Abemaciclib increases the risk of venous thromboembolism in breast cancer: Integrate meta-analysis, pharmacovigilance database analysis, and in vitro validation.

BACKGROUND: Recently, cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have emerged as a novel treatment strategy for breast cancer. However, increasing reports of CDK4/6i-associated venous thromboembolism (VTE) have garnered attention. This study assessed CDK4/6i-associated VTE in breast cancer, and examined the effect of CDK4/6i on platelet/coagulation function for the first time in vitro. METHODS: PubMed and Embase databases were searched for studies published from the establishment of the database to December 31, 2022 for randomized controlled trials (RCTs) and real-world studies of CDK4/6i in patients with breast cancer, and the data obtained from the included studies were used for meta-analysis. A disproportionality analysis by extracting adverse drug reaction signals of CDK4/6i-associated VTE from the FDA Adverse Event Reporting System (FAERS) database was also conducted. Additionally, the in vitro effect of CDK4/6i on platelet function was assessed based on platelet aggregation tests and flow cytometry, and coagulation function was assessed based on the blood clotting function test. FINDINGS: A total of 16,903 patients in 13 RCTs and 6,490 patients in 9 real-world studies were included in the meta-analysis. In RCTs, VTE occurred in 193 (2.1 %) and 55 (0.7 %) patients in the CDK4/6i and control groups, respectively. In real-world studies, the aggregate incidence rate of VTE was 4.2 % (95 % CI: 2.1, 6.3). The meta-analysis of RCTs revealed that abemaciclib (Odds ratio [OR]: 4.40 [95 % CI: 2.74,7.05], p < 0.001) and palbociclib (OR: 2.35 [95 % CI: 1.34, 4.12], p < 0.01) significantly increased the risk of VTE in patients with breast cancer compared to placebo. FAERS database analysis revealed that abemaciclib (reporting odds ratio [ROR]: 1.63 [95 % CI: 1.36, 1.97]; IC025: 0.67) and ribociclib (ROR: 1.17 [95 % CI: 1.0, 1.39]; IC025: 0.18) demonstrated a significantly increased signal of VTE. Similarly, findings from in vitro experiments demonstrated that abemaciclib enhanced agonist-induced platelet activation, especially when collagen was used as the inducer, and this effect became more prominent with increasing its concentration. INTERPRETATION: Use of abemaciclib may increase the risk of VTE in patients with breast cancer, which may be partially attributed to the effect of abemaciclib on platelet function. Close monitoring of VTE occurrence is highly recommended while using abemaciclib, especially in patients at a high risk of VTE.

Chemokine-mediated F-actin dynamics, polarity, and migration in B lymphocytes depend on WNK1 signaling.

Ligand-engaged chemokine receptors trigger nucleotide exchange in heterotrimeric Gαi proteins, which stimulates cytoskeletal reorganization and cell polarity changes. To better understand the signaling events responsible for these cellular changes, we focused on early changes in F-actin dynamics after engagement of the chemokine receptor CXCR5 in murine splenic B cells. Within 10 seconds of exposure to the CXCR5 ligand CXCL13, three-dimensional lamellar-like pseudopods and F-actin-rich ridges appeared. The transient F-actin increase depended on Gαi2/3 signaling, the PI3K/AKT pathway, ERK activation, phospholipase C activity, and Rac1/2 activation mediated by Dock2 (dedicator of cytokinesis 2). Immunoblot analyses identified the kinase WNK1 (with no lysine kinase 1) as a potential early AKT effector. Treating B cells with specific WNK inhibitors disrupted F-actin dynamics and impaired B cell polarity, motility, and chemotaxis. These changes were mimicked in a murine B cell line by CRISPR-Cas9 gene editing of Wnk1, which also suggested that WNK1 contributed to B cell proliferation. Administration of a single dose of a WNK inhibitor transiently reduced B cell motility and polarity in the lymph nodes of live mice. These results indicate that WNK1 signaling maintains B cell responsiveness to CXCL13 and suggest that pharmacological inhibition of WNK1, which is involved in cancer progression and blood pressure regulation, may affect humoral immunity.

ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.

Elevated neutrophil extracellular trap levels in periodontitis: Implications for keratinization and barrier function in gingival epithelium.

