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Abstract Compared to traditional lower-limb prostheses (LLPs), intelligent LLPs are more versatile devices with emerging technologies, such as microcontrollers and user-controlled interfaces (UCIs). As emerging technologies allow a higher level of automation and more involvement from wearers in the LLP setting adjustments, the previous framework established to study human factors elements that affect wearer-LLP interaction may not be sufficient to understand the new elements (e.g., transparency) and dynamics in this interaction. In addition, the increased complexity of interaction amplifies the limitations of the traditional evaluation approaches of wearer-LLP interaction. Therefore, to ensure wearer acceptance and adoption, from a human factors perspective, we propose a new framework to introduce elements and usability requirements for the wearer-LLP interaction. This paper organizes human factors elements that appear with the development of intelligent LLP technologies into three aspects: wearer, device, and task by using a classic model of the human-machine systems. By adopting Nielsen’s five usability requirements, we introduce learnability, efficiency, memorability, use error, and satisfaction into the evaluation of wearer-LLP interaction. We identify two types of wearer-LLP interaction. The first type, direct interaction, occurs when the wearer continuously interacts with the intelligent LLP (primarily when the LLP is in action); the second type, indirect interaction, occurs when the wearer initiates communication with the LLP usually through a UCI to address the current or foreseeable challenges. For each type of interaction, we highlight new elements, such as device transparency and prior knowledge of the wearer with the UCI. In addition, we redefine the usability goals of two types of wearer-LLP interaction with Nelson’s five usability requirements and review methods to evaluate the interaction. Researchers and designers for intelligent LLPs should consider the new device elements that may additionally influence wearers’ acceptance and the need to interpret findings within the constraints of the specific wearer and task characteristics. The proposed framework can also be used to organize literature and identify gaps for future directions. By adopting the holistic usability requirements, findings across empirical studies can be more comparable. At the end of this paper, we discuss research trends and future directions in the human factors design of intelligent LLPs.

Abstract Background Chronic myeloid leukemia (CML) can manifest ocular complications stemming from hematologic irregularities or direct infiltration of neoplastic cells. This article details the case of a patient with newly diagnosed CML exhibiting elevated platelet counts (PLT) who developed panuveitis accompanied by retinal vascular occlusion. Case presentation A 52-year-old woman experienced a notable decline in vision in her left eye over a 2-week period. Classical anterior uveitis, vitreous cavity opacity, optic nerve edema, and retinal vascular obstruction were observed. The right eye exhibited papilledema and retinal vein tortuosity. Despite admission, the condition of both eyes deteriorated, accompanied by a continuous increase in PLT. She was diagnosed with CML based on bone marrow biopsy and chromosomal examination. Following platelet apheresis therapy and chemotherapy, the condition of her right eye significantly improved, but the left eye’s condition remained irreversible. Conclusions This is a rare case of newly diagnosed CML presenting with diverse ocular manifestations in both eyes. The disparate outcomes in eyes with varying lesion stages underscore the importance of prompt diagnosis.

Abstract Latent Autoimmune Diabetes in Adults (LADA) is a type of diabetes mellitus often overlooked in clinical practice for its dual resemblance to Type 1 Diabetes Mellitus (T1DM) in pathogenesis and to Type 2 Diabetes Mellitus (T2DM) in clinical presentation. To better understand LADA’s distinctiveness from T1DM and T2DM, we conducted a comprehensive review encompassing etiology, pathology, clinical features, treatment modalities, and prognostic outcomes. With this comparative lens, we propose that LADA defies simple classification as either T1DM or T2DM. The specific treatments for the disease are limited and should be based on the therapies of T1DM or T2DM that address specific clinical issues at different stages of the disease. It is crucial to identify LADA cases potentially misdiagnosed as T2DM, warranting prompt screening for poor blood sugar control, short-term blood sugar deterioration, and other conditions. If the prognosis for LADA is similar to T2DM, it can be managed as T2DM. However, if the prognosis fundamentally differs, early LADA screening is crucial to optimize patient outcomes and enhance research on tailored treatments. The pathogenesis of LADA is clear, so the prognosis may be the key to determining whether it can be classified as T2DM, which is also the direction of future research. On the one hand, this paper aims to provide suggestions for the clinical screening and treatment of LADA based on the latest progress and provide worthy directions for future research on LADA.

Abstract The cortical cytoskeleton of subpellicular microtubules (SPMTs) supports the Plasmodium ookinete morphogenesis during mosquito transmission of malaria. SPMTs are hypothesized to function as the cytoskeletal tracks in motor-driven cargo transport for apical organelle and structure assembly in ookinetes. However, the SPMT-based transport motor has not been identified in the Plasmodium. The cytoplasmic dynein is the motor moving towards the minus end of microtubules (MTs) and likely be responsible for cargo transport to the apical part in ookinetes. Here we screen 7 putative dynein heavy chain (DHC) proteins in the P. yoelii and identify DHC3 showing peripheral localization in ookinetes. DHC3 is localized at SPMTs throughout ookinete morphogenesis. We also identify five other dynein subunits localizing at SPMTs. DHC3 disruption impairs ookinete development, shape, and gliding, leading to failure in mosquito infection of Plasmodium. The DHC3-deficient ookinetes display defective formation or localization of apical organelles and structures. Rab11A and Rab11B interact with DHC3 at SPMTs in a DHC3-dependent manner, likely functioning as the receptors for the cargoes driven by SPMT-dynein. Disturbing Rab11A or Rab11B phenocopies DHC3 deficiency in ookinete morphogenesis. Our study reveals an SPMT-based dynein motor driving the transport of Rab11A- and Rab11B-labeled cargoes in the ookinete morphogenesis of Plasmodium.

Abstract Land use and land cover change (LULCC) have profoundly altered land surface properties and ecosystem functions, including carbon and water production. While mapping these changes from local to global scales has become more achievable due to advancements in earth observations and remote sensing, linking land cover changes to ecosystem functions remains challenging, especially at regional scale. Our study attempts to fill this gap by employing a computationally efficient method and two types of widely used high-resolution satellite images. We first investigated the contribution of landscape composition to ecosystem function by examining how land cover and proportion affected gross primary production (GPP) and evapotranspiration (ET) at six macro-landscapes in Mongolia and Kazakhstan. We hypothesized that both ecosystem and landscape GPP and ET are disproportionate to their composition and, therefore, changes in land cover will have asymmetrical influences on landscape functions. We leveraged a computational-friendly linear downscaling approach to align the coarse spatial resolution of MODIS (500 m) with a fine-grain and localized land cover map developed from Landsat (30 m) for six provinces in countries where intensive LULCC occurred in recent decades. By establishing two metrics—function to composition ratio (F/C) and function to changes in composition change (ΔF/ΔC)—we tested our hypothesis and evaluated the impact of land cover change on ecosystem functions within and among the landscapes. Our results show three major themes. (1) The five land cover types have signature downscaled ET and GPP that appears to vary between the two countries as well as within each country. (2) F/C of ET and GPP of forests is statistically greater than 1 (i.e., over-contributing), whereas F/C of grasslands and croplands is close to or slightly less than 1 (i.e., under-contribution). F/C of barrens is clearly lower than 1 but greater than zero. Specifically, a unit of forest generates 1.085 unit of ET and 1.123 unit of GPP, a unit of grassland generates 0.993 unit of ET and GPP, and a unit of cropland produces 0.987 unit of ET and 0.983 unit of GPP. The divergent F/C values among the land cover classes support the hypothesis that landscape function is disproportionate to its composition. (3) ΔET/ΔC and ΔGPP/ΔC of forests and croplands showed negative values, while grasslands and barrens showed positive values, indicating that converting a unit of forest to other land cover leads to a decrease in ET and GPP, while converting units of grassland or barren to other land cover classes will result in increased ET and GPP. This linear downscaling approach for calculating F/C and ΔF/ΔC is labor-saving and cost-effective for rapid assessment on the impact of land use land cover change on ecosystem functions.

