskeletal radiologists. Comparisons between CMT1, CMT2, and genetically defined subtypes were conducted.ResultsA proximal-distal gradient (27.6 ± 15.9, 29.9 ± 19.7, and 40.5 ± 21.4, p = 0.015) with a peroneal predominance (p = 0.001) in fat distribution was observed in CMT1. Significant differences in the soleus muscle FFs at proximal (19.1 ± 14.7 vs. 34.8 ± 25.1, p = 0.034) and medial levels (23.5 ± 21 vs. 38.0 ± 25.6, p = 0.044) were observed between CMT1 and CMT2 patients. Between PMP2 duplication and MFN2 mutation group, a significant difference in the soleus muscle FF was also observed (23.5 ± 21.0 vs. 54.7 ± 20.2, p = 0.039). Prominent correlations of calf muscle FFs with functional scores were observed.DiscussionMulti-echo Dixon MRI imaging is a valuable tool for assessing disease severity in CMT. The difference in patterns of fatty infiltration of CMT subtypes is first reported, which could provide references when making targeted training plans.

ObjectivesTo investigate the occurrence rate of urinary tract infections (UTIs) in the early phase after performing intermittent catheterization (IC) and to explore the possible factors associated with UTIs after performing IC among people with spinal cord injury (SCI).SettingAn inpatient rehabilitation department of a teaching hospital in China.DesignRetrospective chart review.MethodsA retrospective chart review was carried out for traumatic and non-traumatic SCI patients after performing IC during their inpatient stay. Demographic information, comorbidity of diabetes, urine analysis results before IC, method of IC (sterile or clean), use of bladder irrigation, cessation of IC and its reasons, and UTI events were collected.ResultsA total of 183 adult individuals were included, of which 60 (32.8%) of them were women. The median age was 49.0 years. The median time post-injury was 2 months. The overall occurrence rate of UTI after performing IC was 1.31 (95% confidence intervals: 0.96–1.77) events per 100 days. Sixty-nine (37.7%) patients discontinued IC during hospitalization, and UTIs were the leading reason for cessation (50.7%). Female sex, use of antibiotics for infections other than UTI, and use of bladder irrigation were found to be associated with a lower occurrence rate of UTI in the early phase after performing IC, with an odds ratio of 0.38 (p = 0.019), 0.20 (p = 0.022), and 0.24 (p

Macrophages, as ubiquitous and functionally diverse immune cells, play a central role in innate immunity and initiate adaptive immunity. Especially, tumor-associated macrophages (TAMs) are crucial contributors to the tumorigenesis and development of cancer. Thus, macrophages are emerging potential targets for cancer treatment. Among the numerous targeted therapeutic options, gene therapy is one of the most potential therapeutic strategies via directly and specifically regulating biological functions of macrophages at the gene level for cancer treatment. This short review briefly introduces the characteristics of macrophage populations, the functions of TAM in the occurrence, and the progress of cancer. It also summarized some representative examples to highlight the current progress in TAM-targeted gene therapy. The review hopes to provide new insights into macrophage-targeted gene therapy for precision cancer therapy.

A series of novel waterborne photosensitive resins were prepared successfully with poly(propylene oxide) bis(2-aminopropyl ether), tricyclodecane dimethanol diacrylate, 2-isocyanatoethyl acrylate, and hydrochloric acid by Michael addition reaction. The results show that with the increasing double bonds content, the double bonds conversion increases from 78.7, 85.6 to 92.8% in the photopolymerization, respectively, and the gel content of the UV-cured film increases from 48.05, 69.10 to 83.28%. In addition, the glass transition temperature and tensile strength of the UV-cured film follow the same increasing trend. Moreover, the content of hydrochloride has a great influence on the hydrophilicity of the waterborne photosensitive resins. The studies indicated that as the hydrochloride content decreases, the surface water contact angle of the UV-cured film increases from 10.8, 22.9 to 51.5°, and water absorption decreases from 26.55, 16.20 to 11.06%, respectively. Moreover, the waterborne photosensitive resins exhibited a high printing accuracy together with a good effect of washing and are promising for 3D printing.

