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Extracellular vesicles (EVs) have emerged as promising candidates for multiple biomedical applications. Major types of EVs include exosomes, microvesicles, and apoptotic bodies (ABs). ABs are conferred most properties from parent cells in the final stages of apoptosis. A wide variety of sources and stable morphological features are endowed to ABs by the rigorous apoptotic program. ABs accommodate more functional biomolecules by relying on the larger volume and maintaining their naturalness in circulation. The predominant body surface ratio of ABs facilitates their recognition by recipient cells and is advantageous for interactions with microenvironments. ABs can modulate and alleviate symptoms of numerous diseases for their origins, circulation, and high biocompatibility. In addition, ABs have been emerging in disease diagnosis, immunotherapy, regenerative therapy, and drug delivery. Here, we aim to present a thorough discussion on current knowledge about ABs. Of particular interest, we will summarize the application of AB-based strategies for diagnosis and disease therapy. Perspectives for the development of ABs in biomedical applications are highlighted. [Display omitted] • Apoptotic bodies (ABs), released during apoptosis, are a unique subset of extracellular vesicles (EVs). • Advanced techniques provide excellent opportunities for studying ABs for biomedical applications. • ABs-mediated transportation of biomolecules is important in physiological processes and disease development. • ABs are playing an emerging role in disease diagnosis, immunotherapy, regenerative therapy, and drug delivery. [ABSTRACT FROM AUTHOR]

• The relationship between aortic pressure and flow rate is governed by the optimized third order ODE. • A dual-source LPM is capable for describing the dynamic interaction of aortic root pressure and flow rate under EECP. • The dynamic behavior of VAC under EECP is subjected to the principle of minimal ventricular output work. • The principle of minimal ventricular output work can serve as a criterion for determining aortic pressure and flow rate. Enhanced external counterpulsation (EECP) is a mechanically assisted circulation technique widely used in the rehabilitation and management of ischemic cardiovascular diseases. It contributes to cardiovascular functions by regulating the afterload of ventricle to improve hemodynamic effects, including increased diastolic blood pressure at aortic root, increased cardiac output and enhanced blood perfusion to multiple organs including coronary circulation. However, the effects of EECP on the coupling of the ventricle and the arterial system, termed ventricular-arterial coupling (VAC), remain elusive. We aimed to investigate the acute effect of EECP on the dynamic interaction between the left ventricle and its afterload of the arterial system from the perspective of ventricular output work. A neural network assisted optimization algorithm was proposed to identify the ordinary differential equation (ODE) relation between aortic root blood pressure and flow rate. Based on the optimized order of ODE, a lumped parameter model (LPM) under EECP was developed taking into consideration of the simultaneous action of cardiac and EECP pressure sources. The ventricular output work, in terms of aortic pressure and flow rate cooperated with the LPM, was used to characterize the VAC of ventricle and its afterload. The VAC subjected to the principle of minimal ventricular output work was validated by solving the Euler-Poisson equation of cost function, ultimately determining the waveforms of aortic pressure and flow rate. A third-order ODE can precisely describe the hemodynamic relationship between aortic pressure and flow rate. An optimized dual-source LPM with three energy-storage elements has been constructed, showing the potential in probing VAC under EECP. The LPM simulation results demonstrated that the VAC in terms of aortic pressure and flow rate yielded to the minimal ventricular output work under different EECP pressures. The ventricular-arterial coupling under EECP is subjected to the minimal ventricular output work, which can serve as a criterion for determining aortic pressure and flow rate. This study provides insight for the understanding of VAC and has the potential in characterizing the performance of the ventricular and arterial system under EECP. [ABSTRACT FROM AUTHOR]