Purpose – Preservice teacher (PST) professional development programs are crucial for cultivating high-quality STEAM teachers of the future, significantly impacting the quality of regional STEAM education. The Guangdong-Hong Kong-Macao Greater Bay Area, as a region of cross-border cooperation, integrates the resources and advantages of Guangdong, Hong Kong, and Macao, possessing rich cultural heritage and innovative capabilities. Transdisciplinary Education for Cultural Inheritance (C-STEAM) is an effective approach to promoting educational collaboration within the Greater Bay Area, facilitating the integration of both technological and humanities education. This study aims to develop a Technology-Enabled University-School-Enterprise (T-USE) collaborative education model and implement it in the Greater Bay Area, to explore its role as a support mechanism in professional development and its impact on C-STEAM PSTs' professional capital. Design/methodology/approach – Adopting a qualitative methodology, the study interviewed PSTs who participated in a C-STEAM teacher education course under the T-USE model. Thematic coding is used to analyze their knowledge acquisition, interaction benefits with community members, and autonomous thinking and decision-making in theoretical learning and teaching practice. Findings – The findings show that the T-USE model significantly enhanced the PSTs' human capital, including teaching beliefs, knowledge, and skills. In terms of social capital, PSTs benefited from collaboration with PST groups, university teaching teams, in-service teachers, and enterprises, though challenges such as varying levels of expertise among in-service teachers and occasional technical instability emerged. For decisional capital, the T-USE model provided opportunities for autonomous thinking and promoted teaching judgment skills through real teaching challenges and scenarios. Reflective practice activities also supported PSTs' professional growth. Originality/value – This study reveals the effectiveness and internal mechanism of the T-USE model in C-STEAM PST training, offering significant theoretical and practical references for future PST education.

Abstract Ischemic stroke (IS) is a severe cerebrovascular disease with high disability and mortality rates, where the inflammatory response is crucial to its progression and prognosis. Efferocytosis, the prompt removal of dead cells, can reduce excessive inflammation after IS injury. While electroacupuncture (EA) has been shown to decrease inflammation post-ischemia/reperfusion (I/R), its link to efferocytosis is unclear. Our research identified ATP-binding cassette transporter A1 (Abca1) as a key regulator of the engulfment process of efferocytosis after IS by analyzing public datasets and validating findings in a mouse model, revealing its close ties to IS progression. We demonstrated that EA can reduce neuronal cell death and excessive inflammation caused by I/R. Furthermore, EA treatment increased Abca1 expression, prevented microglia activation, promoted M2 microglia polarization, and enhanced their ability to phagocytose injured neurons in I/R mice. This suggests that EA's modulation of efferocytosis could be a potential mechanism for reducing cerebral I/R injury, making regulators of efferocytosis steps a promising therapeutic target for EA benefits.

To investigate the processing methods that could improve the quality of Jingning dried apple snacks, the effects of five drying methods (hot air drying, solar drying, vacuum freeze drying, microwave-pressure puffing drying, and heat pump drying) on energy consumption, antioxidant activity, microstructure, and flavor of dried apples were studied. The results showed that compared with the other four drying methods, in terms of energy consumption that vacuum freeze drying had the highest unit energy consumption (69.48±1.69 kW·h/kg), while solar drying had the lowest unit energy consumption (19.60±1.36 kW·h/kg). In terms of hardness and crispness, dried apples that were dried by hot air drying were found to have the highest levels of hardness and lowest levels of crispness, while those that were dried by vacuum freeze drying were found to have the lowest levels of hardness and a higher degree of crispness. In terms of colour difference, vacuum freeze drying had the highest L* value (72.91±0.59) and the ΔE value was closest to the fresh samples (10.48±0.30). In addition, compared with fresh samples, vacuum freeze drying effectively slowed down the loss of antioxidant activity of dried apples, with the contents of ascorbic acid, total phenols and total flavonoids decreased by 35.22%, 39.27% and 32.02%, respectively. Meanwhile, the total antioxidant capacity, hydroxyl radical scavenging rate and superoxide anion scavenging rate decreased by 23.50%, 57.24% and 10.56%, respectively. In terms of microstructure, the cell layer of dried apples with vacuum freeze drying preserved a regular sponge-like porous structure with good texture. In terms of flavor, 96 volatile substances were identified in five types of dried apples, while it made the dried apples with vacuum freeze drying more aromatic and richer in taste. In conclusion, vacuum freeze drying is recommended as a method to improve the quality and flavor of high-quality dried apples, and provides significance in guiding the industrialized production of dried apple products.

Abstract The global epidemic of Mpox virus (MPXV) continues, and a local outbreak has occurred in Shenzhen city since June 2023. Herein, the evolutionary trajectory and characteristics of MPXV in 2023 were analyzed using 92 MPXV sequences from the Shenzhen outbreak and the available genomes from GISAID and GenBank databases. Phylogenetic tracing of the 92 MPXVs suggests that MPXVs in Shenzhen may have multiple sources of importation, and two main transmission chains have been established. The combination of phylogenetic relationships, epidemiological features, and mutation characteristics supports the emergence of a new lineage C.1.1. Together with the B.1 lineage diverging from the A.1 lineage, C.1.1 lineage diverging from the C.1 lineage may serve as another significant evolutionary events of MPXV. Moreover, increasing apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3) related mutations, higher rate of missense mutations, and less mutations in the non-coding regions have been shown during MPXV evolution. Host regulation proteins of MPXV have accumulated considerable amino acid mutations since the B.1 lineage, and a lineage-defining APOBEC3-related mutation that disrupts the N2L gene encoding a viral innate immune modulator has been identified in the C.1.1 lineage. In summary, our study provides compelling evidence for the ongoing evolution of MPXV with specific features.

Inborn errors of the signal transducer and activator of transcription 1 (STAT1) result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function: autosomal recessive (AR) complete STAT1 deficiency, AR partial STAT1 deficiency, autosomal dominant (AD) STAT1 deficiency, and AD STAT1 gain-of-function (STAT1-GOF). Of which, the STAT1-GOF mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections, especially chronic mucocutaneous candidiasis (CMC) and Talaromyces marneffei infection and predisposition to humoral autoimmunity. STAT1-GOF mutations lead to enhanced phosphorylation of STAT1 (pSTAT1), delayed dephosphorylation, and impaired nuclear dephosphorylation. As a result, the development of T helper (Th) 17 cells is impaired, limiting the production of interleukin (IL)-17, which plays an important role in antifungal immunity. Additionally, mutations can also cause a decrease in the proportion of CD4+, CD8+, and natural killer (NK) cells. Recent research demonstrated that in the absence of overt infection, STAT-GOF mice can disrupt naïve CD4+ T cell homeostasis and promote expansion and differentiation of abnormal T-follicular helper/T-helper 1-like (Tfh/Th1-like) T cells and germinal center-like (GC-like) B cells, and thus reminds us of the complex molecular mechanism of autoimmune disease with/without fungal infection, which may further involve specific clinical treatment including antifungal and anti-autoimmunity therapies. In addition, sex and location of mutation were also associated with the clinical phenotype. Individuals with DNA binding domain (DBD) mutations had a higher prevalence of autoimmunity and aberrant B cell activation. Disrupted CD4+ T cell homeostasis occurred sooner and more robustly in females, highlighting the importance of specific treatment to normalize STAT1 expression and restore immune tolerance in patients with STAT1-GOF syndrome. Herein, we provide a comprehensive review of STAT1-GOF aiming to further clarify the regulatory mechanism of cellular and humoral immune deficiency in patients with fungal infection with or without autoimmunity.

Abstract Bacteria rely on two-component systems to sense environmental cues and regulate gene expression for adaptation. The PhoQ/PhoP system exemplifies this crucial role, playing a key part in sensing magnesium (Mg2+) levels, antimicrobial peptides, mild acidic pH, osmotic upshift, and long-chain unsaturated fatty acids, promoting virulence in certain bacterial species. However, the precise details of PhoQ activation remain elusive. To elucidate PhoQ's signaling mechanism at atomic resolution, we combined AlphaFold2 predictions with molecular modeling and carried out extensive Molecular Dynamics (MD) simulations. Our MD simulations revealed three distinct PhoQ conformations that were validated by experimental data. Notably, one conformation was characterized by Mg2+ bridging the acidic patch in the sensor domain to the membrane, potentially representing a repressed state. Furthermore, the high hydration observed in a putative intermediate state lends support to the hypothesis of water-mediated conformational changes during PhoQ signaling. Our findings not only revealed specific conformations within the PhoQ signaling pathway, but also hold significant promise for understanding the broader histidine kinase family due to their shared structural features. Our approach paves the way for a more comprehensive understanding of histidine kinase signaling mechanisms across various bacterial species and opens the door for developing novel therapeutics that target PhoQ modulation.

