Search

Introduction: Humoral immunity plays a key role in the pathogenesis of autoimmune diseases, and B-lymphocyte activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are essential for the maintenance of B-lymphocyte reservoirs and humoral immunity. In March 2021, telitacicept, the world's first dual target three-channel biologic, was approved in China for the treatment of SLE and is currently in clinical trials exploring multiple indications for other autoimmune diseases., Areas Covered: This article summarizes the mechanism of action, pharmacokinetics, and clinical efficacy of telitacicept for the treatment of multiple autoimmune diseases., Expert Opinion: So far, the efficacy and safety of telitacicept in autoimmune diseases have been fully demonstrated in clinical practice. There are still many unresolved issues regarding the timing of initiation and discontinuation, still needs to be evaluated in future studies., Competing Interests: The authors declare no conflicts of interest., (© 2024 Liu et al.)

Objective: Pulmonary hypertension (PH) is a severe complication of systemic lupus erythematosus (SLE). This study investigated the clinical features of patients with SLE-PH in China based on disease manifestations and organ involvement to define precise treatment of SLE and early prevention of complications., Methods: In total, 205 SLE-PH patients were included in this study. A cluster analysis was applied according to six clinical and serological variables to define different subgroups of patients. The survival rates of SLE-PH patients and risk factors that influenced prognosis were also compared and a clinical prediction model was developed for the diagnosis of associated lupus nephritis (LN)., Results: Patients were clustered in five groups. Patients in cluster 1 had severe renal damage (all patients had LN and had the highest creatinine and urea nitrogen and the lowest eGFR levels). Patients in cluster 2 had mild renal damage (more than half of the patients had associated LN and 87.5% had increased urinary protein levels but presented a lower degree of renal damage than those in the first group. Patients in cluster 3 had low-grade proteinuria (all patients had 24h urinary protein < 0.5g). Patients in cluster 4 had hematuria or urinary tubular damage (26% of patients had associated LN, but none of the patients had proteinuria. In cluster 5, patients barely had any major organ involvement. The clinical prediction model for a diagnosis of SLE-PH-LN was anti-dsDNA antibodies > 364.64 IU/mL and neutrophil-to-leukocyte ratio (NLR) > 5.55., Conclusion: Our findings provide evidence indicating that SLE-PH presents varying clinical phenotypes and the treatment varies accordingly, suggesting the need for individualized treatment. Key Points • Clustered grouping of patients with SLE-PH is associated with renal injury. • This may be because PH and LN share a common pathogenesis. • The clinical prediction model for a diagnosis of SLE-PH-LN was anti-dsDNA antibodies >364.64 IU/mL and NLR >5.55., Competing Interests: Declarations. Ethics approval: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Shandong Provincial Hospital, Shandong First Medical University (NSFC: no. 2022–413). All participants signed the informed consent form. Informed consent: Informed consent was obtained from all individual participants included in the study. Disclosures: None., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: With the extensive utilization of immune checkpoint inhibitors (ICIs) across various cancers, ICIs-related thyroid dysfunction (ICI-TD) has become a growing concern in clinical practice. This study aimed to devise an individualized management strategy for ICI-TD to enhance the early identification and proactive management in cancer patients., Methods: We designed and conducted a three-phase study. Initially, we analyzed the influencing factors through a systematic review and meta-analysis, which adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Moreover, the study protocol was registered with PROSPERO (CRD42019131133). Subsequently, prediction models for ICI-TD were developed utilizing 11 algorithms based on the real-world cohort data from July 20, 2018 (the approval date of the first ICIs, Pembrolizumab in China), to October 31, 2022. Considering discrimination, calibration, and clinical utility, we selected the model with the best performance for web calculator development. Finally, individualized management strategies for ICI-TD were proposed by combining evidence-based analysis with practical considerations., Results: The systematic review encompassed 21 observational studies involving 4,145 patients, revealing associations between ICI-TD and factors such as female gender, age, receipt of Pembrolizumab (versus other ICIs), and baseline levels of thyroid-stimulating hormone, free thyroxine, and antithyroid antibodies. In the prediction model development phase, 621 participants were enrolled, with 36 patients developing ICI-TD. The model based on the LightGBM algorithm demonstrated superior performance, leading to the development of a web calculator. Based on these findings and existing guidelines, individualized monitoring and treatment pathways for pharmacists were devised., Conclusion: This study offers comprehensive insights into managing ICI-TD, potentially enhancing tailored cancer immunotherapy management., (© 2024. The Author(s).)

Background: Dysphagia, as a geriatric syndrome, is prevalent in the intensive care unit (ICU). Malnutrition resulting from swallowing disorders is likely to correlate with adverse ICU outcomes, including delirium, thereby escalating the costs of care and hospitalization. However, malnutrition has not received the attention it deserves in ICU clinical nursing practice. As two preventable and correctable conditions-malnutrition and delirium-the advantages of early identification and intervention are substantial. Exploring the relationship between malnutrition and delirium, starting from the high-risk group of elderly patients with swallowing difficulties in the ICU, will aid us in managing patients promptly and effectively., Aim: To investigate the relationship between malnutrition and the incidence of delirium in elderly patients with dysphagia in the ICU., Study Design: This is a retrospective study. Data for this study were obtained from the Medical Information Mart for Intensive Care-IV. All 2273 patients included were dysphagia older patients over 65 years of age admitted to the ICU, and logistic regression was used to explore the relationship between malnutrition and delirium. We also used propensity score matching (PSM) for sensitivity analysis., Results: Among the included patients with swallowing difficulties, 13% individuals (297/2273) exhibited malnutrition, with a delirium incidence rate of 55.9% (166/297). In the non-malnutrition group (1976/2273), the delirium incidence rate is 35.6% (704/1976). After adjusting for 31 covariates, multifactorial logistic regression showed that malnutrition was significantly positively associated with the incidence of delirium in elderly dysphagic patients in the ICU (adjusted odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.47-2.62). The results remained stable after analysis by PSM., Conclusion: Malnutrition was significantly positively associated with the incidence of delirium in elderly dysphagic patients in the ICU. Malnutrition should be given adequate attention in the ICU., Relevance to Clinical Practice: ICU nurses should pay particular attention to malnutrition, especially among the high-prevalence group of patients with dysphagia. Early identification and nutritional intervention for these patients may help reduce the costs of care and health care expenditures., (© 2024 British Association of Critical Care Nurses.)

Aims and Objectives: To provide a viable tool for the early clinical identification of high-risk populations in patients with sepsis., Background: Sepsis-associated delirium (SAD) has the potential to significantly impact the short- and long-term prognosis of patients. However, accurately predicting and effectively managing SAD remains a significant challenge., Methods: This study employed a retrospective analysis of adult sepsis patients admitted to the intensive care unit (ICU) for the first time. Patients were divided into two groups based on their initial Braden score upon admission to the ICU: a high-risk group (≤ 15 points) and a low-risk group (> 15 points). The relationship between Braden score and delirium was assessed using logistic regression and restricted cubic splines, while restricted mean survival time was employed to analyse the relationship between Braden scores and patients' 90- and 180-day mortality., Results: Of the 28,312 patients included in the study, those in the high-risk group exhibited a significantly elevated risk of delirium (44.8% vs. 29.7%) and higher 90-day (28.7% vs. 19.4%) and 180-day (33.2% vs. 24.1%) mortality rates (all p < 0.001). After adjusting for confounding variables, logistic regression demonstrated that the risk of delirium was 1.54 times higher in the high-risk group (95% CI = 1.45-1.64, p < 0.001). Following propensity score matching, the difference in survival was statistically significant at both time points, with the high-risk group having a reduced survival rate of 7.50 days (95% CI = -8.24, -6.75; p < 0.001) and 15.74 days (95% CI = -17.40, -14.08; p < 0.001) at 90 days and 180 days, respectively., Conclusions: The Braden score is a simple and effective tool for the early identification of patients at increased risk of adverse outcomes in sepsis., Design: Retrospective study., Relevance to Clinical Practice: The Braden score can be employed by clinical nurses for the purpose of early identification of poor prognostic risk in patients with sepsis., Reporting Method: This study was conducted according to the Strengthening Research in Observational Studies in Epidemiology (STROBE) guidelines., Patient or Public Contribution: Patients were involved in the sample of the study., (© 2024 John Wiley & Sons Ltd.)

