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Meng-Chang Yang,1,&ast; Peng Li,1,&ast; Wen-Jie Su,1 Rong Jiang,1 Jia Deng,1 Ru-Rong Wang,2 Chao-Li Huang3 1Department of Anesthesiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Internal Medicine, Eastern Hospital, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ru-Rong WangDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaTel +86 18140049936Fax +86 28-87393632Email wangrurong@scu.edu.cnChao-Li HuangDepartment of Internal Medicine, Eastern Hospital, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, No. 585, Damian, Honghe North Road, Longquanyi District, Chengdu, People’s Republic of ChinaTel +86 13350855681Fax +86 28-87775681Email chaoli_huang@126.comPurpose: Several randomized clinical trials (RCTs) investigated the effects of the manual placental removal on hemorrhage or other hemorrhage-related complications compared with the spontaneous placental removal during cesarean section (CS), while the results remained controversial and were inconsistent. The purpose of this meta-analysis was to quantify the pooled effects of the methods of placental removal on hemorrhage during CS.Patients and Methods: A systematic literature search was conducted using PubMed, EMBASE, Web of Science, and Google Scholar. Heterogeneity was tested by I2 statistics and Q-statistic. The random-effects model or fixed-effects model were used to calculate the pooled effect for the included studies according to heterogeneity. And the term of standardized mean difference (SMD) with 95% confidence intervals (CI) was pooled and estimated the effects across all studies.Results: A total of nine RCTs were included in this meta-analysis. Compared with spontaneous group, manual placental removal increased the amount of hemorrhage (SMD = 0.53, 95% CI [0.12, 0.94]; Z = 2.54, P = 0.011) and increased the risk of endometritis (OR = 1.84, 95% CI [1.31, 2.58]; Z = 3.52, P < 0.0001). In contrast, there was no significant difference concerning the operating time (SMD = − 0.30, 95% CI [− 0.85, 0.24]; Z = 1.09, P = 0.276), the length of hospital stays (SMD = 0.11, 95% CI [− 0.08, 0.30]; Z = 1.11, P = 0.265), and blood transfusion requirement (OR = 1.36, 95% CI [0.91, 2.04]; Z = 1.52, P = 0.129), respectively.Conclusion: Comparing with spontaneous placental removal, manual placental removal appeared to be less positive effect during CS. Because of the limitations of this meta-analysis, more high-quality RCTs are needed to confirm our findings.Keywords: cesarean section, manual placental removal, spontaneous placenta removal, hemorrhage, meta-analysis

This study aimed to compare the detection performance of [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in the patients with various oncological and non-oncological lesions. A total of 123 patients underwent contemporaneous [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT were included in this prospective study. The maximum standard uptake value (SUVmax) was measured to compare oncological and non-oncological lesion uptake. The sensitivity, specificity, predictive values, and accuracy of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT for detecting primary, metastatic, and non-oncological lesions were calculated and compared to evaluate the detection efficacy. The study subjects consisted of 123 patients (69 men and 54 women; mean age 56.11 ± 11.94 years). Among the 102 patients with either newly diagnosed (82 patients) or previously treated solid tumor (20 patients), a total of 88 solid primary malignant tumors in 84/102 patients were detected. Two patients had two primary tumors each and 1 patient had three primary tumors. Among them, 58/102 and 43/102 patients had nodal (376 lesions) and distant metastases (406 lesions), respectively. Eight patients had hematological neoplasm. No malignant oncological diseases were detected in the remaining 13 patients. A total of 145 non-oncological lesions and benign tumors in 52/123 patients were detected incidentally. [68 Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated a significantly higher uptake and detection rate for the primary (SUVmax 10.98 ± 5.83 vs. 8.36 ± 6.43, p

Natural chemicals obtained from the renewable resources were widely used in the modification of plant fibers. In this report, in order to develop thermoplasticity of materials, the bamboo powder (BP) after hydrothermal pretreatment (BP-LHW) was efficiently modified with natural rosin acid (BP-LHW-RA) by esterification reaction under heterogeneous condition. The results indicate that the modified BP-LHW-RA presents a strong peak at 1743 cm−1 in the FT-IR spectra, which attributed to the –C = O vibration of the ester group formed by the reaction between rosin acid and the BP-LHW, confirming that BP-LHW was successfully grafted with rosin acid. The C1/C3 ratio of BP-LHW-RA increased 1.35 times as compared with BP-LHW in XPS analysis. Meanwhile, the crystallization index of BP-LHW-RA decreased by 4.62%, and its surface became smooth and full. Moreover, the glass transition temperature of BP-LHW-RA was 200 °C. The work presents a green and feasible route to prepare bio-based materials with desired thermoplasticity by grafting natural rosin onto biomass substrate. The bio-based material with desired thermoplasticity was prepared by grafting natural rosin onto bamboo powder.

Facial nerve palsy (FNP) is extremely rare in Kawasaki disease (KD) and the incidence is just 0.9-1.3%. Our objective was to study the clinical features and prognosis of KD accompanied with FNP and to determine whether FNP indicated an increased risk of coronary artery lesions (CALs) in KD. An observational study was performed on 9 patients diagnosed as KD accompanied with FNP in Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China between September 2012 and December 2019. Patients were followed up from September 2012 till September 2020. Clinical features, laboratory and echocardiography findings, treatments, and prognosis were analyzed retrospectively. And the clinical data of patients with FNP (group A, n = 9) were compared to matched KD patients without FNP (group B, n = 27) in order to determine whether FNP indicated an increased risk of CALs in KD. The matching factors included sex, age, days of illness at the intravenous immunoglobulin use, and classic/incomplete KD forms. Clinical data of 9 patients were analyzed in this study. Patients tended to be younger than 24 months of age (88.9%) and 55.6% were under 12 months. Median onset of FNP was day 10 of illness. Eight patients (88.9%) showed unilateral FNP. The levels of laboratory inflammatory markers (White blood cells count, neutrophil percentage, C-reactive protein, erythrocyte sedimentation rate, etc.) were significantly increased in most cases. CALs were noted in 8 of 9 patients (88.9%). Coronary artery aneurysms occurred in 4 cases (44.4%) and the remaining 4 patients showed coronary artery dilation. All patients were given intravenous immunoglobulin therapy (2 g/kg), aspirin (30-50 mg/kg/day), and short-term dexamethasone. During follow-up, both FNP and CALs were completely recovered in all patients. The duration time of FNP ranged from 10 to 130 days. And the time for CALs to normal ranged from 12 to 282 days. The occurrence of CALs was significantly higher in patients with FNP than those without FNP (88.9% vs. 25.9%, P

