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Diabetic foot ulcer (DFU) is a predominant complication of diabetes mellitus with poor prognosis accompanied by high amputation and mortality rates. Dang-Gui-Si-Ni decoction (DSD), as a classic formula with a long history in China, has been found to improve DFU symptoms. However, mechanism of DSD for DFU therapy remains unclear with no systematic elaboration. In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. With wound healing detection, pathological changes by HE staining, inflammatory factor expression by ELISA and qRT-PCR, oxidative stress levels by ELISA, and AGEs/RAGE/TGF-β/Smad2/3 expression by Western blot were performed. In vitro, intervention with LY2109761 (TGF-β pathway inhibitor) based on DSD treatment in human dermal fibroblast-adult (HDF-a) cells was made. Cell viability by CCK8, migration ability by cell scratch, apoptosis by flow cytometry, and AGEs/RAGE/TGF-β/Smad2/3 expression by Western blot were measured. DFU rats exhibited elevated AGEs/RAGE expression, whereas decreased TGF-β1 and p-Smad3/Smad3 protein expression, accompanied by higher IL-1β, IL-6, TNF-α levels, and oxidative stress. DSD intervention reversed above effects. Glucose induction caused lower cell viability, migration, TGF-β1 and p-Smad3/Smad3 protein expression, with increased apoptosis and AGEs/RAGE expression in HDF-a cells. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. DSD intervention may facilitate wound healing in DFU by regulating expression of AGEs/RAGE/TGF-β/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy. [ABSTRACT FROM AUTHOR]

The clogging phenomenon finds extensive application in both industrial processes and daily life events. While this broad spectrum of application motivated extensive research to identify the general factors underlying the clogging mechanism, it results in a fragmented and system-specific understanding of the entire clogging process. Therefore, it is essential to establish a holistic understanding of all contributing factors of clogging based on the microscopic physical mechanisms. In this paper, we experimentally investigate clogging of granular materials in a two-dimensional hopper flow and present a self-consistent physical mechanism of clogging based on precursory chain structures. These chain structures follow a specific modified restricted random walk, and clogging occurs when they are mechanically stable enough to withstand the flow fluctuations. We introduce a single-particle model that can explain the arch-forming probability. Our results provide insight into the microscopic mechanism behind clogging and a broader understanding of the dynamics of dense granular flow. The study of the general factors underlying clogging are fragmented and application-driven due to its broad spectrum of applications. The authors propose a holistic understanding of the clogging process by investigating the clogging of a granular hopper flow using high-speed imaging, finding a signature formation of precursory chain structures. [ABSTRACT FROM AUTHOR]

Objective: To assess the psychometric properties of the EuroQol-5-Dimension five-level instrument (EQ-5D-5L) proxy in caregivers of children and adolescents with Duchenne muscular dystrophy (DMD) or spinal muscular atrophy (SMA). Method: Data were collected using the EQ-5D-5L proxy for individuals with DMD or SMA, as reported by their caregivers. Ceiling and floor effects, reliability (Cronbach's alpha), convergent and divergent validity (Spearman's correlation coefficient and Bland–Altman plot) and known-group validity (analysis of variance) was used to assess the instrument's psychometric properties. Results: Totally, 855 caregivers completed the questionnaire. Significant floor effects were observed for most dimensions of the EQ-5D-5L in both SMA and DMD samples. The EQ-5D-5L was strongly correlated with the hypothesized subscales of the SF-12, which confirmed satisfactory convergent and divergent validity. The EQ-5D-5L can significantly differentiate between impaired functional groups for individuals, demonstrating satisfactory discriminative ability. The agreement between the EQ-5D-5L utility and EQ-VAS scores was poor. Conclusions: Based on the measurement properties assessed in this study, the EQ-5D-5L proxy is a valid and reliable tool for measuring the health-related quality of life of individuals with DMD or SMA rated by caregivers. Further studies should examine the content validity of the EQ-5D as well as the performance of its young version in these two patient groups. [ABSTRACT FROM AUTHOR]

Background: Janus kinase 2 (JAK2) mutation plays an important role in T cell immunity. However, the effect of JAK2 mutation on immunotherapy is largely uncharacterized. Methods: In this study, we analyzed the effect of JAK2 mutation on the efficacy and outcomes of immune checkpoint inhibitor (ICI) therapy in the discovery cohort (n = 662) and the verification cohort (n = 1423). Furthermore, we explored the association of JAK2 mutation with the tumor immune microenvironment in a multiomics cohort. Results: In the discovery cohort (n = 662), JAK2 mutant-type patients had a better objective response rate (58.8% vs. 26.7%, P = 0.010), durable clinical benefit (64.7% vs. 38.9%, P = 0.043), progression-free survival (hazard ratio [HR] = 0.431, P = 0.015), and overall survival (HR = 0.378, P = 0.025), relative to JAK2 wild-type patients. Moreover, we further verified the prognostic significance of JAK2 mutation in an independent ICI treatment cohort with a larger sample size (n = 1423). In addition, we discovered that the JAK2 mutation was remarkably related to increased immunogenicity, such as a higher TMB, higher expression of costimulatory molecules and stimulation of antigen processing mechanisms. In addition, JAK2 mutation was positively correlated with activated anticancer immunity, such as infiltration of various immune cells and higher expression of chemokines. Conclusion: Our study demonstrates that JAK2 mutation is a novel marker that can be used to effectively predict prognosis and response to ICI therapy. Highlights: JAK2-mutated patients had a better response to ICI therapy. JAK2 mutation was associated with higher levels of immune cell infiltration and immune checkpoints. JAK2 mutation may be served as a potential predictive biomarker for efficacy of ICI therapy. [ABSTRACT FROM AUTHOR]