Abstract Background The coronavirus disease (COVID-19) pandemic has accentuated the need for effective clinical skills training in infectious diseases. This study aimed to explore the influencing factors of infectious disease clinical skills training based on scenario simulation teaching for medical staff in China. Methods This hospital-based, cross-sectional study was conducted at the Third People’s Hospital of Shenzhen between March and December 2022. Scenario simulation teaching was applied, and factors such as gender, educational level, professional background, and previous experience were examined to determine their impact on qualification outcomes. Results The study included participants primarily between the ages of 20–40 years, with a higher proportion of women holding university degrees. Nurses and physicians were more likely to qualify, indicating the significance of professional backgrounds. Women showed a higher likelihood of qualifying than men and higher educational attainment correlated with better qualification rates. Prior experience with protective clothing in isolation wards was a significant determinant of successful qualification. Multivariate analysis underscored the influence of sex, education, and previous experience on training effectiveness. Conclusion Scenario simulation is an effective strategy for training clinical skills in treating infectious diseases. This study highlights the importance of considering sex, education, professional background, and prior experience when designing training programs to enhance the efficacy and relevance of infectious disease training.

Abstract Purpose Since May 2022, Mpox has spread extensively outside of Africa, posing a serious threat to the health of people globally, and particularly to the men who have sex with men (MSM) population. Chongqing, a province in Southwest China, has relatively large MSM and people living with HIV (PLWH) populations, presenting conditions conducive to the wide dissemination of Mpox. In this study, we investigated the clinical characteristics of Mpox patients among MSM and PLWH in Chongqing, aiming to inform the development of targeted prevention, control, and treatment strategies for Mpox. Method We evaluated the clinical characteristics, travel history, time of onset, distribution and number of skin lesions of Mpox patients admitted to the Chongqing Public Health Medical Center between September 2022 and October 2023. Meanwhile, a series of clinical samples were collected and the pathogen of interest was identified as Mpox virus using quantitative polymerase chain reaction (qPCR). The results were presented in the form of cycle thresholds (Ct), which help to approximate the quantification of viral load. Results As of October 11, 2023, the Chongqing Public Health Medical Center reported a total of nine Mpox virus infections. All the patients identified were male and belonged to the MSM population, among whom seven (77.8%) were living with HIV, and maintained a preserved immune system while achieving viral suppression via effective ART. We observed no discernible clinical differences between MSM with Mpox with or without HIV, and no fatalities were recorded. Viral loads were observed to be higher in samples taken from the skin than those from the throat, nasopharynx, blood, or semen. Conclusion In this retrospective study, the clinical manifestations of MPXV infection appeared consistent among MSM patients, regardless of HIV status. Elevated MPXV viral loads in the skin and mucosal tissues, particularly at genital and anal sites, indicate that transmission is more likely to occur via direct physical contact as opposed to respiratory pathways or through exposure to bodily fluids.

Abstract Although decreasing body mass index (BMI) is associated with higher mortality risk in patients undergoing hemodialysis (HD), BMI neither differentiates muscle and fat mass nor provides information about the variations of fat distribution. It remains unclear whether changes over time in fat and muscle mass are associated with mortality. We examined the prognostic significance of trajectory in the triceps skinfold (TSF) thickness and mid-upper arm circumference (MUAC). In this multicenter prospective cohort study, 972 outpatients (mean age, 54.5 years; 55.3% men) undergoing maintenance HD at 22 treatment centers were included. We calculated the relative change in TSF and MUAC over a 1-year period. The outcome was all-cause mortality. Kaplan–Meier, Cox proportional hazard analyses, restricted cubic splines, and Fine and Gray sub-distribution hazards models were performed to examine whether TSF and MUAC trajectories were associated with all-cause mortality. During follow-up (median, 48.0 months), 206 (21.2%) HD patients died. Compared with the lowest trajectory group, the highest trajectories of TSF and MUAC were independently associated with lower risk for all-cause mortality (HR = 0.405, 95% CI 0.257–0.640; HR = 0.537; 95% CI 0.345–0.837; respectively), even adjusting for BMI trajectory. Increasing TSF and MUAC over time, measured as continuous variables and expressed per 1-standard deviation decrease, were associated with a 55.7% (HR = 0.443, 95% CI 0.302–0.649), and 97.8% (HR = 0.022, 95% CI 0.005–0.102) decreased risk of all-cause mortality. Reduction of TSF and MUAC are independently associated with lower all-cause mortality, independent of change in BMI. Our study revealed that the trajectory of TSF thickness and MUAC provides additional prognostic information to the BMI trajectory in HD patients.

Abstract Background Sarcopenia and diabetes are both prevalent health problems worldwide. However, little is known about the relationship between prediabetes and the prevalence and severity of sarcopenia. Therefore, the current study aimed to explore the association between glucose status and the components of sarcopenia, including low muscle mass (LMM), low muscle strength (LMS) and low gait speed (LGS) in US adults. Methods Data from the 1999 to 2002 National Health and Nutrition Examination Survey (NHANES) were analyzed. A total of 4002 participants aged ≥ 50 years with available information on glucose status (NGR: 1939 cases; prediabetes: 1172 cases; diabetes: 891 cases) and sarcopenia were included in this study. Sarcopenia was defined according to the Foundation for National Institute of Health criteria. Muscle mass, muscle strength and gait speed were used to evaluate sarcopenia and its severity. Weighed multivariable logistic regression were used to explore the association between glucose status and the components of sarcopenia. The hypothetical population attributable fraction (PAF) for the glucose status was also calculated. Results The mean age of the cohort was 63.01 ± 9.89 years, with 49.4% being male. Multiple logistic regression analysis suggested that diabetes was an independent risk factor for sarcopenia (OR = 5.470, 95% CI 1.551–19.296) and showed a marginal association with severe sarcopenia (OR = 10.693, 95% CI 0.955–119.73) compared to NGR in men, but not in women. Additionally, prediabetes was independently associated with severe sarcopenia (OR = 3.647, 95% CI 1.532–8.697), LMS (OR = 1.472, 95% CI 1.018–2.127) and LGS (OR = 1.673, 95% CI 1.054–2.655) in the entire cohort. When stratifying by gender, we further observed that prediabetes was significantly associated with LMS in men (OR = 1.897, 95% CI 1.019–3.543) and related to LMM (OR = 3.174, 95% CI 1.287–7.829) and LGS (OR = 2.075, 95% CI 1.155–3.727) in women. HbA1c was positively associated with the prevalence of sarcopenia in men (OR = 1.993, 95% CI 1.511–2.629). PAF showed that diabetes accounted for 16.3% of observed sarcopenia cases. Maintaining NGR in the entire population could have prevented 38.5% of sarcopenia cases and 50.9% of severe sarcopenia cases. Conclusions Prediabetes and diabetes were independently associated with the prevalence and severity of sarcopenia in US population. Slowing down the progression of hyperglycemia could have prevented a significant proportion of sarcopenia cases.

Abstract Differentiation of male gametocytes into flagellated fertile male gametes relies on the assembly of axoneme, a major component of male development for mosquito transmission of the malaria parasite. RNA-binding protein (RBP)-mediated post-transcriptional regulation of mRNA plays important roles in eukaryotic sexual development, including the development of female Plasmodium. However, the role of RBP in defining the Plasmodium male transcriptome and its function in male gametogenesis remains incompletely understood. Here, we performed genome-wide screening for gender-specific RBPs and identified an undescribed male-specific RBP gene Rbpm1 in the Plasmodium. RBPm1 is localized in the nucleus of male gametocytes. RBPm1-deficient parasites fail to assemble the axoneme for male gametogenesis and thus mosquito transmission. RBPm1 interacts with the spliceosome E complex and regulates the splicing initiation of certain introns in a group of 26 axonemal genes. RBPm1 deficiency results in intron retention and protein loss of these axonemal genes. Intron deletion restores axonemal protein expression and partially rectifies axonemal defects in RBPm1-null gametocytes. Further splicing assays in both reporter and endogenous genes exhibit stringent recognition of the axonemal introns by RBPm1. The splicing activator RBPm1 and its target introns constitute an axonemal intron splicing program in the post-transcriptional regulation essential for Plasmodium male development.