Microfluidic-based analyses of single-cell dynamics in response to dynamic biochemical signals are emerging as pivotal approaches for investigating the effects of extracellular microenvironmental biochemical factors on cellular structure, function, and behavior. However, current devices often fail to consistently apply identical dynamic biochemical signals to trapped cells. In this study, we introduce a novel radially distributed single-cell trapping microfluidic array, designed to quantitatively and consistently apply identical biochemical stimulating signals to each trapped cell. Numerical simulations were employed to optimize microchannel geometry, enhancing trapping efficiency while minimizing signal distortion. Experimental validation demonstrated the trapping success rate and the single-cell trapping efficiency exceeding 99% and 85%, respectively. The microarray's capability to deliver identical dynamic biochemical stimulating signals, with various waveforms, to each unit was confirmed through fluorescein transport tests. Furthermore, we examined the intracellular calcium dynamics of U-2 OS human osteosarcoma cells in response to dynamic ATP signals, observing both single-peak calcium responses and calcium oscillations, which were modelled by a second-order system with a natural frequency of 1.6 mHz. Overall, our proposed microfluidic array offers a robust and valuable framework for advancing the understanding of single-cell dynamics. [Display omitted] • A single-cell-trapping microarray capable of delivering identical biochemical stimulating signals to trapped cells for cellular dynamics analysis was presented. • The trapping efficiency and the ability of loading biochemical stimulating signals were numerically and experimentally validated. • Intracellular calcium dynamics of U-2 OS cells in response to various ATP stimulations were investigated. • The intracellular calcium signaling dynamics can be characterized by the second-order system. [ABSTRACT FROM AUTHOR]

Targeted drug delivery to the glioblastoma (GBM) overcoming blood–brain barrier (BBB) has been challenging. Exosomes are promising vehicles for brain tumor drug delivery, but the production and purification hinder its application for nanomedicine. Besides, the formation of protein corona (PC) may affect the behaviour of nanocarriers. Here, multifunctional exosomes-mimetics (EM) are developed and decorated with angiopep-2 (Ang) for enhancing GBM drug delivery by manipulating PC. Docetaxel (DTX)-loaded EM with Ang modification (DTX@Ang-EM) show less absorption of serum proteins and phagocytosis by macrophages. Ang-EM show enhanced BBB penetration ability and targeting ability to the GBM. Ang-EM-mediated delivery increase the concentration of DTX in the tumor area. The multifunctional DTX@Ang-EM exhibits significant inhibition effects on orthotopic GBM growth with reduced side effects of the chemotherapeutic. Findings from this study indicate that the developed DTX@Ang-EM provide a new strategy for targeted brain drug delivery and GBM therapy. [ABSTRACT FROM AUTHOR]

Targeted drug delivery to the glioblastoma (GBM) overcoming blood–brain barrier (BBB) has been challenging. Exosomes are promising vehicles for brain tumor drug delivery, but the production and purification hinder its application for nanomedicine. Besides, the formation of protein corona (PC) may affect the behaviour of nanocarriers. Here, multifunctional exosomes-mimetics (EM) are developed and decorated with angiopep-2 (Ang) for enhancing GBM drug delivery by manipulating PC. Docetaxel (DTX)-loaded EM with Ang modification (DTX@Ang-EM) show less absorption of serum proteins and phagocytosis by macrophages. Ang-EM show enhanced BBB penetration ability and targeting ability to the GBM. Ang-EM-mediated delivery increase the concentration of DTX in the tumor area. The multifunctional DTX@Ang-EM exhibits significant inhibition effects on orthotopic GBM growth with reduced side effects of the chemotherapeutic. Findings from this study indicate that the developed DTX@Ang-EM provide a new strategy for targeted brain drug delivery and GBM therapy. [ABSTRACT FROM AUTHOR]

Exosomes (Exos) are promising vehicles for brain drug delivery due to nanosize and the ability to breach the blood–brain barrier (BBB). But the low yield of natural exosomes limits its application for nanomedicine. The generation of bioinspired nanovesicles (BNVs) that mimicking Exos is attractive, but there is a lack of comparative evaluation of Exos and BNVs. Here, we perform the first head-to-head comparison study of Exos and BNVs for brain tumor drug delivery. We show that BNVs derived from brain-derived endothelial cells are competent alternative nanocarrier to natural exosomes. The drug-loading capacity of Exos and BNVs are similar, but the yield of BNVs is substantially higher (500-fold) than Exos. Doxorubicin (DOX)-loaded BNVs (BNV/DOX) and DOX-loaded Exos (Exo/DOX) showed similar pharmacokinetic profiles and prolonged circulation od DOX. Despite inconsistent mechanisms, BNV/DOX can across the BBB, and exhibit suppression effects similar to Exo/DOX on the progress of glioblastoma (GBM) in zebrafish and in vivo subcutaneous and orthotopic xenografts mice models, with minimal systemic toxicity. Findings from this head-to-head comparison study indicate that autologous BNVs is a effective alternative of Exos for brain tumor nanomedicine. [Display omitted] • bEnd.3 cells-derived bioinspired nanovesicles (BNVs) by serial extrusion method showed 500-fold higher yield than exosomes. • bEnd.3 cells-derived BNVs and exosomes can breach the blood–brain barrier via different mechanisms. • BNVs and exosomes contain doxorubicin exhibited similar effects on suppression of the progression of glioblastoma in mice. [ABSTRACT FROM AUTHOR]