Purpose: The 3D/2D coronary artery registration technique has been developed for the guidance of the percutaneous coronary intervention. It introduces the absent 3D structural information by fusing the pre-operative computed tomography angiography (CTA) volume with the intra-operative X-ray coronary angiography (XCA) image. To conduct the registration, an accurate matching of the coronary artery structures extracted from the two imaging modalities is an essential step. Methods: In this study, we propose an exhaustive matching algorithm to solve this problem. First, by recognizing the fake bifurcations in the XCA image caused by projection and concatenating the fractured centerline fragments, the original XCA topological structure is restored. Then, the vessel segments in the two imaging modalities are removed orderly, which generates all the potential structures to simulate the imperfect segmentation results. Finally, the CTA and XCA structures are compared pairwise, and the matching result is obtained by searching for the structure pair with the minimum similarity score. Results: The experiments were conducted based on a clinical dataset collected from 46 patients and comprising of 240 CTA/XCA data pairs. And the results show that the proposed method is very effective, which achieves an accuracy of 0.960 for recognizing the fake bifurcations in the XCA image and an accuracy of 0.896 for matching the CTA/XCA vascular structures. Conclusion: The proposed exhaustive structure matching algorithm is simple and straightforward without any impractical assumption or time-consuming computations. With this method, the influence of the imperfect segmentations is eliminated and the accurate matching could be achieved efficiently. This lays a good foundation for the subsequent 3D/2D coronary artery registration task. [ABSTRACT FROM AUTHOR]

Objective: This study assessed patient-reported health-related quality of life (HRQoL) using two generic preference-based measures in Chinese patients with spinal and bulbar muscular atrophy (SBMA) and identified demographic and clinical determinants of health utility scores in this population. Methods: This study used cross-sectional data of 212 Chinese patients with SBMA who completed both the EQ-5D and SF-6D. Association between response to EQ-5D and SF-6D dimensions was examined using Spearman's correlation coefficient, and the association between the two utility scores was assessed using Pearson's correlation coefficient. The variations in utility scores across patients in different subgroups were compared using one-way ANOVA. Bland–Altman (B–A) plot was used to assess the agreement of utility scores between EQ-5D and SF-6D. A multivariate Tobit regression model was employed to estimate the association between utility scores and the presence of symptoms and chronic conditions. Results: The mean utility scores for the EQ-5D and SF-6D were 0.54 and 0.56, respectively. The hypothesized correlation between the EQ-5D and SF-6D dimensions ranged from 0.31 to 0.58, and the correlation between their utility scores was 0.64. An acceptable agreement between EQ-5D and SF-6D utility scores was identified by B–A plot. Patients with chronic diseases, misdiagnosis, high financial burden, and several clinical symptoms were highly likely to report a low health utility score. Conclusions: This study is the first to investigate the HRQoL of patients with SBMA worldwide. The estimated health utility scores for EQ-5D and SF-6D can be utilized as baseline data for future cost-utility analyses of SBMA-related interventions. [ABSTRACT FROM AUTHOR]

To explore the impacts of household solid fuel use for cooking and heating on diabetes and fasting blood glucose (FBG) levels, we used data from the China Health and Retirement Longitudinal Study, a national survey including middle-aged and older adults. Multivariable logistic and linear regression models were used to explore the relationship between household solid fuel use (coal, crop residue, and wood) for cooking and heating with diabetes and FBG levels. Subgroup analyses were also performed based on age, sex, region of residence, smoking status, and body mass index to examine potential interactions between the variables and household solid fuel use. Among the 6195 participants, 75.4% and 61.4%, respectively, used solid fuels for heating and cooking. Relative to clean fuel users, solid fuel users had higher odds of diabetes (heating: OR, 1.21; 95% CI, 1.01–1.44; cooking: OR, 1.31; 95% CI, 1.12–1.53) and higher FBG levels (heating: β = 3.23; 95% CI, 1.10–5.36; cooking: β = 2.86; 95% CI, 0.95–4.77). Simultaneous use of solid fuels for cooking/heating was also positively associated with diabetes (OR, 1.31; 95% CI, 1.07–1.61) and FBG (β = 4.30; 95% CI, 1.82–6.78). No significant interactions were detected between subgroup variables and the impacts of solid fuel use on diabetes and FBG. Household solid fuel use is positively associated with diabetes and FBG levels. These findings imply that inhibiting household solid fuel use may contribute to decreasing diabetes development in China. [ABSTRACT FROM AUTHOR]

Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone—an essential metabolic hormone1–3. Aberrant signalling of TSHR by autoantibodies causes Graves’ disease (hyperthyroidism) and hypothyroidism, both of which affect millions of patients worldwide4. Here we report the active structures of TSHR with TSH and the activating autoantibody M225, both bound to the allosteric agonist ML-1096, as well as an inactivated TSHR structure with the inhibitory antibody K1-707. Both TSH and M22 push the extracellular domain (ECD) of TSHR into an upright active conformation. By contrast, K1-70 blocks TSH binding and cannot push the ECD into the upright conformation. Comparisons of the active and inactivated structures of TSHR with those of the luteinizing hormone/choriogonadotropin receptor (LHCGR) reveal a universal activation mechanism of glycoprotein hormone receptors, in which a conserved ten-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain8. One notable feature is that there are more than 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts9. These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, therefore providing the molecular basis for Graves’ disease.Thyroid-stimulating hormone and autoantibody M22 push the extracellular domain of the thyrotropin receptor into an upright active conformation, revealing a universal activation mechanism of glycoprotein hormone receptors and providing the molecular basis of Graves’ disease, hypothyroidism and Hashimoto’s disease. [ABSTRACT FROM AUTHOR]

Coal is a vital energy resource worldwide, but pollutants and greenhouse gases from its combustion cause environmental problems. To explore the non-combustion approach to use and valorize coal, anthracite and lignite were blended with polyamide 12 (PA 12) through FDM printing in this work and compared in the composites. By adding lignite, Young's modulus improved with increasing loading to 50 wt% while tensile strength leveled off among the composites, compared to that of PA 12. By contrast, the addition of anthracite decreased the tensile performance at all loadings. Rheology tests and morphology analyses suggested that the interactions between fillers (anthracite and lignite) and PA 12 may cause differences in tensile properties. In addition, the printed lignite composites showed improved thermal conductivity (~ twofold), indicating lignite demonstrates the potential to build functional composites. This work provides a strategy to use lignite in composites by 3D printing for value-added products and reduces the demand for petroleum-based polymers. Our approach diverts lignite from combustion processes and alleviates the negative impact of lignite use on the environment. [ABSTRACT FROM AUTHOR]

Objective: This study's objective was to develop an algorithm that mapping the Haem-A-QoL scores to EQ-5D-5L utility scores in patients with hemophilia in China. Methods: A national sample of 862 patients with hemophilia completed both the EQ-5D-5L and Haem-A-QoL instruments. Eight regression models were selected to develop the mapping algorithm, they were: the ordinary least squares, general linear regression, Tobit regression, censored least absolute deviation, mixture beta regression, adjusted limited dependent variable mixture, the two-part, and robust MM-estimator model. Root mean squared error (RMSE), mean absolute error (MAE), and R-square (R2) calculated using the tenfold cross-validation and random sample validation methods were used to assess the predictive ability of the models. Results: Based on RMSE, MAE, and R2, the mixture beta regression model with selected Haem-A-QoL subscale scores as the predicted variables showed the best performance. Conclusions: Our mapping algorithm bolsters the calculation of QALYs while conducting an economic evaluation of hemophilia-related interventions when only Haem-A-QoL data are available. The external validity of the algorithm should be further assessed in the other populations. [ABSTRACT FROM AUTHOR]

Background: Ivabradine improves cardiac function and clinical outcomes in chronic heart failure (HF) by reducing heart rate (HR), but there is a lack of real-world data on its effectiveness and safety in Chinese patients. Methods: We designed a prospective, multicenter, observational study of Chinese adults with HF and left ventricular systolic dysfunction, resting HR ≥ 75 beats per minute (bpm), and an indication for ivabradine treatment. An interim analysis was performed using a cut-off date of 31 October 2019. The primary outcome was change in HR at 6 months after the initiation of ivabradine. Secondary endpoints included change in New York Heart Association (NYHA) functional class; quality of life (QoL), measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ); and adverse events (AEs). Results: Overall, 655 subjects were included in the interim analysis. Mean reduction in HR from baseline was 13.2 (95% confidence interval [CI] 11.2–15.2) bpm at Month 1, and 14.5 (95% CI 11.8–17.2) bpm at Month 6 (p < 0.001 for both changes). NYHA functional class and KCCQ scores improved significantly over time (p < 0.001 for all comparisons with baseline), indicating amelioration of symptoms and better QoL, respectively. Forty-four subjects (6.7%) reported a total of 60 ivabradine-related AEs, most frequently phosphenes and bradycardia (both n = 6, 0.9%). Conclusion: Treatment with ivabradine for 6 months effectively reduced HR and improved functional class and QoL in Chinese patients with chronic HF. Treatment was well tolerated. Clinical Trial Registration: ISRCTN11703380; registered on 8 November 2016. [ABSTRACT FROM AUTHOR]

