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In this research, finite-element analysis and failure analysis were performed to analyze delamination failure in quad flat no-lead (QFN) packages. Although a QFN is a traditional package and represents mature technology, the reliability standards of QFNs in automotive applications have become strict. The quality requirements of QFNs are increasing and require that no delamination or voids occur inside the package during the reflow process and precondition tests. Therefore, interfacial delamination is still a critical reliability issue for QFNs. Delamination failure weakens the internal structural strength of a QFN and affects the product reliability. In the interface delamination, initially generated small voids gradually expand due to hygromechanical stress during the moisture sensitivity level test. In addition, moisture penetration into the package can result in not only electrical failure but also chemical reactions that lead to corrosion. In this study, delamination occurs on the interface between the Cu pad and molding compound during the precondition tests. The available evidence indicates that the bonding strength between Ag plating on the Cu pad and molding compound is weak. Most delamination failure sites are located in the area of Ag plating according to scanning acoustic tomography (SAT) observations. To accurately predict the delamination failure in QFNs, the shear force on the molding compound/Ag plating and molding compound/Cu is combined with finite element modeling. Parametric analysis is conducted to determine the optimal design of the geometric structure in the QFN to combat delamination failure. This investigation can help improve the product reliability by preventing delamination failure in the QFN package through the analysis of the physics of failure (PoF).

Prothrombotic and proinflammatory properties of neutrophil extracellular traps (NETs) contribute to brain damage after ischemic stroke. CD21 is a novel phthalide neuroprotectant against cerebral ischemia in rodents. This study investigated effects of CD21 on the platelet-NET-thrombin axis and ischemic brain injury and the underlying mechanism. CD21 exerteddose-dependent neuroprotectionin rats that were subjected to2 h middle cerebral artery occlusion,dose-dependentlyinhibited adenosine diphosphate-mediatedplatelet aggregationin rats, and dose-dependentlyexertedanti-thrombotic activityin rodents that received a collagen-epinephrine combination, ferric chloride, or an arteriovenous shunt. Equimolar CD21 doses exerted stronger efficacy than 3-N-butylphthalide (NBP, natural phthalide for the treatment of ischemic stroke). CD21 dose-dependently improved regional cerebral blood flow, neurobehavioral deficits, and infarct volume in mice that were subjected to photothrombotic stroke (PTS). CD21 (13.79 mg/kg, i.v.) significantly decreased NET components (plasma dsDNA concentrations; mRNA levels of elastase, myeloperoxidase, and neutrophil gelatinase-associated lipocalin and protein level of citrullinated histone H3 in ischemic brain tissues), mRNA and protein levels of peptidyl-arginine deiminase 4 (PDA4, NET formation enzyme), and mRNA levels of NET-related inflammatory mediators (interleukin-1β, interleukin-17A, matrix metalloproteinase 8, and matrix metalloproteinase 9) in ischemic brain tissues, despite no effect on mRNA levels of deoxyribonuclease I (NET elimination enzyme). Pretreatment with compound C (inhibitor of adenosine monophosphate-activated protein kinase [AMPK]) significantly reversed the inhibitory effects of CD21 on NETs, PDA4, and inflammatory mediators in PTS mice. These results suggest that CD21 might regulate the platelet-NET-thrombin axis and protect against ischemic brain injury partly through the induction of AMPK activation.

Background Because more than one neoadjuvant treatment is available for advanced rectal cancer, the aim of this study was to compare the differential clinical and pathologic effects of different combinations of chemoradiation regimens, treatment sequencing, and timing to surgery on patient outcomes. Patients and Methods Between January 2015 and October 2018, 126 newly diagnosed patients with rectal cancer with magnetic resonance imaging-based cT3-4 or N+ rectal disease for curative-intent treatment received 1 of 4 neoadjuvant regimens, followed by immediate surgery or delayed surgery. Whole post-neoadjuvant surgical specimens were assessed by 3-dimensional digital whole-tumor microarray imaging and immunostaining in pathology to analyze the global tumor pathologic regression grades, residual tumor distribution patterns, the extent of lymphovascular permeation, lymph node positivity, and the overall density of lymphocyte infiltration in the tumor microenvironment. These factors were further examined to identify possible correlations with clinical outcomes. Results Among the 4 neoadjuvant treatment groups, including 2 conventional regimens, we found a significant increase of stromal CD3+ and CD8+ immune infiltrates in the postneoadjuvant tumor microenvironment in the 3 groups with delayed surgery after different chemoradiation regimens compared with the group with immediate surgery after a short course of RT alone. Independent of neoadjuvant chemoradiation regimens, the post-induction high-intermediate-low stromal-infiltrating CD8+ T-cell densities corresponded to tumor regression grades, distant metastasis rates, and disease-free survival and were prognostic factors for the further stratification of patients with American Joint Committee on Cancer stage III rectal cancer into different risk groups after surgery. Conclusion The effectiveness of induction strategies on tumor remission and disease recurrence in advanced rectal cancer was significantly correlated with an enhanced cytotoxic immune response in the tumor microenvironment.

Background Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases. Aim The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism. Methods Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Results No significant differences were observed for omeprazole and midazolam, compared to the control group. T max and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (T max h: 0.50±0.00 vs 0.23±0.15; control vs conc CAL). C max of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P Conclusion Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.