The mechanisms of brain injury after intracerebral hemorrhage (ICH) involve mass effect-induced primary injury and secondary injury caused by a pathologic response to the hematoma. Considerable attentions have recently been paid to the mechanisms and therapeutic strategy for secondary brain injury due to no overall benefit from early surgery compared with initial conservative treatment. However, it is unclear whether there is a causal relationship between mass effect and secondary brain injury. Here, the role of mass effect on early erythrolysis after experimental ICH was investigated based on the poly(N-isopropylacrylamide) (PNIPAM) ICH model. Autologous blood and PNIPAM hydrogel were co-injected into the right basal ganglia of rats to induce different degrees of mass effect, but with a constant hematoma. The influences of different mass effect and time courses on erythrolysis and brain damages after ICH were investigated. Furthermore, the protective effect of trehalose against erythrolysis after ICH was evaluated. The results showed that mass effect caused erythrocyte morphological change at 24 hr after ICH. The released hemoglobin was quantitatively evaluated by a polynomial concerning with the mass effect, the volume of hematoma, and the time of ICH. An obvious increase in heme oxygenase-1 (HO-1) and ionized calcium binding adaptor molecule-1 (Iba-1) expression, iron deposition, cell death, and neurological deficits was observed with increasing mass effect. Moreover, trehalose alleviated brain injury by inhibiting erythrolysis after ICH. These data demonstrated that mass effect accelerated the erythrolysis and brain damages after ICH, which could be relieved through trehalose therapy.

Saponins from Camellia fascicularis leaves, which ultrasonic-assisted extraction process parameters were optimized with Box–Behnken design and antioxidant activities were assessed, were reported in this study. The highest yield of crude saponins was up to 3.68% when the optimal extraction conditions were ratio of solvent to solid of 52.1 mL/g, methanol concentration of 71.1%, and ultrasonic temperature of 50.3 °C. The crude saponins from C. fascicularis leaves were purified using HP-20 macroporous resin with methanol and three fractions (SCF-1, SCF-2 and SCF-3) were obtained. Subsequently, the in vitro scavenging activity assay showed that the fractions proved significant antioxidant capacities as dose-dependent manner on 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl radical and azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS). SCF-1 possessed significantly higher antioxidant activity than that SCF-2 and SCF-3. Overall, ultrasonic-assisted extraction could be effectively used to extract C. fascicularis leaves saponins, which possessed potential antioxidant capabilities and is expected to be developed as food materials.

Sox9 has been previously characterized as a transcription factor responsible for the extracellular matrix production during liver fibrosis. However, the deregulation and functional role of hepatocyte Sox9 in the progression of liver fibrosis remains elusive. Here, we found a significant increase of Sox9 in the hepatocytes isolated from CCl4-induced fibrotic liver and showed that antisense oligoribonucleotides depletion of Sox9 was sufficient to attenuate CCl4-induced liver fibrosis. Notably, the increase of Sox9 in hepatocyte was associated with the upregulation of long noncoding RNA H19 in both in vitro and in vivo systems. Mechanistic studies revealed that Sox9 induced H19 by binding to a conserved promoter region of H19. In vitro, hepatocyte injury triggered the increase of Sox9/H19 axis, whereas silence of H19 greatly alleviated the H2O2-induced hepatocyte apoptosis, suggesting that H19 functions as a downstream effector of Sox9 signaling and is involved in hepatocyte apoptosis. In animal experiments, inhibition of H19 alleviated the activation of hepatic stellate cells and reduced the extent of liver fibrosis, whereas ectopic expression of H19 abolished the inhibitory effects of Sox9 depletion on liver fibrosis, suggesting that the profibrotic effect of hepatocyte Sox9 depends on H19. Finally, we investigated the clinical relevance of Sox9/H19 axis to liver fibrosis and identified the increase of Sox9/H19 axis in liver cirrhosis patients. In conclusion, our findings link Sox9/H19 axis to the intrinsic mechanisms of hepatocyte apoptosis and may represent a hitherto unknown paradigm in hepatocyte injury associated with the progression of liver fibrosis.

The local microenvironment may influence the success of stem cell therapy. Iron overload occurs in many hemorrhagic injuries due to hemolysis and hemoglobin degradation, which not only mediates local cell injury, but also induces damage to the transplanted cells. Here, an injectable nanoparticle encapsulated core-shell hydrogel was fabricated for simultaneous iron overload clearance and bone marrow mesenchymal stem cells (BMSCs) transplantation following intracerebral hemorrhage (ICH). The iron chelator-loaded low-molecular-weight keratin hydrogel with quick degradation property was selected as the outer shell to eliminate iron overload, and BMSCs implantation with high-molecular-weight keratin hydrogel was selected as the inner core. The epidermal growth factor and the basic fibroblast growth factor were entrapped within the poly (lactic-co-glycolic acid) (PLGA) nanoparticle, which was then encapsulated into the core hydrogel to support the BMSC growth and differentiation. The core-shell hydrogel can be easily formed by programmed injections, and the core-shell hydrogel displayed a strong protective effect against the toxicity of hemoglobin in cell experiments. Furthermore, more BMSCs survived in the core-shell hydrogel group in vivo as compared to that in the core hydrogel group and the vehicle group. Less iron deposition and ventricular enlargement, lower brain water content, and faster neurological recovery were also observed. The data demonstrated that this core-shell hydrogel is an effective strategy for promoting transplanted cell survival under the condition of an iron overload.