Adipose tissue is a major component for the regulation of energy homeostasis by storage and release of lipids. As a core element of RNA‐induced silencing complex, argonaute2 (Ago2) plays critical role in maintenance of systemic metabolic demand. Here, we show that high‐fat‐diet‐fed mice exhibit an increase in body mass alongside systematic insulin resistance and altered rate of energy expenditure. Interestingly, Ago2 expression is associated with obesity and an increased amount of adipose tissue. Moreover, increased levels of Ago2 inhibited the expression of AMPKα by promoting its targeting by miR‐148a, the most abundant microRNA in adipose tissues. Those results suggested that Ago2–miR‐148a–AMPKα signaling pathway play an important function in the developing obesity and adiposity, and will further provide basic research data for the potential clinical treatment of obesity.

Abstract Patient reported outcome measures (PROMs) capture impact of disease and treatment on quality of life, and have an emerging role in clinical trial outcome measurement. This study included a systematic review and quality appraisal of PROMs developed or validated for use in adults with uveitis or scleritis. We searched MEDLINE, EMBASE, PsycINFO, CINAHL and grey literature sources, to 5 November 2021. We used established quality criteria to grade each PROM instrument in multiple domains from A (high quality) to C (low quality), and assessed content development, validity, reliability and responsiveness. For instruments developed using classic test theory-based psychometric approaches, we assessed acceptability, item targeting and internal consistency. For instruments developed using Item Response Theory (IRT) (e.g. Rasch analysis), we assessed response categories, dimensionality, measurement precision, item fit statistics, differential item functioning and targeting. We identified and appraised four instruments applicable to certain uveitis types, but none for scleritis. Specifically, the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ), a 3-part PROM for Birdshot retinochoroiditis (Birdshot Disease & Medication Symptoms Questionnaire [BD&MSQ], the quality of life (QoL) impact of Birdshot Chorioretinopathy [QoL BCR], and the QoL impact of BCR medication [QoL Meds], the Kings Sarcoidosis Questionnaire (KSQ), and a PROM for cytomegalovirus retinitis. These instruments had limited coverage for these heterogeneous conditions, with a focus on very rare subtypes. Psychometric appraisal revealed considerable variability between instruments, limited content development, and only one developed using Item Response Theory. In conclusion, there are few validated PROMs for patients with uveitis and none for scleritis, and existing instruments have suboptimal psychometric performance. We articulate why we do not recommend their inclusion as clinical trial outcome measures for drug licensing purposes, and highlight an unmet need for PROMs applicable to uveitis and scleritis.

Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited neurological disorder suffered in childhood. To date, the disease features have not been extensively characterized in the Chinese paediatric population. In this study, we aimed to analyse the clinical profiles and genetic distributions of a paediatric CMT cohort in China.Methods: A total of 181 paediatric CMT patients were enrolled. After preexcluding PMP22 duplication/deletion by multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, targeted next-generation sequencing (NGS) or whole-exome sequencing (WES) was performed to obtain a genetic diagnosis. Detailed information was collected to explore the spectrum of subtypes and genotype-phenotype correlations.Results: Pathogenic mutations were identified in 68% of patients in this study; with PMP22 duplication, MFN2 and GJB1 were the most frequent disease-causing genes. Of note, respect to the higher prevalence worldwide, CMT1A (18.2%) was relatively lower in our cohort. Besides, the mean age at onset (8.3 ± 5.7 years) was significantly older in our series. In genotype-phenotype analyse, PMP22 point mutations were considered the most severe genotypes and were mostly de novo. In addition, the de novo mutations were identified in up to 12.7% of all patients, which was higher than that in other studies.Conclusion: We identified a relatively lower detection rate of PMP22 duplication and a higher frequency of de novo variants among paediatric patients in China. We also identified the genetic and phenotypic heterogeneity of this cohort, which may provide clues for clinicians in directing genetic testing strategies for Chinese patients with early-onset CMT.