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis, is predominant in young adults and children. Corticosteroid therapy has been controversial over several past decades. TESTING (Therapeutic Effects of Steroids in IgA Nephropathy Global) study, initiated in 2012, is an international, multicenter, double-blinded, randomized and placebo-controlled trial for evaluating oral methylprednisolone’s safety and long-term efficacy under conditions of optimized supportive treatment in IgAN patients at an elevated risk of progression. After one decade of efforts, successful completion of TESTING indicated that a 6 to 9 month course of oral methylprednisolone has been an effective regimen of protecting kidney function in high-risk IgAN patients. Some safety concerns persisted. Compared with a full-dose regimen, reduced-dose regimen was beneficial with higher safety. Overall, the TESTING trial provided more robust data regarding the treatment dosage and safety of corticosteroids. It has important implications for IgAN children. With a deeper pathogenetic understanding of IgAN, ongoing studies of novel therapeutic regimens shall further optimize the benefit-risk ratio.

Abstract Background TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. Methods In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18–75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. Results A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 μg*h/mL, and AUC0-inf ranged from 159 to 340 μg*h/mL. TG103 had a half-life of 110–116 h, with a median Tmax of 36–48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p

Abstract Background Clostridioides difficile is the main pathogen of antimicrobial-associated diarrhoea and health care facility-associated infectious diarrhoea. This study aimed to investigate the prevalence, toxin genotypes, and antibiotic resistance of C. difficile among hospitalized patients in Xi’an, China. Results We isolated and cultured 156 strains of C. difficile, representing 12.67% of the 1231 inpatient stool samples collected. Among the isolates, tcdA + B + strains were predominant, accounting for 78.2% (122/156), followed by 27 tcdA-B + strains (27/156, 17.3%) and 6 binary toxin gene-positive strains. The positive rates of three regulatory genes, tcdC, tcdR, and tcdE, were 89.1% (139/156), 96.8% (151/156), and 100%, respectively. All isolates were sensitive to metronidazole, and the resistance rates to clindamycin and cephalosporins were also high. Six strains were found to be resistant to vancomycin. Conclusion Currently, the prevalence rate of C. difficile infection (CDI) in Xi’an is 12.67% (156/1231), with the major toxin genotype of the isolates being tcdA + tcdB + cdtA-/B-. Metronidazole and vancomycin were still effective drugs for the treatment of CDI, but we should pay attention to antibiotic management and epidemiological surveillance of CDI.

Abstract Background Knowledge of pharmacovigilance (PV) and adverse drug reactions (ADRs) are the core competencies that healthcare students should acquire during their studies. The objective of this study was to assess attitudes towards and knowledge of PV and ADRs among healthcare students in China. Methods An online, cross-sectional survey was conducted nationally among healthcare students in China from April through October 2023. Knowledge of PV and ADRs was assessed using a questionnaire based on current PV guidelines. We performed logistic regression analysis to determine the potential factors related to knowledge of and attitudes towards PV and ADRs. Results A total of 345 students were included in the analysis. Among the healthcare students who participated in the survey, 225 (65.22%) students correctly defined PV, while only 68 (19.71%) had a correct understanding of ADRs. Among all respondents included in the analysis, only 71 (20.58%) reported having taken a PV course. Pharmacy students were more likely to have taken PV courses at a university and to demonstrate superior knowledge compared to other healthcare students. The logistic regression model revealed that the significant predictors of a higher level of PV knowledge were being female (odds ratio [OR]: 1.76; 95% confidence interval (CI): 1.06–2.92; P value: 0.028) and having previously taken PV-related courses (OR: 2.00; 95% CI: 1.06–3.80; P value: 0.034). Conclusions This study revealed that healthcare students’ knowledge of PV and ADRs is unsatisfactory. However, there were a limited number of universities providing PV education. Given the vital role of healthcare professionals in identifying and reporting ADRs, our findings raise significant concerns. Hence, more efforts should be made to enhance PV education for future healthcare professionals.

IntroductionIn China, diabetes mellitus (DM) significantly contributes to end-stage renal disease (ESRD), necessitating treatments like hemodialysis. This study investigates hemodialysis outcomes in diabetic nephropathy patients in Guizhou Province, aiming to enhance care for this high-risk group.MethodsThe cross-sectional survey design to screen haemodialysis patients with end-stage diabetic nephropathy, a structured questionnaire was designed. The collected data were collated and coded and analyzed using GraphPad Prism 9.5.0 (730).ResultsPatients with end-stage diabetic nephropathy undergoing dialysis are primarily concentrated in the middle-aged and elderly population, with a higher proportion of males than females. Male patients also have a higher history of smoking and alcohol consumption compared to females. The disease progression from diabetes to diabetic nephropathy and from nephropathy to end-stage renal disease varies, with a lower dialysis vintage. Hemodialysis is the most commonly chosen treatment modality, with the highest proportion of patients selecting non-tunneled catheters. However, among patients receiving dialysis, the proportion of autogenous arteriovenous fistula (AVF) is the highest. With the increase in the duration of diabetes, the prevalence of multiple complications also increases.ConclusionEarly intervention and management strategies are crucial for diabetic nephropathy patients in Guizhou, considering the rapid disease progression to ESRD and high complication rates. The study underscores the need for targeted healthcare policies to address the unique challenges of this population, with future research required to deepen the understanding of disease mechanisms and improve patient outcomes.

Learning multi-scale feature representations is essential for medical image segmentation. Most existing frameworks are based on U-shape architecture in which the high-resolution representation is recovered progressively by connecting different levels of the decoder with the low-resolution representation from the encoder. However, intrinsic defects in complementary feature fusion inhibit the U-shape from aggregating efficient global and discriminative features along object boundaries. While Transformer can help model the global features, their computation complexity limits the application in real-time medical scenarios. To address these issues, we propose a Cross-scale Fusion Network (CFNet), combining a cross-scale attention module and pyramidal module to fuse multi-stage/global context information. Specifically, we first utilize large kernel convolution to design the basic building block capable of extracting global and local information. Then, we propose a Bidirectional Atrous Spatial Pyramid Pooling (BiASPP), which employs atrous convolution in the bidirectional paths to capture various shapes and sizes of brain tumors. Furthermore, we introduce a cross-stage attention mechanism to reduce redundant information when merging features from two stages with different semantics. Extensive evaluation was performed on five medical image segmentation datasets: a 3D volumetric dataset, namely Brats benchmarks. CFNet-L achieves 85.74% and 90.98% dice score for Enhanced Tumor and Whole Tumor on Brats2018, respectively. Furthermore, our largest model CFNet-L outperformed other methods on 2D medical image. It achieved 71.95%, 82.79%, and 80.79% SE for STARE, DRIVE, and CHASEDB1, respectively. The code will be available at https://github.com/aminabenabid/CFNet

Background The tcdA gene codes for an important toxin produced by Clostridioides difficile (C. difficile), but there is currently no simple and cost-effective method of detecting it. This article establishes and validates a rapid and visual loop-mediated isothermal amplification (LAMP) assay for the detection of the tcdA gene. Methods Three sets of primers were designed and optimized to amplify the tcdA gene in C. difficile using a LAMP assay. To evaluate the specificity of the LAMP assay, C. difficile VPI10463 was used as a positive control, while 26 pathogenic bacterial strains lacking the tcdA gene and distilled water were utilized as negative controls. For sensitivity analysis, the LAMP assay was compared to PCR using ten-fold serial dilutions of DNA from C. difficile VPI10463, ranging from 207 ng/µl to 0.000207 pg/µl. The tcdA gene of C.difficile was detected in 164 stool specimens using both LAMP and polymerase chain reaction (PCR). Positive and negative results were distinguished using real-time monitoring of turbidity and chromogenic reaction. Results At a temperature of 66 °C, the target DNA was successfully amplified with a set of primers designated, and visualized within 60 min. Under the same conditions, the target DNA was not amplified with the tcdA12 primers for 26 pathogenic bacterial strains that do not carry the tcdA gene. The detection limit of LAMP was 20.700 pg/µl, which was 10 times more sensitive than that of conventional PCR. The detection rate of tcdA in 164 stool specimens using the LAMP method was 17% (28/164), significantly higher than the 10% (16/164) detection rate of the PCR method (X2 = 47, p < 0.01). Conclusion LAMP method is an effective technique for the rapid and visual detection of the tcdA gene of C. difficile, and shows potential advantages over PCR in terms of speed, simplicity, and sensitivity. The tcdA-LAMP assay is particularly suitable for medical diagnostic environments with limited resources and is a promising diagnostic strategy for the screening and detection of C. difficile infection in populations at high risk.