The dynamic behavior of impacting droplet shearing by the surface edge with different wettabilities is complicated and has great significance for engineering application. The morphological evolution of droplet with various Weber numbers ( We ) and wettability impacting on the edge of square substrate is investigated by high-speed photography. Moreover, the effects of the contact angle (α) and Weber numbers ( We ) on the shear breaking process of droplets are obtained. There are three types morphological evolution of impacting droplet are observed experimentally, including unbroken, tensile breakup, and shear breakup. Contact angle and Weber number have been proved to be the significant factors affecting the type of droplet morphological evolution. Meanwhile, the critical Weber number of different types are obtained quantitatively. Moreover, as α increases, the critical Weber numbers for breakup increase. In the shear breakup process, the mass ratio between the droplets remaining on the substrate and the initial droplets is maintained at 50%. Particularly, a reliable prediction model for the spreading of droplet impacting the side wall is proposed and compared with the experimental data. Overall, this study provides new direction and guidance for exploring droplet breakup kinetics.

Background: Frailty and sepsis have a significant impact on patient prognosis. However, research into the relationship between frailty and sepsis in the general adult population remains inadequate. This paper aims to investigate the association between frailty and adverse outcomes in this population., Method: This retrospective analysis investigated sepsis patients who were initially admitted to the intensive care unit (ICU). The Modified Frailty Index (MFI) was derived by tracking patients' International Classification of Diseases (ICD) codes during their hospitalization. Patients were classified into two groups based on their MFI scores: a frail group (MFI ≥ 3) and a non-frail group (MFI = 0-2). The key outcomes were mortality rates at 90 and 180 days, with secondary outcomes including the incidence of delirium and pressure injury., Result: Of the 21,338 patients who were recruited for this study (median age about 68 years, 41.8 % female), 5,507 were classified as frail and 15,831 were classified as non-frail. Frail patients were significantly more likely to have delirium (48.9 % vs. 36.1 %, p < 0.001) and pressure injury (60.5 % vs. 51.4 %, p < 0.001). After controlling for confounding variables, the multifactorial Cox proportional hazard regression analyses revealed a significantly elevated mortality rate at 90 days (adjusted HR: 1.58, 95 % CI: 1.24-2.02, p < 0.001) and 180 days (adjusted HR: 1.47, 95 % CI: 1.18, 1.83, p < 0.001) in the frail group compared to their non-frail counterparts., Conclusions: Frailty independently predisposes adult sepsis patients in the ICU to adverse outcomes. Future investigations should concentrate on evaluating frailty and developing targeted interventions to improve patient prognosis., Implication for Clinical Practice: The MFI provides a simple clinical assessment tool that can be integrated into electronic medical records for immediate calculation. This simplifies the assessment process and plays a key role in predicting patient outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Ischaemic stroke remains a significant global health challenge, associated with high mortality rates. While the Braden Scale is traditionally employed to assess pressure ulcer risk, its potential to predict mortality among the intensive care unit (ICU) patients with ischaemic stroke has not been thoroughly investigated., Aim/s: This study evaluates the predictive value of the Braden Scale for 30-day mortality among patients with ischaemic stroke admitted to ICU., Study Design: We conducted a retrospective analysis of 4710 adult patients with ischaemic stroke from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The association between the Braden Scale scores and 30-day mortality was assessed using receiver operating characteristic (ROC) curve analysis, Cox regression models and Kaplan-Meier survival estimates., Results: Patients with Braden Scale scores ≤ 15.5 showed significantly higher 30-day mortality rates (p-value < 0.001; hazard ratio (HR): 2.08, 95% confidence interval (CI): 1.71-2.53). The area under the ROC curve (AUC) was 0.71, demonstrating good predictive performance. Multivariate analysis confirmed the Braden Scale as an independent predictor of mortality, after adjusting for age, gender and comorbidities., Conclusions: The Braden Scale effectively identifies high-risk ischaemic stroke patients in ICU settings, endorsing its integration into routine assessments to facilitate early intervention strategies., Relevance to Clinical Practice: Integrating the Braden Scale into routine ICU evaluations can enhance mortality risk stratification and improve patient care tailoring., (© 2024 British Association of Critical Care Nurses.)

Background/objectives: Increased free fatty acid (FFA) promotes adiponectin secretion in healthy subjects and induces inflammation in diabetes. Given the potential pro-inflammatory role of adiponectin in "adiponectin paradox", we performed this study in patients with type 2 diabetes mellitus (T2DM) to assess the association of FFA with adiponectin and to investigate whether adiponectin mediates FFA-related inflammation., Methods: This cross-sectional study consisted of adult patients with T2DM. FFA, adiponectin, and tumor necrosis factor-α (TNF-α) were assayed from fasting venous blood after overnight fasting for at least 8 h. Multivariable linear regression analysis and restricted cubic splines (RCS) analysis were performed to identify the association between FFA and adiponectin. Mediation analysis was performed to determine the mediating effect of adiponectin on the association between FFA and TNF-α., Results: This study included 495 participants, with 332 males (67.1%) and a mean age of 47.0 ± 11.2 years. FFA was positively associated with adiponectin (b = 0.126, 95%CI: 0.036-0.215, P = 0.006) and was the main contributor to the increase of adiponectin (standardized b = 0.141). The RCS analysis demonstrated that adiponectin increased with FFA when FFA was less than 0.7 mmol/L but did not further increase thereafter (P overall  < 0.001 and P non-linear  < 0.001). In addition, adiponectin mediated the association between FFA and TNF-α. The mediating effect was 0.08 (95%CI: 0.03-0.13, P = 0.003) and the mediating effect percentage was 26.8% (95%CI: 4.5-49.2, P = 0.02)., Conclusions: In patients with T2DM, FFA was positively associated with adiponectin when FFA was less than 0.7 mmol/L. Elevated adiponectin mediated FFA-related inflammation. This study may provide insights into the pro-inflammatory effect of adiponectin in T2DM., (© 2024. The Author(s).)