AIM: To explore the levels of neutrophil extracellular traps (NETs) in patients with periodontitis and examine their effects on keratinization, barrier function of human gingival keratinocytes (HGKs) and the associated mechanisms. MATERIALS AND METHODS: Saliva, gingival crevicular fluid (GCF), clinical periodontal parameters and gingival specimens were collected from 10 healthy control subjects and 10 patients with stage II-IV periodontitis to measure the NET levels. Subsequently, mRNA and protein levels of keratinization and barrier indicators, as well as intracellular calcium and epithelial barrier permeability, were analysed in HGKs after NET stimulation. RESULTS: The study showed that NET levels significantly elevated in patients with periodontitis, across multiple specimens including saliva, GCF and gingival tissues. Stimulation of HGKs with NETs resulted in a decrease in the expressions of involucrin, cytokeratin 10, zonula occludens 1 and E-cadherin, along with decreased intracellular calcium levels and increased epithelial barrier permeability. Furthermore, the inhibition of keratinization by NETs is ERK-KLF4-dependent. CONCLUSIONS: This study indicates that NETs impair the barrier function of HGKs and suppress keratinization through ERK/KLF4 axis. These findings provide potential targets for therapeutic approaches in periodontitis to address impaired gingival keratinization.

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review).

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low­density lipoprotein­cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti­PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.

The effects of repeated freezing and thawing on bovine sperm morphometry and function.

Refreezing the remaining genetic resources after in vitro fertilization (IVF) can conserve genetic materials. However, the precise damage inflicted by repeated freezing and thawing on bovine sperm and its underlying mechanism remain largely unexplored. Thus, this study investigates the impact of repeated freeze-thaw cycles on sperm. Our findings indicate that such cycles significantly reduce sperm viability and motility. Furthermore, the integrity of the sperm plasma membrane and acrosome is compromised during this process, exacerbating the advanced apoptosis triggered by oxidative stress. Additionally, transmission electron microscopy exposed severe damage to the plasma membranes of both the sperm head and tail. Notably, the "9 + 2" structure of the tail was disrupted, along with a significant decrease in the level of the axonemal protein DNAH10, leading to reduced sperm motility. IVF outcomes revealed that repeated freeze-thaw cycles considerably impair sperm fertilization capability, ultimately reducing the blastocyst rate. In summary, our research demonstrates that repeated freeze-thaw cycles lead to a decline in sperm viability and motility, attributed to oxidative stress-induced apoptosis and DNAH10-related dynamic deficiency. As a result, the utility of semen is compromised after repeated freezing.

Gravity-based focusing and size-dependent separation of metal microparticles in lubricating oil.

The separation of wear microparticles in lubricating oil is crucial for improving the accuracy and throughput of the subsequent detection. However, there are few kinds of research on the separation of high-density metallic microparticles in high-viscosity lubricating oil. In this paper, a passive method for separating the metallic microparticles in oil is proposed. Gravity sedimentation was adopted to realize three-dimensional (3D) focusing of the particle by using an inclined capillary. The gravity-based 3D focusing made the sheath flow no longer responsible for the particle focusing and effectively reduced the sheath flow. Then, the separation of different-sized metallic microparticles was achieved in a horizontal channel with the aid of a sheath flow based on the different driving forces. The present method solved the problem of nonsynchronous separation of the particle in comparison to the traditional methods. This device has a simple structure with high separation efficiency, and it is easy to integrate with the detection channel. The influence of numerous parameters on the gravity-based focusing and separation was systematically studied by the numerical simulation and the experiment. The design criteria were established, which is useful in designing and employing the device, expanding its application to other non-neutral buoyancy particle separation cases, and opening up more prospects for microfluidic technology.

Dihydroartemisinin inhibits plasmid transfer in drug-resistant Escherichia coli via limiting energy supply.

Conjugative transfer of antibiotic resistance genes (ARGs) by plasmids is an important route for ARG dissemination. An increasing number of antibiotic and nonantibiotic compounds have been reported to aid the spread of ARGs, highlighting potential challenges for controlling this type of horizontal transfer. Development of conjugation inhibitors that block or delay the transfer of ARG-bearing plasmids is a promising strategy to control the propagation of antibiotic resistance. Although such inhibitors are rare, they typically exhibit relatively high toxicity and low efficacy in vivo and their mechanisms of action are inadequately understood. Here, we studied the effects of dihydroartemisinin (DHA), an artemisinin derivative used to treat malaria, on conjugation. DHA inhibited the conjugation of the IncI2 and IncX4 plasmids carrying the mobile colistin resistance gene ( mcr-1) by more than 160-fold in vitro in Escherichia coli, and more than two-fold (IncI2 plasmid) in vivo in a mouse model. It also suppressed the transfer of the IncX3 plasmid carrying the carbapenem resistance gene bla NDM-5 by more than two-fold in vitro. Detection of intracellular adenosine triphosphate (ATP) and proton motive force (PMF), in combination with transcriptomic and metabolomic analyses, revealed that DHA impaired the function of the electron transport chain (ETC) by inhibiting the tricarboxylic acid (TCA) cycle pathway, thereby disrupting PMF and limiting the availability of intracellular ATP for plasmid conjugative transfer. Furthermore, expression levels of genes related to conjugation and pilus generation were significantly down-regulated during DHA exposure, indicating that the transfer apparatus for conjugation may be inhibited. Our findings provide new insights into the control of antibiotic resistance and the potential use of DHA.