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy. Postmortem analyses provide useful information for COVID-19 etiology. Here the authors profile 22 deceased severe COVID-19 patients with transcriptomic and histological approaches to find correlations between the presence of viral antigens with lymphocyte suppression yet myeloid activation, hinting distinct functions of these cells during pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to develop a mapping function that links the acromegaly quality of life (AcroQoL) questionnaire to EQ-5D-5L to obtain a preference-based utility value to inform economic evaluation. Methods: A nationwide cross-sectional questionnaire survey among patients with acromegaly was conducted online in China during 17 December 2019 to 6 January 2020. The study sample was randomly divided into a training set and a validation set. Ordinary least squares (OLS), Tobit, beta-based mixture, and adjusted limited dependent variable mixture models were tested for development of the function in the training set. Total and subscale scores and individual items of AcroQoL were included as predictors in the models along with their squared terms and demographic and clinical characteristics, and selected by backward stepwise selection. The root mean square error, mean absolute error, Akaike's information criterion, Bayesian information criterion and adjusted R-square were used to assess goodness of fit and predictive ability of the models. Results: There were 424 adult patients with acromegaly eligible for this analysis. Average EQ-5D-5L index score and AcroQoL score for them was 0.82 (SD = 0.15) and 44.3 (SD = 22.9), respectively. A total of 60 candidate models were tested. Considering model simplicity and predictive ability in both training and validation set, the best model was the OLS model using scores of physical dimension and its square term as predictors. Conclusion: A validated mapping function was developed in this study for estimating EQ-5D scores using AcroQoL outcomes. Its external validity can be further tested in other population with Acromegaly. [ABSTRACT FROM AUTHOR]

Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone1,2. Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs3–6. They activate the same G-protein-coupled receptor, luteinizing hormone–choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain3. Here we report four cryo-electron microscopy structures of LHCGR: two structures of the wild-type receptor in the inactive and active states; and two structures of the constitutively active mutated receptor. The active structures are bound to chorionic gonadotropin and the stimulatory G protein (Gs), and one of the structures also contains Org43553, an allosteric agonist7. The structures reveal a distinct ‘push-and-pull’ mechanism of receptor activation, in which the extracellular domain is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain. A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the interface between the extracellular domain and the transmembrane domain functions as a tethered agonist to induce conformational changes in the transmembrane domain and G-protein coupling. Org43553 binds to a pocket of the transmembrane domain and interacts directly with P10, which further stabilizes the active conformation. Together, these structures provide a common model for understanding the signalling of glycoprotein hormone receptors and a basis for drug discovery for endocrine diseases.Cryo-electron microscopy structures of the luteinizing hormone–choriogonadotropin receptor (LHCGR), in complex with Gs and in various states of activation, reveal a distinct mechanism of receptor activation, with implications for drug discovery. [ABSTRACT FROM AUTHOR]