Background: Delirium is a common and severe complication in intensive care unit (ICU) patients with acute ischemic stroke, exacerbating cognitive and physical impairments. It prolongs hospitalization, increases healthcare costs, and raises mortality risk. Early prediction is crucial because it facilitates prompt interventions that could possibly reverse or alleviate the detrimental consequences of delirium. Braden scores, traditionally used to assess pressure injury risk, could also signal frailty, providing an early warning of delirium and aiding in prompt and effective patient management., Objective: To examine the association between the Braden score and delirium., Methods: A retrospective analysis of adult ischemic stroke patients in the ICU of a tertiary academic medical center in Boston from 2008 to 2019 was performed. Braden scores were obtained on admission for each patient. Delirium, the primary study outcome, was assessed using the Confusion Assessment Method for Intensive Care Unit and a review of nursing notes. The association between Braden score and delirium was determined using Cox proportional hazards modeling, with hazard ratios (HR) and 95% confidence intervals (CI) calculated., Results: The study included 3,680 patients with a median age of 72 years, of whom 1,798 were women (48.9 %). The median Braden score at ICU admission was 15 (interquartile range 13-17). After adjustment for demographics, laboratory tests, severity of illness, and comorbidities, the Braden score was inversely associated with the risk of delirium (adjusted HR: 0.94, 95 % CI: 0.92-0.96, P < 0.001)., Conclusions: The Braden score may serve as a convenient and simple screening tool to identify the risk of delirium in ICU patients with ischemic stroke., Implication for Clinical Practice: The use of the Braden score as a predictor of delirium in ischemic stroke patients in the ICU allows early identification of high-risk patients. This facilitates timely intervention, thereby improving patient outcomes and potentially reducing healthcare costs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the association between frailty and postoperative delirium (POD) in elderly cardiac surgery patients., Methods: A retrospective study was conducted of older patients admitted to the intensive care unit after cardiac surgery at a tertiary academic medical center in Boston from 2008 to 2019. Frailty was measured using the Modified Frailty Index (MFI), which categorized patients into frail (MFI ≥3) and non-frail (MFI = 0-2) groups. Delirium was identified using the confusion assessment method for the intensive care unit and nursing notes. Logistic regression models were used to examine the association between frailty and POD, and odds ratios (OR) with 95% confidence intervals (CI) were calculated., Results: Of the 2080 patients included (median age approximately 74 years, 30.9% female), 614 were frail and 1466 were non-frail. The incidence of delirium was significantly higher in the frail group (29.2% vs. 16.4%, p < 0.05). After adjustment for age, sex, race, marital status, Acute Physiology Score III (APSIII), sequential organ failure assessment (SOFA), albumin, creatinine, hemoglobin, white blood cell count, type of surgery, alcohol use, smoking, cerebrovascular disease, use of benzodiazepines, and mechanical ventilation, multivariate logistic regression indicated a significantly increased risk of delirium in frail patients (adjusted OR: 1.61, 95% CI: 1.23-2.10, p < 0.001, E-value: 1.85)., Conclusions: Frailty is an independent risk factor for POD in older patients after cardiac surgery. Further research should focus on frailty assessment and tailored interventions to improve outcomes., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Compared with anti-infective drugs, immunosuppressants and other fields, the application of therapeutic drug monitoring (TDM) in oncology is somewhat limited., Objective: We aimed to provide a comprehensive understanding of TDM guidelines for antineoplastic drugs and to promote the development of individualized drug therapy in oncology., Design: This study type is a systematic review., Data Sources and Methods: This study was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. Databases including PubMed, Embase, the official websites of TDM-related associations and Chinese databases were comprehensively searched up to March 2023. Two investigators independently screened the literature and extracted data. The methodological and reporting quality was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT), respectively. Recommendations and quality evaluation results were presented by visual plots. This study was registered in PROSPERO (No. CRD42022325661)., Results: A total of eight studies were included, with publication years ranging from 2014 to 2022. From the perspective of guideline development, two guidelines were developed using evidence-based methods. Among the included guidelines, four guidelines were for cytotoxic antineoplastic drugs, three for small molecule kinase inhibitors, and one for antineoplastic biosimilars. Currently available guidelines and clinical practice provided recommendations of individualized medication in oncology based on TDM, as well as influencing factors. With regard to methodological quality based on AGREE II, the average overall quality score was 55.21%. As for the reporting quality by RIGHT evaluation, the average reporting rate was 53.57%., Conclusion: From the perspective of current guidelines, TDM in oncology is now being expanded from cytotoxic antineoplastic drugs to newer targeted treatments. Whereas, the types of antineoplastic drugs involved are still small, and there is still room for quality improvement. Furthermore, the reflected gaps warrant future studies into the exposure-response relationships and population pharmacokinetics models., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background: Atrial fibrillation (AF) and frailty are significant global public health problems associated with advancing age. However, the relationship between frailty and older patients with AF in the intensive care unit (ICU) has not been thoroughly investigated. This study aimed to investigate whether the hospital frailty risk score (HFRS) is associated with adverse outcomes in older patients with AF in the ICU., Methods: This was the first retrospective analysis of older patients with AF admitted to the ICU between 2008 and 2019 at a tertiary academic medical center in Boston. The HFRS was used to measure frailty severity. The outcomes of interest were in-hospital and 30-day mortality and the incidence of sepsis and ischemic stroke., Results: There were 7,792 participants aged approximately 80 years, almost half (44.9%) of whom were female. Among this group, 2,876 individuals were identified as non-frail, while 4,916 were classified as frail. The analysis revealed a significantly greater incidence of in-hospital (18.8% compared to 7.6%) and 30-day mortality (24.5% versus 12.3%) in the frail group. After accounting for potential confounding factors, a multivariate Cox proportional hazards regression analysis revealed that frail participants had a 1.56-fold greater risk of mortality within 30 days (95% CI = 1.38-1.76, p < 0.001)., Conclusions: Frailty is an independent risk factor for adverse outcomes in older patients with AF admitted to the ICU. Therefore, prioritizing frailty assessment and implementing specific intervention strategies to improve prognostic outcomes are recommended., Competing Interests: Competing interests The authors declare that they have no competing interests.

Background: Dementia is a significant cause of death in the older population and is becoming an important public health issue as the population ages and the prevalence of dementia increases. The Braden score is one of the most commonly used clinical tools to assess the risk of skin pressure injury in patients, and some studies have reported that it may reflect the state of frailty of patients. The present study attempted to explore the association between Braden score and 90-day mortality, pressure injury, and aspiration pneumonia in older patients with dementia in the intensive care unit (ICU)., Methods: The study involved extracting crucial data from the Medical Information Market for Intensive Care IV (MIMIC-IV) database using Structured Query Language, with a license certificate obtained after completing the necessary training and examination available on the MIMIC-IV website. A retrospective analysis was performed on older patients with dementia, aged 65 or older, who were first admitted to the ICU. Ninth and tenth revision International Classification of Diseases codes were used to identify patients with dementia. The primary outcome was 90-day mortality. Cox proportional hazards models were used to determine the association between Braden score and death, and hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Propensity score matching and E-value assessments were employed for sensitivity analysis., Results: A total of 2892 patients with a median age of approximately 85 years (interquartile range 78.74-89.59) were included, of whom 1625 were female (56.2%). Patients had a median Braden score of 14 (interquartile range 12-15) at ICU admission. Braden score at ICU admission was inversely associated with 90-day mortality risk after adjustment for demographics, severity of illness, treatment and medications, delirium, and sepsis (adjusted HR: 0.92, 95% CI: 0.87-0.98, p = 0.006). Patients were divided into two groups with a cut-off value of 15: high-risk group and low-risk group. Compared to the low-risk group (Braden score >15), the risk of 90-day mortality was significantly increased in the high-risk group (Braden score ≤15) (adjusted HR: 1.52, 95% CI: 1.10-2.09, p = 0.011, E-value: 2.01), the risk of pressure injury (adjusted OR: 2.62, 95% CI: 2.02-3.43, E-value: 2.62) and aspiration pneumonia (adjusted OR: 2.55, 95% CI: 1.84-3.61, E-value: 2.57) was also significantly higher., Conclusions: The Braden score may be a quick and simple screening tool to identify the risk of adverse outcomes in critically ill older adults with dementia., (© 2024 John Wiley & Sons Ltd.)