ß-hydroxybutyrate impairs bovine oocyte maturation via pyruvate dehydrogenase (PDH) associated energy metabolism abnormality.

Background: Ketosis is one of the most frequent and costly metabolic disorders in high-producing dairy cows, and negatively associated with the health and reproductive performance of bovine. Ketosis is mainly caused by the accumulation of ketone body ß-hydroxybutyric acid and its diagnosis is based on ß-hydroxybutyrate (ßHB) concentration in blood. Methods: In this study, we investigated the effects of ßHB on bovine oocyte maturation in the concentration of subclinical (1.2 mM) ßHB and clinical (3.6 mM). Results: The results showed ßHB disrupted bovine oocyte maturation and development capacity. Further analysis showed that ßHB induced oxidative stress and mitochondrial dysfunction, as indicated by the increased level of reactive oxygen species (ROS), disrupted mitochondrial structure and distribution, and depolarized membrane potential. Furthermore, oxidative stress triggered early apoptosis, as shown by the enhanced levels of Caspase-3 and Annexin-V. Moreover, 3.6 mM ßHB induced the disruption of the pyruvate dehydrogenase (PDH) activity, showing with the decrease of the global acetylation modification and the increase of the abnormal spindle rate. Conclusion: Our study showed that ßHB in subclinical/clinical concentration had toxic effects on mitochondrial function and PDH activity, which might affect energy metabolism and epigenetic modification of bovine oocytes and embryos.

Salvianolic acid B ameliorates retinal deficits in an early-stage Alzheimer's disease mouse model through downregulating BACE1 and Aß generation.

Alzheimer's disease (AD) is a neurodegenerative disease with subtle onset, early diagnosis remains challenging. Accumulating evidence suggests that the emergence of retinal damage in AD precedes cognitive impairment, and may serve as a critical indicator for early diagnosis and disease progression. Salvianolic acid B (Sal B), a bioactive compound isolated from the traditional Chinese medicinal herb Salvia miltiorrhiza, has been shown promise in treating neurodegenerative diseases, such as AD and Parkinson's disease. In this study we investigated the therapeutic effects of Sal B on retinopathy in early-stage AD. One-month-old transgenic mice carrying five familial AD mutations (5×FAD) were treated with Sal B (20 mg·kg-1·d-1, i.g.) for 3 months. At the end of treatment, retinal function and structure were assessed, cognitive function was evaluated in Morris water maze test. We showed that 4-month-old 5×FAD mice displayed distinct structural and functional deficits in the retinas, which were significantly ameliorated by Sal B treatment. In contrast, untreated, 4-month-old 5×FAD mice did not exhibit cognitive impairment compared to wild-type mice. In SH-SY5Y-APP751 cells, we demonstrated that Sal B (10 µM) significantly decreased BACE1 expression and sorting into the Golgi apparatus, thereby reducing Aß generation by inhibiting the ß-cleavage of APP. Moreover, we found that Sal B effectively attenuated microglial activation and the associated inflammatory cytokine release induced by Aß plaque deposition in the retinas of 5×FAD mice. Taken together, our results demonstrate that functional impairments in the retina occur before cognitive decline, suggesting that the retina is a valuable reference for early diagnosis of AD. Sal B ameliorates retinal deficits by regulating APP processing and Aß generation in early AD, which is a potential therapeutic intervention for early AD treatment.

Amelioration of olfactory dysfunction in a mouse model of Parkinson's disease via enhancing GABAergic signaling.

BACKGROUND: Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson's disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. RESULTS: We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. CONCLUSIONS: Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

[Development and clinical application of a new reduction device for the treatment of tibial plateau fracture under arthroscopic monitoring].