In this paper, warpage of fan-out wafer-level packaging (FOWLP) throughout the manufacturing process is investigated to minimize the warpage. FOWLP technology has the advantages of low cost, small form factor, efficient electrical performance, and increased input–output counts. The main benefit of fan-out packaging is that it utilizes the redistribution layer to interconnect the die and solder joints instead of using the substrate. However, warpage control is still a critical issue in the wafer molding process. Warpage is induced by the coefficient of thermal expansion mismatch between the die and the molding compound. Throughout the manufacturing process, the warpage of each step was recorded by utilizing the continuity simulation. The debonding process, grinding process, and annealing process at room temperature were analyzed via the simulation results and the experimental results. To simulate the wafer molding process in a continuous manner, the element birth and death technique was employed using finite-element modeling. This method can be used to reactive and deactivate elements when the material is added to or removed from the system. The results of the measurement and simulation were highly similar, with a difference of less than 10%. However, the results differed considerably when the wafer thickness was small. The results revealed a gap between the experimental testing and simulation modeling. Because of the wafer stiffness, the wafer is too thin to support the gravity force in the experimental testing process. Therefore, it is important to determine the calibration factor to decrease the gap between experimental testing and simulation modeling. In addition, it is crucial to determine the key factor controlling the warpage behavior and to minimize the warpage by evaluating the die arrangement and the die size in this paper. Overall, the simulation modeling represents a feasible approach for predicting the warpage during the manufacturing process.

Seizures are a common neurologic disorder observed in children. A virtual reality (VR) simulator trains nursing students to understand and respond to pediatric seizures.The aim of this study was to examine knowledge acquisition and acceptance of a pediatric seizure management VR simulator.A quasi-experimental design was used to study the effectiveness of VR in nursing education.Two out of nine possible third-year Pediatric Nursing classes were assigned by the office of academic affairs. A total of 105 students participated. The two classes were randomly allocated into the intervention (n = 53) and control (n = 52) groups.The intervention group was taught using a pediatric seizure management simulator; the control group was taught by in-person lecture. The Seizure Management Knowledge Test was administered to all participants before each group underwent their VR simulator and lecture respectively. The Pediatric Seizure Management Virtual Reality Acceptance Questionnaire and the Virtual Reality Sickness Questionnaire were given to participants in the intervention group. Independent t-tests and chi-square tests were used to test differences in knowledge acquisition between the two groups.The posttest knowledge score in the intervention group was significantly higher than that in the control group (t = 5.05, p .001). The intervention group had a mean cybersickness score of 18.17 of 100. The average score of the acceptance questionnaire for perceived usefulness was 3.26 of 4; ease of use was 3.09 of 4; attitude toward use was 3.26 of 4; and willingness to use was 3.32 of 4. Over 90 % of participants expressed willingness to use the VR simulator.The newly developed pediatric seizure management VR simulator is acceptable and worthwhile for training nursing students to develop their skills and professionalism. Follow-up research is needed to evaluate the long-term effect of VR education in nursing practice.

Background Cardiac arrest has been a great threat, regardless of its occurrence in or out of the hospital (OHCA and IHCA). ECMO has been regarded as the last resort to save these endangering lives. This prospective cohort intended to clarify how ECMO-assisted CPR (ECPR) benefited patients of cardiac arrests, both OHCA and IHCA, and addressed the survival benefit of left ventricular decompression. Methods Consecutive patients of OHCA and IHCA, refractory to resuscitation and without certain exclusion criteria for mechanical support, were enrolled since 2018. Primary endpoint was in-hospital mortality. Results From 2018 Jan. to 2021 Mar., 147 patients of both OHCA and IHCA were put on ECPR. Acute coronary syndrome took 63.3%. Rate of weaning-off from ECMO/modified LVAD was 45.6%, and the in-hospital mortality rate was 67.3%. Peak serum lactate (10.9 ± 5.5 vs. 16.4 ± 7.7 mmol/L, p

The nasopharyngeal epithelium is highly susceptible to pathogenic infection. More than 95% of nasopharyngeal carcinomas (NPCs) are Epstein–Barr virus (EBV)-associated epithelial cancers densely infiltrated with EBV-free lymphocytes. It remains unknown whether the immune modulating effects of concurrent chemoradiotherapy (CCRT) on the tumor-infiltrating T-cell priming against EBV, tumor-associated antigens, and/or neoantigens can elicit systemic anti-tumor immunity and decrease recurrence or distant metastasis. Using matched EBV-associated NPCs, nasopharyngeal mucosal tissues, and longitudinal serial peripheral blood samples, we explored the spatiotemporal and quantitative changes in expansion and contraction of intratumoral T-cell clonotypes (ITCs) in peripheral blood samples from before, during, and after CCRT. The pre-treatment nasopharyngeal ITC repertoire contained unique mucosa-resident and commonly system-shared T-cell receptors (TCRs), portraying an individualized tumor-associated and/or metagenomic landscape. We found that the long-term disease-free patients had significantly more robust unique mucosa-resident ITCs that migrated into and expanded in the peripheral blood after CCRT than in the patients with recurrence or distant metastasis (Mann–Whitney U test, p = .0110). However, the system-shared productive ITC TCRs specific to the common viruses, such as EBV, cytomegalovirus, and influenzaA, in all the patients with and without recurrence demonstrated almost no expansion after CCRT. Thus, these findings underline the importance of determining the impact of unique intratumoral immune responses, reflected in the peripheral blood, on disease prognosis after treatment and challenge of mechanistically understanding the common systemic immune evasion of EBV in NPC patients.

In this work, a finite element model of Ball Grid Array (BGA) package is established to predict the solder joint failure under the high-G drop impact test. To be deemed acceptable, the electronic packaging has to sustain the peak acceleration generated during the high-G drop impact test. Unlike the electronic devices intended for mass consumption, the electronic products designed specifically for military and aerospace industry must be capable of operating in very harsh environments, often involving high impact loading. Thus, the packaging encasing those electronic products must exhibit sufficient impact resistance. This has motivated the present study, comprising of finite element modeling and experimental testing. The proposed finite element model is used to simulate the stress distribution of electronic packaging during high-G impact loading. The simulation model is built using ANSYS LS-DYNA, which is also used to analyze the stress values recorded for the electronic packaging. The model not only simulates the high-G impact loading conditions, but also generates the resulting stress distribution. Its reliability is subsequently tested by comparing its output to the results of a high-G drop impact test. In the experiment, the BGA package failure primarily occurs due to the solder joint fracture, but may also involve copper trace cracking. Thus, the simulation results can be used in practice to reduce the impact loading on the solder joints and lower the probability of failure. Moreover, the thickness of the soft dielectric layer can be increased to absorb a greater amount of the impact force. Most importantly, the stress distribution generated by the proposed model can reveal any further weak points in the electronic packaging.