Objective: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is commonly subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) based on the extent of skin involvement. This subclassification may not reflect the full range of clinical phenotypic variation. This study aimed to investigate clinical features and aggregation of patients with SSc in Chinese based on SSc manifestations and organ involvements, in order to achieve precise treatment of SSc early prevention of complications., Methods: In total 287 SSc patients were included in this study. A cluster analysis was applied according to 13 clinical and serologic variables to determine subgroups of patients. Survival rates between obtained clusters and risk factors affecting prognosis were also compared., Result: In this study, six clusters were observed: cluster 1 (n = 66) represented the skin type, with all patients showing skin thickening. In cluster 2 (n = 56), most patients had vascular and articular involvement. Cluster 3 (n = 14) individuals mostly had cardiac and pulmonary involvement. In cluster 4 (n = 52), the gastrointestinal type, 50 patients presented with stomach symptoms and 28 patients presented with esophageal symptoms. In cluster 5 (n = 50), patients barely had any major organ involvement. Cluster 6 (n = 49) included 46% of all patients presenting with renal crisis., Conclusion: The results of our cluster analysis study implied that limiting SSc patient subgroups to those based only on skin involvement might not capture the full heterogeneity of the disease. Organ damage and antibody profiles should be considered when identifying homogeneous patient groups with a specific prognosis. Key Points • Provides a new method of categorizing SSc patients. • Can better explain disease progression and guide subsequent treatment., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Intracellular pharmacokinetics (PK) of activated drugs is a window to understanding the pharmacodynamics of prodrug-enzyme-ultrasound therapy. Herein PK of ZD2767D (i.e., activated drug) in the ZD2767P+CPG2+US system on A549, A549/DDP, SKOV3, and SKOV3/DDP cells were evaluated (A549/DDP and SKOV3/DDP were cisplatin-resistant sublines). The noncompartment model under extravascular input mode was deemed appropriate for evaluating drug level vs time curves; C max , AUC last , MRT last , V z , and Cl can reflect the PK feature, but t 1/2 , AUC inf , and MRT inf were irrational; higher accumulation and slower elimination characterized the PK mechanism of ZD2767P+CPG2+US; enhanced permeability and retention effect can be assessed with C max , AUC last , MRT last , and t last ; ultrasound equivalently modulated C max and AUC last in sensitive and resistant cells. The experimental design and dose proportionality were discussed., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Background: Investigations into the rivaroxaban response from the perspective of genetic variation have been relatively recent and wide in scope, whereas there is no consensus on the necessity of genetic testing of rivaroxaban. Thus, this systematic review aims to thoroughly evaluate the relationship between genetic polymorphisms and rivaroxaban outcomes., Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Chinese databases were searched to 23 October 2022. We included cohort studies reporting the pharmacogenetic correlation of rivaroxaban. Outcomes measured included efficacy (all-cause mortality, thromboembolic events and coagulation-related tests), safety (major bleeding, clinically relevant non-major bleeding [CRNMB] and any hemorrhage), and pharmacokinetic outcomes. A narrative synthesis was performed to summarize findings from individual studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the reporting guideline for Synthesis Without Meta-Analysis., Results: A total of 12 studies published between 2019 and 2022 involving 1364 patients were included. Ten, one, and six studies focused on the ABCB1, ABCG2, and CYP gene polymorphisms, respectively. Pharmacokinetic outcomes accounted for the majority of the outcomes reported (n = 11), followed by efficacy (n = 5) [including prothrombin time (PT) or international normalized ratio (n = 3), platelet inhibition rate (PIR) or platelet reactivity units (PRUs; n = 1), thromboembolic events (n = 1)], and safety (n = 5) [including major bleeding (n = 2), CRNMB (n = 2), any hemorrhage (n = 1)]. For ABCB1 gene polymorphism, the relationship between PT and ABCB1 rs1045642 was inconsistent across studies, however there was no pharmacogenetic relationship with other efficacy outcomes. Safety associations were found in ABCB1 rs4148738 and major bleeding, ABCB1 rs4148738 and CRNMB, ABCB1 rs1045642 and CRNMB, and ABCB1 rs2032582 and hemorrhage. Pharmacokinetic results were inconsistent among studies. For ABCG2 gene polymorphism, no correlation was observed between ABCG2 rs2231142 and dose-adjusted trough concentration (C min /D). For CYP gene polymorphisms, PIR or PRUs have a relationship with CYP2C19 rs12248560, however bleeding or pharmacokinetic effects did not show similar results., Conclusions: Currently available data are insufficient to confirm the relationship between clinical or pharmacokinetic outcomes of rivaroxaban and gene polymorphisms. Proactive strategies are advised as a priority in clinical practice rather than detection of SNP genotyping., Clinical Trials Registration: PROSPERO registration number CRD42022347907., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Prospective controlled trials of high-intensity focused ultrasound for cancers were evaluated. Post-hoc power was <0.80 in 30/47 trials and in 22/39 trials with positive results, indicating low quality in most trials. Unscientific endpoints, small sample sizes, and high dropout rates led to low post-hoc power that caused inter-trial heterogeneity and overestimated the therapeutic effect. The objective response rate was not a substitute for survival time for estimating the sample size and assessing the efficacy. The present data can interpret a paradox: HIFU is considered to have slighter cytotoxicity to non-cancer tissues and no radiation but is frequently combined with chemotherapy and/or radiotherapy in practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Bromhidrosis, also known as body odor, is a common disease in life, which often occurs in young adults. The histological basis of bromhidrosis is the hyperplasia of apocrine sweat glands., Objective: To compare the effects of different methods of endoscopy in microdynamic axillary osmidrosis removal on curative effect, complications, and surgical efficiency., Methods: A total of 149 patients with axillary osmidrosis were treated in our hospital from January 2020 to December 2021. They were treated with endoscopic assistance in the whole process of operation (Group A) and endoscope-assisted exploration after blind rotary cutter suction (Group B), respectively, and the curative effect, complication rate, and surgical efficiency were evaluated., Results: There was no significant difference in the curative effect and complication rate between the two groups, but the endoscope-assisted exploration group after suction with rotary cutter (Group B) had higher surgical efficiency., Conclusion: On the basis of professional use of rotary cutter, it is efficient to choose endoscope to check the excision of sweat gland in the operation area and stop bleeding in time after blind suction., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: With the progress of therapeutic drug monitoring (TDM) technology and the development of evidence-based medicine, many guidelines were developed and implemented in recent decades., Objective: The aim was to evaluate the current status of TDM guidelines and provide suggestions for their development and updates based on Appraisal of Guidelines for Research and Evaluation (AGREE) II., Methods: The TDM guidelines were systematically searched for among databases including PubMed, Embase, China National Knowledge Infrastructure, Wanfang Data, and the Chinese biomedical literature service system and the official websites of TDM-related associations. The search period was from inception to 6 April 2023. Four researchers independently screened the literature and extracted data. Any disagreement was discussed and reconciled by another researcher. The quality of guidelines was assessed using the AGREE II instrument., Results: A total of 92 guidelines were included, including 57 technical guidelines, three management guidelines, and 32 comprehensive guidelines. The number of TDM guidelines has gradually increased since 1979. The United States published the most guidelines (20 guidelines), followed by China (15 guidelines) and the United Kingdom (ten guidelines), and 23 guidelines were developed by international organizations. Most guidelines are aimed at adult patients only, while 28 guidelines include special populations. With respect to formulation methods, there are 23 evidence-based guidelines. As for quality evaluation results based on AGREE II, comprehensive guidelines scored higher (58.16%) than technical guidelines (51.36%) and administrative guidelines (50.00%)., Conclusion: The number of TDM guidelines, especially technical and comprehensive ones, has significantly increased in recent years. Most guidelines are confronted with the problems of unclear methodology and low quality of evidence according to AGREE II. More evidence-based research on TDM and high-quality guideline development is recommended to promote individualized therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Rapidly progressive interstitial lung disease (RP-ILD) is the most serious complication of anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5 + DM). This study was performed to assess the prognostic factors of patients with anti-MDA5 + DM and the clinical characteristics and predictors of anti-MDA5 + DM in combination with RP-ILD., Methods: In total, 73 MDA5 + DM patients were enrolled in this study from March 2017 to December 2021. They were divided into survival and non-survival subgroups and non-RP-ILD and RP-ILD subgroups., Results: The lactate dehydrogenase (LDH) concentration and prognostic nutritional index (PNI) were independent prognostic factors in patients with anti-MDA5 + DM: the elevated LDH was associated with increased mortality ( p = 0.01), whereas the elevated PNI was associated with reduced mortality ( p < 0.001). The elevated LDH was independent risk prognostic factor for patients with anti-MDA5 + DM (HR 2.42, 95% CI: 1.02-4.83, p = 0.039), and the elevated PNI was independent protective prognostic factor (HR, 0.27; 95% CI, 0.08 - 0.94; p = 0.039). Patients who had anti-MDA5 + DM with RP-ILD had a significantly higher white blood cell count and LDH concentration than those without RP-ILD ( p = 0.007 and p = 0.019, respectively). In contrast, PNI was significantly lower in patients with RP-ILD than those without RP-ILD ( p < 0.001). The white blood cell count and elevated LDH were independent and significant risk factors for RP-ILD (OR 1.54, 95% CI: 1.12 - 2.13, p = 0.009 and OR 8.68, 95% CI: 1.28 - 58.83, p = 0.027, respectively), whereas the lymphocyte was an independent protective factor (OR, 0.11; 95% CI, 0.01 - 0.81; p = 0.03)., Conclusion: The elevated LDH and elevated PNI were independent prognostic factors for patients with anti-MDA5 + DM. The elevated LDH was independent risk factor for RP-ILD. Patients with anti-MDA5 + DM could benefit from the measurement of LDH and PNI, which are inexpensive and simple parameters that could be used for diagnosis as well as prediction of the extent of lung involvement and prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Zhao, Liu, Zhao, Li, Ma and Yang.)