Exosomes are lipid bilayer membrane vesicles and are emerging as competent nanocarriers for drug delivery. The clinical translation of exosomes faces many challenges such as massive production, standard isolation, drug loading, stability and quality control. In recent years, artificial exosomes are emerging based on nanobiotechnology to overcome the limitations of natural exosomes. Major types of artificial exosomes include 'nanovesicles (NVs)', 'exosome-mimetic (EM)' and 'hybrid exosomes (HEs)', which are obtained by top-down, bottom-up and biohybrid strategies, respectively. Artificial exosomes are powerful alternatives to natural exosomes for drug delivery. Here, we outline recent advances in artificial exosomes through nanobiotechnology and discuss their strengths, limitations and future perspectives. The development of artificial exosomes holds great values for translational nanomedicine. [ABSTRACT FROM AUTHOR]

Background: Small extracellular vesicles (sEVs) are nanosized vesicles involved in cell-to-cell communication. sEVs have been widely studied for clinical applications such as early detection of diseases and as therapeutics. Various methods for sEVs isolation are been using, but different methods may result in different qualities of sEVs and impact downstream analysis and applications. Here, we compared current isolation methods and performed a comparative analysis of sEVs from supernatant of cultured pancreatic cancer cells. Methods: Ultracentrifugation, ultrafiltration and co-precipitation as concentration methods were firstly evaluated for yield, size, morphology and protein level of pellets. Then, isolate sEVs obtained by four different purification methods: size exclusion chromatography, density gradient ultracentrifugation, ultracentrifugation, and immunoaffinity capturing, were analysed and compared. Results: For the concentration process, ultracentrifugation method obtained high quality and high concentration of pellets. For the purification process, immunoaffinity capturing method obtained the purest sEVs with less contaminants, while density gradient ultracentrifugation-based method obtained sEVs with the smallest size. Proteomic analysis revealed distinct protein contents of purified sEVs from different methods. Conclusions: For isolating sEVs derived from supernatant of cultured pancreatic cancer cell line, ultracentrifugation-based method is recommended for concentration of sEVs, density gradient ultracentrifugation-based method may be applied for obtaining purified sEVs with controlled size, immunoaffinity capturing may be suitable for studies requiring sEVs with high purity but may loss subtypes of sEVs without specific protein marker. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are cell-derived lipid bilayer-enclosed nanovesicles. EVs are emerging as keys for identifying molecular mechanisms by mediating intercellular communication. EVs allow the exchange of various components with neighboring and distant cells through the extracellular environment, thereby involving in various biological processes in both physiological and pathological conditions such as wound healing, immune response, and tumorigenesis. EVs are also growing rapidly as cargo carrier for their natural delivery properties. Development of bioinspired delivery nanoplatforms based on exosomes-like mimetics also showed potentials to overcome limitations of synthetic nanoparticles. EVs offer a window to multicomponent diagnosis and a tool for design therapeutics. However, for successful clinical translation of EVs, the understanding of in vivo behavior is essential. Advancements in molecular imaging enabled high-resolution in vivo tracking of EVs, providing valuable information regarding trafficking, biodistribution, cellular uptake and molecular mechanism of EVs. Recent studies have explored various methods for visualizing EVs, each imaging technique has certain strengths and limitations. Highly specific, sensitive and biocompatible labeling and tracking strategies still in demand in EV visualization. In this review, we summarized methods for labeling and tracking of EVs and discussed benefits and drawbacks for each method. Future novel imaging modalities and combined strategies will provide avenues for understanding EV behavior and accelerate their clinical translation. Unlabelled Image • Extracellular vesicles (EVs) are interesting therapeutic tools but their in vivo behavior has not been fully understood. • Commonly methods used for visualization of EVs were comprehaneively summareized and compared. • Strategies such as photoacoustic imaging and Raman spectroscopy are emerging for labeling and tracking of EVs. • Powerful molecular imaging strategies would accelerate clinical translation of EVs-based therapy. [ABSTRACT FROM AUTHOR]

