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Any clinical decision support (CDS) design project integrating computational technologies with clinician workflows will require the merging of multiple perspectives and fields of expertise in multidisciplinary teams. Much like the tools these teams aim to create, the team itself will need to continuously build, monitor, and repair a mutually beneficial relationship between each of its members. From our experience during the early development stages of an AI-enabled CDS tool for hospital-acquired infection (HAI) prevention, we abstract three central tenets of a symbiotic design process we have found to be vital for aligning goals, priorities, mental models, and techniques among a multidisciplinary team: (1) recurrent bottom-up feedback, (2) continual model (re-)alignment, and (3) openness to co-direction. With regards to these tenets, we discuss the successes and challenges our team has faced during the symbiotic design process through a series of vignettes and how these experiences coalescing diverse human design teams can influence the design of human-machine teams.

Background One-lung ventilation (OLV) is widely used in thoracic surgery. However, OLV may also increase CERO2 and aggravate delayed cognitive recovery. Here, we aimed to investigate the effect of dexmedetomidine (DEX) on cognitive function in rats undergoing OLV. Methods Sprague-Dawley rats were randomly divided into two-lung ventilation (TLV) group, OLV group and OLV treated with DEX group. Group DEX received 25 μg/kg DEX i.p. 30 min before induction. After mechanical ventilation (MV), Morris water maze (MWM) test was carried out to examine spatial memory function. Western blotting was used to detect pERK1/2, pCREB, Bcl-2 and BAX in hippocampal tissues. Transmission electron microscopy (TEM) was used to observe the hippocampal CA1 region. Results Post-MV, compared with group OLV, group DEX showed increases in percentage of target quadrant time (P P 2 (P P P P Conclusions DEX improved post-MV cognitive function in rats undergoing OLV, reduced cerebral oxygen consumption, protected synaptic structure and upregulated ERK1/2-CREB anti-apoptotic signaling pathway in hippocampal CA1 region.

Chinese government is trying to use the Public-Private Partnership (PPP) to help the development of China’s elderly care industry. This article will analyze the characteristics of pension PPP projects, summarize the current status of China’s pension PPP projects and existing problems, and make some suggestions for these problems. Firstly, the article reviews the literature of China’s pension PPP projects, then introduces the common types of pension PPPs, and analyzes 107 pension service projects in the project management library of the Ministry of Finance’s PPP Center. Finally, it proposes the problems of existing PPP projects, and made some suggestions. The results of this study describe the current status of pension PPPs in China and provide useful references for future research.

Background/aims: Type 2 diabetes mellitus aggravates myocardial ischemia/reperfusion injury (MI/RI). Activation of adenosine receptors (ARs) confer to attenuated MI/RI in nondiabetic animals and human. However, this effects and mechanism of ARs in the type 2 diabetic state are still unknown. In present study, we established a type 2 diabetic rat in vivo myocardial ischemia/reperfusion (MI/R) model to evaluate the effect of ARs on MI/RI with a focus on the A2A adenosine receptor (A2 AR) -mediated cardioprotective effects. Methods: Type 2 diabetic rat were subjected to myocardial infarction by LAD ligation in situ and randomly received ARs agonist and/or antagonists or vehicle treatment. After 2h marker of the extent of myocardial damage(ejection fraction of the LV, Infarct size, plasma cardiac troponin I) were measured and pro- and anti-apoptotic signals (protein kinase Cα，Bcl-2, Bax, miR-15), and marker of apoptosis execution (cleaved caspase-3, TUNEL) were quantified in the infarcted myocardium.Results: non-selective adenosine receptor agonist 5′-(N-ethylcarboxamido) adenosine treatment attenuates MI/RI, improve post-MI/R left ventricular function, limit infarct size, reduce cardiac troponin I release, reduce myocardial apoptosis, up-regulates bcl2 and down-regulates miR-15a, bax and cleaved caspase-3 expression; This protective effects were attenuated by pretreatment with selective A2AR antagonist ZM241385 or PKCα-selective inhibitor Go6976; and duplicated by treatment with A2AR-selective agonist CGS21680 or PKCα-potent activator PMA.Conclusions: NECA reduces MI/RI in T2DM rats via the A2AR/PKCα/miR-15a signaling pathway; NECA is a useful target candidate for the treatment of MI/RI in patient with type 2diabetes.

Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death–inducing (ICD-inducing) drugs available that can kill cancer cells, enhance tumor immunogenicity, increase in vivo immune infiltration, and thereby boost a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immunostimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still being investigated. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and a T cell activation assay. We showed that teniposide, a DNA topoisomerase II inhibitor, could induce high-mobility group box 1 (HMGB1) release and type I IFN signaling in tumor cells and that teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling, including NF-κB activation and stimulator of IFN genes–dependent (STING-dependent) type I IFN signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 in multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity and enabled a potential chemoimmunotherapeutic approach to potentiating the therapeutic efficacy of anti-PD1 immunotherapy.

The purpose of our present study was to investigate the expression of cation transport regulator-like protein 1 (CHAC1) in uveal melanoma (UM) tissues and its function in UM progression. The mRNA expression of CHAC1 in UM tissues and its prognostic value were investigated based on Gene Expression Omnibus database and The Cancer Genome Atlas database. SP6.5 and M23 UM cell lines with depleted CHAC1 were constructed using small interfering RNA. The viability and migration ability of SP6.5 and M23 UM cells were determined by MTT and wound healing assays, respectively. Western blot was conducted to test the influences of CHAC1 depletion on PI3K signaling pathway. Higher expression of CHAC1 was observed in the UM tissues from patients with liver metastases compared to that from patients without metastases. High CHAC1 expression was correlated with poor prognostic and was an independent predictor for UM patients. Depletion of CHAC1 remarkably inhibited the proliferation and motility of SP6.5 and M23 UM cells. Moreover, the ratios of p-AKT/AKT and p-mTOR/mTOR were reduced notably after silencing CHAC1. Our results suggested that CHAC1 functioned as a facilitator in UM cell proliferation and migration and possessed the potential to be a predictor as well as a therapeutic target for UM patients.

BackgroundDendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy.MethodsIn vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3−/− mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment.ResultsBy screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody.ConclusionsOur findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.

Background: The tumor microenvironment (TME) plays a crucial role in lung cancer development and outcome. The objective of this study was to construct a prognostic model using TME-related genes. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) provided transcriptome profile and clinical characteristics. We examined and selected the key genes to obtain a predictive risk model for lung adenocarcinoma (LUAD) prognosis. We also assessed the efficiency of the model and the interaction of key genes with immune-related genes. Findings: After screening 760 TME-related genes, we established a risk model using ANGPTL4, FUT4, CDC25C, FLNC, KRT6A, NEIL3 , HS3ST2, and DAAM2 to independently predict LUAD prognosis using TCGA data. The ROC curve and C-index confirmed the usefulness of this risk model, and a nomogram that integrated this predictive risk model with age and TNM stages was more effective on prediction of LUAD prognosis. The risk model was further confirmed using the GEO data. Furthermore, the risk model of genes interacted with 11 types of immune cells and three immune checkpoint proteins (LAG3, PDL1 and TDO2) in LUAD. Interpretation: Our predictive risk model was effective on survival prediction and helpful for immune targeted therapy in LUAD patients. Funding Information: This study was supported in part by grants from the National Natural Science Foundation of China (#81703087, #81903185, and #81972916), the United Fund of the Second Hospital of Dalian Medical University and Dalian Institute of Chemical Physics, Chinese Academy of Sciences (#UF-ZD-202011), and Project of Education Department of Liaoning Province (#LZ2020009). Declaration of Interests: The authors declared that there is no conflict of interest in this work. 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.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in premature infants, and alveolar dysplasia and pulmonary vascular development disorders are the predominant pathological features. Apoptosis of lung epithelial cells is a key factor in the pathological process of alveolar developmental arrest. Endoplasmic reticulum stress (ERS)‑associated apoptosis is a noncanonical apoptotic pathway involved in the development of several pulmonary diseases. Previous studies have demonstrated that protein kinase RNA‑like endoplasmic reticulum kinase, inositol‑requiring enzyme 1α (IRE1α) and activating transcription factor 6 can initiate the apoptosis signaling pathway mediated by ERS and induce apoptosis of injured cells. Among them, the IRE1α pathway is the most conservative pathway in the unfolded protein response, which serves an important role in a number of pathological environments, to the extent of determining cell fate; however, it is rarely reported in BPD. Based on the establishment of a rat BPD model, the present study verified the activation of ERS in BPD and further confirmed that prolonged ERS inhibited the protective pathway, IRE1α/X‑box binding proteins, and activated the proapoptotic pathway, IRE1α/c‑Jun N‑terminal kinase, to induce the apoptosis of lung epitheliums.