In this paper, we research the effects of wheel rotation speed, wafer rotation speed and feed rate on roughness are discussed. The model is used to simulate the effect of stress distribution and process parameters on the wafer surface during the polishing process, as well as to establish a set of standards that cause the least damage to the wafer surface. In addition, the influence of process parameters on the optimal silicon wafer radius is delineated. The damage caused to the wafer surface by grinding is assessed by the surface finish measuring instrument. This allows the relationship between surface micro-cracks and surface stress to be determined, as well as explore the relationship between roughness and residual stress. The findings indicate that the proposed finite element model, when combined with the theoretical data and experimental results, can be used to accurately predict any changes in stress trends.

In this article, we discuss the influence of the lead frame design on the amount of deformation with the view of enhancing the quad flat no-leads (QFN) package reliability. Our study commenced with designing two types of the lead frame which were assessed using a simulation model based on finite element analysis. The aim was to determine the differences in the performance of the two designs based on simulated temperature distribution and deformation after thermal expansion during heating. The simulation results show that the lead frame design with release holes exhibits less deformation, and that the 12-row lead frame design is more reliable than that based on 6-row lead frame.

As the electronic products, such as smart phones, notebooks, and micro-control parts for vehicles, are becoming increasingly popular and their size continues do decrease, there is also a need to reduce the volume of ultra-thin silicon wafers while improving their performance. At present, backside grinding is typically used for this purpose, and requires that the wafer is placed on the chuck of a self-rotating wheel, while controlling the feed rate in order to reduce wafer thickness. Although this process is efficient and effective, it may result in subsurface damage, surface cracks, micro-cracks, warpage, and other undesirable effects. One of its main drawbacks is residual stress, which becomes more pronounced in very thin wafers, as this increases rigidity. Stoney equation is widely used to examine the residual stress and curvature radius in a silicon wafer due to the backside grinding process. However, the relationship between the residual stress generated in the wafer during the grinding process and the process parameters is rarely analyzed through simulations. This gap is addressed in the present study, whereby the finite element method (FEM) is adopted to examine the effects of different process parameters, as well as wafer thickness, on the residual stress. As dynamic simulation is adopted, this allows the process parameters to be adjusted at runtime to predict the residual stress, while Stoney’s equation is employed to predict the influence of different process parameters on warpage. Based on the obtained results, the wafer warpage caused by the process can be predicted with acceptable accuracy, which can in turn be used to optimize the process parameter values to minimize wafer warpage.

The major problem with quad flat no-lead package (QFN) packages is the delamination between the copper lead-frame and the molding compound (MC) due to relatively weak adhesion. The copper lead frame has excellent electrical and thermal conductivity. However, moisture penetration not only reduces the adhesion between the interfaces of the two materials, but also adversely affects the conductivity of Cu. Interface stratification is attributed to different material properties such as mismatch of coefficient of moisture expansion (CME), surface treatment of the mold pad, thermal strain, vapor pressure at high temperatures, and reduced interface strength due to moisture and temperature effects.The work presented in this paper focused on moisture, thermal and vapor pressure effects on the lead-frame and molding compound in the QFN during the precondition test and reflow process. The causes of delamination were examined both experimentally and via simulations. In an electronic package, the main failure effect stems from molding compound. To accurately simulate the moisture distribution in QFN, in this work, the moisture mechanism pertaining to material properties was investigated. This investigation focused on the MC and epoxy coefficient of moisture expansion and vapor pressure, and the parameters obtained by experimental study were incorporated into a simulation model to verify the fit between the experimental and the simulation findings. The electronic components employed in this work are standard for moisture sensitive testing, according to JEDEC J-STD-020D. To measure the specimen weight gain and geometric size, electronic balance and microscope were used, and these values were obtained under moisture sensitive level 1, level 2 and level 3 in order to establish the moisture desorption rate of the QFN package. And also according to the different degree of oxidation on the leadframe, the surface analysis of the material is carried out by environmental scanning electron microscope (ESEM) to understand the element distribution and interfacial strength. In addition, finite element analysis (FEA) was performed to analyze the stress, warpage and delamination in QFN packages. In this research will discuss the coupling forces of moisture, thermal stress and vapor pressure under MSL-3 and Reflow, and discuss the interface strength under different reliability test stages. To verify the accuracy of simulation modeling, the delamination site was observed and was aligned with the simulation results by applying scan acoustic tomography (SAT). Finally, the reliability of QFN was enhanced by investigating the moisture behavior of the materials co mprising the QFN.

In this paper, a novel Ni-doped SAC 1205 (Sn–1.2Ag–0.5Cu) solder alloy is investigated to determine its mechanical behavior at a high strain rate. The Ni-doped SAC 1205 solder alloy has never been discussed in terms of high-strain-rate testing. The purpose of the SAC 1205 solder material doped with Ni is to enhance the mechanism of the solder alloy and delay the formation of the brittle intermetallic compound. In the drop test standard (Joint Electron Device Engineering Council condition B), the test vehicle was subjected to impact loading with a peak acceleration of 1500G and a time duration of 0.5 ms. Because the test board supported the impact loading for a very short time, the solder joint material was considered to have a rate-dependent elastic–plastic behavior. The quasi-static mechanical behavior and dynamic behavior were estimated for the simulation modeling by conducting a quasi-static tensile test and a split Hopkinson tensile bar test. A finite-element model was used to analyze the stress and strain of the solder joint during the drop test. The experimental results revealed that Young’s modulus and yielding strength of the Ni-doped SAC 1205 solder alloy increased during the high-strain-rate testing. Therefore, a rate-dependent elastic–plastic model of the Ni-doped SAC 1205 solder alloy was designed and implemented to describe the real mechanical behavior of a solder joint at a high strain rate during a drop test. The primary failure mode occurs at the top of the solder joint (package side) during the drop test. The predicted fatigue model we provided was focused on the primary failure mode. Eventually, the fatigue life curve of the rate-dependent elastic–plastic model offered the greatest accuracy in predicting the solder joint fatigue life.