Objectives To assess the recall of a deep learning (DL) method to automatically detect kidney stones composition from digital photographs of stones. Materials and methods A total of 63 human kidney stones of varied compositions were obtained from a stone laboratory including calcium oxalate monohydrate (COM), uric acid (UA), magnesium ammonium phosphate hexahydrate (MAPH/struvite), calcium hydrogen phosphate dihydrate (CHPD/brushite), and cystine stones. At least two images of the stones, both surface and inner core, were captured on a digital camera for all stones. A deep convolutional neural network (CNN), ResNet-101 (ResNet, Microsoft), was applied as a multi-class classification model, to each image. This model was assessed using leave-one-out cross-validation with the primary outcome being network prediction recall. Results The composition prediction recall for each composition was as follows: UA 94% (n = 17), COM 90% (n = 21), MAPH/struvite 86% (n = 7), cystine 75% (n = 4), CHPD/brushite 71% (n = 14). The overall weighted recall of the CNNs composition analysis was 85% for the entire cohort. Specificity and precision for each stone type were as follows: UA (97.83%, 94.12%), COM (97.62%, 95%), struvite (91.84%, 71.43%), cystine (98.31%, 75%), and brushite (96.43%, 75%). Conclusion Deep CNNs can be used to identify kidney stone composition from digital photographs with good recall. Future work is needed to see if DL can be used for detecting stone composition during digital endoscopy. This technology may enable integrated endoscopic and laser systems that automatically provide laser settings based on stone composition recognition with the goal to improve surgical efficiency.

Thermal atomic force microscope (AFM) nanolithography enables many nanofabrication applications, but it requires special thermal probes. In this paper, we developed a vibration-assisted sample heating approach to implement the nanomachining of poly(methyl methacrylate) (PMMA) with a regular AFM probe with low stiffness (~0.16 N/m). The joule heating softens the PMMA, which lowers the normal force. The in-plane vibration with high frequency was applied to reduce the adhesion force between the AFM tip and the PMMA with elevated temperature, which enhances nanomachining performances. By using this approach, uniform nanopatterns with controllable dimensions were fabricated on PMMA films with small setpoint force.

Backgrounds: The plasma colloid osmotic pressure (COP) values for predicting mortality are not well-estimated. A user-friendly nomogram could predict mortality by incorporating clinical factors and scoring systems to facilitate physicians modify decision-making when caring for patients with serious neurological conditions.Methods: Patients were prospectively recruited from March 2017 to September 2018 from a tertiary hospital to establish the development cohort for the internal test of the nomogram, while patients recruited from October 2018 to June 2019 from another tertiary hospital prospectively constituted the validation cohort for the external validation of the nomogram. A multivariate logistic regression analysis was performed in the development cohort using a backward stepwise method to determine the best-fit model for the nomogram. The nomogram was subsequently validated in an independent external validation cohort for discrimination and calibration. A decision-curve analysis was also performed to evaluate the net benefit of the insertion decision using the nomogram.Results: A total of 280 patients were enrolled in the development cohort, of whom 42 (15.0%) died, whereas 237 patients were enrolled in the validation cohort, of which 43 (18.1%) died. COP, neurological pathogenesis and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were predictors in the prediction nomogram. The derived cohort demonstrated good discriminative ability, and the area under the receiver operating characteristic curve (AUC) was 0.895 [95% confidence interval (CI), 0.840–0.951], showing good correction ability. The application of this nomogram to the validation cohort also provided good discrimination, with an AUC of 0.934 (95% CI, 0.892–0.976) and good calibration. The decision-curve analysis of this nomogram showed a better net benefit.Conclusions : A prediction nomogram incorporating COP, neurological pathogenesis and APACHE II score could be convenient in predicting mortality for critically ill neurological patients.

The mechanical response of brain tissue closely relates to cerebral blood flow and brain diseases. During intracerebral haemorrhage (ICH), a mass effect occurs during the initial bleeding and results in significant tissue deformation. However, fewer studies have focused on the brain damage mechanisms and treatment approaches associated with mass effects compared to the secondary brain injuries after ICH, which may be a result of the absence of acceptable animal models mimicking a mass effect. Thus, a thermo-sensitive poly (N-isopropylacrylamide) (PNIPAM) hydrogel was synthesized and injected into the rat brain to establish an ICH model for mass effect research. The PNIPAM hydrogel or autologous blood was injected to establish an ICH animal model, and the space-occupying volumes, brain tissue elasticity, brain oedema, neuronal cell death, iron deposition and behavioural recovery were evaluated. The lower critical solution temperature of PNIPAM hydrogel was 32 °C, and the PNIPAM hydrogel had a rough surface with similar topography and pore structure to a blood clot. Furthermore, the ICH model animals who received an injection of PNIPAM and blood produced similar lesion volumes, elasticity changes and mechanically activated ion channel piezo-2 upregulation in brain tissue. Meanwhile, slight iron deposition, neuronal cell death and brain oedema were observed in the PNIPAM hydrogel model compared to the blood model. In addition, the PNIPAM hydrogel showed good biocompatibility and stability in vivo via subcutaneous implantation. Our findings show that PNIPAM hydrogel cerebral infusion can form a mass effect similar to haematoma and minimize the interference of blood, and the establishment of a mass effect ICH model is beneficial for understanding the mechanism of primary brain injury and the role of mass effects in secondary brain damage after ICH.

The blue mold caused by Penicillium italicum in grapefruit fruit was controlled by the antifungal activities of Carboxymethyl chitosan (CMCS) alone and combined with Cryptococcus laurentii treatments in this study. According to the study results spore germination of P. italicum can be inhibited by both CMSC and C. laurentii treatment. Moreover, the growth of C. laurentii can be maintained by low CMCS concentration in vitro. The blue mold in grapefruit fruit inoculated with P. italicum was decreased in all treatments compared with the control fruit. The combination of CMSC and C. laurentii treatment resulted in a significantly synergistic effects in smallest lesion diameter and decay incidence. The defense enzyme activities, such as phenylalanine ammonia-lyase, polyphenol oxidase, peroxidase and antifungal compounds like total phenolic related to disease resistance can be induced by combined treatment. Furthermore, the commercial quality parameters of the CMCS combined with C. laurentii treatment which were measured by ascorbic acid, titratable acidity, weight loss and total soluble solid, were better than those treated with treatments alone. According to the results, the combination of CMSC and C. laurentii treatment can maintain fruit quality and control postharvest decay more effectively than single treatment, and can be commercially used in grapefruit fruit.