Background Mixed phenotype acute leukemia (MPAL) is a rare leukemia and is regarded as a high-risk entity with a poor prognosis. Induction therapy of an acute lymphoblastic leukemia type or hybrid regimen and hematopoietic stem cell transplantation has been recommended for MPAL. However, the optimal therapies for relapsed or refractory MPAL remain unclear, especially for relapse after stem cell transplantation. Donor-derived chimeric antigen receptor T (CAR-T) cell therapy may be a promising therapeutic option for patients with MPAL who express target antigens and have relapsed after stem cell transplantation. However, recurrence remains a challenge, and reinfusion of CAR-T cells is not always effective. An infusion of secondary donor-derived humanized CD19-modified CAR-T cells may be effective in inducing remission. Case presentation We report a case of MPAL with CD19 expression. The patient was treated with acute lymphoblastic leukemia-like induction and consolidation therapies but remained positive for SET-NUP214 fusion gene transcript. He subsequently underwent a haploidentical stem cell transplantation but relapsed within 6 months. He then underwent donor-derived CD19-targeted CAR-T cell therapy and achieved a sustained, complete molecular remission. Unfortunately, he developed a CD19-positive relapse after 2 years. Donor-derived humanized CD19-directed CAR-T cells induced a second complete molecular remission without severe cytokine release syndrome or acute graft-versus-host disease. Conclusion This case demonstrated the efficacy and safety of humanized donor-derived CD19-modified CAR-T cell infusion for treating the recurrence of MPAL previously exposed to murine-derived CD19-directed CAR-T cells.

Background Neuropathic pain (NP) is the comorbidity in spinal cord injury(SCI), which is the hardest to cure. Non-coding RNA dysregulations are related to the development of NP. NEAT1(nuclear paraspeckle assembly transcript 1) is a new type of lncRNA. This study explores the role and specific mechanism of NEAT1 in SCI-mediated NP. Methods Firstly, the NEAT1 expression in SCI rats and the control group was detected with RT-PCR to analyze the relationship between NEAT13 and NP symptoms. Then, SCI rats were intrathecally injected with NEAT13 overexpressing and knocking down lentiviruses. Afterward, ELISA was utilized to assess the expression of IL-6, IL-1β and TNFα in rats. Subsequently, immunohistochemistry was adopted to verify the activation of microglial cells. After that, bioinformatics analysis was employed to further predict the downstream target genes of NEAT1, while RT-PCR and Western blot were conducted to determine the relative expression of miR-128-3p and aquaporin-4(AQP4). Meanwhile, a dual-luciferase reporter assay was performed to further study the targeting relationship between NEAT1 and miR-128-3p, and miR-128-3p and AQP4. Results SCI rats showed distinctly higher NEAT1 expression compared with that of the control group. ELISA experiment confirmed that the over-expression of NEAT1 enhanced the expression of IL-6, IL-1β, and TNFα in SCI rats. Other related mechanism studies revealed that NEAT13 targeted and inhibited miR-128-3p as its competing endogenous RNA (ceRNA), and enhanced AQP4 expression, while miR-128-3p targeted AQP4 to regulate its expression. Summary NEAT1 affects AQP4 signaling pathway to alleviate the spinal cord injury-induced NP via promoting miR-128-3p expression.