BackgroundPeriaxins (encoded by PRX) play an important role in the stabilization of peripheral nerve myelin. Mutations in PRX can lead to Charcot-Marie-Tooth disease type 4F (CMT4F).MethodsIn this study, we screened for PRX mutations using next-generation sequencing and whole-exome sequencing in a large Chinese CMT cohort consisting of 465 unrelated index patients and 650 healthy controls. Sanger sequencing was used for the validation of all identified variants. We also reviewed all previously reported PRX-related CMT cases and summarized the clinical manifestations and genetic features of PRX-related CMTs.ResultsThe hit rate for biallelic PRX variants in our cohort of Chinese CMT patients was 0.43% (2/465). One patient carried a previously unreported splice-site mutation (c.25_27 + 9del) compound heterozygous with a known nonsense variant. Compiling data on CMT4F cases and PRX variants from the medical literature confirmed that early-onset (95.2%), distal amyotrophy or weakness (94.0%), feet deformity (75.0%), sensory impairment or sensory ataxia (65.5%), delayed motor milestones (60.7%), and spinal deformity (59.5%) are typical features for CMT4F. Less frequent features were auditory impairments, respiratory symptoms, late onset, dysarthria or hoarseness, ophthalmic problems, and central nervous system involvement. The two cases with biallelic missense mutations have later onset age than those with nonsense or frameshift mutations. We did not note clear correlations between the type and site of mutations and clinical severity or distinct constellations of symptoms.ConclusionConsistent with observations in other countries and ethnic groups, PRX-related CMT is rare in China. The clinical spectrum is wider than previously anticipated.

ABSTRACT Expression of the hypermucoviscosity (HMV) phenotype and capsular polysaccharide (CPS) biosynthesis in Klebsiella pneumoniae were reported to be encoded by genes located in the chromosomal rmp locus. However, the functions of the rmp locus in the virulence plasmid remained unclear, and most of the rmp loci in clinical K. pneumoniae are plasmid carried. In this study, we investigated the functional characteristics of plasmid-borne rmp homologues in clinical hypervirulent K. pneumoniae (hvKP) strains by cloning and introducing such gene homologues into K. pneumoniae strains of different capsule types, followed by the evaluation of phenotypic changes in these strains. Acquisition of the plasmid-borne prmpADC and prmpA2D2 loci were found to result in an increase in mucoviscosity and CPS production in K1 and K2 K. pneumoniae, while only the prmpA2D2 locus contributed to phenotypic changes in the ST11/KL64 strain. Consistently, both rmpD and rmpD2 increased HMV in K1 and K2 K. pneumoniae, while only rmpD2 contributed to HMV in the ST11/KL64 strain; rmpC contributed to CPS overproduction in K1 and K2 strains but not in the ST11/KL64 strain. Furthermore, we proposed a logistic molecular basis of the HMV phenotype of K. pneumoniae on which prmpD2-mediated HMV is attributed to the increase of cell-free CPS production. Our data confirm that the rmp homologues carried by the virulence plasmid play a key role in virulence expression in K. pneumoniae, but the phenotype is highly dependent on the genetic background of the host strain and explained why most of the clinical ST11 strains carry only the prmpA2D2 locus. IMPORTANCE Klebsiella pneumoniae has become the most frequently isolated bacterial pathogen in hospital settings, with a very high mortality rate worldwide. Factors contributing to the virulence of K. pneumoniae are the overproduction of capsular polysaccharide (CPS) as well as the hypermucoviscosity (HMV) phenotype. These two phenotypes were reported to be regulated by rmpA/A2 homologues, which are often carried by virulence plasmids. Here, we determined the functional role of two plasmid-borne rmpA in mediating expression of the HMV phenotype and CPS production in K. pneumoniae. Different capsule types exhibited differences in the expression of HMV and CPS production although they harbored an identical plasmid-borne rmpA or rmpA2 locus, indicating that these virulence-related phenotypes are strongly related to the genetic background of the host strains. Our study provides a novel understanding of the regulation of virulence-related phenotypes and clinical management of K. pneumoniae infections.