Transcatheter aortic valve implantation (TAVI) is a micro-invasive surgery used to treat patients with aortic stenosis (AS) efficiently. However, the uneven valve expansion can cause a non-circular annulus, which is one of the main factors leading to complications after TAVI. As a preliminary work, the main purpose of this study was to evaluate the risk of adverse aortic events in patients with a non-circular aortic annulus after TAVI. This study numerically investigated the distribution of four wall shear stress (WSS)-based indicators and three helicity-based indicators in eight patient-specific aortas with different annulus including circular, type I elliptical and type II elliptical shapes. Both elliptical annulus features can significantly enhance the intensity of the helicity (h2) in the ascending aorta (p < 0.001). However, for the type I elliptical annulus, the spiral flow structure was changed into low-velocity and disturbed flow pattern close to the inner side of the aortic arch. For the type II elliptical annulus, the spiral flow remained but became skewed in distribution. The elliptical annulus feature could increase the general level WSS-based indicators, especially in the ascending aorta. However, due to the disturbance of spiral flow or second helical flow in ascending aortas, areas with low TAWSS accompanied by high oscillatory shear index (OSI) and cross flow index (CFI) were observed in all the ascending aortas with non-circular annulus. The elliptical annulus feature can change the hemodynamic environment in the aortic arch, especially in the ascending aorta. Although both elliptical annulus features enhanced the strength of helicity, the uniform distribution of the helical flow was disturbed, especially in the ascending aorta, indicating the potential risk of adverse aortic events may increase. Therefore, for the patients without paravalvular leak but elliptical annulus shape after TAVI treatment, surgeons may be needed to consider further dilatation to make the non-circular annulus become circular., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer KY declared a shared parent affiliation with the authors to the handling editor at the time of review.

Background: In April 2009, the Chinese government launched Zero Markup Drug Policy (ZMDP) to adjust medical institutions' revenue and expenditure structures., Objective: This study evaluated the impact of implementing ZMDP (as an intervention) on the drug costs for managing Parkinson's disease (PD) and its complications from the healthcare providers' perspective., Methods: The drug costs for managing PD and its complications per outpatient visit or inpatient stay were estimated using electronic health data from a tertiary hospital in China from January 2016 to August 2018. An interrupted time series analysis was conducted to evaluate the immediate change following the intervention (step change, β 1 ) and the change in slope, comparing post-intervention with the pre-intervention period (trend change, β 2 ). Subgroup analyses were conducted in outpatients within the strata of age, patients with or without health insurance, and whether drugs were listed in the national Essential Medicine List (EML)., Results: Overall, 18,158 outpatient visits and 366 inpatient stays were included. Outpatient (β 1 = -201.7, 95%CI: -285.4, -117.9) and inpatient (β 1 = -372.1, 95% CI: -643.6, -100.6) drug costs for managing PD significantly decreased when implementing ZMDP. However, for outpatients without health insurance, the trend change in drug costs for managing PD (β 2 = 16.8, 95% CI: 8.0, 25.6) or PD complications (β 2 = 12.6, 95% CI: 5.5, 19.7) significantly increased. Trend changes in outpatient drug costs for managing PD differed when stratifying drugs listed in EML (β 2 = -1.4, 95% CI: -2.6, -0.2) or not (β 2 = 6.3, 95%CI: 2.0, 10.7). Trend changes of outpatient drug costs for managing PD complications significantly increased in drugs listed in EML (β 2 = 14.7, 95% CI 9.2, 20.3), patients without health insurance (β 2 = 12.6, 95% CI 5.5, 19.7), and age under 65 (β 2 = 24.3, 95% CI 17.3, 31.4)., Conclusions: Drug costs for managing PD and its complications significantly decreased when implementing ZMDP. However, the trend in drug costs increased significantly in several subgroups, which may offset the decrease at the implementation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Li, Gu, Cai, Wang, Yi and Chen.)

Dexamethasone is the first and an important therapy that significantly reduces the risk of death in patients with severe COVID-19 disease. Nevertheless, a lot of studies have revealed that it has adverse impacts on multiple systems of the body especially the reproductive system, and dexamethasone exposure during the human foetal period may be associated with various diseases. In this paper, we reviewed the literature regarding the adverse effects of COVID-19 and dexamethasone administration on the reproductive system as well as related disease pathogenesis, in an attempt to clarify the potential harms of dexamethasone treatment in COVID-19 patients. Overall, we strongly support the application of dexamethasone as a pharmaceutical therapy in critical COVID-19 patients before a better therapy is developed, but the adverse side effects that may arise cannot be ignored. Our review will help medical professionals in the prognosis and follow-up of patients treated with dexamethasone. In addition, given that a considerable amount of uncertainty, confusion and even controversy that still remains, further studies and more clinical trials are urgently needed to improve the understanding of the parameters and the effects of dexamethasone on reproductive function of patients with severe acute respiratory syndrome coronavirus 2 infection.

COVID-19 has affected traditional instructional activities. Home-based isolation and restrictive movement measures have forced most learning activities to move from an offline to an online environment. Multiple studies have also demonstrated that teaching with virtual tools during the COVID-19 pandemic is always ineffective. This study examines the different characteristics and challenges that virtual tools brought to online education in the pre-pandemic and pandemic era, with the aim of providing experience of how virtual tools supported purely online learning during a health crisis. By searching keywords in public databases and review publications, this study tries to summarize the major topics related to the research theme. These topics are the characteristics of learning supported by technologies in pre-pandemic and pandemic era, the challenges that education systems have faced during the COVID-19 pandemic. This study also compares the functions, advantages and limitations of typical virtual tools, which has rarely been done in previous studies. This study tries to present the features of virtual tools that support online learning and the challenges regarding real-life risk scenarios, and tries to provide educational institutions with a distinct perspective for efficient teaching and learning in future potential health crises.

The prodrug-enzyme regimen ZD2767P+CPG2 is limited by low efficacy. Here, ultrasound was used to modulate ZD2767P+CPG2 (i.e., ZD2767P+CPG2+US) against cisplatin-resistant human lung cancer cells. A549 and A549/DDP (resistant subline) cells received ZD2767P+CPG2 or ZD2767P+CPG2+US. Either ZD2767P+CPG2 or ZD2767P+CPG2+US led to cell death and apoptosis, and ZD2767P+CPG2+US produced stronger effects; comet assays revealed that these two means directly caused DNA double-strand break. Z-VAD-fmk and/or ferrostatin-1 increased the cell survival percentage, and Z-VAD-fmk decreased the apoptosis percentage. The level of transferrin was increased in treated cells, but those of ferroportin and glutathione peroxidase 4 (GPX4) were reduced, with higher intracellular levels of reactive oxygen species and of iron. Intracellular pharmacokinetics of ZD2767D (activated drug) indicated that the peak level, area under the drug level vs. time curve, and mean residence time in ZD2767P+CPG2+US were higher than those in ZD2767P+CPG2. Both ZD2767P+CPG2 and ZD2767P+CPG2+US were effective on xenograft tumors in nude mice; inhibitory rates were 39.7% and 63.5% in A549 tumors and 50.0% and 70.1% in A549/DDP tumors, respectively. A higher apoptosis level and a lower GPX4 level were noted in tumors receiving treatments. No severe adverse events were observed. These data demonstrated that ZD2767P+CPG2+US deactivated cancer cells via apoptosis and ferroptosis pathways, being a candidate therapy for cisplatin-resistant lung cancer., Competing Interests: The authors declare no competing financial interest., (Copyright © 2022 Qianfen Liu et al.)