More and more attention has been paid to the application of Building Information Modeling (BIM) in the field of greenhouse-gas (GHG) emissions in Architecture, Engineering and Construction (AEC). However, systematic analysis and visualization of its development trend have not been carried out. This paper combined digital statistical method and scientometrics to analyse major documents published in the Scopus database from 2008 to September 2019 and discussed the development trend, the main journals co-citation and keywords co-occurrence of this field. And then main challenges and future research were summarized by content analysis. The results show that: (1) the number of articles related to integrating BIM with GHG emissions has increased significantly in AEC, which deserves more and more scholars to study in this field; (2) top cited journals mainly focus on built environment, BIM and clean technology; (3) BIM and Life Cycle Assessment (LCA) are the mainstream issues in the calculation, analysis and decisionmaking of GHG emissions. This review provides status quo and existing main challenges of knowledge system of BIM applied to GHG emissions in AEC, and also offers inspiration for future research.

Buildings produce a large amount of carbon emissions in their life cycle, which intensifies greenhouse-gas effects and has become a great threat to the survival of humans and other species. Although many previous studies shed light on the calculation of carbon emissions, a systematic analysis framework is still missing. Therefore, this study proposes an analysis framework of carbon emissions based on building information modeling (BIM) and life cycle assessment (LCA), which consists of four steps: (1) defining the boundary of carbon emissions in a life cycle, (2) establishing a carbon emission coefficients database for Chinese buildings and adopting Revit, GTJ2018, and Green Building Studio for inventory analysis, (3) calculating carbon emissions at each stage of the life cycle, and (4) explaining the calculation results of carbon emissions. The framework developed is validated using a case study of a hospital project, which is located in areas in Anhui, China with a hot summer and a cold winter. The results show that the reinforced concrete engineering contributes to the largest proportion of carbon emissions (around 49.64%) in the construction stage, and the HVAC (heating, ventilation, and air conditioning) generates the largest proportion (around 53.63%) in the operational stage. This study provides a practical reference for similar buildings in analogous areas and for additional insights on reducing carbon emissions in the future.

The intravenous use of nalmefene has been found to exert neuroprotective effect in patients with severe traumatic brain injury and acute cerebral infarction; nonetheless, it is unknown whether nalmefene alleviates delayed neurocognitive recovery. Our purpose of the current research was to clarify the impact of nalmefene on delayed neurocognitive recovery in aged patients experiencing video-assisted thoracic surgery (VATS) with intraoperative use of one lung ventilation (OLV). The present study involved 120 patients undergoing selective VATS, randomized to accept low-dose nalmefene (N1 group, n=40), high-dose nalmefene (N2 group, n=40) or equal volume of physiologic saline (control group, n=40). A battery of neuropsychological tests were used to estimate cognitive function 1 day before surgery (t0) and 10 days after surgery or before discharge (t1). Regional cerebral oxygen saturation (rSO2) was detected 5 min before induction (t0), 5 min after induction (t1), 15 and 60 min after onset of OLV (t2 and t3), and 15 min after termination of OLV (t4). The plasma values of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and adiponectin (ADP) were also detected prior to induction of anesthesia (T0), 1 h, 2 h and 6 h after surgery (T1, T2, T3). On t1, delayed neurocognitive recovery occurred in 5/40 (12.5%) patients of N1 group, in 5/40 (12.5%) patients of N2 group and in 13/40 (32.5%) patients of control group (P0.05). There were no statistical differences in rSO2 among three groups at different time points. At T1, T2 and T3, IL-1β, IL-6 and TNF-α values significantly increased and ADP value significantly decreased (P0.05) in control group. In contrast, at T1, T2 and T3, IL-1β, IL-6 and TNF-α values decreased and ADP value decreased less in N1 and N2 groups (P0.05). At T1, T2 and T3, IL-1β, IL-6 and TNF-α concentrations presented a trend of N2 group N1 group control group and ADP presented a trend of N2 groupN1 groupcontrol group (P0.05). The result of our present research supports the hypothesis that the perioperative intravenous treatment with nalmefene to VATS with OLV ameliorates postoperative cognitive function and decreases the incidence of delayed neurocognitive recovery, most likely by suppression of inflammatory responses.