In this paper, finite element simulations are used to analyze the plastic deformation of the solder ball and its stress and strain distributions. The bonding forces that depend on the forming temperature are investigated. The contact areas between the solder ball and the copper trace are also discussed. The largest contact area is regarded as the optimization condition during the thermal compression bonding processes. The effects of different pillar-trace shift ratios on the contact areas are also discussed to provide a guideline for avoiding product failure. Finally, an empirical equation adopting a four-parameter logistic nonlinear regression model for the pillar-trace gap in terms of the forming temperature and bonding forces is established.

The persistence of hepatitis B surface antigen (HBsAg) is a risk factor for the development of steatosis-associated tumors in chronic hepatitis B virus (HBV) infection, yet little is known about the metabolic link with this factor. We correlated HBV-related pathogenesis in genetically engineered mice and human carriers with metabolic proteomics and lipogenic gene expression profiles. The immunohistochemistry showed that the promyelocytic leukemia protein (PML, a tumor suppressor involved in genome maintenance and fatty acid oxidation), being inversely influenced by the dynamic HBsAg levels from acute phase to seroclearance, appeared as a lipo-metabolic switch linking HBsAg-induced steatosis (lipogenesis) to HBsAg-lost fat-burning hepatocarcinogenesis (lipolysis). Knockdown of PML in HBsAg-transgenic mice predisposed to obesity and drove early steatosis-specific liver tumorigenesis. Proteome analysis revealed that the signaling pathways corresponding to energy metabolism and its regulators were frequently altered by suppression or depletion of PML in the HBsAg-transgenic mice, mainly including oxidative phosphorylation and fatty acid metabolism. Expression profiling further identified upregulation of stearoyl-CoA desaturase 1 (Scd1) and epigenetic methylation of NDUFA13 in the mitochondrial respiratory chain and the cell cycle inhibitor CDKN1c in concordance to the increased severity of lipodystrophy and neoplasia in the livers of HBsAg-transgenic mice with PML insufficiency. The defect in lipolysis in PML-deficient HBsAg-transgenic mice made the HBsAg-induced adipose-like liver tumors vulnerable to synthetic lethality from toxic saturated fat accumulation with a Scd1 inhibitor. Our findings provide mechanistic insights into the evolution of steatosis-associated hepatic tumors driven by reciprocal interactions of HBsAg and PML, and a potential utility of lipid metabolic reprogramming as a treatment target.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated lymphoepithelioma. The aim of this study was to characterize the homogeneity and distinctness of the T-cell repertoires within and between primary and metastatic NPCs. We used ultra-deep sequencing of the hypervariably rearranged antigen-binding CDR3 regions of T-cell receptor beta (TCRbeta ) to comprehensively profile the T-cell repertoires in NPC patients receiving definitive chemoradiotherapy with long-term follow-up. We observed not only various spatially heterogeneous patient-specific TCRbeta clone compositions that changed with time but also several commonly enriched TCRbeta subclones that were constantly shared between primary NPCs in the head and neck regions, locally recurrent tumors after treatment and later-developed distant metastatic tumors in the liver, lung and bone. Comparison of the overlap frequency of the T-cell clonality between TCRbeta repertoires enabled us to calculate the pairwise genetic distance between primary NPCs of different patients and different sites of metastatic or recurrent NPCs. The constructed NPC phylogeny clearly differentiated the low-risk patients without relapse from the high-risk patients with distant metastasis after chemoradiotherapy. In contrast to the rather low frequency of nonsilent somatic mutations in NPC cells, the degrees of similarity and divergence of NPC-infiltrating lymphocyte TCRbeta repertoires among different patients showed prognostication. Moreover, the persistent presence of commonly NPC-shared in-frame TCRbeta CDR3 gene sequences spatiotemporally identified in the NPC-infiltrating lymphocytes within varied EBV-positive NPCs and their metastases suggest the existence of frequently shared epitopes of neoantigens virally or nonvirally displayed on cancer cells, thereby providing opportunities for the development of precisely tumor-targeted immunotherapy for distant metastasis.

The structural transition temperature T t increases largely with the introduction of Si in Mn 0.9 Cu 0.1 CoGe 1- x Si x alloys due to the enhancement of degree of hexagonal distortion. Thus, the first-order magnetostructural transformation from ferromagnetic orthorhombic to paramagnetic hexagonal phase can be obtained in the range of 0.15 x S M ) value for x = 0.16 is 10.3 J/kg K at 297 K, which is comparable to or even larger than those of some typical room-temperature magnetocaloric materials. The nature of magnetostructural transition has been studied by different methods, and it is found that the Arrott plots fail to determine the order of phase transition. In contrast, the universal curve of Δ S M is proved to be a more effective criterion to distinguish the order of phase transition. Besides, a linear relationship between -Δ S M and Δ μ 0 H is found, and so the -Δ S M values for higher field changes can be estimated by linear fitting. Consequently, large MCE induced by magnetostructural transformation suggests that Mn 0.9 Cu 0.1 CoGe 1- x Si x alloys could be promising candidates for room-temperature magnetocaloric materials.

The Nb-Si system ultrahigh temperature alloys were prepared by vacuum non-consumable arc melting. The influence of micro-alloying elements of B and Ce on the hardness, room-temperature fracture toughness and compressive strength at 1250°C of the Nb-22Ti-3Si alloys was investigated and estimated systematically. The results showed that the hardness of the Nb-22Ti-3Si alloy increased obviously with trace B addition, but decreased slightly with trace Ce addition. The room-temperature fracture toughness of the Nb-22Ti-3Si alloy was degraded by the Ce addition but improved by the trace addition of B. The trace addition of B improved the compressive strength of the alloy at 1250°C. In contrast, the trace Ce addition degraded the compressive strength at 1250°C. The relationship between the microstructure and the mechanical properties was discussed.