Summary: Individuals with autism spectrum disorder (ASD) or attention‐deficit hyperactivity disorder (ADHD) may have unhealthy bodyweight. This meta‐analysis was performed to understand the weight status in individuals with ASD or ADHD. PubMed, Embase, Cochrane and ISI Web of Science databases were searched from inception until June 2020 to identify relevant studies. Prevalence estimates and their 95% confidence intervals (CIs) of obesity, overweight and underweight were separately pooled using random‐effects models. A total of 95 studies were included in the meta‐analysis. The pooled estimates of the prevalence of obesity, overweight and underweight were 21.8%, 19.8% and 6.4% in individuals with ASD and 14.7%, 20.9% and 4.0% in individuals with ADHD. In subgroup analyses, an increasing trend in the prevalence of unhealthy weight was observed from children aged 2 to 5 years to adults with ASD (obesity: from 16.7% to 31.3%, overweight: from 16.2% to 27.2%, underweight from 5.3% to 8.6%) and from children aged 6 to 12 years to adults with ADHD (obesity: from 13.5% to 19.3%, overweight: from 18.8% to 31.2%). The worrisome epidemic of obesity and overweight in individuals with ASD, ADHD highlighted the need for weight management. [ABSTRACT FROM AUTHOR]

In the present study, we report a microfluidic platform that enables real-time control of biochemical stimuli to biological cells. The microfluidic platform is designed by integrating a 'Christmas tree' inlet for pre-generating spatially linear concentration gradient, with a Y-shaped channel to modulate dynamic signals with an external programmable air pump. The proposed design is simple and straightforward, has negligible response time compared to the traditional Y-shaped channel, and for the first time, provides the capability of generating versatile waveforms of dynamic stimuli and implementing multiple dynamic stimulating signals with different amplitudes synchronously. The feasibility of the microfluidic platform is proved by both computational fluid dynamics simulation and fluorescein experiment. The applicability of the proposed platform is demonstrated by characterizing the intracellular calcium ion dynamics in human umbilical vein endothelial cells in response to multiple dynamic stimuli within a single run. The proposed platform provides a simple approach to rapidly control dynamic stimuli with versatile waveforms to biological cells and shows the potential for the quantitative study of biological cellular dynamic responses. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is highly metastatic with very short survival and increasing mortality rates. Recent advances in therapeutic regimes and other adjuvant therapies improved slightly overall survival of pancreatic cancer, but fighting metastasis has been challenging and is necessary for achieving cure. Nanomedicine, not limited to drug delivery, offers opportunities for targeting cancer metastasis. Research regarding the prevention of metastasis of this malignancy is highly demanded. Herein, we focus on advances of nanomedicine-based strategies for targeting different stages of metastasis, including cancer stem cells, tumor microenvironment, circulating tumor cells and tumor exosomes. A greater emphasis on targeting metastasis of pancreatic cancer using nanomedicine-based strategies provides avenues for improving pancreatic cancer treatment outcomes in the future. Unlabelled Image • Pancreatic cancer is highly metastatic, but nanomedicine offered opportunities for fighting against metastasis. • Targeting cancer stem cells in the first place is important for preventing metastasis spread. • Remodeling the tumor microenvironment is preferable for intratumoral delivery of chemotherapeutics. • Targeting circulating tumor cells is a feasible strategy for preventing metastatic colony formation • Targeting oncogenic exosomes using specific markers may also to prevent metastasis of PDAC [ABSTRACT FROM AUTHOR]