Gut fungi is known to play many important roles in human health regulations. Herein, we investigate the anti-obesity efficacy of the antifungal antibiotics (amphotericin B, fluconazole and 5-fluorocytosine) in the high fat diet-fed (HFD) mice. Supplementation of amphotericin B or fluconazole in water can effectively inhibit obesity and its related disorders, whereas 5-fluorocytosine exhibit little effects. The gut fungus Candida parapsilosis is identified as a key commensal fungus related to the diet-induced obesity by the culture-dependent method and the inoculation assay with C. parapsilosis in the fungi-free mice. In addition, the increase of free fatty acids in the gut due to the production of fungal lipases from C. parapsilosis is confirmed as one mechanism by which C. parapsilosis promotes obesity. The current study demonstrates the gut C. parapsilosis as a causal fungus for the development of diet-induced obesity in mice and highlights the therapeutic strategy targeting the gut fungi. Shanshan Sun, Li Sun, Kai Wang, et al. report that the gut commensal Candida parapsilosis is a causative fungus for the development of high fat-diet induced obesity in mice. Their results suggest that fungi could represent possible targets for combating obesity. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the psychometric properties of the EQ-5D-5L and SF-6D, and to compare their performance among patients living with haemophilia in China.Methods: A total of 875 Chinese patients completed the EQ-5D-5L, SF-6D, and Haem-A-QoL questionnaires. Construct validity of the EQ-5D-5L and SF-6D dimensions and indices was assessed by testing hypotheses relating these measures to Haem-A-QoL and clinical measures. The Spearman correlation coefficient was used to assess convergent validity, and one-way analysis of variance (F statistic) was used to assess the known-groups validity (discriminatory power). The agreement between EQ-5D-5L and SF-6D indices was assessed using the intraclass correlation coefficient (ICC) and the Bland-Altman plot.Results: Both the EQ-5D-5L and SF-6D indices showed acceptable ceiling and floor effects. As hypothesised, both EQ-5D-5L and SF-6D were significantly correlated with Haem-A-QoL (both dimensions and overall score). EQ-5D-5L and SF-6D indices as well as EQ-VAS differentiated patients are known to differ in severity of haemophilia, bleeding status, disabling levels, and comorbidity. The F statistics in the known-groups comparisons suggested that the EQ-5D-5L was slightly more discriminative than the SF-6D. ICC (0.41) and Bland-Altman plot confirmed that the agreement between the EQ-5D-5L and SF-6D indices was poor.Conclusion: Both EQ-5D-5L and SF-6D showed satisfactory construct validity in the measurement of the HRQoL among patients with haemophilia. However, the two instruments may not be used interchangeably in this patient population due to their poor agreement and differing discriminatory power. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease (COVID-19) has become a universally prevalent infectious disease. The causative virus of COVID-19 is severe acute respiratory syndrome coronavirus type 2. Recent retrospective clinical studies have established a significant association between the incidence of vascular thrombotic events and the severity of COVID-19. The enhancement in serum levels of markers that reflect a hypercoagulable state has been suggested to indicate a poor prognosis. Therefore, at present, it is crucial to understand the mechanisms that foster the hypercoagulable state in COVID-19. Over-activated inflammatory response, which is manifested as excessive cytokine release in COVID-19 patients, is also associated with COVID-19 severity. This review discusses the immuno-pathological basis of the excessive cytokine release in COVID-19. Besides, this article reviews the role of pro-inflammatory or anti-inflammatory cytokines, whose significant elevations in their serum levels have been consistently detected in multiple different clinical studies, in promoting the hypercoagulable state. Since the expression of angiotensin-converting enzyme 2 (ACE2) is potentially down-regulated in COVID-19, as proposed by a recent bio-informatic analysis, mechanisms through which reduced ACE2 expressions promote vascular thrombosis are summarized. In addition, the reciprocal-enhancing effects of the excessive cytokine release and the downregulated ACE2 expression on their pro-thrombotic activities are further discussed. Here, based on currently available evidence, we review the pathogenic mechanisms of the hypercoagulable state associated with severe cases of COVID-19 to give insights into prevention and treatment of the vascular thrombotic events in COVID-19. [ABSTRACT FROM AUTHOR]

Recent studies have shown that acute blood glucose elevation in patients with ST-segment elevation myocardial infarction (STEMI) suggests a poor prognosis. To investigate the effect of fasting blood glucose (FBG) on the risk of heart failure (HF) and left ventricular systolic dysfunction (LVSD) in non-diabetic patients undergoing primary percutaneous coronary intervention (PCI) for acute STEMI, we retrospectively recruited consecutive non-diabetic patients who underwent primary PCI for STEMI in our hospital from February 2003 to March 2015. The patients were divided into two groups according to the FBG level. A total of 623 patients were recruited with an age of 61.3 ± 12.9 years, of whom 514 (82.5%) were male. The HF risk (odds ratio 3.401, 95% confidence interval (CI) 2.144–5.395, P < 0.001) was significantly increased in patients with elevated FBG than those with normal FBG. Elevated FBG was also independently related to LVSD (β 1.513, 95%CI 1.282–1.785, P < 0.001) in a multiple logistics regression analysis. In conclusion, elevated FBG was independently associated with 30-day HF and LVSD risk in non-diabetic patients undergoing primary PCI for STEMI. [ABSTRACT FROM AUTHOR]

Background: 99mTc-PYP scintigraphy provides differential diagnosis of ATTR cardiomyopathy (ATTR-CM) from light chain cardiac amyloidosis and other myocardial disorders without biopsy. This study was aimed to assess the diagnostic feasibility and the operator reproducibility of 99mTc-PYP quantitative SPECT. Method: Thirty-seven consecutive patients who underwent a 99mTc-PYP thorax planar scan followed by SPECT and CT scans to diagnose suspected ATTR-CM were enrolled. For the quantitative SPECT, phantom studies were initially performed to determine the image conversion factor (ICF) and partial volume correction (PVC) factor to recover 99mTc-PYP activity concentration in the myocardium for calculating the standardized uptake value (SUV) (unit: g/ml). SUVmax was compared among groups of ATTR-CM, AL cardiac amyloidosis, and other pathogens (others) and among categories of Perugini visual scores (grades 0–3). The intra- and inter-operator reproducibility of quantitative SPECT was verified, and the corresponded repeatability coefficient (RPC) was calculated. Results: The ICF was 79,327 Bq/ml to convert count rate in pixel to 99mTc activity concentration. PVC factor as a function of the measured activity concentration ratio in the myocardium and blood-pool was [y = 1.424 × (1 − exp(− 0.759 × x)) + 0.104]. SUVmax of ATTR-CM (7.50 ± 2.68) was significantly higher than those of AL (1.96 ± 0.35) and others (2.00 ± 0.74) (all p < 0.05). SUVmax of grade 3 (8.95 ± 1.89) and grade 2 (4.71 ± 0.23) were also significantly higher than those of grade 1 (1.92 ± 0.31) and grade 0 (1.59 ± 0.39) (all p < 0.05). Correlation coefficient (R2) of SUVmax reached 0.966 to 0.978 with only small systematic difference (intra = − 0.14; inter = − 0.23) between two repeated measurements. Intra- and inter-operator RPCs were 0.688 and 0.877. Conclusions: 99mTc-PYP quantitative SPECT integrated with adjustable PVC factors is feasible to quantitatively and objectively assess the burden of cardiac amyloidosis for diagnosis of ATTR-CM. [ABSTRACT FROM AUTHOR]