OBJECTIVE: To develop a reduction device for the arthroscopy-assisted treatment of tibial plateau fracture and explore its clinical efficacy. METHODS: From May 2018 to September 2019, 21 patients with tibial plateau fracture were treated, including 17 males and 4 females. Their ages ranged from 18 to 55 years old with an average of (38.6±8.7) years old. There were 5 cases of Schatzker typeⅡand 16 cases of Schatzker type Ⅲ. The self-designed reductor combined with arthroscope was used for auxiliary reduction and fixation(minimally invasive percutaneous plate osteosynthesis). The efficacy was analyzed by observing the operation time, blood loss, fracture healing time and knee function(HSS and IKDC scoring criteria). RESULTS: All the 21 patients were followed up for 8 to 24 with an average of(14.0±3.1) months. The operative time ranged from 70 to 95 min with an average of(81.7±7.6)min, incision length ranged from 4 to 7 cm with an average of(5.3±0.9) cm, intraoperative blood loss ranged from 20 to 50 ml with an average of(35.3±5.2) ml, postoperative weight-bearing time ranged from 30 to 50 d with an average of(35.1±9.2) d, fracture healing time ranged from 65 to 90 d with an average of(75.0±4.4) d, and complications were 0 cases, respectively. The fracture was well healed and no screw plate fracture was observed. The knee function scores of HSS and IKDC 18 months after operation were significantly higher than those before operation(P<0.05). CONCLUSION: The custom-made reduction tool for the arthroscopic management of tibial plateau fracture is reasonable in design and simple in operation. The specific reduction tool could effectively reduce the fracture, and shorten the fixation time with minimally invasive procedure.

Evaluation of clinical factors and outcome of systemic glucocorticoid therapy discontinuation in patients with pemphigus achieving complete remission.

Therapy discontinuation of systemic glucocorticoid treatment for pemphigus remains uncertain at the clinical end point of complete remission. The objective of this study was to identify the factors associated with achieving complete remission off therapy (CROT) and analyze the occurrence of relapse after therapy discontinuation. A retrospective cohort study was conducted at the Department of Dermatology of Peking University First Hospital. A total of 447 patients with pemphigus treated from 2005 to 2020 were identified. Univariate and multivariate analyses were conducted to analyze the associated factors of CROT and to evaluate the outcomes. The mean age was 48 years (±13.4 years), and 54.6% of the patients were women. During a median follow-up of 59 months (43-87.5 months), 160 of 447 (35.8%) patients achieved CROT after a median treatment duration of 51 months (38-66.2 months). Patients with a shorter therapy duration to complete remission on minimal therapy and negative desmoglein antibodies tested in remission were more likely to achieve early CROT. Thirty-five of 160 (21.9%) patients experienced relapse after CROT. Patients who discontinued therapy without guidance experienced significantly faster and higher occurrences of relapse than those withdrawing under guidance (log-rank p = 0.01). Minimal therapy maintenance ≤8 months from complete remission on minimal therapy and positive desmoglein antibodies tested at withdrawal increased the risk of early relapse after CROT.

Application of plasma-activated water in the food industry: A review of recent research developments.

Plasma-activated water (PAW) is liquid treated with plasma. This liquid develops a higher oxygen reduction potential, a lower pH, and conductivity due to the delivery of reactive species from plasma to water. In this article, we review the antimicrobial activity and other applications of PAW in various food products. We discuss the effects of PAW treatment parameters on microbial inactivation efficiency as well as the underlying mechanisms, pesticide dissipation and its degradation pathway, meat curing and strategies to improve the nitrite amount in PAW, enhancement of food functional characteristics, and seed germination and plant growth. Additionally, we highlight the effects of PAW on food quality attributes. We further introduce the synergistic interaction of PAW with other technologies. Finally, we provide an overview of future challenges that must be resolved in the application of PAW in the food industry.