Studies have examined the association between parental body mass index (BMI) and autism spectrum disorder (ASD) in offspring, with inconsistent results, especially regarding maternal obesity, overweight and underweight. Cochrane Library, EMBASE, PubMed and PsycINFO databases were searched up to March 2018 for relevant observational studies with no language restriction. Our literature search identified 13 eligible studies for meta-analysis (involving 943,293 children and 30,337 cases). For maternal BMI (13 studies), both maternal obesity [OR 1.41 (95% CI 1.19–1.67)] and maternal overweight [OR 1.16 (95% CI 1.05–1.27)] were significantly associated with ASD, while maternal underweight was not associated with ASD [OR 1.08 (95% CI 0.98–1.20)]. For paternal BMI (three studies), no association was found (paternal obesity: OR 1.28, 95% CI 0.94–1.74; overweight: OR 1.07, 95% CI 0.99–1.15; underweight: OR 1.12, 95% CI 0.87–1.44). Pooled estimates were robust in sensitivity analysis and subgroup analyses. Publication bias may exist for studies assessing maternal BMI and ASD risk, but the filled estimates were not altered. Relative to normal weight, maternal obesity and overweight were significantly associated with increased ASD risk, while maternal underweight was not associated with ASD. Although no association between paternal BMI and ASD was found, current evidence is limited (three studies). Future studies are warranted to address more confounding factors and to identify potential mediators of the association, but pre-pregnancy weight control is suggested. [ABSTRACT FROM AUTHOR]

Puerarin (PUE) and tetramethylpyrazine (TMP) are central nervous system (CNS) drugs used in cerebrovascular diseases. Poor brain-blood barrier (BBB) permeability limited their clinical application. Borneol and α-asarone have been proposed as an oral brain-targeting enhancer. In this study, we aimed to first evaluate the 'orifice-opening' effect of borneol and α-asarone, both aromatic resuscitation drugs, on improvement of brain delivery of PUE and TMP and second to investigate whether the enhancing effects were associated with adenosine receptors (ARs)-mediated trans-BBB pathway. In vitro BBB model was established and borneol and α-asarone significantly increased the cumulative amount of permeated PUE and TMP and the enhancing effects could be counteracted by AR inhibitors. Borneol and α-asarone could decrease expression of ZO-1, an important BBB junction protein, but inversely increase the expression of A1AR and A2AAR. In vivo pharmacokinetic study also confirmed that oral co-administration of borneol or α-asarone significantly increased AUCbrain for PUE and TMP. These results suggested that borneol and α-asarone are both effective adjuvant agents for delivery of PUE and TMP to the brain. [ABSTRACT FROM AUTHOR]

Highlights • COX-2 was expressed in a subset of CTCs in NPC patients, and the expression status evolved from baseline (87/131, 66.4%) to the end of concurrent radiochemotherapy (53/115, 46.1%). • Post-therapeutic COX-2 expression on CTCs remained an independent prognostic indicator for poorer progression-free survival (HR 2.17, P = 0.019) and overall survival (HR 2.41, P = 0.024) in NPC patients. • NPC patients with post-therapeutic COX-2 expression on CTCs had significantly poorer treatment response (P = 0.011) and higher risk of tumor relapse (P = 0.026) and metastasis (P = 0.007). Abstract Background and purpose The prognostic significance of circulating tumor cells (CTCs) in head and neck cancer is still under debate, as only a few studies have been reported and limited conclusions are reached. Besides, CTCs' count alone was utilized as an indicator in the previous researches. As a form of 'liquid biopsy', the further identification of genetic or phenotypic biomarkers on CTCs could possibly provide further clinical significance. Materials and methods The prospective study enrolled 131 patients with nasopharyngeal carcinoma (NPC). CTCs were isolated at baseline and at the end of concurrent chemoradiotherapy, and cyclooxygenase-2 (COX-2) expression status of CTCs was detected by RNA-in situ hybridization (ISH) method. Results were correlated with patient's clinicopathological parameters and treatment outcomes. Univariate and multivariate survival analyses were performed to determine the prognostic significance. Results COX-2 expression was found in 87/131 (66.4%) patients at baseline and 53/115 (46.1%) patients at the end of concurrent chemoradiotherapy. Patients with post-therapeutic COX-2 expression had significantly poorer treatment response (P = 0.011) and higher risk of tumor relapse (P = 0.026) and metastasis (P = 0.007). Besides, multivariate analysis revealed that post-therapeutic COX-2 expression on CTCs remained an independent prognostic indicator for poorer progression-free survival (HR 2.17, P = 0.019) and overall survival (HR 2.41, P = 0.024). Conclusion The study demonstrated that post-therapeutic COX-2 expression on CTCs was a novel and promising prognostic indicator for NPC patients. Future studies are needed to validate our findings and further clarify the value of integrating the indicator with current clinical strategies in improving survival of NPC patients. [ABSTRACT FROM AUTHOR]