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase that may play a part in chemoresistance in ovarian cancer. However, its role in cisplatin (DDP) resistance is unclear. Here, the expression level of IDO1 in tumors in platinum-resistant ( n = 22) and -sensitive ( n = 46) ovarian cancer patients was determined, and then how IDO1 modulated DDP resistance was explored in vitro and in vivo. The IDO1 expression level in platinum-resistant patients was higher than that in -sensitive patients, and a higher IDO1 level was correlated with poor prognosis in type II cancer patients. Up-regulating IDO1 decreased DDP-induced apoptosis in SKOV3 cells via inhibiting the ROS/p53 cell-death pathway, thereby attenuating cytotoxicity of DDP. Silencing IDO1 enhanced p53-dependent apoptosis by increasing ROS accumulation, thereby enhancing DDP against SKOV3 cells. Down-knocking IDO1 augmented the action of DDP in vivo. These data demonstrated that silencing IDO1 enhanced the efficacy of DDP by intensifying p53-dependent apoptosis, and that targeting IDO1 can be a strategy to modulate DDP-based chemotherapy for epithelial ovarian cancer.

Proportionally converting the applied mechanical energy into photons by individual mechanoluminescent (ML) micrometer-sized particles opens a new way to develop intelligent electronic skins as it promises high-resolution stress distribution visualization and fast response. However, a big challenge for ML sensing technology is its low sensitivity in detecting stress. In this work, a novel stress distribution sensor with the detection sensitivity enhanced by two orders of magnitude is developed by combining a proposed near-distance ML imaging scheme with an improved mechano-to-photon convertor. The enhanced sensitivity is the main contributor to the realization of a maximum photon harvesting rate of ≈80% in the near-distance ML imaging scheme. The developed near-distance ML sensor shows a high sensitivity with a detection limit down to ≈kPa level, high spatial resolution of 254 dpi, and fast response with an interval of 3.3 ms, which allows for high-resolution and real-time visualization of complex mechanical actions such as irregular solid contacts or fluid impacts, and thus enables use in intelligent electronic skin, structural health monitoring, and human-computer interaction., (© 2022 Wiley-VCH GmbH.)

Myeloid differentiation factor 88 (MyD88) is a key adapter molecule in Toll-like receptor signal transduction that triggers downstream immune cascades involved in the host defense response to exogenous pathogens. However, the function of MyD88s in mollusks, especially in freshwater shellfish, remains poorly understood. In this study, a novel freshwater shellfish MyD88 (denoted Aw MyD88) was characterized from Anodonta woodiana . The present Aw MyD88 protein consists of 474 amino acids and contains a conserved a typical death domain (DD) and a conservative Toll/IL-1R (TIR) domain with three typical boxes. Quantitative real-time PCR (qRT-PCR) analysis showed that Aw MyD88 was broadly expressed in all the examined tissues, and the highest expression level was observed in hemocytes of A. woodiana . When challenged with Aeromonas hydrophila and lipopolysaccharide (LPS), the mRNA expression levels of Aw MyD88 were significantly induced in hemocytes of A. woodiana in vivo and in vitro . In addition, in vivo injection experiments revealed that MyD88 signaling pathway genes showed strong responsiveness to A. hydrophila challenge, and their expression levels were significantly upregulated in hemocytes. Knockdown of Aw MyD88 reduced the transcript levels of immune related transcription factors ( Aw NF-κB and Aw AP-1) and effectors ( Aw TNF, Aw LYZ, Aw Defense and Aw AIF) during A. hydrophila infection. Moreover, subcellular localization analysis indicated that Aw MyD88 was mainly localized to the cytoplasm in HEK293T cells. Finally, luciferase reporter assays revealed that Aw MyD88 associates with Aw TLR to activate the NF-κB and AP-1 signaling pathways in HEK293T cells. These results suggested that Aw MyD88 might be involved in the host defense response to bacterial challenge, providing new insight into the immune function of the MyD88 signaling pathway in freshwater shellfish., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qu, She, Li, Zeng, Li, Liu, Ren, Liu, Gao, Lu, Long and Li.)

Dexamethasone has been widely used in clinical practice to promote fetal lung maturity and reduce neonatal respiratory distress syndrome and perinatal mortality. Nevertheless, its administration is a double-edged sword, as a large number of studies have shown that there are obvious disadvantages in pregnant women and fetal development. In this review, we comprehensively retrospect the latest literature on the toxicological effects and mechanisms of dexamethasone on fetal development, in an attempt to provide a valuable basis for further studies and clinical trials in the future. Overall, prenatal dexamethasone exposure could lead to some adverse consequences on fetal organ systems through intrauterine programming based on the results of current animal and human researches. Potential sequelae include osteoarthritis, hypertension, fatty liver, glomerulosclerosis, depression, diabetes and infertility, some of which can pass on to the next generation. It must be noted that the evidence in humans is preliminary and limited by the small sample size. More studies in large-scale populations are needed to confirm if it raises the risk of sequelae in humans. In addition, we strongly support the application of dexamethasone as a pharmaceutical therapy in pregnant women with coronavirus disease 2019 before a better therapy is developed. However, the adverse side effects that may arise also cannot be ignored., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Thioridazine was used to sensitize cisplatin against cisplatin-resistant human lung cancer cells. Cells received thioridazine, cisplatin, or both drugs (the combination). Thioridazine synergized cisplatin to increase percentages of dead and apoptotic cells. DNA damage was detected using the comet assays; the combination led to the highest alkaline- and neutral-comet percentages, demonstrating exacerbation of both single- and double-strand breaks. After thioridazine treatment, levels of glutathione, and BRCA2, RAD51, and ERCC1 proteins were decreased. These data manifested that thioridazine decreased the capacities of detoxification and DNA repair, thereby enhancing cisplatin-induced DNA damage in resistant cells., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Yuanyuan Luo et al.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented and catastrophic impact on humanity and continues to progress. In addition to typical respiratory symptoms such as fever, cough, and dyspnea, a large percentage of COVID-19 patients experience gastrointestinal (GI) complaints, with the most common symptoms being diarrhea, nausea, vomiting, and abdominal discomfort., Summary: We comprehensively summarize the latest knowledge of the adverse effects of COVID-19 and therapeutic drugs on the GI system, as well as related disease pathogenesis, and then provide a discussion focusing on the management and vaccination of patients who have inflammatory bowel disease (IBD) and GI cancer. The virus can affect the digestive system via binding to ACE2 receptors and subsequent gut microbiome dysbiosis. Through a variety of molecular pathways and mechanisms, numerous drugs for the treatment of COVID-19 could interfere with GI function and lead to multiple clinical manifestations, which may further intensify the risk and severity of GI symptoms of COVID-19 infection, such as nausea, vomiting, gastroparesis, and gastric ulcers., Key Messages: We should monitor GI manifestations closely while managing COVID-19 patients and take timely measures to reduce the incidence of SARS-CoV-2 infections in GI cancer patients. IBD patients should receive vaccination timely, but corticosteroid use should be minimized when they are vaccinated. Simultaneously, for persons with IBD who have known or suspected COVID-19, immunosuppressive agents, especially thiopurines, should be avoided/minimized if possible., (© 2021 S. Karger AG, Basel.)

To understand the arsenic (As) toxicity to aquatic organisms in the phosphors-polluted aquatic ecosystem, the growth, the physiological response of Chlorella vulgaris exposed to As (V), and the underlying mechanism were investigated under different phosphorus (P) levels (0, 6, 13, 32 μM). Results showed that As toxicity to the marine microalga C. vulgaris was enhanced under P-limited condition. P supply distinctly altered the effect of As on the light-harvesting efficiency of photosystem. Insufficient P supply also resulted in an enhanced level of membrane integrity loss, which probably facilitated As entering cells and led to stronger toxicity to C. vulgaris under low P supply. At high concentrations of As, the relative superoxide dismutase (SOD) activity was significantly enhanced. When phosphorus was limited, the activation of peroxidase (POD) was significantly enhanced after adding As (V). When intracellular SOD activity was at its highest level, the level of membrane peroxidation (MDA) was also at the highest level, and membrane peroxidation level was positively related to the level of membrane integrity loss (Pearson R 2 =0.8977). These results suggested that alternation of light-harvesting efficiency of photosystem and As-induced oxidative damage, resulting in membrane peroxidation and integrity loss, were the possible mechanism of As toxicity to C. vulgaris. This study provided insight into the understanding of As toxicity to algae in the eutrophication aquatic system and the potential application of algae in As remediation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chromatin interactions play important roles in regulating gene expression. However, the availability of genome-wide chromatin interaction data is limited. We develop a computational method, chromatin interaction neural network (ChINN), to predict chromatin interactions between open chromatin regions using only DNA sequences. ChINN predicts CTCF- and RNA polymerase II-associated and Hi-C chromatin interactions. ChINN shows good across-sample performances and captures various sequence features for chromatin interaction prediction. We apply ChINN to 6 chronic lymphocytic leukemia (CLL) patient samples and a published cohort of 84 CLL open chromatin samples. Our results demonstrate extensive heterogeneity in chromatin interactions among CLL patient samples., (© 2021. The Author(s).)