Background Fatigue is the most common and unpleasant symptom of patients with systemic lupus erythematosus (SLE). However, there is limited information regarding how exercise affects fatigue. Aims The purpose of this study is to review and synthesize the current knowledge concerning the effectiveness of exercise training for treating fatigue among adults with SLE. The characteristics of beneficial exercise training are further evaluated. Methods We conducted a systematic review and meta-analysis. The databases searched were MEDLINE, CINAHL, PEDro, Cochrane Library, Scopus, and PQDT from their inception to February 3, 2016. The quality of each selected study was assessed using the PEDro scale. A between-group analysis was performed to evaluate the effectiveness of the exercise training. Data were analyzed using the Cochrane Collaboration's RevMan 5.3 (Copenhagen, Denmark). Results Two randomized controlled trials and one quasiexperimental study were included in this systematic review and meta-analysis. Aerobic exercise, three times a week and of moderate intensity, was a common component of the three studies. Two studies were conducted in a supervised setting and one study was based at home. One study lasted 8 weeks and two studies lasted 12 weeks. The meta-analysis showed that aerobic exercise could decrease fatigue (MD = –.52, 95% confidence interval [CI] [–.91, –.13], p = .009) and increase vitality (MD = 14.98, 95% CI [7.45, 22.52], p < .001). The subgroup analysis indicated that 12 weeks of exercise training and exercise under a supervised setting significantly benefited fatigue. Linking Evidence to Action The pooled data indicate that 12 weeks of an aerobic exercise program that is supervised by health professionals could reduce fatigue and increase vitality for patients with SLE. SLE patients with mild disease should begin with moderate intensity for at least 20 minutes, 3 days a week.

Purpose The purpose of this study was to investigate the changes in solder joint stress when subjected to mechanical bending. The analytical theory pertaining to the stresses in the solder joint between the components (including the molding compound, the chip and the substrate) was described, and the printed circuit board (PCB) with a discontinuity function when the PCB assembly is subjected to mechanical bending was developed. Thus, the findings reported here may lead to a better understanding of the solder joint failure based on the Physics of Failure model. Design/methodology/approach This paper discusses the analytical model for calculating the stress in solder joints, as well as presents a simulation model that can be used for calculating the strain energy density of solder joint. First, the multilayer plate theory is used in discussing the composite material for the component, including the molding compound, the silicon chip and the substrate, or the PCB, including the copper layers, the fiber and the epoxy. Finally, the complete structure of the analytical model developed as a part of this current work is presented. Findings For the analytical model of multilayer structures in which the interconnection layer is discrete, mechanical bending has been modeled with respect to varying silicon chip length. The analytical model that describes the stress of the outermost solder joint experiences is chosen, as this is the typical solder joint failure. The analytical model can be applied to discrete solder joints, which are evaluated by calculating the matrix form. Owing to its use of the matrix equation, the analytical model can be highly combinatorial and thus more capable of calculating the solution. Research limitations/implications The analytical solution based on a simple concept was presented and validated using the finite element model for the stress experienced by solder joints subjected to mechanical bending. To verify that the simulation represents a real PCB case, the authors use the finite element method (FEM) to compare their case with the multilayer plate theory. Owing to the good agreement between the theory and simulation results, the authors conclude that the multilayer plate theory can be correctly applied in multilayer PCB and be used in an analytical model for the PCB assembly subjected to mechanical bending. Practical implications Owing to the good agreement between the theory and simulation results, the authors conclude that the multilayer plate theory can be correctly applied in multilayer PCB and be used in an analytical model for the PCB assembly subjected to mechanical bending. Social implications The analytical model is validated with the FEM model and provides the way to physically examine the solder joint failure mechanism. In this paper, the analytical model is developed as a means to assess the solder joint stress subjected to mechanical bending. Originality/value The analytical model treats the solder joint as discrete and has been successfully validated against the finite element model. The complete structure model (the second analytical model) is presented to discuss the effects of varying silicon chip length on the normal stress in solder joints. When the silicon chip length exceeds to 80 per cent of the total package length, the stress of the outermost solder joint increases rapidly. The design analysis findings have suggested that the failure of the outermost solder joint subjected to mechanical bending on the PCB assembly can be reduced by analyzing the analytical model.

Background Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases. Aim The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism. Methods Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Results No significant differences were observed for omeprazole and midazolam, compared to the control group. Tmax and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (Tmax h: 0.50±0.00 vs 0.23±0.15; control vs conc CAL). Cmax of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P

In Drosophila, the deposition of the germ plasm at the posterior pole of the oocyte is essential for the abdomen and germ cell formation during embryogenesis. To assemble the germ plasm, oskar (osk) mRNA, produced by nurse cells, should be localized and anchored on the posterior cortex of the oocyte. Processing bodies (P-bodies) are cytoplasmic RNA granules responsible for the 5'-3' mRNA degradation. Evidence suggests that the components of P-bodies, such as Drosophila decapping protein 1 and Ge-1, are involved in the posterior localization of osk. However, whether the decapping core enzyme, Drosophila decapping protein 2 (dDcp2), is also involved remains unclear. Herein, we generated a dDcp2 null allele and showed that dDcp2 was required for the posterior localization of germ plasm components including osk. dDcp2 was distributed on the oocyte cortex and was localized posterior to the osk. In the posterior pole of dDcp2 mutant oocytes, osk was mislocalized and colocalized with F-actin detached from the cortex; moreover, considerably fewer F-actin projections were observed. Using the F-actin cosedimentation assay, we proved that dDcp2 interacted with F-actin through its middle region. In conclusion, our findings explored a novel function of dDcp2 in assisting osk localization by modulating the formation of F-actin projections on the posterior cortex.