Purpose: Nutritional supplements have been used for correction of deficiencies that may occur in patient with autism spectrum disorder (ASD) and to improve core symptoms. We aim to provide current best evidence about supplements for nutritional deficiencies and core symptoms in children with ASD and to evaluate the effectiveness and safety.Methods: A systematic literature search of scientific databases was performed to retrieve relevant randomized controlled trials. Risk of bias was assessed for each study.Results: 18 randomized controlled trials of five supplements were included. B6/Mg was not helpful for improving ASD symptoms (seven RCTs). Two RCTs of methyl B12 reported some improvement in ASD severity but the effects on the correction of deficiencies were inconclusive. Two RCTs of vitamin D3 both reported increased levels of mean 25(OH)D in serum but inconsistent results in behavioral outcomes. Omega-3 fatty acid supplementation did not affect ASD behaviors but may correct deficiencies (six RCTs). One RCT of folinic acid reported positive results in improving ASD symptoms measured by various behavioral scales.Conclusions: Current evidence for the use of supplements for correcting nutritional deficiencies in children with ASD and to improve the symptoms is little. More studies are needed. [ABSTRACT FROM AUTHOR]

The prognostic significance of CXC chemokine receptor 4 (CXCR4) in patients with bone and soft tissue sarcomas remains controversial. To investigate the impact of its expression on survival and clinicopathological features, we performed a meta-analysis. Comprehensive literature searches were conducted in PubMed, Web of Science, Embase and Cochrane Library for relevant studies. In total, 12 studies with 997 sarcoma patients were included. CXCR4 expression was found to be significantly associated with poor overall survival (HR 2.37, 95 % CI 1.86-3.01; P < 0.001). Further, when the analysis was stratified by histological subtypes (bony sarcoma including osteosarcoma and Ewing sarcoma and soft tissue sarcoma including synovial sarcoma and rhabdomyosarcoma), statistical analysis method (multivariate analysis and univariate analysis) and CXCR4 measuring method (IHC or RT-PCR), the significant correlation to poor overall survival was also observed except for that in Ewing sarcoma and RT-PCR groups. As for clinicopathological features, CXCR4 expression was significantly associated with higher rate of metastasis (OR 6.97, 95 % CI 2.28-21.31; P = 0.001) and higher tumor stage (OR 7.55, 95 % CI 1.25-45.47; P = 0.027), but not associated with gender, age and tumor site. In conclusion, CXCR4 expression may be an effective predictive factor of poor prognosis and clinicopathological features for bone and soft tissue sarcomas. Further studies are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Berberine hydrochloride (BBH) has a variety of pharmacological activities such as antitumor, antimicrobial, anti-inflammation, and reduce irritable bowel syndrome. However, poor stability and low oral bioavailability limited its usage. Herein, an oil-in-water nanoemulsion system of BBH was developed to improve its stability and oral bioavailability. The pseudoternary phase diagrams were constructed for the determination of composition of various nanoemulsions. The nanoemulsions of BBH composed of Labrafil M 1944 CS (oil phase), RH-40 (surfactant), glycerin (co-surfactant), and water (aqueous phase). The O/W nanoemulsion of BBH showed a relative bioavailability of 440.40% compared with unencapsulated BBH and was stable in our 6-month stability study. Further, there was a significant increase in intestinal permeability of BBH as assessed by Caco-2 cell monolayers and a significant reduction in efflux of BBH by the multidrug efflux pump P-glycoprotein. This study confirmed that the nanoemulsion formulation could be used as an alternative oral formulation of BBH to improve its stability, oral bioavailability and permeability. [ABSTRACT FROM AUTHOR]