In this paper, the original RSEI model (including greenness index, humidity index, heat index and dryness index) and their contribution rate (%) are used to evaluate the change of ecological environment. To study how natural and anthropogenic changes in ecological environment affect ecosystem function and how these factors interact, CASA model was used to estimate the correlation between the net primary productivity of vegetation (NPP), population density and land use. This could reveal the influence factors of ecological environment change in the Wanjiang River Basin from 2000 to 2022. The results show that the combing RSEI and CASA models can effectively show the spatial-temporal variation and spatial distribution of NPP of vegetation in Wanjiang Basin. During this period, RSEI of the basin showed an overall upward trend, and the RSEI increased by about 0.1/10 a. The vegetation productivity in most areas was gradually improved, the ecological environment was restored, and the ecological environment quality was gradually improved. The average annual NPP simulated by CASA was 266.81 g C·m-2·a-1. The variation trend of NPP in vegetation showed a slight decrease, but the overall NPP level was basically unchanged. There is a significant correlation between NPP and population density, a negative correlation between NPP and population density areas such as city centers, and a positive correlation between NPP and population density in areas with frequent agricultural activities. From 2010 to 2020, there is a significant positive correlation between population density and land use.

BackgroundPatients who were infected by the Human Immunodeficiency Virus (HIV) could have weakened immunity that is complicated by opportunistic infections, especially for Mycobacterium tuberculosis (MTB). Notably, the HIV-MTB co-infection will accelerate the course of disease progress and greatly increase the mortality of patients. Since the traditional diagnostic methods are time-consuming and have low sensitivity, we aim to investigate the performance of mNGS (metagenomic Next-Generation Sequencing) and mNPS (metagenomic NanoPore Sequencing) for the rapid diagnosis of tuberculosis in HIV-infected patients.MethodsThe 122 HIV-infected patients were enrolled for the retrospective analysis. All of the patients underwent traditional microbiological tests, mNGS, and (or) mNPS tests. The clinical comprehensive diagnosis was used as the reference standard to compare the diagnostic performance of culture, mNGS, and mNPS on tuberculosis. We also investigate the diagnostic value of mNGS and mNPS on mixed-infection. Furthermore, the treatment adjustment directed by mNGS and mNPS was analyzed.ResultsCompared with the composite reference standard, the culture showed 42.6% clinical sensitivity and 100% specificity, and the OMT(other microbiological testing) had 38.9% sensitivity and 100% specificity. The mNGS had 58.6% clinical sensitivity and 96.8% specificity, and the mNPS had 68.0% clinical sensitivity and 100% specificity. The proportion of mixed-infection cases (88.9%) in the TB group was higher than those in the non-TB group (54.8%) and the mNGS and mNPS are more competitive on mixed-infection diagnosis compared with the traditional methods. Furthermore, there are 63 patients (69.2%) and 36 patients (63.2%) achieved effective treatment after receiving the detection of mNPS and mNGS, respectively.ConclusionOur study indicated that mNPS and mNGS have high sensitivity and specificity for TB diagnosis compared with the traditional methods, and mNPS seems to have better diagnostic performance than mNGS. Moreover, mNGS and mNPS showed apparent advantages in detecting mixed infection. The mNPS and mNGS-directed medication adjustment have effective treatment outcomes for HIV-infected patients who have lower immunity.

BackgroundThe systemic immune-inflammation index (SII) is a novel inflammatory marker used to assess the immune-inflammatory status of the human body. The systemic immune inflammation has an interplay and mutual relationship with neurological disorders. Serum neurofilament light chain (sNfL) is widely regarded as a potential biomarker for various neurological diseases. The study aimed to examine the association between SII and sNfL.MethodsThis cross-sectional investigation was conducted in a population with complete data on SII and sNfL from the 2013–2014 National Health and Nutrition Examination Survey (NHANES). The SII was calculated by dividing the product of platelet count and neutrophil count by the lymphocyte count. Multivariate linear regression models and smooth curves were used to explore the linear connection between SII and sNfL. Sensitivity analyses, interaction tests, and diabetes subgroup smoothing curve fitting were also performed.ResultsA total of 2,025 participants were included in our present research. SII showed a significant positive association with the natural logarithm-transformed sNfL (ln-sNfL) in crude model [0.17 (0.07, 0.28)], partially adjusted model [0.13 (0.03, 0.22)], and fully adjusted model [0.12 (0.02, 0.22)]. In all participants, the positive association between SII and ln-sNfL served as a linear relationship, as indicated by a smooth curve. Interaction tests showed that age, gender, BMI, hypertension, and diabetes did not have a significant impact on this positive association (p for interaction >0.05). The subgroup analysis of diabetes was conducted using smooth curve fitting. It was found that compared to the group without diabetes and the group in a pre-diabetic state, the effect was more pronounced in the group with diabetes.ConclusionOur findings suggest that there is a positive association between SII and sNfL. Furthermore, in comparison to individuals without diabetes and those in a pre-diabetic state, the positive association between SII and sNfL was more pronounced in individuals with diabetes. Further large-scale prospective studies are needed to confirm the association between SII and sNfL.

We collected respiratory specimens from 128 pediatric patients diagnosed with pneumonia in Beijing in late 2023. Mycoplasma pneumoniae was detected in 77.3% (99/128) patients, with 36.4% (4/11), 82.9% (34/41), 80.3% (61/76) in children aged less than 3 years, 3–6 years, over 7 years, respectively. Mycoplasma pneumoniae (M. pneumoniae) was characterized using P1 gene typing, MLVA typing and sequencing of domain V of the 23S rRNA gene. P1 gene type 1 (P1-1; 76.1%, 54/71) and MLVA type 4-5-7-2 (73.7%, 73/99) were predominant. MLVA identified a new genotype: 3–4–6-2. Macrolide resistance-associated mutations were detected in 100% of samples, with A2063G accounting for 99% and A2064G for 1%. The positive rate of M. pneumoniae was higher compared to previous reports, especially in children less than 3 years, suggesting a M. pneumoniae epidemic showing a younger age trend occurred in late 2023 in Beijing, China. Higher proportions of macrolide-resistant M. pneumoniae, P1-1 and 4-5-7-2 genotype M. pneumoniae indicated increased macrolide resistance rate and genotyping shift phenomenon, which might be attributable to this epidemic. Additionally, complete clinical information from 73 M. pneumoniae pneumonia inpatients were analyzed. The incidence of severe M. pneumoniae pneumonia was 56.2% (41/73). Mycoplasma pneumoniae pneumonia patients exhibited longer duration of fever, with a median value of 10.0 days (IQR, 8.0–13.0), and higher incidence of complications (74.0%, 54/73). However, in this cohort, we found that the severity of M. pneumoniae pneumonia, co-infection, or complications were not associated with M. pneumoniae P1 gene or MLVA types. Clinicians should be aware that patients infected with macrolide-resistant M. pneumoniae exhibited more severe clinical presentations.

The elevated levels of antibiotic resistance genes (ARGs) in livestock manure represent a significant threat to both the environment and human health. Composting has been recognized as an effective strategy to mitigate the abundance of ARGs in manure. However, notable rebounds in ARGs abundance have been observed during this process. This study explored the changes in ARGs abundance and the underlying influencing factors during the composting of carnivore (chicken and pig) and herbivore (sheep and cow) manures, along with mushroom residues. The findings revealed that the total relative abundance of ARGs increased by 6.96 and 10.94 folds in chicken and pig manure composts, respectively, whereas it decreased by a remarkable 91.72% and 98.37% in sheep and cow manure composts. Nitrogen content emerged as the primary physicochemical factors governing the abundance of ARGs in chicken and pig manure composts. Conversely, carbon content played a pivotal role in determining ARGs abundance in chicken and pig manure composts. Furthermore, the presence of dominant hosts, such as Corynebacterium, Bacillus, and Clostridium, along with emerging bacteria like Thermobifida, Saccharomonospora, and Actinomadura, contributed significantly to the enrichment of total ARGs, including tetG, tetO, tetX, and sul2, in chicken and pig manure composts. The coexistence of these genes with mobile genetic elements and a plethora of host bacteria, coupled with their high abundance, renders them particularly high-risk ARGs. On the other hand, the observed decrease in the abundance of total ARGs in sheep and cow manure composts can be attributed to the decline in the population of host bacteria, specifically Atopostipes, Psychrobacter, and Corynebacterium. Collectively, these results provide crucial insights into the management of ARGs risks and offer essential theoretical support for enhancing the safe utilization of organic fertilizer in agriculture.