BACKGROUND Low physical activity is common in systemic lupus erythematosus populations. AIM To evaluate the effect of physical activity counselling on physical activity and the association between physical activity changes and changes in fatigue, quality of sleep, and quality of life in women with systemic lupus erythematosus. METHODS A randomized, controlled, single-blind trial was conducted from March 2015 to August 2016. Seventy-six women with systemic lupus erythematosus were randomly assigned to the intervention or control groups. The intervention group received three sessions of physical activity counselling at 1, 4, and 8 weeks and three telephone follow-ups over 13 weeks. Outcome measures, which include daily steps, fatigue, quality of sleep, and the quality of life, were collected at baseline and 8 and 12 weeks. RESULTS The study showed that daily steps, quality of sleep, and vitality in the intervention group were significantly improved compared with those in the control group at weeks 8 and 12. Mental health was significantly improved only at week 8 in the counselling group. A positive correlation between physical activity changes and changes in vitality and mental health was observed. CONCLUSIONS Physical activity counselling can improve physical activity. As physical activity increases, systemic lupus erythematosus women feel more energetic and happier.

In this research, the delamination issue in the Quad Flat Package (QFP) after molding and post-mold cure processes is investigated through experiments and simulation modeling. The delamination failure is occurred at the interface between the Cu pad and the molding compound. The resulting interfacial delamination failure weakens the structural strength of the package and adversely affects the electronic device reliability. In the present study, the delamination failure in QFP under the reflow process is analyzed and the underlying mechanisms are investigated using different types of pad design and geometric parameters. The simulation modeling can predict the most of delamination failures in the QFP. However, the delamination failure in QFP is subject to some uncertainties. Specifically, as Cu oxidation gradually increases under the reflow process and plasma, this results in the formation of a non-uniform oxide layer on the Cu frame surface. These uncertainty factors influence the delamination failure index, limiting the accuracy of the QFP module delamination failure prediction model. The purpose of this research was to improve the shear stress and the von-Mises stress of Cu pad by discussing the pad design, the die arrangement, and the structure design in the QFP.

In this work, finite element analysis and experimental testing were performed to analyze the delamination failure in quad flat no-lead (QFN). Interfacial delamination during post-mold cure process and precondition test is a critical reliability issue for plastic IC packages. The delamination failure weakens the internal structural strength of the package and affects product reliability. Available evidence indicates that, in the interface delamination, initially generated small voids gradually expand due to thermal stress or hygro-mechanical stress. Furthermore, due to the cracks on the interface, moisture easily penetrates into the package. In plastic IC packages, this can result in not only electrical failure, but also chemical reactions that would lead to corrosion. In the present study, delamination occurred on the interface between the Cu pad and the molding compound, as well as on the interface between the die and the molding compound and the Cu pad and molding during the precondition test. This research can help in improving product reliability by preventing the delamination failure in the QFN package by analyzing physics of failure (PoF).

A hermetic Micro-Electro-Mechanical Systems (MEMS) package with a metal lid is investigated to prevent lid-off failure and improve its reliability during the precondition test. While the MEMS package benefits from miniaturization and low cost, a hermetic version is highly sensitive to internal pressure caused by moisture penetration and the reflow process, thus affecting its reliability. In this research, the finite element method is applied to analyze the contact stress between the metal lid and the silver epoxy by applying the cohesive zone model (CZM). Moreover, the red dye penetration test is applied, revealing a microcrack at the metal lid/silver epoxy interface. Further analyses indicate that the crack is caused by internal pressure. According to the experimental testing and simulation results, the silver epoxy material, the curing process, the metal lid geometry, and the bonding layer contact area can enhance the bonding strength between the metal lid and the substrate.

For a passenger railway system with a published timetable, train timetable adherence and punctuality are critical performance indicators. Compared with other resource allocation methods, timetable adjustment is a relatively cost-effective approach for improving timetable adherence. The insertion of appropriate time supplement and buffer time into a timetable to reduce delays as well as their propagation can improve punctuality. However, to appropriately distribute available supplement/buffer time is a challenging task, especially for real-world cases. Moreover, a very robust timetable may not necessarily be a good choice, since ideal punctuality might come at the cost of large time slacks. In this study, we propose a simulation-based approach that embeds a linear programming model to effectively adjust the time supplement and buffer time in a given passenger railway timetable to reduce the average delay. The proposed solution approach is empirically applied to instances of various sizes. It is shown that the heuristic can quantify the relationship between timetable efficiency and robustness, which helps railway operators select their ideal balance between these two important yet conflicting issues. Further, numerical studies with a real timetable demonstrate that the timetable can achieve better punctuality with an even lower time supplement after adjustment, and the insights observed in this work have not only academic value but also value for practitioners in their preparation of timetables.

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a trinucleotide repeat (CAG) expansion in the coding region of ATXN3 gene resulting in production of ataxin-3 with an elongated polyglutamine tract. Here, we generated induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of a male patient with SCA3 by using the Sendai-virus delivery system. The resulting iPSCs had a normal karyotype, retained the disease-causing ATXN3 mutation, expressed pluripotent markers and could differentiate into the three germ layers. Potentially, the iPSCs could be a useful tool for the investigation of disease mechanisms of SCA3.

In this paper, the solder joint failure and the solder joint fatigue life in the Thin-profile Fine-pitch Ball Grid Array (TFBGA) Package was investigated by performing the drop test, and implementing a simulation model. Owing to the need to meet the increasing demands for functionality, microelectronic package reliability can be compromised and has become the key issue when executing drop tests. During impact in drop test, the deformation of PCB due to bending and mechanical shocks can cause solder joint crack. While this is a well-known issue, observing the solder joint responses during the test execution can be a challenge. Therefore, in this work, a simulation model approach has been developed to investigate the stress and strain of the solder joint during the drop test. In this research, the JEDEC Condition B drop test was simulated, characterized by 1500G peak acceleration and 0.5 ms duration. The drop test simulation model was successful in predicting the solder joint fatigue life with different solder joint materials, such as SAC105 and SAC1205N, while also facilitating result comparison to identify the most optimal structure.