Acoustic telemetry has been used extensively to study the behavior of aquatic animals. The Juvenile Salmon Acoustic Telemetry System (JSATS) is one such system; it was developed for studying juvenile salmonids but has been used to study numerous species. A recent innovation of the JSATS system is an acoustic transmitter that is small enough to be implanted through injection or small incision that doesn't require sutures. Use of the JSATS system involves deploying cabled acoustic receivers at hydroelectric dams, or other structures, and autonomous acoustic receivers in free-flowing sections of a river. The raw detections from acoustic-tagged fish are processed to remove potential false positives. The clean detections (5,147,996 total) are used to generate detection events and to compute 3-D trajectories (403,900 total), which are used to assign fish to a passage route through a dam. Controlled field testing involving a high-accuracy Global Positioning System receiver is done to validate the submeter accuracy of the trajectories. The JSATS dataset could be reused for expanding the understanding of near-dam fish behavior., (© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Cisplatin resistance is a challenge in the treatment of epithelial ovarian cancer. Here, clinical data showed that the level of netrin-G1 (NTNG1) in cisplatin-resistant cancer was higher than that in cisplatin-sensitive cancer (2.2-fold, p = 0.005); patients with a high NTNG1 level in cancer tissues had shorter progression-free survival (11.0 vs. 25.0 months, p = 0.010) and platinum-free interval (5.0 vs. 20.0 months, p = 0.021) compared with patients with a low level. Category- or stage-adjusted analyses demonstrated that the association between the NTNG1 level and prognosis occurred in type II or FIGO III/IV cancer. The basal level of NTNG1 in SKOV3/DDP cells (a cisplatin-resistant subline) was higher than that in SKOV3 cells; therefore, NTNG1 was overexpressed in SKOV3 cells, or silenced in SKOV3/DDP cells. Knocking in NTNG1 reduced the action of cisplatin to decrease cell death and apoptosis of SKOV3 cells, accompanied by upregulation of p-AXL, p-Akt and RAD51; however, opposite effects were observed in SKOV3/DDP cells after knocking down NTNG1. Co-immunoprecipitation demonstrated that NTNG1 bound GAS6/AXL. Silencing NTNG1 enhanced cisplatin effects in vivo , decreasing tumor volume/mass. These data suggested that a high NTNG1 level can result in cisplatin resistance in ovarian cancer cells via the GAS6/AXL/Akt pathway and that NTNG1 may be a useful target to overcome resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fang, Luo, Zhang, Wang, Liu, Li and Yu.)

Acute myocardial infarction (AMI) is a common cardiac disease. Long non‑coding RNA maternally expressed 3 (MEG3) is associated with cellular processes in numerous complicated diseases, including AMI. However, the mechanism underlying MEG3 in myocardial hypoxia is not completely understood. The present study aimed to investigate the underlying mechanism of MEG3 in myocardial hypoxia. The expression levels of hypoxia‑inducible factor 1α (HIF1α), MEG3, microRNA (miR)‑325‑3p, and transient receptor potential cation channel subfamily V member 4 (TRPV4) in hypoxia‑treated H9c2 cells were detected via reverse transcription‑quantitative PCR. The protein expression levels of HIF1α, Bcl‑2, Bax, cleaved caspase‑3 and TRPV4 were detected via western blotting. Cell viability and apoptosis were assessed by performing an MTT assay and flow cytometry, respectively. Lactate dehydrogenase (LDH) release was monitored by conducting an LDH determination assay. The dual‑luciferase reporter assay was performed to verify the targeted relationship between miR‑325‑3p and MEG3 or TRPV4. The expression levels of MEG3 and TRPV4 were significantly increased, whereas miR‑325‑3p expression levels were significantly decreased in hypoxic H9c2 cells compared with normoxic H9c2 cells. In addition, miR‑325‑3p was downregulated by MEG3 compared with the vector group, and miR‑325‑3p targeted TRPV4 in hypoxia‑treated H9c2 cells. The results indicated that MEG3 knockdown attenuated hypoxia‑stimulated injury in H9c2 cells by regulating miR‑325‑3p. TRPV4 knockdown also mitigated hypoxia‑induced injury in H9c2 cells via miR‑325‑3p. Furthermore, compared with the vector group, MEG3 increased TRPV4 expression in hypoxia‑treated H9c2 cells by sponging miR‑325‑3p. Collectively, the results of the present study suggested that MEG3 modulated TRPV4 expression to aggravate hypoxia‑induced injury in rat cardiomyocytes by sponging miR‑325‑3p.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Patients with TNBC have poor overall survival because of limited molecular therapeutic targets. Recently, exosomes have been recognized as key mediators in cancer progression, but the molecular components and function of TNBC-derived exosomes remain unknown. The main goal of this study was to reveal the proteomic landscape of serum exosomes derived from ten patients with TNBC and 17 healthy donors to identify potential therapeutic targets. Using a tandem mass tag-based quantitative proteomics approach, we characterized the proteomes of individual patient-derived serum exosomes, identified exosomal protein signatures specific to patients with TNBC, and filtered out differentially expressed proteins. Most importantly, we found that the tetraspanin CD151 expression levels in TNBC-derived serum exosomes were significantly higher than those exosomes from healthy subjects, and we validated our findings with samples from 16 additional donors. Furthermore, utilizing quantitative proteomics approach to reveal the proteomes of CD151-deleted exosomes and cells, we found that exosomal CD151 facilitated secretion of ribosomal proteins via exosomes while inhibiting exosome secretion of complement proteins. Moreover, we proved that CD151-deleted exosomes significantly decreased the migration and invasion of TNBC cells. This is the first comparative study of the proteomes of TNBC patient-derived and CD151-deleted exosomes. Our findings indicate that profiling of TNBC-derived exosomal proteins is a useful tool to extend our understanding of TNBC, and exosomal CD151 may be a potential therapeutic target for TNBC., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The relationship between perioperative hyperchloremia and postoperative acute kidney injury (AKI) is not well established. Our study aimed to evaluate the association between perioperative hyperchloremia and acute kidney injury in patients undergoing off-pump coronary artery bypass grafting (CABG)., Methods: Patients with coronary disease who underwent off-pump CABG between April 2017 and December 2019 were enrolled in this retrospective study. The patients with perioperative hyperchloremia were matched 1:1 to patients without perioperative hyperchloremia. The primary outcome was the postoperative acute kidney injury rate. The secondary outcomes included intensive care unit (ICU)-free days, postoperative hospitalization days, wound infection rate, and in-hospital mortality. Propensity score matching and univariate and multivariate logistic regression analyses were used in this study., Results: A total of 321 patients who underwent off-pump CABG were included in the analysis. Propensity score matching selected 83 pairs for the final comparison. The results showed that the postoperative AKI rate was significantly different between the hyperchloremia and no hyperchloremia groups (56.6% versus 15.7%; P < .001). The number of ICU-free days, postoperative hospitalization days, wound infection rate, and in-hospital mortality were similar between the two groups. In the multivariable, logistic regression analysis, hyperchloremia was independently associated with the development of postoperative AKI (odds ratio [OR] = 1.814, 95% confidence interval [CI]: 1.072-3.070, P = .026)., Conclusions: Perioperative hyperchloremia is associated with an increase in the postoperative AKI rate among patients undergoing off-pump CABG.