Summary: Evidence concerning PM1 exposure, maternal blood pressure (BP), and hypertensive disorders of pregnancy (HDP) is sparse. We evaluated the associations using 105,063 participants from a nationwide cohort. PM1 concentrations were evaluated using generalized additive model. BP was measured according to the American Heart Association recommendations. Generalized linear mixed models were used to assess the PM1-BP/HDP associations. Each 10 μg/m3 higher first-trimester PM1 was significantly associated with 1.696 mmHg and 1.056 mmHg higher first-trimester SBP and DBP, and with 11.4% higher odds for HDP, respectively. The above associations were stronger among older participants (> 35 years) or those educated longer than 17 years or those with higher household annual income (> 400,000 CNY). To conclude, first-trimester PM1 were positively associated with BP/HDP, which may be modified by maternal age, education level, and household annual income. Further research is warranted to provide more information for both health management of HDP and environmental policies enactment.

Perovskite (PVK) solar cells (PSCs) have garnered considerable research interest owing to their cost-effectiveness and high efficiency. A systematic annual review of the research on PSCs is essential for gaining a comprehensive understanding of the current research trends. Herein, systematic analysis of the research papers on PSCs reporting key findings in 2023 was conducted. Based on the results, the papers were categorized into six classifications, including regular n–i–p PSCs, inverted p–i–n PSCs, PVK-based tandem solar cells, PVK solar modules, device stability, and lead toxicity and green solvents. Subsequently, a detailed overview and summary of the annual research advancements within each classification were presented. Overall, this review serves as a valuable resource for guiding future research endeavors in the field of PSCs.

Abstract Background Falls are common but dangerous in the elderly. More and more seniors are searching for healthcare information online. YouTube has become the world’s most popular video streaming platform. Albeit thousands of fall prevention videos are available on YouTube, their reliability, functional quality, understandability, and actionability have not been verified. Methods The top 300 watched videos on YouTube related to fall prevention were retrieved. After exclusion, all qualified sample videos were evaluated by three validated assessment instruments (the PEMAT scale, the HONCode scale, and the DISCERN instrument) regarding their reliability, functional quality, understandability, and actionability. Each video’s length, number of views/likes/comments, forms of expression, and the uploader’s profile were collected as well. The Wilcoxon rank sum test was performed for further analysis from the perspective of expression forms and uploaders’ identities. Results One hundred thirty-seven videos (45.67%) were qualified as sample videos, and individuals/organizations with medical backgrounds posted 54.01% of them. Most of the excluded videos (n = 163) were irrelevant (n = 91, 55.83%), and commercial (n = 52, 31.90%). The median video length for sample videos was 470 seconds. The DISCERN instrument indicated that 115 videos (83.94%) were of moderate to high overall quality. Medical practitioners and organizations gained the highest scores in functional quality and reliability (P

Abstract Background β-glucosidase is an important biomass-degrading enzyme and plays a vital role in generating renewable biofuels through enzymatic saccharification. In this study, we analyzed the transcriptome of Trichoderma harzianum HTASA derived from Hainan mangrove and identified a new gene encoding β-glucosidase Bgl3HB. And the biochemically characterization of β-glucosidase activity was performed. Results Bgl3HB showed substantial catalytic activity in the pH range of 3.0–5.0 and at temperatures of 40 ℃-60 ℃. The enzyme was found quite stable at 50 ℃ with a loss of only 33.4% relative activity after 240 min of heat exposure. In addition, all tested metal ions were found to promote the enzyme activity. The β-glucosidase activity of Bgl3HB was enhanced by 2.12-fold of its original activity in the presence of 5 M NaCl. Surprisingly, Bgl3HB also showed a remarkable ability to hydrolyze laminarin compared to other measured substrates. Enzyme efficiency was examined in the sugarcane bagasse saccharification processes, in which Bgl3HB with 5 M NaCl worked better supplementing Celluclast 1.5L than the commercial Novozyme 188 ascertained it as an admirably suited biocatalyst for the utilization of agricultural waste. In this work, this is the first report of a halophilic β-glucosidase from Trichoderma harzianum, and represents the β-glucosidase with the highest known NaCl activation concentration. And adding 5 M NaCl could enhance saccharification performance even better than commercial cellulase. Conclusions These results show that Bgl3HB has great promise as a highly stable and highly efficient cellulase with important future applications in the industrial production of biofuels.