Since the outbreak of COVID-19 in China at the end of 2019, the world has experienced a large-scale epidemic caused by the SARS-CoV-2. The epidemiological and clinical course of COVID-19 patients has been reported, but there have been few analyses about the characteristics, predictive risk factors, and outcomes of critical patients. In this single-center retrospective case–control study, 90 adult inpatients hospitalized at Tongji Hospital (Wuhan, China) were included. Demographic, clinical, laboratory tests, and treatment data were obtained and compared between critical and non-critical patients. We found that compared with non-critical patients, the critical patients had higher SOFA score and qSOFA scores. Critical patients had lower lymphocyte and platelet count, elevated D-dimer, decreased fibrinogen, and elevated high-sensitivity C-reactive protein (hsCRP), and interleukin-6(IL-6). More critical patients received treatment including antibiotics, anticoagulation, corticosteroid, and oxygen therapy than non-critical ones. Multivariable regression showed higher qSOFA score and elevation of IL-6 were related to critical patients. Antibiotic usage and anticoagulation were associated with decreased in-hospital mortality. And critical grouping contributed greatly to in-hospital death. Critical COVID-19 patients have a more severe clinical course. qSOFA score and elevation of IL-6 are risk factors for critical condition. Non-critical grouping, positive antibiotic application, and anticoagulation may be beneficial for patient survival. [ABSTRACT FROM AUTHOR]

A putative glutamine synthetase (GS) was detected in a psychrophilic bacterium, Cryobacterium soli GCJ02. For gaining greater insight into its functioning, the gene was cloned and expressed in a heterologous host, Escherichia coli. The monomer enzyme with a molecular weight of 53.03 kDa was expressed primarily in cytosolic compartment. The enzyme activity was detected using glutamate and ATP. The optimum conditions of its biosynthesis were observed to be 60 °C and pH value 7.5. Its thermostability was relatively high with a half-life of 50 min at 40 °C. GS activity was enhanced in the presence of metal ions such as Mg2+ and Mn2+, whereas Fe2+, Cu2+ and Ca2+ proved inhibitory. The consensus pattern [EXE]-D-KP-[XGXGXH] in the GS lies between residues 132 and 272. The catalytic active sites consisting of EAE and NGSGMH were verified by site-directed mutagenesis. Based on the analysis of the consensus pattern, the GS/glutamate synthase cycle of C. soli GCJ02 is expected to contribute to the GS synthesic activity. [ABSTRACT FROM AUTHOR]

Marfan syndrome (MFS) is a systemic connective tissue disease principally affecting the ocular, skeletal and cardiovascular systems. This autosomal dominant disorder carries a prevalence of 1:3,000 to 1:5,000. This study aims to define the mutational spectrum of MFS related genes in Chinese patients and to establish genotype-phenotype correlations in MFS. Panel-based targeted next-generation sequencing was used to analyze the FBN1, TGFBR1 and TGFBR2 genes in 123 unrelated Chinese individuals with MFS or a related disease. Genotype-phenotype correlation analyses were performed in mutation-positive patients. The results showed that 97 cases/families (78.9%; 97/123) harbor at least one (likely) pathogenic mutation, most of which were in FBN1; four patients had TGFBR1/2 mutations; and one patient harbored a SMAD3 mutation. Three patients had two FBN1 mutations, and all patients showed classical MFS phenotypes. Patients with a dominant negative-FBN1 mutation had a higher prevalence of ectopia lentis (EL). Patients carrying a haploinsufficiency-FBN1 mutation tended to have aortic dissection without EL. This study extends the spectrum of genetic backgrounds of MFS and enriches our knowledge of genotype-phenotype correlations. [ABSTRACT FROM AUTHOR]

We introduce ShadowGAN, a generative adversarial network (GAN) for synthesizing shadows for virtual objects inserted in images. Given a target image containing several existing objects with shadows, and an input source object with a specified insertion position, the network generates a realistic shadow for the source object. The shadow is synthesized by a generator; using the proposed local adversarial and global adversarial discriminators, the synthetic shadow's appearance is locally realistic in shape, and globally consistent with other objects' shadows in terms of shadow direction and area. To overcome the lack of training data, we produced training samples based on public 3D models and rendering technology. Experimental results from a user study show that the synthetic shadowed results look natural and authentic. [ABSTRACT FROM AUTHOR]