Large animal models of optic nerve injury are essential for translating novel findings into effective therapies due to their similarity to humans in many respects. However, most current tests evaluating the integrity of retinal ganglion cells (RGCs) and optic nerve (ON) are based on rodent animal models. We aimed to evaluate and optimize the in vivo methods to assess RGCs and ON's function and structure in large animals in terms of reproducibility, simplicity and sensitivity. Both goats and rhesus macaques were employed in this study. By using goats, we found anesthesia with isoflurane or xylazine resulted in different effects on reproducibility of flash visual evoked potential (FVEP) and pattern electroretinogram (PERG). FVEP with the large-Ganzfeld stimulator was significantly more stable than that with mini-Ganzfeld stimulator. PERG with simultaneous binocular stimulation, with superior simplicity over separate monocular stimulation, was appliable in goats due to undetectable interocular crosstalk of PERG signals. After ON crush in goats, some FVEP components, PERG, OCT and PLR demonstrated significant changes, in line with the histological study. By using rhesus macaque, we found the implicit time of PVEP, FVEP and PERG were significantly more reproducible than amplitudes, and OCT and PLR demonstrated small intersession variation. In summary, we established an optimized system to evaluate integrity of RGCs and ON in large animals in vivo, facilitating usage of large animal models of optic nerve diseases.

Bronchopulmonary dysplasia (BPD) seriously affects the health and prognosis of children, but the efficacy of treatments is poor. The present study aimed to examine the effects of C/EBP homologous protein (CHOP), activating transcription factor 4 (ATF4) and microtubule‑associated protein light chain 3β (LC3B), and the interaction between CHOP and LC3B, in newborn rats with BPD. At 1, 7, 14 and 21 days, the rats in the model [fraction of inspired oxygen (FiO2)=80‑85%] and control groups (FiO2=21%) were randomly sacrificed, and lung samples were collected. Alveolar development was evaluated according to the radial alveolar count (RAC) and alveolar septum thickness. Ultrastructural changes were observed by transmission electron microscopy (TEM), the expression levels of CHOP, ATF4 and LC3B were determined by immunohistochemistry, and western blot and reverse transcription‑quantitative polymerase chain reaction analyses. The co‑localization of CHOP and LC3B in lung tissues was determined by immunofluorescence. The results showed that, compared with the control group, alveolarization arrest was present in the model group. The TEM observations revealed that, at 14 days, type II alveolar epithelial cell (AECII) lamellar bodies were damaged, with an apparent dilation of the endoplasmic reticulum (ER) and autophagy in cells within the model group. Between days 7 and 14, the protein levels of ATF4, CHOP and LC3B were significantly increased in the model group. The mRNA levels of CHOP and LC3B were lower at days 7‑21. CHOP and LC3B were co‑localized in the cells of the lung tissues at day 14 in the model group. Pearson's correlation analysis showed that the protein levels of CHOP and LC3B‑II were positively correlated in the model groups. As in previous studies, the present study demonstrated that BPD damaged the AECII cells, which exhibited detached and sparse microvilli and the vacuolization of lamellar bodies. In addition, it was found that the ER was dilated, with autophagosomes containing ER and other organelles in AECII cells; the expression levels of CHOP and LC3B‑II were upregulated. CHOP and LC3B‑II may have joint involvement in the occurrence and development of BPD.

The sustainable production has received extensive attention. With the aim, reducing the energy consumption in the manufacturing stage is particularly important. This paper presents a new mixed-integer linear programming (MILP) model for the complex production scheduling of remanufacturing job shop. This model is suitable for the job shop that batch processing machines and non-batch processing machines exist at the same time. According to the time-of-use (TOU) electricity pricing, dispatch reasonably to optimize the makespan and the electricity cost. Reach the target of increasing production efficiency and reducing environmental impact, promoting sustainable production.