Intranasal drug delivery provided an alternative and effective approach for the intervention of an intracerebral hemorrhage (ICH). However, the short retention time at the absorption site and slow drug transport in intranasal gel influence the drug bioavailability and outcome of ICH. Herein, we fabricated a novel intranasal gel with oriented drug migration utilizing a charge-driven strategy to attenuate brain injury after ICH. Nicardipine hydrochloride (NCD) was entrapped in chitosan nanoparticles (CS NPs) and dispersed in an HAMC gel. Subsequently, one side of the gel was coated with a positively charged film. The oriented migration of CS NPs in the HAMC gel was determined, and the drug bioavailability was also enhanced. Furthermore, a blood-induced ICH rat model was established to evaluate the therapeutic effect of CS NPs + HAMC composites. Intranasal administration of the CS NPs + HAMC (+) composite showed a stronger neuroprotective effect in terms of brain edema reduction and neural apoptosis inhibition compared to the CS NPs + HAMC composite. These results suggested that the oriented and rapid drug transport from nose to brain can be achieved using the charge-driven strategy, and this intranasal drug delivery system has the potential to provide a new therapeutic strategy for the treatment of ICH.

Accelerating and regulating collagen formation during wound healing repair is key issues for skin regeneration. Insulin can promote the healing of damaged skin by stimulating cellular migration and angiogenesis. Here, human hair keratin-conjugated insulin was synthesized to enhance full-thickness skin regeneration based on the excellent wound healing and hemostatic effects of keratin and the collagen deposition regulation ability of insulin. The insulin-conjugated keratin (Ins-K) was synthesized through the EDC/NHS reaction, which can supply a sustained release of insulin. The Ins-K hydrogel displayed similar water absorption, porosity and rheology properties to those of the keratin hydrogel. However, the Ins-K hydrogel shows a stronger hemostatic ability than the keratin hydrogel group, with a stronger wound healing effect found for the Ins-K hydrogel in the early regeneration stage (first 2 weeks) than for the keratin hydrogel treatment, resulting in smoother skin tissues at an excision section realized by regulating transforming growth factor β1 (TGF-β1) and hydroxyproline (HYP) expression. The results demonstrate that keratin promotes hemostasis and wound healing after insulin conjugation, which highlights the potential of keratin-based materials in tissue regeneration applications.

Ciprofloxacin (CIP) is a widely used third generation fluoroquinolone antibiotics, and has been often detected in wastewater treatment plants. Finding an effective way to remove them from wastewater is of great concern. Ultraviolet (UV)/chlorine advanced oxidation process (AOP) has many advantages in micropollutant removal. In this study, CIP degradation in UV/chlorine process was investigated. Only 41.2% of CIP was degraded by UV photolysis and 30.5% by dark chlorination in 30 min, while 98.5% of CIP was degraded by UV/chlorine process in 9 min. HCO3− had markedly inhibition, NO3− and SO42- had slight inhibition, and Cl− had a marginal inhibition on CIP degradation in UV/chlorine system. The degradation of CIP in UV/chlorine process was mainly attributed to the attack of reactive species. The relative contributions of hydrated electrons (eaq ), hydroxyl radicals (HO ), chlorine atoms (Cl ), and UV photolysis were investigated. Under neutral condition in aqueous solution, CIP degradation had highest pseudo first-order reaction rate constant, in which eaq had the highest contribution, followed by Cl , HO , and UV photolysis. The intermediates and byproducts were identified and the degradation pathway was proposed. The total organic chlorine (TOCl) and biotoxicity were further assessed. CIP and natural organic matters (NOMs) were removed efficiently in real water. UV/chlorine showed the potential for the wastewater treatment containing CIP.

Surgery is an important therapeutic strategy for intracerebral hemorrhage (ICH) in the clinic and is theoretically beneficial for the outcome of ICH by decreasing hematoma, reducing nervous tissue damage, and removing harmful chemicals. However, the outcome of ICH surgery is always unsatisfactory due to postoperative rebleeding. We hypothesized that the injection of hemostatic agents in situ after aspiration surgery could immediately activate hemostasis once rebleeding occurs. Therefore, keratin hydrogels (K-gels) were easily prepared as a hemostatic material via a rehydration method and had a porous structure. Collagenase was injected into the basal lamina to mimic ICH rebleeding, and the K-gels were then injected into the same injured site after 2 h for hemostatic therapy. The hematoma volume was significantly reduced by K-gel treatment, indicating that in situ infusion of the K-gels inhibited hematoma enlargement when rebleeding occurred. Moreover, brain damage, including cell apoptosis, neuroinflammatory reactions, and neurological deficits, was also relieved after K-gel treatment. These results suggested that in situ injection of the K-gels into the hematoma area after ICH surgery improves the therapeutic outcome by stopping postoperative rebleeding. K-gels have great potential for clinical hemostatic application because of their excellent hemostatic properties and biocompatibility.

Microlens arrays (MLAs), as one of the key features in the optoelectronics field, have attracted a lot of attention recently. Unfortunately, existing fabrication methods of MLAs have many disadvantages, such as complex fabrication procedures and difficult morphology control. This paper presents a low-cost and tunable fabrication approach for concave MLAs on ultraviolet (UV) polymer surfaces. We used condensed water droplets, formed by initiative cooling, as the template for the formation of concave MLAs in this approach. A sacrificial layer of polymer material was introduced to fabricate concave MLAs with different morphology parameters. The three most important parameters of MLAs, i.e. diameter, cross-sectional profile, and packing distance, can be tuned by the proposed novel fabrication approach. By controlling the condensation time of water droplets, we can control the diameter of the concave MLAs. Moreover, the cross-sectional profile can be controlled by replacing the sacrificial layer material to change the interaction among the water droplets, sacrificial polymers, and UV polymers. In addition, the packing distance of the MLAs can also be adjusted by introducing the lateral flow of the sacrificial polymer, which was driven by the additional sacrificial polymer dispensed on the substrate. Furthermore, the UV polymer film with MLAs on its surface was applied for the packaging of high power green LEDs. Consequently, the optical output power of green LED modules is enhanced by 11.4% when using the MLAs at the driving current of 500 mA.