Introduction: As one of the main yield components, grain number per panicle (GNP) played critical role in the rice yield improvement. The identification of natural advantageous variations under different situations will promote the sustainable genetic improvement in rice yield. Objectives: This study was designed to identify natural genotypes in a rice mini-core collection, to examine the genotypic effects across the indica and japonica genetic background in different environments, and excavating the superior genotypes that had drove the modern genetic improvement. Methods: The association mapping of GNP was carried out using a mini-core collection including 154 indica and 119 japonica accessions in seven different environments. Genotypic effects of each genotype for each QTL were calculated and genotype frequency distortion between the commercial rice cultivars and landraces was screened by χ2-test. Results: In total, 74 QTLs containing stable and sensitive QTLs in various environments were detected. Within them, 20 positive and 24 negative genotypes in indica, and 24 positive and 16 negative genotypes in japonica were identified. When checking the accumulation of positive genotypes identified in indica across cultivars in each of the two subspecies, it indicated that increased number of positive genotypes identified in indica results in the substantially increased GNP in both indica and japonica across all of the environments, while this trend was not obvious for the positive genotypes identified in japonica especially in short day environments. Moreover, the positive and negative genotype frequency distortion between the landraces and commercial rice cultivars indicated that both positive selection of positive genotypes and negative selection of negative genotypes had driven the genetic improvement on GNP. Conclusion: Our findings suggested that the accumulation of positive genotypes and purifying negative genotypes played equivalently important roles in the improvement of rice yield, but the efficient use for some QTLs or genotypes depends on the comprehensive evaluation of their effect under diverse genetic backgrounds and environments. [ABSTRACT FROM AUTHOR]

Purpose: For patients with myocardial infarction (MI), delayed enhancement (DE) cardiovascular magnetic resonance imaging (MRI) is a sensitive and well-validated technique for the detection and visualization of MI. The myocardium viability assessment with DE MRI is important in diagnosis and treatment management, where myocardium segmentation is a prerequisite. However, few academic works have focused on automated myocardium segmentation from DE images. In this study, we aim to develop an automatic myocardium segmentation algorithm that targets DE images.Methods: We propose a segmentation framework based on both prior shape knowledge and image intensity. Instead of the strong request of the pre-segmentation of cine MRI in the same session, we use the sparse representation method to model the myocardium shape. Data from the Cardiac MR Left Ventricle Segmentation Challenge (2009) are used to build the shape template repository. The method of guided random walks is used to integrate the shape model and intensity information. An iterative approach is used to gradually improve the results.Results: The proposed method was tested on the DE MRI data from 30 MI patients. The proposed method achieved Dice similarity coefficients (DSC) of 74.60 ± 7.79% with 201 shape templates and 73.56 ± 6.32% with 56 shape templates, which were close to the inter-observer difference (73.94 ± 5.12%). To test the generalization of the proposed method to routine clinical images, the DE images of 10 successive new patients were collected, which were unseen during the method development and parameter tuning, and a DSC of 76.02 ± 7.43% was achieved.Conclusion: The authors propose a novel approach for the segmentation of myocardium from DE MRI by using the sparse representation-based shape model and guided random walks. The sparse representation method effectively models the prior shape with a small number of shape templates, and the proposed method has the potential to achieve clinically relevant results. [ABSTRACT FROM AUTHOR]

Purpose: A realistic guidewire behavior simulation is a vital component of a virtual vascular intervention system. Such systems are a safe, low-cost means of establishing a training environment to help inexperienced surgeons develop their intervention skills. Previous attempts to simulate the complex movement of a guidewire inside blood vessels have rarely considered the influence of blood flow. In this paper, we address this problem by integrating blood flow analysis and propose a novel guidewire simulation model. Methods: The blood flow distribution inside the arterial vasculature was computed by separating the vascular model into discrete cylindrical vessels and modeling the flow in each vessel according to Poiseuille Law. The blood flow computation was then integrated into a robust Kirchhoff elastic model. With hardware acceleration, the guidewire simulation can be run in real time. To evaluate the simulation, an experimental environment with a 3D-printed vascular phantom and an electromagnetic tracking system was set up, with clinically used guidewire sensors applied to trace its motion as the standard for comparison. Results: The virtual guidewire motion trace was assessed by comparing it to the comparison standard. The root-mean-square (RMS) value of the newly proposed guidewire model was 2.14 mm ± 1.24 mm, lower than the value of 4.81 mm ± 3.80 mm for the previous Kirchhoff model, while maintaining a computation speed of at least 30 fps. Conclusion: The experimental results revealed that the blood flow-induced model exhibits better performance and physical credibility with a lower and more stable RMS error than the previous Kirchhoff model. [ABSTRACT FROM AUTHOR]