Background: We conducted a meta-analysis from randomized controlled trials (RCTs) and non-RCTs to assess the efficacy of aminocaproic acid in cases of primary total hip arthroplasty (THA) or total knee arthroplasty (TKA). Methods: Potentially relevant academic articles were identified from the Cochrane Library, MEDLINE (1966–2017 October 31), PubMed (1966–2017 October 31), EMBASE (1980–2017 October 31), and ScienceDirect (1985–2017 October 31). Secondary sources were identified from the references of the included literature. The pooled data were analyzed using RevMan 5.1. Results: Three RCTs and four non-RCTs met the inclusion criteria. There were significant differences in total blood loss (mean difference (MD) = − 495.80, 95% CI − 837.29 to − 154.32, P = 0.004), drainage volume (MD = − 249.43, 95% CI − 286.78 to − 212.08, P < 0.00001), postoperative hemoglobin level (MD = 0.90, 95% CI 0.78 to 1.02, P < 0.00001), hemoglobin reduction (MD = − 0.75, 95% CI − 0.93 to − 0.57, P < 0.00001), transfusion rates (risk difference (RD) = − 0.17, 95% CI − 0.25 to − 0.09, P < 0.0001), average transfusion units (MD = − 0.28, 95% CI − 0.48 to − 0.09, P = 0.004), and length of hospital stay (MD = − 0.33, 95% CI − 0.43 to − 0.24, P < 0.00001) between the two groups. No significant differences were found regarding deep vein thrombosis (DVT) (RD = − 0.00, 95% CI − 0.01 to 0.00, P = 0.36) between the two groups. Conclusions: The present meta-analysis indicated that the application of aminocaproic acid in THA or TKA decreases the total blood loss, drainage volume, transfusion rate, transfusion units per patient, and length of hospital stay and does not increase the risk of DVT. [ABSTRACT FROM AUTHOR]

Studies have investigated the risk of autism spectrum disorder (ASD) in children exposed in utero to antidepressant, with inconsistent results. Given the substantial public health implications on this topic, here, we presented an updated meta-analysis of the association between maternal antidepressant use during pregnancy and ASD. Cochrane Library, EMBASE, PsycINFO, and PubMed databases were systematically searched. A random effects model was used to pool the adjusted relative risk (RR) for cohort studies and the adjusted odds ratio (OR) for case-control studies as well as their corresponding 95% confidence intervals (CIs). Meta-analysis restricted to sibling studies was also conducted. Publication bias was systematically assessed. Fourteen studies were identified (eight cohort studies and six case-control studies). Pooled adjusted RR for cohort studies (n = 2,839,980) was 1.13 (0.93–1.39) showed a non-significant association; while two studies were potentially missing from the test of publication bias, filled estimates also showed a non-significant association (filled RR 0.97, 95% CI 0.79–1.19). Pooled OR was 1.51 (1.15–1.99) for case-control studies (n = 117,737) showed a significant association; two studies were potentially missing; however, the filled estimates suggested a non-significant association (filled OR 1.26, 95% CI 0.98–1.62). Analyses restricted to sibling studies also showed a non-significant association (RR 0.99, 95% CI 0.81–1.22). In summary, we did not evidence a significant association between maternal antidepressant use during pregnancy and ASD. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on the effects of gestational selective serotonin reuptake inhibitor.

To reproduce hemodynamic stress microenvironments of endothelial cells in vitro is of vital significance, by which one could exploit the quantitative impact of hemodynamic stresses on endothelial function and seek innovative approaches to prevent circulatory system diseases. Although microfluidic technology has been regarded as an effective method to create physiological microenvironments, a microfluidic system to precisely reproduce physiological arterial hemodynamic stress microenvironments has not been reported yet. In this paper, a novel microfluidic chip consisting of a cell culture chamber with on-chip afterload components designed by the principle of input impedance to mimic the global hemodynamic behaviors is proposed. An external feedback control system is developed to accurately generate the input pressure waveform. A lumped parameter hemodynamic model (LPHM) is built to represent the input impedance to mimic the on-chip global hemodynamic behaviors. Sensitivity analysis of the model parameters is also elaborated. The performance of reproducing physiological blood pressure and wall shear stress is validated by both numerical characterization and flow experiment. Investigation of intracellular calcium ion dynamics in human umbilical vein endothelial cells is finally conducted to demonstrate the biological applicability of the proposed microfluidic system. [ABSTRACT FROM AUTHOR]