Individualized drug delivery improves drug efficacy and safety for patients. To implement individualized drug delivery, patient-specific tailored dosages produced on a small scale are needed. However, current pharmaceutical manufacturing is not suitable for personalized dosage forms. Although convenient to deliver various drugs, current gelatin capsules using animal collagen protein have many limitations, such as releasing drugs too fast and incompatibility with some diets. In contrast, 3D printed capsules have great potential to advance individualized treatments. In this paper, we 3D printed and tested non-animal-based capsule shells for the delivery of acetaminophen. Capsule shells were composed of poly(vinyl) alcohol (PVA) and PVA blends with 5-25% hydroxypropyl methylcellulose (HPMC). Dissolution of acetaminophen when delivered in –hese capsule shells was tested using a USP dissolution test apparatus 2 (paddle type) at gastric pH. The novel shells were compared to each other and to commercially available hard gelatin capsules. Dissolution results show that acetaminophen when delivered in 3D printed capsules was slower than when delivered by gelatin capsules. Increasing the percentage of HPMC in the blend further delayed its release and dissolution. This delay could potentially increase the efficacy and reduce the side effects of acetaminophen. These shells also offer a non-animal-based alternative to gelatin capsules. Furthermore, 3D printing of capsule shells with specific polymer blends may be useful for patient-specific therapy in compounding pharmacies across the country.

We presented a case of 67-year-old man with epigastric discomfort and anorexia for more than 2 months. No abnormal 18F-FDG uptake was found throughout the gastrointestinal tract on 18F-FDG PET/CT. The patient was enrolled in the 68Ga-FAPI PET/CT clinical trial, and a 68Ga-FAPI PET/CT was performed to help detect primary lesion. This examination demonstrated a nodular thickening of the gastric wall with an increased 68Ga-FAPI uptake in the greater curvature of the stomach. Finally, the pathological result confirmed the diagnosis of gastric stromal tumor. This case highlights that 68Ga-FAPI PET/CT might outperform 18F-FDG PET/CT in helping identify gastrointestinal stromal tumors.

Age-related level changes of hormones, endocannabinoids and their ratios are of pathophysiological significance for understanding functions, activities and interactions of the endocrine systems, including the hypothalamic-pituitaryadrenal (HPA), hypothalamic-pituitary-gonadal (HPG) axes and endogenous cannabinoid system (ECS). The present study aimed to investigate the age-dependent fluctuations of glucocorticoids, gonadal steroids, endocannabinoids and their ratios from 21 days to 10 months in both plasma and hair from the male C57BL/6 mice. A novel framework based on the liquid chromatography-tandem mass spectrometry was developed to simultaneously determine ten hormones and two endocannabinoids in plasma and hair. Results showed that glucocorticoids, corticosterone (CORT), aldosterone (ALD), 11-dehydrocorticosterone (11-DHC), gonadal steroids, progesterone (P), dehydroepiandrosterone (DHEA), testosterone (T) and dihydrotestosterone (DHT) in plasma were unimodally fluctuated (ps < 0.001) along age with the maximum value at 2.7-month-old. In contrast, the other two gonadal steroids, estrone (E1) and estradiol (E2) were declined with age (ps < 0.001). Differently, endocannabinoids, N-arachidonoyl-ethanolamine (AEA) and 1-arachydonoyl glycerol (1-AG) showed nadir and zenith values at 2.7-month-old and 3.4-month-old, respectively (ps < 0.001). Additionally, the ratios of CORT to 11-DHC and ALD in plasma were dropped similarly with age (ps < 0.001). The ratios of 1-AG to AEA, and of T to A4 and DHT, and of DHEA to A4 were unimodally changed (ps < 0.001) along age with maximum value at 2.7- or 3.4-month-old. In contrast, the ratios of E2 to T and E1 to A4 were decreased with age (ps < 0.05). The rest six ratios that reflected the interactions among the three endocrine systems, were similar age-dependent and showed nadir and zenith values at 2.7-month-old and 3.4-month-old, respectively (ps < 0.05). Most importantly, these findings in light of age-related changing patterns in plasma were repeated in hair, suggesting that the fi41-ndings in the two matrices were mutually validated. However, it was worth noting that their magnitude of levels in the two bio-matrices were markedly different. The current findings could provide reliable hormone and endocannabinoid signatures with age on neuroendocrine profiles as well as their ratios for the male C57BL/6 mice.

Objective To explore the characteristics of coagulase‐negative Staphylococci other than Staphylococci epidermidis (Nse‐CoNS) meningitis and to apply cerebrospinal fluid (CSF) times to positivity culture (TTPC) for the precise differentiation of meningitis from contamination. Methods We conducted a case‐control study to accomplish the following: First, we retrospectively reviewed records of post‐neurosurgical patients’ CSF that yielded Nse‐CoNS from January to October 2019 at the Beijing Tiantan Hospital; 17 clinical and 12 laboratory characteristics were reviewed. Second, we investigated the TTPC of the Nse‐CoNS, the cutoffs, and corresponding parameters to differentiate Nse‐CoNS meningitis from contamination. Results In this study, a total of 146 patients with Nse‐CoNS CSF culture positive were enrolled. The average TTPC in the Nse‐CoNS meningitis group was significantly shorter than in the contamination group (20.2 ± 5.0 hours and 30.2 ± 12.6 hours, respectively, P, Cerebrospinal fluids times to positivity culture(TTPC) can differentiate coagulase‐negative Staphylococci other thanStaphylococci epidermidis (Nse‐CoNS) meningitis from contamination. A TTPC shorter than 20.0 h was associated with Nse‐CoNS meningitis, while a TTPC longer than 20.0 h was associated with Nse‐CoNS contamination.

Background Lidocaine is a commonly used local anesthetic, and low-dose lidocaine has neuroprotective effects on cerebral ischemia/reperfusion (CI/R) injury; the mechanism for this, however, is still unclear. The aim of this study was to investigate the role and the possible mechanisms of lidocaine on CI/R injury in rats. Methods We constructed a rat (male Sprague-Dawley rats, 6-8 weeks old) model of CI/R injury induced by middle cerebral artery occlusion (MCAO). Histopathology, neuronal apoptosis, oxidative stress, and inflammatory response were evaluated using hematoxylin and eosin (HE) staining, Nissl staining, enzyme-linked immunosorbent assay (ELISA) and western blotting, respectively. In addition, brain water content, infarct volume, neurological deficit score each evaluated. Results The findings showed that lidocaine improved spatial learning and memory impairment, protected I/R-induced brain injury and attenuated neuronal death and apoptosis. Furthermore, lidocaine also regulated the levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), IL-6, IL-10, iNOS, and IL-4.Notably, lidocaine markedly inhibited the expression of p65 and p38. Conclusions The results indicate that lidocaine protects against cerebral injury induced by I/R in rats via the nuclear factor kappa-B (NF-κB) p65 and p38 mitogen-activated protein kinase (MAPK) signaling pathway, it provided a candidate for the treatment of CI/R-induced injury.