Abstract Myocardial infarction (MI) is the leading cause of premature death. The death of cardiomyocytes (CMs) and the dysfunction of the remaining viable CMs are the main pathological factors contributing to heart failure (HF) following MI. This study aims to determine the transcriptional profile of CMs and investigate the heterogeneity among CMs under hypoxic conditions. Single-cell atlases of the heart in both the sham and MI groups were developed using single-cell data (GSE214611) downloaded from Gene Expression Omnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/ ). The heterogeneity among CMs was explored through various analyses including enrichment, pseudo time, and intercellular communication analysis. The marker gene of C5 was identified using differential expression analysis (DEA). Real-time polymerase chain reaction (RT-PCR), bulk RNA-sequencing dataset analysis, western blotting, immunohistochemical and immunofluorescence staining, Mito-Tracker staining, TUNEL staining, and flow cytometry analysis were conducted to validate the impact of the marker gene on mitochondrial function and cell apoptosis of CMs under hypoxic conditions. We identified a cell subcluster named C5 that exhibited a close association with mitochondrial malfunction and cellular apoptosis characteristics, and identified Slc25a4 as a significant biomarker of C5. Furthermore, our findings indicated that the expression of Slc25a4 was increased in failing hearts, and the downregulation of Slc25a4 improved mitochondrial function and reduced cell apoptosis. Our study significantly identified a distinct subcluster of CMs that exhibited strong associations with ventricular remodeling following MI. Slc25a4 served as the hub gene for C5, highlighting its significant potential as a novel therapeutic target for MI.

Abstract Background The main cause of anesthesia-related deaths is the failure to manage difficult airways. Difficult laryngoscopic exposure is a major cause of unsuccessful management of difficult airways. Inadequate preoperative airway assessment hinders the clinical management of difficult airways cases, emphasizing the critical need for accurate identification of difficult airways. Currently, no definitive and reliable indicators are available to predict a difficult airway. Our study aims to predict laryngoscope exposure risk factors by combining ultrasonically measured upper airway anatomic parameters with physical examination indicators. Methods Patients aged 18 to 75 years, classified as American Standards Association (ASA) I-III, and scheduled for elective general anesthesia with endotracheal intubation were included. All patients received the upper airway and ultrasonographic measurements. After anesthesia induction, laryngoscope exposure was analyzed using the Cormack-Lehane grading system, with Grades III and IV as indicative of difficult laryngoscopy. Univariate and multivariate logistic regression analyses were performed to identify reliable indicators for predicting difficult laryngoscopy. Receiver Operating Characteristic (ROC) curve analysis was utilized to assess the predictive performance of each indicator. Results A total of 1120 patients finished the study, with 710 cases found in Grade I laryngoscopic exposure group, 360 cases in Grade II group, and 50 cases in Grade III group. There was no case observed in Grade IV group, thereby resulting in an incidence of difficult laryngoscopy of 4.46%. Univariate logistic regression analysis revealed that several parameters including age, Body Mass Index (BMI), neck circumference, neck mobility, snoring intensity, as well as ultrasound measurements of the pre-epiglottic space and thyromental distance were identified as significant risk factors for difficult laryngoscopy (P

Abstract Background The diagnosis of adolescent Depressive Disorder (DD) lacks specific biomarkers, posing significant challenges. This study investigates the potential of Niacin Skin Flush Response (NSFR) as a biomarker for identifying and assessing the severity of adolescent Depressive Disorder, as well as distinguishing it from Behavioral and Emotional Disorders typically emerging in childhood and adolescence(BED). Methods In a case-control study involving 196 adolescents, including 128 Depressive Disorder, 32 Behavioral and Emotional Disorders, and 36 healthy controls (HCs), NSFR was assessed. Depressive symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9) and anxious symptoms with the Generalized Anxiety Disorder 7-item scale (GAD-7). Pearson correlation analysis determined the relationships between NSFR and the severity of depression in DD patients. Receiver Operating Characteristic (ROC) was used to identify DD from BED integrating NSFR data with clinical symptom measures. Results The adolescent Depressive Disorder group exhibited a higher rate of severe blunted NSFR (21.4%) compared to BED (12.5%) and HC ( 8.3%). Adolescent Depressive Disorder with psychotic symptoms showed a significant increase in blunted NSFR (p = 0.016). NSFR had negative correlations with depressive (r = -0.240, p = 0.006) and anxious (r = -0.2, p = 0.023) symptoms in adolescent Depressive Disorder. Integrating NSFR with three clinical scales improved the differentiation between adolescent Depressive Disorder and BED (AUC increased from 0.694 to 0.712). Conclusion The NSFR demonstrates potential as an objective biomarker for adolescent Depressive Disorder, aiding in screening, assessing severity, and enhancing insights into its pathophysiology and diagnostic precision.

AbstractStrobilanthes dalzielii of Acanthaceae is an herb species with potentially extensive applications for its pharmaceutical and ornamental values. Due to taxonomic complications and limited genetic information, the structural characteristics, and phylogenetic relationships of the S. dalzielii chloroplast genome were assembled and characterized here for the first time. The complete chloroplast genome of S. dalzielii was 144,580 bp in length. The genome is quadripartite in structure and consists of a large single-copy region (92,137 bp) and a small single-copy region (17,669 bp), which are separated by a pair of inverted repeats (each 17,387 bp). A total of 125 genes were annotated, including 80 protein-coding, 37 transfer RNA, and eight ribosomal RNA genes. The overall GC content was 36.4%. Phylogenetic analysis based on the complete chloroplast genome sequence of 21 taxa within the tribe Ruellieae of Acanthaceae using the maximum likelihood and Bayesian inference methods revealed that Strobilanthes diverged after Ruellia; S. dalzielii is closely related to S. tonkinensis. The genomic data obtained from this study will serve as valuable information to the species delimitation and genetic classification of Strobilanthes.

Abstract Brainbow is a genetic cell-labeling technique that allows random colorization of multiple cells and real-time visualization of cell fate within a tissue, providing valuable insights into understanding complex biological processes. However, fluorescent proteins (FPs) in Brainbow have distinct excitation spectra with peak difference greater than 35 nm, which requires sequential imaging under multiple excitations and thus leads to long acquisition times. In addition, they are not easily used together with other fluorophores due to severe spectral bleed-through. Here, we report the development of a single-wavelength excitable Brainbow, UFObow, incorporating three newly developed blue-excitable FPs. We have demonstrated that UFObow enables not only tracking the growth dynamics of tumor cells in vivo but also mapping spatial distribution of immune cells within a sub-cubic centimeter tissue, revealing cell heterogeneity. This provides a powerful means to explore complex biology in a simultaneous imaging manner at a single-cell resolution in organs or in vivo.