Purpose This paper aims to develop the thermal resistance network model based on the heat dissipation paths from the multi-die stack to the ambient and takes into account the composite effects of the thermal spreading resistance and one-dimensional (1D) thermal resistance. The thermal spreading resistance comprises majority of the thermal resistance when heat flows in the horizontal direction of a large plate. The present study investigates the role of determining the temperature increase compared to the thermal resistances intrinsic to the 3D technology, including the thermal resistances of bonding layers and through silicon vias (TSVs). Design/methodology/approach This paper presents an effective method that can be applied to predict the thermal failure of the heat source of silicon chips. An analytical model of the 3D integrated circuit (IC) package, including the full structure, is developed to estimate the temperature of stacked chips. Two fundamental theories are used in this paper – Laplace’s equation and the thermal resistance network – to calculate 1D thermal resistance and thermal spreading resistance on the 3D IC package. Findings This paper provides a comprehensive model of the 3D IC package, thus improving the existing analytical approach for predicting the temperature of the heat source on the chip for the 3D IC package. Research limitations/implications Based on the aforementioned shortcomings, the present study aims to determine if the use of an analytical resistance model would improve the handling of a temperature increase on the silicon chips in a 3D IC package. To achieve this aim, a simple rectangular plate is utilized to analyze the temperature of the heat source when applying the heat flux on the area of the heat source. Next, the analytical model of a pure plate is applied to the 3D IC package, and the temperature increase is analyzed and discussed. Practical implications The main contribution of this paper is the use of a simple concept and a theoretical resistance network model to improve the current understanding of thermal failure by redesigning the parameters or materials of a printed circuit board. Social implications In this paper, an analytical model of a 3D IC package was proposed based on the calculation of the thermal resistance and the analysis of the network model. Originality/value The aim of this work was to estimate the mean temperature of the silicon chips and understand the heat convection paths in the 3D IC package. The results reveal these phenomena of the complete structure, including TSV and bump, and highlight the different thermal conductivities of the materials used in creating the 3D IC packages.

Incorporating the intriguing covalent organic framework (COF) into devices and performing their advanced electronic nature are still challenging. Herein, we demonstrate the direct growth of 2D full-conjugated COF ultrathin films on dielectric hexagonal boron nitride (hBN) for the first time and study the carrier transporting characteristics of π-conjugated COF films. Under the optimized solvothermal conditions, few-layered COF-366 films with the covalent connection of tetra(p-aminophenyl)porphyrin and terephthalaldehyde are selectively fabricated on mechanically exfoliated hBN flakes. COF-366 films on hBN substrate present red-shift absorption edge and decreased band gap compared to the bulk COF powders. The organic field-effect transistor device based on COF-366 ultrathin films demonstrates p-type current modulation with an on/off ratio of 105 and mobility of 0.015 cm2 V–1 s–1. The present work represents a universal method for COF film growth on dielectric surface and also provides important insight int...

// Yih-Lin Chung 1 , and Mei-Ling Wu 2 1 Department of Radiation Oncology, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan 2 Department of Pathology and Laboratory Medicine, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan Correspondence to: Yih-Lin Chung, email: ylchung@kfsyscc.org Keywords: hepatitis B virus, hepatocarcinogenesis, PML, tumor suppressor, oncogene Received: November 05, 2015 Accepted: March 18, 2016 Published: April 6, 2016 ABSTRACT Proteasome-mediated degradation of promyelocytic leukemia tumor suppressor (PML) is upregulated in many viral infections and cancers. We previously showed that PML knockdown promotes early-onset hepatocellular carcinoma (HCC) in hepatitis B virus surface antigen ( HBsAg) -transgenic mice. Here we report the effects of PML restoration on late-onset HBsAg-induced HCC. We compared protein expression patterns, genetic mutations and the effects of pharmacologically targeting PML in wild-type , PML -/- , PML +/+ HBsAg tg/o and PML -/- HBsAg tg/o mice. PML -/- mice exhibited somatic mutations in DNA repair genes and developed severe steatosis and proliferative disorders, but not HCC. PML -/- HBsAg tg/o mice exhibited early mutations in cancer driver genes and developed hyperplasia, fatty livers and indolent adipose-like HCC. In PML +/+ HBsAg -transgenic mice, HBsAg expression declined over time, and HBsAg-associated PML suppression was concomitantly relieved. Nevertheless, these mice accumulated mutations in genes contributing to oxidative stress pathways and developed aggressive late-onset angiogenic trabecular HCC. PML inhibition using non-toxic doses of arsenic trioxide selectively killed long-term HBsAg-affected liver cells in PML +/+ HBsAg tg/o mice with falling HBsAg and rising PML levels, but not normal liver cells or early-onset HCC cells in PML -/- HBsAg tg/0 mice. These findings suggest dual roles for PML as a tumor-suppressor lost in early-onset HBsAg-induced hepatocarcinogenesis and as an oncogenic promoter in late-onset HBsAg-related HCC progression.

Age-related cognitive decline is associated with chronic low grade neuroinflammation that may result from a complex interplay among many factors, such as bidirectional communication between the central nervous system (CNS) and gut microbiota. The present study used 2-month-old (young group) and 15-month-old (aged group) male C57BL/6 mice to explore the potential association between age-related cognitive decline and the microbiota-gut-brain axis disorder. We observed that aged mice exhibited significant deficits in learning and memory, neuronal and synaptic function compared with young mice. Aged mice also exhibited significant dysbiosis of the gut microbiota. Disruptions of the intestinal barrier and blood-brain barrier were also observed, including increases in intestinal, low-grade systemic and cerebral inflammation. Furthermore, plasma and brain levels of lipopolysaccharide (LPS) were significantly higher in aged mice compared with young mice, with increasing expression of Toll-like receptor 4 (TLR4) and myeloid differential protein-88 (MyD88) and the nuclear translocation of nuclear factor κB (NF-κB) in intestinal and brain tissues. These findings showed that microbiota-gut-brain axis dysfunction that occurs through LPS-induced activation of the TLR4/NF-κB signaling pathway is implicated in age-related neuroinflammation and cognitive decline.