Objective: The aim of this study was to compare the treatment effects of high-intensity focused ultrasound (HIFU) and laparoscopic excision (LE) in patients with adenomyosis and infertility.Materials and methods: A total of 93 patients with adenomyosis and infertility who were treated with HIFU (50 patients) or LE (43 patients) from January 2012 to January 2017 at the Third Xiangya Hospital of Central South University were retrospectively analyzed. Clinical characteristics including dysmenorrhea severity pain score, menorrhagia severity scores, reproductive outcomes, complications during pregnancy and delivery, adverse effects, surgical complications, and other clinical variables were compared between the HIFU and LE groups.Results: Of the total 93 patients with adenomyosis and infertility, 50 were treated with HIFU and 43 underwent LE. Both HIFU and LE treatments achieved significant relief of dysmenorrhea and menorrhagia. The total hospital stay was shorter in patients treated with HIFU than in those who underwent LE surgery. Neither HIFU nor LE treatment led to severe complications after treatment. Most importantly, patients treated with HIFU showed significantly higher pregnancy rates and natural conception rates than those who underwent LE surgery. Notably, in the HIFU treatment group, those with diffuse adenomyotic lesions had significantly lower postoperative pregnancy rates than those with focal adenomyosis.Conclusion: HIFU showed a safe and effective profile as a therapeutic management option for patients with adenomyosis. In comparison with LE, HIFU treatment achieved better postoperative reproductive outcomes. HIFU treatment should be encouraged and implemented in clinical practice.

A lower mortality rate is observed in obese patients with acute lung injury (ALI), which is referred to as the obesity paradox, in several studies and recent meta-analyses. Hyperinsulinemia is characterized as the primary effect of obesity, and exogenous insulin attenuates LPS-induced pulmonary edema. The detailed mechanism responsible for the effect of hyperinsulinemia on pulmonary edema and alveolar filling needs to be elucidated. SD rats were fed with a high-fat diet (HFD) for a total of 14 weeks. SD rats were anesthetized and intraperitoneally injected with 10 mg/kg lipopolysaccharide (LPS), while control rats received only saline vehicle. Insulin receptor antagonist S961 (20 nmol/kg) was given by the tail vein and serum, and glucocorticoid-induced protein kinase-1 (SGK-1) inhibitor EMD638683 (20 mg/kg) was administrated intragastrically prior to LPS exposure. The lungs were isolated for the measurement of alveolar fluid clearance. The protein expression of epithelial sodium channel (ENaC) was detected by Western blot. Insulin level in serum was significantly higher in HFD rats compared with normal diet rats in the presence or absence of LPS pretreatment. Hyperinsulinemia induced by high fat feeding increased alveolar fluid clearance and the abundance of α-ENaC, β-ENaC, and γ-ENaC in both normal rats and ALI rats. Moreover, these effects were reversed in response to S961. EMD638683 prevented the simulation of alveolar fluid clearance and protein expression of ENaC in HFD rats with ALI. These findings suggest that hyperinsulinemia induced by obesity results in the stimulation of alveolar fluid clearance via the upregulation of the abundance of ENaC in clinical acute lung injury, whereas theses effects are prevented by an SGK-1 inhibitor.

OBJECTIVE The aim of the study was to examine whether an electrical impedance tomography (EIT) electrode belt changed the lung function in healthy volunteers and patients with respiratory muscle weakness (RMW) and chronic obstructive pulmonary disease (COPD). APPROACH In total, thirty subjects were included (10 healthy volunteers, 10 subjects with RMW, maximum inspiratory pressure < 40 cmH2O, and 10 COPD, grade I-IV). Spirometry measurements were conducted in a sitting position once a day at similar times on two consecutive days. Slow expiratory vital capacity (VC), forced vital capacity (FVC) and maximum voluntary ventilation (MVV) manoeuvres were performed. On day 1, spirometry was performed without the EIT electrode belt, and on day 2, the belt was attached to the thorax. MAIN RESULTS Lung function was not influenced by the electrode belt in healthy subjects. The test-retest reliability in the healthy group was 0.89, 0.89 and 0.85 for VC, FVC and MVV, respectively. On the other hand, all investigated parameters were significantly decreased in the RMW group (VC, 51.3 ± 18.0 versus 46.5 ± 18.0% predicted, without versus with EIT belt, p< 0.01; FVC, 51.7 ± 19.0 versus 45.8 ± 18.1% predicted, p< 0.01; MVV, 41.0 ± 20.0 versus 38.8 ± 19.6% predicted, p< 0.01). VC and MVV also decreased significantly in the COPD group (VC, 77.4 ± 20.5 versus 74.6 ± 18.8% predicted, p< 0.05; MVV, 57.4 ± 15.7 versus 54.4 ± 12.5% predicted, p< 0.05). SIGNIFICANCE An EIT electrode belt could reduce lung volumes in subjects with pre-existing lung diseases. Comparing lung function acquired with an electrode belt to corresponding values obtained without the belt should be avoided.