Abstract The mortality rates for patients undergoing hemodialysis (HD) remain unacceptably high compared to the general population, and more specific information about the causes of death is not known. The study aimed to develop and validate a risk prediction model that uses common clinical factors to predict the probability of cardiovascular events in maintenance hemodialysis (MHD) patients. The study involved 3488 adult patients who received regular scheduled hemodialysis treatment at 20 hemodialysis centers in southwest China between June 2015 and August 2020, with follow-up until August 2021. The optimal parameter set was identified by multivariable Cox regression analyses and Cross-LASSO regression analyses and was used to establish a nomogram for predicting the risk of cardiovascular events in maintenance hemodialysis patients at 3 and 5 years. The performance of the model was evaluated using the consistency index (Harrell’s C-index), the area under the receiver operating characteristic (ROC) curve, and calibration plots. The model was validated by tenfold cross-validation and bootstrapping with 1000 resamples. In the derivation cohort, the model yields an AUC of 0.764 [95% confidence interval (CI), 0.737–0.790] and 0.793 [CI, 0.757–0.829] for predicting the risk of cardiovascular events of MHD patients at 3 and 5 years. In the internal validation cohort AUC of 0.803 [95% CI, 0.756–0.849], AUC of 0.766 [95% CI, 0.686–0.846], and the external validation cohort AUC of 0.826 [95% CI, 0.765–0.888], AUC of 0.817 [95% CI, 0.745–0.889] at 3 and 5 years. The model’s calibration curve is close to the ideal diagonal. By tenfold cross-validation analyses, the 3- and 5-year risk of cardiovascular events (AUC 0.732 and 0.771, respectively). By the bootstrap resampling method, the derivation cohort and validation cohort (Harrell’s C-index 0.695 and 0.667, respectively) showed good uniformity with the model. The constructed model accurately predicted cardiovascular events of MHD patients in the 3rd and 5th years after dialysis. And the further research is needed to determine whether use of the risk prediction tool improves clinical outcomes.

Abstract Background Narrative Medicine (NM), a contemporary medical concept proposed in the 21st century, emphasizes the use of narrative as a literary form in medicine. This study aims to explore the understanding about NM and willingness to learn NM among medical students in our hospital. Methods A questionnaire survey was conducted among 130 students at Xiangya Medical College of Central South University. Results The findings revealed that a small percentage of students (3.1%) were familiar with narrative medicine and its training methods. Knowledge about the treatment skills (77.7%) and core content (55.4%) of narrative medicine was limited among the students. Despite this, a majority (63.1%) expressed a lack of interest in further understanding and learning about narrative medicine. Surprisingly, the survey indicated that students possessed a high level of narrative literacy, even without formal training in narrative medicine. Additionally, over half of the surveyed students (61.5%) believed that narrative medicine could benefit their clinical practice. Conclusions This study serves as a preliminary basis for the future development of narrative medicine education in China. It highlights the need to prioritize medical humanities education and provide medical students with more opportunities to access information on narrative medicine. By doing so, we can strive to enhance the visibility and promote the integration of narrative medicine into medical humanities education in China.

Abstract Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.

Abstract Osteoarthritis (OA) is the most prevalent degenerative musculoskeletal disease, severely impacting the function of patients and potentially leading to disability, especially among the elderly population. Natural products (NPs), obtained from components or metabolites of plants, animals, microorganisms etc., have gained significant attention as important conservative treatments for various diseases. Recently, NPs have been well studied in preclinical and clinical researches, showing promising potential in the treatment of OA. In this review, we summed up the main signaling pathways affected by NPs in OA treatment, including NF-κB, MAPKs, PI3K/AKT, SIRT1, and other pathways, which are related to inflammation, anabolism and catabolism, and cell death. In addition, we described the therapeutic effects of NPs in different OA animal models and the current clinical studies in OA patients. At last, we discussed the potential research directions including in-depth analysis of the mechanisms and new application strategies of NPs for the OA treatment, so as to promote the basic research and clinical transformation in the future. We hope that this review may allow us to get a better understanding about the potential bioeffects and mechanisms of NPs in OA therapy, and ultimately improve the effectiveness of NPs-based clinical conservative treatment for OA patients.

Abstract Background The long-term sequelae of Coronavirus disease 2019 (COVID-19) in children are unclear. We investigated COVID-19 symptoms in school-aged children to determine their impact on patients and their families. Methods This cross-sectional study, conducted on February 25–28, 2023, selected a representative kindergarten and 9-year school from Shenzhen, China. There were randomly two classes each for the 12 grades from kindergarten to junior high school. The school-aged children were aged 3–16 years. Literate parents completed an online questionnaire related to their children’s COVID-19 symptoms since December 1, 2022. Descriptive statistics were computed as necessary. Univariate and multivariable linear regression analyses were performed, and variables with a p-value

Klebsiella pneumoniae is a common, conditionally pathogenic bacterium that often has a multidrug-resistant phenotype, leading to failure of antibiotic therapies. It can therefore induce serious diseases, including community-acquired pneumonia and bloodstream infections. As an emerging alternative to antibiotics, phages are considered key to solving the problem of drug-resistant bacterial infections. Here, we report a novel phage, pK3–24, that mainly targets ST447 K. pneumoniae. Phage pK3–24 is a T7-like short-tailed phage with a fast adsorption capacity that forms translucent plaques with halos on bacterial lawns. The optimal multiplicity of infection (MOI) is 0.01, and the average burst size is 50 PFU/mL. Phage pK3–24 shows environmental stability, surviving at below 50 °C and at pH values of 6–10. It has a double-stranded DNA genome of 40,327 bp and carries no antibiotic-resistance, virulence, or lysogeny genes. Phylogenetic analysis assigned phage pK3–24 to the genus Przondovirus as a new species. Phage pK3–24 inhibited the production of biofilm. Moreover, treatment with pK3–24 at doses with an MOI > 1 effectively reduced the mortality of Galleria mellonella larvae infected with ST447 K. pneumoniae.

Background Patients receiving maintenance hemodialysis (MHD) frequently encounter a drop in blood pressure during dialysis, known as intradialytic hypotension (IDH). The AIP is associated with diseases such as diabetes and cardiovascular events. It remains unclear whether the AIP is associated with IDH. The present study aimed to explore the association between AIP and IDH in MHD patients.Methods In this multi-center cross-sectional study, we included 1946 adult hemodialysis patients from twenty dialysis centers. Patients were divided into four groups based on the AIP quartiles. Linear regression and multiple logistic regression models were used to analyze the relationship between AIP and IDH. Subgroup analyses were further conducted to assess the robustness of the association between the AIP and IDH.Results After adjusting for potential confounding variables, each 1-unit increase in AIP was associated with a 21% increase in the odds of IDH. The odds ratios (ORs) of IDH increased gradually with higher quartiles of AIP compared with the Q1 reference group (Q2: OR, 1.41, 95% CI: 0.91-2.18; Q3: OR, 1.63, 95% CI: 1.07-2.49; Q4: OR, 1.57, 95% CI: 1.01-2.42). No interaction was observed in the subgroup analysis stratified by age, sex, history of diabetes, heart failure, and myocardial infarction.Conclusion Elevated AIP levels are associated with a heightened risk of IDH in MHD patients.

ABSTRACTSwash flow poses a significant hazard to pedestrians standing on the slope of the seawall. Unlike the forces of overtopping flow or open channel flow on the human body, which have been studied before, swash flow has two distinct cycles within one wave period: onshore flow and offshore flow. Both cycles can risk human safety by exerting hydrodynamic forces on the body. This paper presents a numerical study to examine the hydrodynamic forces exerted on the human body when subjected to swash flow on a smooth and impermeable slope. A Reynolds-averaged Navier-Stokes (RANS) model is set up in OpenFOAM, where the numerical results are compared with experimental data obtained from wave tank tests. Reasonable agreement has been achieved, which validates the numerical model. We examine the kinematics of swash flow generated by plunging and surging breakers. In the case of a plunging breaker, we observe that the instantaneous runup height exhibited asymmetry, whereas it is nearly symmetric for a surging breaker. The velocity profile is then used to compute the momentum flux of the swash flow, which is shown to be associated with the inline forces exerted on the human body. We have defined an instability index to assess the risk of pedestrian mobilisation by swash flow, demonstrating its dependence on the Iribarren number and the body's position. The analysis reveals that the associated risk is substantially reduced as the Iribarren number increases and when the body moves towards the shoreline.

The introduction of anti-tumor necrosis factor α (TNFα) biologics significantly innovated inflammatory bowel disease (IBD) treatment and increased medical costs. The recent expiration of patents of some anti-TNFα biologics (such as infliximab and adalimumab) facilitated the development of biosimilars. Comparable pharmacokinetic, efficacy, safety, and immunogenicity profiles between anti-TNFα originators and biosimilars were demonstrated in different studies. Anti-TNFα biosimilars hold promise for reducing the high cost of biologics and increasing patient access to biologics. In this review, we outline the current data on the use of anti-TNFα originators and biosimilars in patients with IBD, with a focus on the efficacy, safety, and immunogenicity profiles of infliximab and adalimumab biosimilars. The potential benefits, challenges, and future directions of anti-TNFα biosimilars are also discussed in the review.