Prodrug-carboxypeptidase G2 (e.g., ZD2767P+CPG2) can realize a targeted treatment where the specific advantage is a lack of CPG2 analogues in humans, but it is limited by low efficacy. Here ultrasound was employed to enhance ZD2767P+CPG2 (i.e., ZD2767P+CPG2+US) against chemoresistant human ovarian cancer cells. The release dynamics of ZD2767D (activated drug) by CPG2 were investigated. The in vitro efficacy was explored in SKOV3 and SKOV3/DDP (cisplatin-resistant subline) cells; spectrophotometry was established to quantify ZD2767P and ZD2767D, and then intracellular pharmacokinetics were evaluated. The in vivo efficacy was validated in both subcutaneous and orthotopic tumors. With insonation, the ZD2767D concentration was increased during an early period. Insonation synergized ZD2767P+CPG2 to enhance cell death and apoptosis, and efficacies in SKOV3 and SKOV3/DDP cells were similar. Intracellular pharmacokinetics of ZD2767D were nonproportional, and insonation increased the peak level, area under the level vs time curve, and mean residence time. In subcutaneous xenografts, ZD2767P+CPG2 and ZD2767P+CPG2+US resulted in volume-inhibitory rates of 20.4% and 26.5% in SKOV3 tumors and 36.8% and 81.6% in SKOV3/DDP tumors, respectively. In the orthotopic tumor model, the survival time in group ZD2767P+CPG2 or ZD2767P+CPG2+US was prolonged compared with group control, in SKOV3 (33.0 ± 3.5 or 39.2 ± 1.8 vs 25.0 ± 1.6 days, p < 0.0001) and SKOV3/DDP (16.2 ± 4.8 or 22.3 ± 7.3 vs 8.7 ± 3.9 days, p = 0.0015) tumors. These data indicated that ZD2767P+CPG2+US was effective against resistant ovarian cancer cells.

Endophytic fungal communities of Dysphania ambrosioides, a hyperaccumulator growing at two Pb-Zn-contaminated sites, were investigated through culture-dependent and culture-independent approaches. A total of 237 culturable endophytic fungi (EF) were isolated from 368 tissue (shoot and roots) segments, and the colonization rate (CR) ranged from 9.64% to 65.98%. The isolates were identified to 43 taxa based on morphological characteristics and rDNA ITS sequence analysis. Among them, 13 taxa (30.23%) were common in plant tissues from both sites; however, dominant EF were dissimilar. In culture-dependent study, 1989 OTUs were obtained through Illumina Miseq sequencing, and dominant EF were almost same in plant tissues from both sites. However, some culturable EF were not observed in total endophytic communities. We suggest that combination of both culture-dependent and culture-independent methods will provide more chances for the precise estimation of endophytic fungal community than using either of them. The tissue had more influence on the culturable fungal community structure, whereas the location had more influence on the total fungal community structure (including culturable and unculturable). Both culture-dependent and culture-independent studies illustrated that endophytic fungal communities of D. ambrosioides varied across the sites, which suggested that HM concentration of the soil may have some influence on endophytic fungal diversity., (© 2018 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.)

Machine learning classification and regression algorithms were applied to calibrate the localization errors of a time-difference-of-arrival (TDOA)-based acoustic sensor array used for tracking salmon passage through a hydroelectric dam on the Snake River, Washington, USA. The locations of stationary and mobile acoustic tags were first tracked using the approximate maximum likelihood algorithm. Next, ensembles of classification trees successfully identified and filtered data points with large localization errors. This prefiltering step allowed the creation of a machine-learned regression model function, which decreased the median distance error by 50% for the stationary tracks and by 34% for the mobile tracks. It also extended the previous range of sub-meter localization accuracy from 100 m to 250 m horizontal distance from the dam face (the receivers). Median distance errors in the depth direction were especially decreased, falling from 0.49 m to 0.04 m in the stationary tracks and from 0.38 m to 0.07 m in the mobile tracks. These methods would have application to the calibration of error in any TDOA-based sensor network with a steady environment and array configuration.

To acquire 3-D tracking data on juvenile salmonids, Juvenile Salmon Acoustic Telemetry System (JSATS) cabled hydrophone arrays were deployed in the forebays of two dams on the Snake River and at a mid-reach reservoir between the dams. The depth distributions of fish were estimated by statistical analyses performed on large 3-D tracking data sets from ~33,500 individual acoustic tagged yearling and subyearling Chinook salmon and juvenile steelhead at the two dams in 2012 and subyearling Chinook salmon at the two dams and the mid-reach reservoir in 2013. This research investigated the correlation between vertical migration behavior and passage routes. The depth distributions of fish within the forebays of the dams were significantly different from fish passing the mid-reach reservoir. Fish residing deeper in the forebay tended to pass the dam using deeper powerhouse routes. This difference in depth distributions indicated that the depth distribution of fish at the mid-reach reservoir was not related to behaviors of fish passing through certain routes of the adjacent dams. For fish that were detected deeper than 17.5 m in the forebays, the probability of powerhouse passage (i.e., turbine) increased significantly. Another important finding was the variation in depth distributions during dam passage associated with the diel period, especially the crepuscular periods.

Purpose: To conduct a cost-effectiveness analysis study of sevelamer versus calcium-based binders (CBBs) in treating hyperphosphatemia among patients with end-stage renal disease (ESRD) in China., Methods: A decision-analytic model of a lifetime horizon was used for base case analysis from the payers' perspective. The transition probabilities between different health states were derived from survival analysis. The overall survival of CBBs was derived from the Dialysis Clinical Outcomes Revisited study for up to 44 months and a Weibull regression model was used to extrapolate the overall survival to a lifetime horizon. A hazard ratio (0.54; 95% CI, 0.32-0.93) of the overall survival for sevelamer versus CBBs was used to calculate the survival of the sevelamer group. Clinical and cost data were derived from literature and health care system in the local setting. Incremental life year and quality-adjusted life year (QALY) were the primary outcomes. One-way and probabilistic sensitivity analyses were conducted to assess the uncertainty of the model assumptions and parameters. The results were reported in 2015 Chinese Renminbi., Findings: The incremental cost per life year and per QALY gained of sevelamer versus CBBs was ¥44,475 and ¥57,910, respectively. The incremental cost per QALY gained was below the World Health Organization's recommended cost-effectiveness threshold (¥151,070), which is 3 times the gross domestic product per capita of 2015 in China. The incremental cost-effectiveness ratio was most sensitive to the hazard ratio of overall survival with sevelamer versus CBBs in the 1-way sensitivity analysis. The cost-effectiveness acceptability curve indicated that sevelamer had a 89.6% likelihood of cost-effectiveness at the ¥151,070 threshold., Implications: Sevelamer is likely to be a cost-effective option in treating hyperphosphatemia among patients with ESRD compared with CBBs in the local context of China., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer's disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APP/PS1 transgenic mice. Our findings reveal that deacetylation of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.

Locating the position of fixed or mobile sources (i.e., transmitters) based on measurements obtained from sensors (i.e., receivers) is an important research area that is attracting much interest. In this paper, we review several representative localization algorithms that use time of arrivals (TOAs) and time difference of arrivals (TDOAs) to achieve high signal source position estimation accuracy when a transmitter is in the line-of-sight of a receiver. Circular (TOA) and hyperbolic (TDOA) position estimation approaches both use nonlinear equations that relate the known locations of receivers and unknown locations of transmitters. Estimation of the location of transmitters using the standard nonlinear equations may not be very accurate because of receiver location errors, receiver measurement errors, and computational efficiency challenges that result in high computational burdens. Least squares and maximum likelihood based algorithms have become the most popular computational approaches to transmitter location estimation. In this paper, we summarize the computational characteristics and position estimation accuracies of various positioning algorithms. By improving methods for estimating the time-of-arrival of transmissions at receivers and transmitter location estimation algorithms, transmitter location estimation may be applied across a range of applications and technologies such as radar, sonar, the Global Positioning System, wireless sensor networks, underwater animal tracking, mobile communications, and multimedia.