Hepatic alveolar echinococcosis (HAE) is a severe and common parasitic disease in Tibetan Plateau of China. The infected patients have to move to plain areas to receive treatments due to the poor medical conditions in plateau areas. Our aim was to investigate the application of Enhanced Recovery after Surgery (ERAS) program in perioperative management for HAE patients from Tibet Plateau and the notes for patients with landform changes.A total of 89 HAE patients from Tibet Plateau (altitude: average of 4500 m) prior received adaptive treatments at the cooperative hospital (altitude: 1500-2000 m) and accepted surgery at plain regions (altitude: 200-400 m). The patients in ERAS group received ERAS program care and patients in conventional management group received conventional care during perioperative period.Patients in ERAS group displayed significant shorter hospital stay and shorter time for recovery of gurgling compared with conventional management group (ERAS group versus conventional management group: 10.48 ± 3.525 d versus 20.29 ± 8.632 d; 1.56 ± 1.236 d versus 2.8 ± 1.19 d; all P 0.01). The number of patients with complications of bloating, nausea/vomiting, pulmonary infection, urinary tract infection, upper gastrointestinal hemorrhage, and pulmonary edema was remarkably reduced (number, ERAS group versus conventional management group: 14 versus 24; 5 versus 16; 7 versus 24; 4 versus 13; 0 versus 10; all P 0.05), and the visual analog scale scores in postoperative days 1 and 2 were obviously decreased in patients of ERAS group (score, ERAS group versus conventional management group: 2.5 ± 1.288 versus 3.83 ± 1.87; 2.25 ± 0.838 versus 3.51 ± 1.468; all P 0.01).Patients from Tibet Plateau need to receive adaptive treatments for landform changes before receiving surgeries at plain regions. ERAS program is effective and safe for Tibetan HAE patients during perioperative period.

Hepatocyte death, as well as the following inflammatory and fibrogenic signaling cascades, is the key trigger of liver fibrosis. Here, we isolated hepatocytes from CCl4-induced fibrotic liver and found that hepatocyte lincRNA-p21 significantly increased during liver fibrosis. The increase of hepatocyte lincRNA-p21 was associated with the loss of miR-30, which can inhibit TGF-β signaling by targeting KLF11. We revealed that lincRNA-p21 modulated miR-30 availability by acting as a competing endogenous RNA (ceRNA). The physiological significance of this interaction is highlighted by the feedback loop, in which lincRNA-p21 works as a downstream effector of the TGF-β signaling to strengthen TGF-β signaling and mediate its role in promoting liver fibrosis by interacting with miR-30. In vivo results showed that knockdown of hepatocyte lincRNA-p21 greatly reduced CCl4-induced liver fibrosis and inflammation, whereas ectopic expression of miR-30 in hepatocyte exhibited the similar results. Mechanistic studies further revealed that inhibition of miR-30 impaired the effects of lincRNA-p21 on liver fibrosis. Additionally, lincRNA-p21 promoted hepatocyte apoptosis in vitro and in vivo, whereas the proliferation rate of hepatocyte was suppressed by lincRNA-p21. The pleiotropic roles of hepatocyte lincRNA-p21 suggest that it may represent an unknown paradigm in liver fibrosis and serve as a potential target for therapy.

Merged satellite ocean color data were used to examine trends in the timing and magnitude of phytoplankton blooms. Special emphasis was placed on the peak shift of spring and autumn/winter blooms in the North Pacific and North Atlantic Oceans with bimodal seasonal cycles. Ensemble empirical mode decomposition and Holo-Hilbert spectral analysis were combined to extract seasonal signals and investigate their modulation at multiple time-scales. In the temperate North Atlantic Ocean, earlier and decreasing spring blooms were detected with delayed and increased autumn blooms. The temperate North Pacific Ocean presented delayed and increased spring and autumn blooms, with the delay in fall blooms was larger than spring ones. The separation between two bloom peaks was increasing in both temperate North Atlantic and Pacific regions. The intrinsic variation in bloom timing and magnitude in these selected regions could be clearly extracted by ensemble empirical mode decomposition. Further Holo-Hilbert spectral results showed that changes in the annual cycle and bloom characteristics were modulated by interannual variability. These results suggest the critical role of interannual variability in the modulation of phytoplankton seasonality.

The contents of steroids and endocannabinoids along with the ratios between them would be candidate biomarkers for sensitively and comprehensively assessing the role of testosterone in regulating the activities of the hypothalamus-pituitary-gonadal (HPG) axis, the hypothalamus-pituitaryadrenal (HPA) axis and endogenous cannabinoid system (ECS). However, previous studies mostly used the contents rather than the ratios as biomarkers. This study aimed to systematically screen and identify sensitive biomarkers from 21 candidates including both the contents of nine steroids and one endocannabinoid and their ratios in saliva. Three screening criteria were whether there were intergroup differences, time-dependent changes and considerable relative stability during a 4-h period after exogenous testosterone administration. This study used LC-APCI+-MS/MS to determine the salivary levels of the candidate biomarkers on 62 male healthy undergraduates who were divided into testosterone administration and placebo control groups. The results revealed that salivary testosterone, androstenedione, DHEA and the ratios of testosterone to estradiol and AEA, and of cortisol to testosterone and DHEA were sensitive biomarkers for assessing the effects of testosterone administration on the three neuroendocrine systems because they all showed significant intergroup differences and time-dependent changes and good relative stability. Salivary cortisol, cortisone and the ratios of testosterone to androstenedione and DHEA and of androstenedione to estrone, and of cortisol to cortisone, androstenedione and AEA might be suitable biomarkers because they met only two of the three criteria, but needed to be validated in the future. The rest biomarkers were unsuitable because they mostly showed no significant intergroup differences, blunt time-dependent changes and poor relative stability.

INTRODUCTION AND OBJECTIVES:Deep learning is a subset of machine learning and artificial intelligence in which algorithms are developed to train machines/computers to detect a specific feature or c...

In situ keratin hydrogel offer a promising strategy to relieve the brain injury after intracerebral hemorrhage (ICH) by delivering the iron chelator directly to the stroke site. However, the injectable property of traditional keratin hydrogel is unsatisfactory, which can’t provide adaptable filling of lesion defects with irregular shapes. Herein, the thermo sensitive keratin-g-PNIPAM polymers with different graft ratios were synthesized, and deferoxamine mesylate (DFO) loaded thermo sensitive keratin hydrogels (TKGs) were prepared using the oxidative crosslinking method. The lower critical solution temperature of TKGs can be tailored from 28.5 to 31.8 °C by varying the graft ratios of keratin to NIPAM, and TKG can fill up the complex shapes of lesion cavities easily due to the characteristic of sol-gel transition. In addition, TKGs exhibit stronger adsorption and clearance capacities for the Fe2+ than keratin gel. Meanwhile, in situ injection of TKG with different DFO loadings (0.1, 1.0, and 10 mg/mL) into the hematoma region after ICH surgery showed a stronger effect on the reduction of ICH-induced iron deposits, brain non-heme iron content, brain edema and ROS level compared to the DFO treatment by intraperitoneal administration. Thus, the developed TKG can be potentially exploited for iron-induced brain injury after ICH.