Introduction Infectious keratitis (IK) represents the fifth-leading cause of blindness worldwide. A delay in diagnosis is often a major factor in progression to irreversible visual impairment and/or blindness from IK. The diagnostic challenge is further compounded by low microbiological culture yield, long turnaround time, poorly differentiated clinical features and polymicrobial infections. In recent years, deep learning (DL), a subfield of artificial intelligence, has rapidly emerged as a promising tool in assisting automated medical diagnosis, clinical triage and decision-making, and improving workflow efficiency in healthcare services. Recent studies have demonstrated the potential of using DL in assisting the diagnosis of IK, though the accuracy remains to be elucidated. This systematic review and meta-analysis aims to critically examine and compare the performance of various DL models with clinical experts and/or microbiological results (the current ‘gold standard’) in diagnosing IK, with an aim to inform practice on the clinical applicability and deployment of DL-assisted diagnostic models.Methods and analysis This review will consider studies that included application of any DL models to diagnose patients with suspected IK, encompassing bacterial, fungal, protozoal and/or viral origins. We will search various electronic databases, including EMBASE and MEDLINE, and trial registries. There will be no restriction to the language and publication date. Two independent reviewers will assess the titles, abstracts and full-text articles. Extracted data will include details of each primary studies, including title, year of publication, authors, types of DL models used, populations, sample size, decision threshold and diagnostic performance. We will perform meta-analyses for the included primary studies when there are sufficient similarities in outcome reporting.Ethics and dissemination No ethical approval is required for this systematic review. We plan to disseminate our findings via presentation/publication in a peer-reviewed journal.PROSPERO registration number CRD42022348596.

Abstract Background GNE myopathy is a rare distal myopathy caused by mutations of the GNE gene. A few cases of GNE myopathy accompanied by neurogenic features of electrophysiology mimicking hereditary motor neuropathy were reported recently. We confirmed this feature and described the clinical phenotype and mutations of GNE myopathy in these rare cases. Results The absence of lower limb tendon reflexes, decreased compound muscle action potentials in lower leg motor nerves, and neurogenic pattern of electromyography suggested neuropathy in four patients. However, muscle pathology revealed a predominantly myogenic pattern. The follow-up electroneurography results implied that the compound motor action potential amplitudes deteriorated over time. Next-generation sequencing identified three novel variants of the GNE gene, c.2054T > C (p.Val685Ala), c.424G > A (p.Gly142Arg) and c.944T > C (p.Phe315Ser), as well as two hotspot mutations, c.115C > T(p.Arg39*) and c.620A > T(p.Asp207Val), in these patients. These novel mutations cosegregated with disease in the family. Conclusions These rare cases supported the existence of neurogenic features of electrophysiology different from the typical myopathic pattern of GNE myopathy.

Messenger RNA (mRNA) has recently made important progress in clinical implementation, offering a promising therapeutic option for infectious disease and cancer. However, the nature of mRNA molecules rendered them poorly bioavailable and unstable in vivo, impeding their further clinical application. Therefore, safe and efficient delivery of mRNA therapeutics to the target site is crucial for their successful translation into the clinical setting. Various vectors have been explored for mRNA delivery. Among them, polyesters and their analogs, a family of biodegradable polymers, have exhibited great potential for mRNA delivery. In this short review, the authors briefly introduce mRNA therapeutics, their therapeutic applications and delivery challenges. The authors then presented the typical examples of polyester materials for mRNA delivery to highlight the current progress and discuss the challenges for the rational design of polyester based mRNA delivery vectors. The authors hope to provide a new insight for the design of biodegradable vectors for nucleic acids delivery, thereby promoting their further clinic translation.