Development and clinical application of a new reduction device for the treatment of tibial plateau fracture under arthroscopic monitoring / 中国骨伤

OBJECTIVE@#To develop a reduction device for the arthroscopy-assisted treatment of tibial plateau fracture and explore its clinical efficacy.@*METHODS@#From May 2018 to September 2019, 21 patients with tibial plateau fracture were treated, including 17 males and 4 females. Their ages ranged from 18 to 55 years old with an average of (38.6±8.7) years old. There were 5 cases of Schatzker typeⅡand 16 cases of Schatzker type Ⅲ. The self-designed reductor combined with arthroscope was used for auxiliary reduction and fixation(minimally invasive percutaneous plate osteosynthesis). The efficacy was analyzed by observing the operation time, blood loss, fracture healing time and knee function(HSS and IKDC scoring criteria).@*RESULTS@#All the 21 patients were followed up for 8 to 24 with an average of(14.0±3.1) months. The operative time ranged from 70 to 95 min with an average of(81.7±7.6)min, incision length ranged from 4 to 7 cm with an average of(5.3±0.9) cm, intraoperative blood loss ranged from 20 to 50 ml with an average of(35.3±5.2) ml, postoperative weight-bearing time ranged from 30 to 50 d with an average of(35.1±9.2) d, fracture healing time ranged from 65 to 90 d with an average of(75.0±4.4) d, and complications were 0 cases, respectively. The fracture was well healed and no screw plate fracture was observed. The knee function scores of HSS and IKDC 18 months after operation were significantly higher than those before operation(P<0.05).@*CONCLUSION@#The custom-made reduction tool for the arthroscopic management of tibial plateau fracture is reasonable in design and simple in operation. The specific reduction tool could effectively reduce the fracture, and shorten the fixation time with minimally invasive procedure.

Assessment of shoulder range of motion using a commercially available wearable sensor-a validation study.

Background: Our study aims to validate a commercially available inertial measurement unit (IMU) system against a standard laboratory-based optical motion capture (OMC) system for shoulder measurements in a clinical context. Methods: The validation analyses were conducted on 19 healthy male volunteers. Twelve reflective markers were placed on each participant's trunk, scapula and across the arm and one IMU was attached via a self-adhesive strap on the forearm. A single tester simultaneously collected shoulder kinematic data for four shoulder movements: flexion, extension, external rotation, and abduction. Agreement between OMC system and IMU measurements was assessed with Bland-Altman analyses. Secondary analysis included mean biases, root mean square error (RMSE) analysis and Welch's t-test. Results: Bland-Altman limits of agreement (LoA) exceeded the acceptable range of mean difference for 95% of the population (-22.27°, 11.31°). The mean bias showed high levels of agreement within 8° for all four movements. More than 60% of participants demonstrated mean bias less than 10° between methods. Statistically significant differences were found between measurements for abduction (P<0.001) and flexion (P=0.027) but not for extension and external rotation (P≥0.05). Conclusions: Our study shows preliminary evidence for acceptable accuracy of a commercially available IMU against an OMC system for assessment of shoulder movements by a single tester. The IMU also exhibits similar whole degree of error compared to a standard goniometer with potential for application in remote rehabilitation.

Risk stratification system for skin and soft tissue infections after allogeneic hematopoietic stem cell transplantation: PAH risk score.

Skin and soft tissue infections (SSTIs) refer to infections involving the skin, subcutaneous tissue, fascia, and muscle. In transplant populations with hematological malignancies, an immunocompromised status and the routine use of immunosuppressants increase the risk of SSTIs greatly. However, to date, the profiles and clinical outcomes of SSTIs in hematopoietic stem cell transplantation (HSCT) patients remain unclear. This study included 228 patients (3.67%) who developed SSTIs within 180 days after allogeneic HSCT from January 2004 to December 2019 in Peking University People's Hospital. The overall annual survival rate was 71.5%. We compared the differences between survivors and non-survivors a year after transplant and found that primary platelet graft failure (PPGF), comorbidities of acute kidney injury (AKI), and hospital-acquired pneumonia (HAP) were independent risk factors for death in the study population. A PPGF-AKI-HAP risk stratification system was established with a mortality risk score of 1×PPGF+1×AKI+1×HAP. The areas under the curves of internal and external validation were 0.833 (95% CI 0.760-0.906) and 0.826 (95% CI 0.715-0.937), respectively. The calibration plot revealed the high consistency of the estimated risks, and decision curve analysis showed considerable net benefits for patients.

Risk of infection in roxadustat treatment for anemia in patients with chronic kidney disease: A systematic review with meta-analysis and trial sequential analysis.