BackgroundThe lower limb motor dysfunction caused by stroke is one of the main sequelae affecting patients’ ability to live normally in the later period. Acupuncture treatment of limb movement dysfunction after stroke has been recommended by authoritative guidelines for reducing limb spasticity, enhancing limb strength and so on. However, the efficacy of different acupuncture methods in treating lower limb motor dysfunction after stroke remains controversial.ObjectiveIn this paper, network meta-analysis (NMA) was used to prioritize various acupuncture intervention combinations commonly used in clinical practice, try to screen the acupuncture intervention scheme with the highest clinical efficacy and safety, and explore its rationality in guiding clinical practice.MethodsWe searched a total of 4,312 studies from 8 databases and 2 clinical trial registries, and selected 43 articles for systematic review. We used pairwise meta-analysis and network meta-analysis to evaluate the efficacy and ranking of various acupuncture interventions. At the same time, the risk of bias, publication bias, and sensitivity of included randomized controlled trials were analyzed. The main outcome indicator was Fugl-Meyer assessment of lower extremity (FMA-LE), and the secondary outcome indicators were Modified Barthel Index (MBI), Berg balance scale (BBS) and Modified Ashworth scale (MAS).ResultsA total of 4,134 patients in 43 studies were included. The intervention included 9 acupuncture-related treatments, of which 20.9% were classified as high-risk. Among the four outcome indicators in pairwise meta-analysis, the effect of body acupuncture combined with conventional rehabilitation has the highest comprehensive credibility in terms of efficacy and safety comparing with conventional rehabilitation [SMD = 1.14, 95%CI (0.81, 1.46)], [SMD = 1.35, 95%CI (0.97, 1.72)], [SMD = 1.22, 95%CI (0.39, 2.05)], [SMD = 1.21, 95%CI (0.74, 1.44)]. In addition, multiple intervention methods, for example, warm acupuncture plus rehabilitation treatment for MBI and electroacupuncture plus body acupuncture plus rehabilitation treatment for BBS, may increase certain additional effects on different outcome indicators.ConclusionThis study proves that body acupuncture combined with rehabilitation treatment is the most widely used intervention method with the highest evidence quality in the treatment of lower limb motor dysfunction after stroke. However, for some other acupuncture methods, large samples and high-quality clinical randomized controlled trials are still needed to be fully verified.

Summary: Alzheimer’s disease (AD) is a complex pathophysiological disease. Allowing for heterogeneity, not only in disease manifestations but also in different progression patterns, is critical for developing effective disease models that can be used in clinical and research settings. We introduce a machine learning model for identifying underlying patterns in Alzheimer’s disease (AD) trajectory using longitudinal multi-modal data from the ADNI cohort and the AIBL cohort. Ten biologically and clinically meaningful disease-related states were identified from data, which constitute three non-overlapping stages (i.e., neocortical atrophy [NCA], medial temporal atrophy [MTA], and whole brain atrophy [WBA]) and two distinct disease progression patterns (i.e., NCA → WBA and MTA → WBA). The index of disease-related states provided a remarkable performance in predicting the time to conversion to AD dementia (C-Index: 0.923 ± 0.007). Our model shows potential for promoting the understanding of heterogeneous disease progression and early predicting the conversion time to AD dementia.

Background: Compliance to sublingual immunotherapy (SLIT) is generally low, resulting in reduced short- and long-term clinical efficacy. Compliance is a critical factor determining the success of allergic rhinitis (AR) treatment. Objective: To analyze the compliance of patients with house dust mite (HDM)-induced AR to SLIT and the impact of coronavirus disease 2019 (COVID-19) on compliance. Methods: The clinical data of 3117 patients with HDM-induced AR who started SLIT between July 2018 and April 2022 were retrospectively reviewed. We assessed the reasons for non-compliance and the changes in non-compliance during the COVID-19 pandemic compared to the pre-pandemic period. Results: Of 3117 patients, 507 (16.27%) patients (ages, 5–67 years) were identified as non-compliant. The most common reason for non-compliance was poor efficacy (27.22%). The non-compliance rate was highest during 24–36 months of SLIT (28.13%, 153/544), followed by 12–24 months (7.02%, 91/1296). Non-compliance was significantly higher in adolescents/adults than in children (P = 0.000). Although the generalized linear model analysis indicated that compliance was affected by the COVID-19 pandemic during 3–6 months of SLIT, the overall compliance to SLIT was not significantly affected by the pandemic, according to the Kaplan-Meier survival analysis. Conclusions: The non-compliance rate of SLIT in this study was low, and poor efficacy was the most common reason for non-compliance. The compliance of adolescents/adults was lower than that of children. The COVID-19 pandemic did not significantly impact compliance to SLIT, which is an appropriate strategy for the home treatment of AR patients during major public health events.

Candidatus Accumulibacter, a prominent polyphosphate-accumulating organism (PAO) in wastewater treatment, plays a crucial role in enhanced biological phosphorus removal (EBPR). The genetic underpinnings of its polyphosphate accumulation capabilities, however, remain largely unknown. Here, we conducted a comprehensive genomic analysis of Ca. Accumulibacter-PAOs and their relatives within the Rhodocyclaceae family, identifying 124 core genes acquired via horizontal gene transfer (HGT) at its least common ancestor. Metatranscriptomic analysis of an enrichment culture of Ca. Accumulibacter revealed active transcription of 44 of these genes during an EBPR cycle, notably including the polyphosphate kinase 2 (PPK2) gene instead of the commonly recognized polyphosphate kinase 1 (PPK1) gene. Intriguingly, the phosphate regulon (Pho) genes showed minimal transcriptions, pointing to a distinctive fact of Pho dysregulation, where PhoU, the phosphate signaling complex protein, was not regulating the high-affinity phosphate transport (Pst) system, resulting in continuous phosphate uptake. To prevent phosphate toxicity, Ca. Accumulibacter utilized the laterally acquired PPK2 to condense phosphate into polyphosphate, resulting in the polyphosphate-accumulating feature. This study provides novel insights into the evolutionary emergence of the polyphosphate-accumulating trait in Ca. Accumulibacter, offering potential advancements in understanding the PAO phenotype in the EBPR process.

BackgroundSystemic lupus erythematosus (SLE) is frequently accompanied by various complications, with cardiovascular diseases being particularly concerning due to their high mortality rate. Although there is clinical evidence suggesting a potential correlation between SLE and heart failure (HF), the underlying shared mechanism is not fully understood. Therefore, it is imperative to explore the potential mechanisms and shared therapeutic targets between SLE and HF.MethodsThe SLE and HF datasets were downloaded from the NCBI Gene Expression Omnibus database. Differentially expressed genes (DEGs) in both SLE and HF were performed using “limma” R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genes (KEGG) analyses were conducted to analyze the enriched functions and pathways of DEGs in both SLE and HF datasets. Protein–Protein Interaction network (PPI) and the molecular complex detection (MCODE) plugins in the Cytoscape software were performed to identify the shared hub genes between SLE and HF datasets. R package “limma” was utilized to validate the expression of hub genes based on SLE (GSE122459) and HF (GSE196656) datasets. CIBERSORT algorithm was utilized to analyze the immune cell infiltration of SLE and HF samples based on SLE (GSE112087) and HF (GSE116250) datasets. A weighted gene co-expression network analysis (WGCNA) network was established to further validate the hub genes based on HF dataset (GSE116250). Molecular biology techniques were conducted to validate the hub genes.Results999 shared DGEs were identified between SLE and HF datasets, which were mainly enriched in pathways related to Th17 cell differentiation. 5 shared hub genes among the common DGEs between SLE and HF datasets were screened and validated, including HSP90AB1, NEDD8, RPLP0, UBB, and UBC. Additionally, 5 hub genes were identified in the central part of the MEbrown module, showing the strongest correlation with dilated cardiomyopathy. HSP90AB1 and UBC were upregulated in failing hearts compared to non-failing hearts, while UBB, NEDD8, and RPLP0 did not show significant changes.ConclusionHSP90AB1 and UBC are closely related to the co-pathogenesis of SLE and HF mediated by immune cell infiltration. They serve as promising molecular markers and potential therapeutic targets for the treatment of SLE combined with HF.