Body pain, often considered as an early sign of injury in young players, warrants thorough study. This study aimed to examine the distribution of badminton-related pain and prevalence in pre-adolescent and adolescent badminton players. Profiles of badminton-related pain were surveyed using a questionnaire among 366 pre-adolescent and adolescent badminton players aged 7–12 years. The distribution of badminton-related pain was described, and the pain incidence was calculated. Proportions of pain per 1000-training-hour exposures were the main outcome measures. The analysis considered various age groups (7–8, 9–10, and 11–12 years) and years of badminton experience (≤2, 2–3, and > 3 years). In total, 554 cases of badminton-related pain were reported. The ankle was the most common site, followed by knee, plantar, shoulder, and lower back. The overall pain rate per 1000-training-hour exposure was 3.06. The 11–12-year-old group showed the highest pain rate, significantly greater than the 7–8-year-old group and the 9–10-year-old group. Additionally, the prevalence of pain exhibited an increasing trend with age. Finally, regardless of the age groups, participants with 2–3 years of badminton experience had the highest pain rate. These findings might help inform targeted interventions to reduce the high prevalence of pain in various body regions across pre-adolescent and adolescent badminton players.

The computation of perceived attractiveness from facial images has long been a research topic. Many models have been developed to predict the attractiveness of the face from the individual models that have been used to describe the geometry of the face (symmetry, golden ratio and neoclassical canons, according to artists from the Middle Ages, and a combination of the three). An experiment was conducted based on Oriental and South Asian ethnic groups, represented by Chinese and Pakistani facial images. Visual assessments of perceived attractiveness were carried out using a 6-point categorical scale and the results were used to derive a new set of facial feature ratios that maximized the perceived attractiveness of the two ethnic groups. The results were also used to develop a new polynomial model of attractiveness, and to test four existing models. The new model performed the best for Oriental faces. The new model was also best for South Asian faces together with the combined model. Ethnic group differences did not have a significant impact on the perceived attractiveness of the two groups. A set of new facial ratios for the two ethnic groups was determined to maximise attractiveness.

Background: Hereditary spastic paraplegia (HSP) constitutes a group of clinically and genetically rare neurodegenerative diseases characterized by progressive corticospinal tract degeneration. The phenotypes and genotypes of HSP are still expanding. In this study, we aimed to analyse the differential diagnosis, clinical features, and genetic distributions of a Chinese HSP patients in a 14-year cohort and to improve our understanding of the disease.Methods: The clinical data of patients with a primary diagnosis of HSP at the initial visit to the Department of the Neurology, Peking University Third Hospital, from 2008 to 2022 were retrospectively collected. Next-generation sequencing gene panels (NGS) combined with a multiplex ligation-amplification assay (MLPA) were conducted. Epidemiological and clinical features and candidate variants in HSP-related genes were analyzed and summarized.Results: 54 cases (probands from 25 different pedigrees and 29 sporadic cases) from 95 patients with a primary diagnosis of HSP were finally confirmed to have a clinical diagnosis of HSP based on clinical criteria, including their clinical findings, family history and long-term follow-up. Earlier disease onset was associated with longer diagnostic delay and longer disease duration and was associated with a lower risk of loss of ability to walk independently. In addition, 20 candidate variants in reported HSP-related genes were identified in these clinically diagnosed HSP patients, including variants in SPAST, ALT1, WASHC5, SPG11, B4GALNT1, and REEP1. The genetic diagnostic rate in these 54 patients was 35.18%.Conclusion: Hereditary spastic paraplegia has high clinical and genetic heterogeneity and is prone to misdiagnosis. Long-term follow-up and genetic testing can partially assist in diagnosing HSP. Our study summarized the clinical features of Chinese HSP patients in a 14-year cohort, expanded the genotype spectrum, and improved our understanding of the disease.