The activation of osteoblasts is significantly correlated to prostate tumor bone metastasis and bone loss. Oncostatin M (OSM) could promote breast cancer metastasis to bone. However, its role and mechanism in prostate cancer bone metastasis remain unclear. MicroRNAs (miRNAs) could play important roles in cancers via post-transcriptionally regulating target genes via binding to specific sequences in the 3' UTR of downstream target genes. In the present study, we performed microarray profiling analyses to identify differentially-expressed miRNAs in preosteoclast before and after osteoclast differentiation that could target OSM. miR-181b-5p was downregulated during Raw264.7 cells differentiation into osteoclast. By direct targeting OSM 3' UTR, miR-181b-5p inhibited OSM messenger RNA expression and protein levels, subsequently decreasing IL-6 and AREG and increasing OPG, while OSM overexpression exerted an opposing effect. More importantly, co-culture with miR-181b-5p-overexpressing differentiated Raw264.7 cells suppressed proliferation, migration, and invasion of mouse prostate cancer RM-1 cells, while co-culture with OSM-overexpressing Raw264.7 cells led to opposing cellular effects. More importantly, the effects of miR-181b-5p on osteoclastogenic factors and RM-1 cells could be significantly reversed by OSM overexpression. In summary, miR-181b-5p/OSM axis could be a viable therapeutic target for patients with surgically removed primary tumors to reduce bone metastasis and prevent bone loss.

Polydactyly is a condition in which the supernumerary digits or duplications of digital parts manifest either as an integral part or in association with ∼300 well-defined syndromes. Polydactyly is the most frequently observed congenital limb anomaly at birth. The reported incidence of polydactyly

Background: Traditional Chinese medicine injections (TCMJ) used in the treatment of severe pneumonia have been widely implemented in clinical practice, but their overall efficacy and safety remain unclear. This paper aims to evaluate the efficacy and safety of TCMJ in the treatment of severe pneumonia. Methods: PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WanFang, and the Chongqing VIP Chinese Science and Technology Periodical Database were all searched for randomized controlled trials focusing on the administration of TCMJ for severe pneumonia. Two researchers independently screened titles, abstracts, full texts, and extracted relevant data. The RevMan 5.3 software (The Cochrane Collaboration, Software Update, Oxford, UK) and Stata 14 software (STATA Corporation, College Station, TX) were used for statistical analysis. Results: This study summarizes the related randomized controlled trials to assess the effect and safety of TCMJ in the treatment of severe pneumonia. Conclusion: This article provides theoretical support for the clinical application of TCMJ in the treatment of severe pneumonia. PROSPERO Registration number: CRD42020185072

The effect of gut microbiota on the activity of the HPA and HPG axes and ECS is a short-term or long-lasting process remains unclear in rodents. However, the extant studies focused only on its short-term effect on the HPA activity because there is lack of reliable biomarkers characterizing short-term activity of the HPG axis and ECS and long-term activities of the three endocrine systems. The endogenous levels of aldosterone (ALD), 11-dehydrocorticosterone (11-DHC), estradiol (E2), estrone (E1), androstenedione (A4), dihydrotestosterone (DHT), corticosterone (CORT), dehydroepiandrosterone (DHEA), testosterone (T), progesterone (P), N-arachidonoyl ethanoamide (AEA) and 1-arachydonoyl glycerol (1-AG) in hair and plasma are the potential long-term and short-term biomarkers of the three systems. This study aimed to develop the sensitive and selective methods for simultaneous quantitation of the twelve compounds in rodent’s hair and plasma. Then the methods were used to explore the differences in the hair levels of the twelve compounds between the mice in XZ group possibly having gut microbiota with more diversity and SPF group possibly having gut microbiota with less diversity and the inter-group differences in the plasma levels in the response to 1-h restraint stress. The methods were based on high performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization in positive mode. The methods were adopted for 20 mg hair and 100 μL plasma, respectively. Hair samples were incubated in methanol at 40 ℃ for 24 h, and were performed by solid phase extraction. Plasma samples were implemented by liquid-liquid extraction with ethyl acetate. The methods showed limit of quantification at 0.06–1.3 pg/mg and 0.03-0.6 ng/mL and recovery ranging between 87.7–115.1 % and 86.1–114.6 % for all compounds in rodent’s hair and plasma, and the intra-day and inter-day coefficients of variation less than 15 %, and good freeze/thaw and short-term stability. The present methods also had good reliability as demonstrated by the sex difference in the testosterone levels in hair and plasma. The inter-group comparison revealed that the mice in XZ group showed significantly higher hair levels than those in SPF group for 1-AG and most of hormones except for T and P. The non-stressed female mice in SPF showed significantly higher plasma levels than those in XZ for AEA and most of hormones except for E2, A4, DHT, T and 1-AG, but there were no inter-group differences for the stressed mice except for DHEA and 11-DHC and for the non-stressed male mice. Additionally, the stressed mice showed significantly higher corticosterone level in plasma than controls for male and female mice in XZ and male mice in SPF, but it was not true for female mice in SPF.

Electromyographic (EMG) signal is playing an important role on hand function training as a neuromuscular rehabilitation tool. Various pattern recognition algorithms (PRAs) have been compared and evaluated in previous research, and Linear Discriminant Analysis (LDA) showed the higher offline accuracy for motion classification. However, it is rarely of comparison for different types of Discriminant Analysis (DA), and the surface electrodes are common methods for signal acquisition. This paper proposes to evaluate the offline performance of LDA and other types of DA, and using Myo armband for recording signals. The offline data was acquired by Myo armband, processing recognizing the data in BioPatRec, an open source platform for motion classification and hand prosthetics control. From the results of average offline accuracy, training time, and testing time of the five types, LDA and Quadratic Discriminant Analysis (QDA) have the better performance than others, and LDA is the fastest algorithm with simple computing.