Urothelial carcinoma is estimated to be the fourth most common cancer among men in the U.S. in 2019. The key to successful management of this cancer is early detection and timely monitoring after treatment. Urine cytology is an inexpensive, noninvasive, and easily available diagnostic method of urine analysis, but the usage of this tool for urothelial malignancy is still not satisfactory in its sensitivity and specificity. It is time-consuming and labor-intensive to find rare neoplastic cells from hundreds or even thousands of a variety of types of cells in the background, even by well-trained cytopathologists or cytotechnicians. Therefore, it is a crucial issue to avoid false-positive and false-negative results when applying urine cytology in clinical practice. Recent advances in artificial intelligence (AI) offer potential solutions to these issues through the development of an automated, impartial, and specialized computation model to 1) reduce false-negative rates and interpretation times and 2) assist pathologists with reporting using The Paris System for Reporting Urinary Cytopathology. In this study, we tested a deep learning-based image analysis model for cell classification and enumeration in urine cytology. Deidentified whole-slide images were digitalized after performing standard urine cytology examination. We used an “active learning” approach that requires minimal upfront training and improves with more usage. We collected 3 sub-images (total 3,335 cells) from one whole-slide image annotated by 3 domain experts to train the initial model. Cells were classified into seven categories: high-grade urothelial carcinoma (HGUC), cluster HGUC, atypical neoplastic cell, atypical reactive cell, inflammatory cell, epithelial cell, and unidentified cell. Domain experts reviewed and provided feedback to initiate the model training process. After the initial model was established, we performed a pilot study using 2 sub-images from five digitalized sample slides (total 10 sub-images) to further improve the training model. Our results showed that the AI model was able to learn the morphologies of six cell types. It was then able to automatically quantify total cell counts in each class that correlated with annotations by domain experts. We are now attempting to integrate this AI model with The Paris System to create a clinical decision support system for urologists, as there is a clear unmet clinical need to establish a computational model since The Paris System requires a significant amount of complex and accurate analysis, which many clinical decisions are based upon. In conclusion, our AI model demonstrates its value in providing an automated and unbiased method to analyze urine cytology with high throughput, accuracy, and reproducibility. Introduction and integration of our AI model with The Paris System will be a giant stride to optimize clinical practices in the field of urology in the imminent future. Citation Format: Wei-Lei Yang, Ching-Ming Lee, Mei-Ling Wu, Yu-Ching Peng, Ten-Jen Liu, Yi-Hsin Liu. Applying machine learning for urine cytology—computational urothelial carcinoma analysis and diagnosis [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B13.

Background. Imbalanced oxidative stress and antioxidant defense are involved in airway remodeling in asthma. It has been demonstrated that Tetrandrine has a potent role in antioxidant defense in rheumatoid arthritis and hypertension. However, the correlation between Tetrandrine and oxidative stress in asthma is utterly blurry. This study aimed to investigate the role of Tetrandrine on oxidative stress-mediated airway remolding. Materials and Methods. Chronic asthma was established by ovalbumin (OVA) administration in male Wistar rats. Histopathology was determined by HE staining. Immunofluorescence was employed to detect the expression of α-SMA and Nrf-2. Level of oxidative stress and matrix metalloproteinases were examined by ELISA kits. Cell viability and cell cycle of primary airway smooth muscle cells (ASMCs) were evaluated by CCK8 and flow cytometry, respectively. Signal molecules were detected using western blot. Results. Tetrandrine effectively impairs OVA-induced airway inflammatory and airway remodeling by inhibiting the expression of CysLT1 and CysLTR1. The increase of oxidative stress and subsequent enhancement of MMP9 and TGF-β1 expression were rescued by the administration of Tetrandrine in the rat model of asthma. In in vitro experiments, Tetrandrine markedly suppressed TGF-β1-evoked cell viability and cell cycle promotion of ASMCs in a dose-dependent manner. Furthermore, Tetrandrine promoted Nrf-2 nuclear transcription and activated its downstream HO-1 in vivo and in vitro. Conclusion. Tetrandrine attenuates airway inflammatory and airway remodeling in rat model of asthma and TGF-β1-induced cell proliferation of ASMCs by regulating oxidative stress in primary ASMCs, suggesting that Tetrandrine possibly is an effective candidate therapy for asthma.

Lid is an important structure as it protects the IC chips in the Micro-Electro-Mechanical System (MEMS) packaging. In this paper, the authors investigated a cavity sensor with a flat lid. Through a detailed investigation, our study showed that revealed that, in the event of failure, the lid would slip off the substrate. This failure was attributed to the crack generated in the interface between the lid and the epoxy when the air expands under high-temperature conditions. To conduct the finite element analysis, a parameterized, three-dimensional sensor model was developed in ANSYS 17.0 to identify and examine the key factors contributing to the failure.

The work presented in this paper focused on moisture effects in quad flat no-lead (QFN) during the precondition test. It is well established that microelectronic packaging absorbs moisture when exposed to humid ambient conditions during the precondition test and storage. In such cases, polymer materials (molding compound and epoxy) absorb the moisture and expand, resulting in hygro-mechanical stress that causes interface delamination. To accurately simulate the moisture distribution in QFN, in this work, the moisture mechanism pertaining to material properties was investigated. Molding compound and silver epoxy were evaluated to obtain the moisture distribution according to measure data in the reference paper. In addition, finite element analysis (FEA) was performed to analyze the wetness distribution in QFN packages. Finally, the reliability of QFN was enhanced by investigating the moisture behavior of the materials comprising the QFN.