Periodic dynamic flow, including pulsatile flow and oscillatory flow, has many applications at the microscopic scale in chemistry, biology, and pharmacy. Conventional devices for periodic flow are either bulky, complicated, or inflexible. Here, we propose a novel on-chip flow generator with multi-pattern outputs possessing the obvious advantages of small size, simple structure, and being easy to be implemented. The fluid flow is synergistically driven by the constant pressure and the alternating pressure in a pair of conical channels. We design and fabricate a simple on-chip prototype following this conical-channel-based constant–alternating (C3A) driving method, and validate its performance through both numerical simulation and flow experiment. The results demonstrate the synergistic effects of the constant and alternating pressures on the fluid flow, and can implement four flow modes, i.e., steady flow, oscillatory flow, pulsatile flow, and complex flow, simply by modulating the input voltage. The proposed flow generator with multi-pattern outputs, simple structure and small footprint can be flexibly integrated with other on-chip devices for various biomedical applications, and the proposed strategy utilizing multiple synchronous sources can also inspire more delicate manipulation in the context of microfluidics. [Display omitted] • A conical-channel-based constant-alternating (C3A) driving method is proposed to drive fluid flow in a microchannel. • A novel on-chip flow generator for multi-pattern periodic dynamic (PD) flow is developed following the proposed C3A driving strategy. • Four flow modes can be implemented using the proposed on-chip prototype. • The proposed flow generator has the advantages of small size, simple structure, and being easy to be implemented. [ABSTRACT FROM AUTHOR]

Background: Radiation for Graves' ophthalmopathy (GO) has traditionally utilized lateral opposing fields (LOF) or three-dimensional conformal radiotherapy (3DCRT) technique. The current study was conducted to report clinical outcomes and therapeutic effects of intensity modulated radiation therapy (IMRT) in treating GO patients.Methods: One hundred sixteen patients with GO were treated with IMRT as initial local therapy between July 2010 and August 2013, with a median follow-up of 62 months (range 45-81 months). Radiotherapy dose was 20 Gy in 10 fractions within two to three weeks. The immediate and long-term response to IMRT was evaluated in GO severity score and in each category of symptoms. Acute and long-term complications were recorded to assess its safety.Results: Symptom severity score significantly fell from the start of treatment to 4- or 6- month post-IMRT (P < 0.01). In total, 85 patients (73.3%) experienced improvement of GO symptoms in the first half-year, and only 4 of them (4.7%) suffered recurrence of the GO symptoms during the subsequent follow-ups. Orbital pain, tearing and extraocular muscle dysfunction had the best treatment reaction to IMRT, while proptosis and blurred vision were the most refractory symptoms. Acute complications were slight and self-limited, mainly including intermittent eye redness in 9 patients (7.8%), sideburns hair loss in 19 patients (16.4%), increased milphosis or madarosis in 23 patients (19.8%) and pseudo-progression of GO symptoms in 15 patients (12.9%). For long-term complications, chronic xerophthalmias occurred in 7 patients (6.03%), cataract developed in 2 patients (1.72%), and all were well-managed by medical interventions. Radiation retinopathy and secondary malignancy was not presented in the cohort.Conclusion: The study demonstrated that IMRT could serve as a viable option in treating GO patients, with a satisfactory symptom control ability, and relatively slight and acceptable post-radiotherapeutic complications. [ABSTRACT FROM AUTHOR]

Generating precise in vivo arterial endothelial hemodynamic microenvironments using microfluidics is essential for exploring endothelial mechanobiology. However, a hemodynamic principle guiding the fabrication of microfluidic systems is still lacking. We propose a hemodynamic similarity principle for quickly obtaining the input impedance of the microfluidic system in vitro derived from that of the arterial system in vivo to precisely generate the desired endothelial hemodynamic microenvironments. First, based on the equivalent of blood pressure (BP) and wall shear stress (WSS) waveforms, we establish a hemodynamic similarity principle to efficiently map the input impedance in vivo to that in vitro , after which the multi-component microfluidic system is designed and fabricated using a lumped parameter hemodynamic model. Second, numerical simulation and experimental studies are carried out to validate the performance of the designed microfluidic system. Finally, the intracellular Ca2+ responses after exposure to different intensities of exercise-induced BP and WSS waveforms are measured to improve the reliability of EC mechanobiological studies using the designed microfluidic system. Overall, the proposed hemodynamic similarity principle can guide the fabrication of a multi-component microfluidic system for endothelial cell mechanobiology. [Display omitted] • Generating precise in vivo hemodynamic microenvironments using microfluidics is essential for exploring endothelial mechanobiology. • A hemodynamic similarity principle for guiding the fabrication of a multi-component microfluidic system. • The input impedance of the microfluidic system can be derived from that of the arterial system using the proposed principle. • The proposed microfluidic system can precisely generate local and global hemodynamics under different exercise states. • A multi-component microfluidic system is designed and fabricated for generating precise in vivo arterial endothelial hemodynamic microenvironments. [ABSTRACT FROM AUTHOR]