Background: Many studies demonstrated that roxadustat (FG-4592) could increase hemoglobin (Hb) levels effectively in anemia patients with chronic kidney disease (CKD). However, its safety remains controversial. This study aims to explore the risk of infection for CKD patients treated with roxadustat, especially focused on sepsis. Methods: We thoroughly searched for the randomized controlled trials (RCTs) comparing treatment with roxadustat versus erythropoiesis stimulating agents (ESAs) or placebo in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, European Union Clinical Trials Register. Both on and not on dialysis anemia patients with CKD were included. Primary outcomes contained the incidence rates of sepsis. Secondary outcomes included infection-related consequences (septic shock and other infection events), general safety outcomes [all-cause mortality, treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)] and iron parameters. Moreover, a trial sequential analysis (TSA) was conducted to assess if the results were supposed to be a robust conclusion. Results: Eighteen RCTs (n = 11,305) were included. Overall, the incidence of sepsis (RR: 2.42, 95% CI [1.50, 3.89], p = 0.0003) and cellulitis (RR: 2.07, 95% CI [1.24, 3.44], p = 0.005) were increased in the roxadustat group compared with placebo group. In non-dialysis-dependent (NDD) CKD patients, the incidence of cellulitis (RR 2.01, 95% CI [1.23, 3.28], p = 0.005) was significantly higher in roxadustat group than that in the ESAs or placebo group. Both groups showed similar results in the incidence of septic shock (RR 1.29, 95% CI [0.86, 1.94], p = 0.22). A significant increased risk of all-cause mortality [risk ratios (RR): 1.15, 95% confidence interval (CI) [1.05, 1.26], p = 0.002] was found in roxadustat treatment, and TSA confirmed the result. Compared with ESAs or placebo, both the incident rates of TEAEs (RR:1.03, 95% CI [1.01, 1.04], p = 0.008) and TESAEs (RR: 1.06, 95% CI [1.02, 1.11], p = 0.002) were significantly increased in roxadustat group. As for iron parameters, changes from baseline (Δ) of hepcidin (MD: -26.46, 95% CI [-39.83, -13.09], p = 0.0001), Δ ferritin and Δ TSAT were remarkably lower in the roxadustat group, while Δ Hb, Δ iron and Δ TIBC increased significantly versus those in ESAs or placebo group. Conclusion: We found evidence that incidence rates of sepsis and cellulitis are higher in roxadustat group compared with placebo. This may be the result of improved iron homeostasis. The risk of all-cause mortality, TEAEs and TESAEs in CKD patients also increased in patients treated with roxadustat. We need more clinical and mechanistic studies to confirm whether roxadustat really causes infection.

Elastic-inertial separation of microparticle in a gradually contracted microchannel.

Separation of microparticle in viscoelastic fluid is highly required in the field of biology and clinical medicine. For instance, the separation of the target cell from blood is an important prerequisite step for the drug screening and design. The microfluidic device is an efficient way to achieve the separation of the microparticle in the viscoelastic fluid. However, the existing microfluidic methods often have some limitations, including the requirement of the long channel length, the labeling process, and the low throughput. In this work, based on the elastic-inertial effect in the viscoelastic fluid, a new separation method is proposed where a gradually contracted microchannel is designed to efficiently adjust the forces exerted on the particle, eventually achieving the high-efficiency separation of different sized particles in a short channel length and at a high throughput. In addition, the separation of WBCs and RBCs is also validated in the present device. The effect of the flow rate, the fluid property, and the channel geometry on the particle separation is systematically investigated by the experiment. With the advantage of small footprint, simple structure, high throughput, and high efficiency, the present microfluidic device could be utilized in the biological and clinical fields, such as the cell analysis and disease diagnosis.

Executive function predict the quality of life and negative emotion in older adults with diabetes: A longitudinal study.

AIMS: To investigate the influence of executive function (EF) on current and future quality of life (QoL) and negative emotion (NE) in older adults with diabetes. METHODS: A total of 128 older adults with diabetes were recruited. Independent variables (demographic information, health and medical conditions, cognitive function, life function) were collected in the first year. Dependent variables (QoL and NE) were collected for 3 years. Pearson's correlation coefficient analysis and stepwise multiple linear regression analysis were performed to identify the predictors of QoL and NE. RESULTS: EF was the strongest predictor for overall QoL and NE in all 3 years, and accounted for 23.0-36.2% and 11.1-17.1% of the variance, respectively. The second strongest predictor for overall QoL in all 3 years was pain interference, which accounted for 3.2-5.8% of the variance. Pain interference was also the second strongest predictor for NE in the second year, accounting for 5.5% of the variance. CONCLUSIONS: The present study revealed that EF is more predictive than pain for current and future QoL and NE in older adults with diabetes. We recommend that EF be included as an indicator for diabetes surveillance, and that prevention of EF decline be a part of diabetes management plans.