An abdominal aortic aneurysm (AAA) is a permanent, localized dilatation of the abdominal aorta. In western countries, the morbidity of AAA is approximately 8%. Currently, pharmacotherapies for AAA are limited. Here, we demonstrate that baicalein (BAI), the main component of the Chinese traditional drug 'Huang Qin', attenuates the incidence and severity of AAA in Apoe mice infused with angiotensin II (AngII). Mechanically, BAI treatment decreases AngII-induced reactive oxygen species (ROS) production in the aortic wall. Moreover, BAI inhibits inflammatory cell accumulation in the aortas of mice infused with AngII. It also inhibits AngII-induced activation of matrix metalloproteinase 2 (MMP-2) and MMP-9 to maintain elastin content in vivo. In addition, it blocks AngII cascade by downregulating angiotensin type 1 receptor (AT1R) and inhibiting mitogen-activated protein kinases (MAPKs). Taken together, our findings show that BAI is an effective agent for AAA prevention. [ABSTRACT FROM AUTHOR]

Two types of homemade poly( l-lactide) (PLLA)-grafted SiO nanoparticles with totally different topological structures are introduced into PLLA to prepare PLLA nanocomposites with different interface interactions and study the effect of the topology of polymer grafted nanoparticle on crystallization of PLLA. Differential scanning calorimetry (DSC) and polarized optical photomicrographs (POM) results show that the crystallization rate of PLLA has been greatly improved by the introduction of grafted SiO, due to the improved heterogeneous nucleating effect. The nucleation constant of the two modified nanoparticles is evaluated by Hoffman-Lauritzen analysis; it is suggested that by introducing modified nanoparticles with long grafted chains, the interaction between the nanofiller and PLLA matrix will be enhanced, leading to the improved nucleation effective (the larger nucleation constant Kg), and the changed crystalline morphology, from large spherocrystals to tiny crystals. These observations are explained on the basis of different nucleation mechanism caused by the different surface structures of grafted SiO, through the application of time-resolved Fourier transform infrared (FTIR) spectroscopy in the molecular level. The special long grafted PLLA chains can be acted as a more efficient nucleating agent for PLLA, and the conformational ordering of PLLA during the crystallization is significantly influenced by the topology of modified nanoparticles. [ABSTRACT FROM AUTHOR]

Dysregulation of the metabolism of the extracellular matrix (ECM) may contribute to coronary artery ectasia (CAE). This study evaluated the turnover of main ECM components and related proteolytic enzymes activities. In this study, thirty patients with CAE, 30 patients with coronary artery disease (CAD) and 30 subjects with normal coronary arteries (Control) were selected. The following circulating ECM metabolism markers were measured: soluble elastin (sElastin), collagen type I cross-linked telopeptides (ICTP), procollagen type I carboxy terminal peptide (PICP), protocollagen III N-terminal propeptide (PIIINP), and procollagen a1(III) C-terminal propeptide (PIIICP). Serum total elastase activity and total matrix metalloproteinase (MMP) activity were also determined. The level of sElastin was higher in the CAE group than in the CAD and Control groups ( P1 = 0.009, P2 = 0.000). There was no difference in ICTP ( P = 0.168) or PIIICP ( P = 0.079) among the three groups. PICP was significantly elevated in CAE ( P1 = 0.001, P2 = 0.002). PIIINP was also significantly increased in CAE ( P1 = 0.002, P2 = 0.007). Total elastase activity was higher in the CAE group than in the other two groups ( P1 = 0.006, P2 = 0.022). Total MMP activity was significantly higher in the CAE group than the Control group ( P2 = 0.013) but not higher than the CAD group ( P1 = 0.477). In conclusion, within CAE patients the main changes in ECM metabolism were increased degradation of elastin fibres and the transition of collagen from type III to type I. Elastase and MMPs appear to be associated with this kind of ECM turnover. [ABSTRACT FROM AUTHOR]

Motor impairment is common in the elderly population. Disrupted white matter tracts and the resultant loss of connectivity between cortical regions play an essential role in motor control. Using diffusion tensor imaging (DTI), we investigated the effect of white matter microstructure on upper-extremity and lower-extremity motor function in a community-based sample. A total of 766 participants (57.3 ± 9.2 years) completed the assessment of motor performance, including 3-m walking speed, 5-repeat chair-stand time, 10-repeat hand pronation-supination time, and 10-repeat finger-tapping time. Fractional anisotropy (FA), mean diffusivity (MD), and structural network connectivity parameters were calculated based on DTI. Lower FA and higher MD were associated with poor performance in walking, chair-stand, hand pronation-supination, and finger-tapping tests, independent of the presence of lacunes, white matter hyperintensities volume, and brain atrophy. Reduced network density, network strength, and global efficiency related to slower hand pronation-supination and finger-tapping, but not related to walking speed and chair-stand time. Disrupted white matter integrity and reduced cerebral network connectivity were associated with poor motor performance. Diffusion-based methods provide a more in-depth insight into the neural basis of motor dysfunction. [ABSTRACT FROM AUTHOR]