Electrical micro flow cytometry with LSTM and its application in leukocyte differential.

This paper developed an electrical micro flow cytometry to realize leukocyte differentials leveraging a constrictional microchannel and a deep neural network. Firstly, purified granulocytes, lymphocytes or monocytes traveled through the constrictional microchannel with a cross-sectional area marginally larger than individual cells and produced large impedance variations by blocking focused electric field lines. By optimizing key elements (e.g., normalization, learning rate, batch size and neuron number) of the recurrent neural network (RNN), electrical results of purified leukocytes were analyzed to establish a leukocyte differential system with a classification accuracy of 95.2%. Then the leukocyte mixtures were forced to travel through the same constrictional microchannel, producing mixed impedance profiles which were classified into granulocytes, lymphocytes and monocytes based on the aforementioned differential system. As to the classification results, two leukocyte mixtures from the same donor were processed, producing comparable classification results, which were 57% versus 59% of granulocytes, 37% versus 34% of lymphocytes and 6% versus 7% of monocytes. These results validated the established classification system based on the constrictional microchannel and the recurrent neural network, providing a new perspective of differentiating white blood cells by electrical flow cytometry.

Advance of microfluidic flow cytometry enabling high-throughput characterization of single-cell electrical and structural properties.

This paper reported a micro flow cytometer capable of high-throughput characterization of single-cell electrical and structural features based on constrictional microchannels and deep neural networks. When single cells traveled through microchannels with constricted cross-sectional areas, they effectively blocked concentrated electric field lines, producing large impedance variations. Meanwhile, the traveling cells were confined within the cross-sectional areas of the constrictional microchannels, enabling the capture of high-quality images without losing focuses. Then single-cell features from impedance profiles and optical images were extracted from customized recurrent and convolution networks (RNN and CNN), which were further fused for cell-type classification based on support vector machines (SVM). As a demonstration, two leukemia cell lines (e.g., HL60 vs. Jurkat) were analyzed, producing high-classification accuracies of 99.3% based on electrical features extracted from Long Short-Term Memory (LSTM) of RNN, 96.7% based on structural features extracted from Resnet18 of CNN and 100.0% based on combined features enabled by SVM. The microfluidic flow cytometry developed in this study may provide a new perspective for the field of single-cell analysis.

Toward five-part differential of leukocytes based on electrical impedances of single cells and neural network.

The five-part differential of leukocytes plays key roles in the diagnosis of a variety of diseases and is realized by optical examinations of single cells, which is prone to various artifacts due to chemical treatments. The classification of leukocytes based on electrical impedances without cell treatments has not been demonstrated because of limitations in approaches of impedance acquisition and data processing. In this study, based on treatment-free single-cell impedance profiles collected from impedance flow cytometry leveraging constriction microchannels, two types of neural pattern recognition were conducted for comparisons with the purpose of realizing the five-part differential of leukocytes. In the first approach, 30 features from impedance profiles were defined manually and extracted automatically, and then a feedforward neural network was conducted, producing a classification accuracy of 84.9% in the five-part leukocyte differential. In the second approach, a customized recurrent neural network was developed to process impedance profiles directly and based on deep learning, a classification accuracy of 97.5% in the five-part leukocyte differential was reported. These results validated the feasibility of the five-part leukocyte differential based on label-free impedance profiles of single cells and thus provide a new perspective of differentiating white blood cells based on impedance flow cytometry.

A giant invasive macroprolactinoma with recurrent nasal bleeding as the first clinical presentation: case report and review of literature.

BACKGROUND: Giant prolactinoma (> 4 cm in dimension) is a rare disorder. Invasive macroprolactinoma has the potential to cause base of skull erosion and extend into the nasal cavity or even the sphenoid sinus. Nasal bleeding caused by intranasal tumor extension is a rare complication associated with invasive giant prolactinoma. We report a case of giant invasive macroprolactinoma with repeated nasal bleeding as the initial symptom. CASE PRESENTATION: A 24-year-old man with an invasive giant prolactinoma in the nasal cavity and sellar region who presented with nasal bleeding as the initial symptom, misdiagnosed as olfactory neuroblastoma. However, markedly elevated serum prolactin levels (4700 ng/mL), and a 7.8-cm invasive sellar mass confirmed the diagnosis of invasive giant prolactinoma. He was treated with oral bromocriptine. Serum prolactin was reduced to near normal after 6 months of treatment. Follow-up magnetic resonance imaging showed that the sellar lesion had disappeared completely and the skull base lesions were reduced. CONCLUSION: This case is notable in demonstrating the aggressive nature of untreated invasive giant prolactinomas which can cause a diagnostic difficulty with potential serious consequences. Early detection of hormonal levels can avoid unnecessary nasal biopsy. Early identification of pituitary adenoma with nasal bleeding as the first symptom is particularly important.

Heterogeneity and associated factors of patients with polycystic ovary syndrome health behaviors: a latent class analysis.

OBJECTIVE: Using latent class to analyze whether there are subtypes of health behaviors in patients with PCOS can be addressed using targeted interventions. METHODS: October 2021 to June 2022, 471 PCOS patients were surveyed using the Health Promoting Lifestyle Profile Questionnaire. Latent class analysis (LCA) was used to identify subgroups of PCOS patients. Subsequent multinomial latent variable regressions identified factors that were associated with health behaviors. RESULTS: A three-class subtypes was the optimum grouping classification: (1)High healthy behavior risk; (2)high healthy responsibility and physical activity risk; (3)low healthy behavior risk. The multinomial logistic regression analysis revealed that (1)Single (OR = 2.061,95% CI = 1.207-3.659), Education level is primary school or below (OR = 4.997,95%CI = 1.732-14.416), participants is student (OR = 0.362,95%=0.138-0.948), participants with pregnancy needs (OR = 1.869,95%=1.009-3.463) were significantly more likely to be in the high healthy behavior risk subtypes; (2)The older the age (OR = 0.953,95%=0.867-1.047) and the larger the WC (OR = 0.954,95%=0.916-0.993), participants is married (OR = 1.126,95%=0.725-1.961), participants is employed ( OR = 1.418,95%=0.667-3.012) were significantly more likely to be in the high health responsibility and physical activity risk subtypes. CONCLUSION: Patients with PCOS are a heterogeneous population with potential subtypes that may be suitable for customized multi-level care and targeted interventions.

Global prevalence of congenital hypothyroidism among neonates from 1969 to 2020: a systematic review and meta-analysis.

Little is known about the global prevalence of congenital hypothyroidism (CH), though it is known to vary across countries and time periods. This meta-analysis aims to estimate the global and regional prevalence of CH among births between 1969 and 2020. PubMed, Web of Sciences, and Embase databases were searched for relevant studies between January 1, 1975, and March 2, 2020. Pooled prevalence was calculated using a generalized linear mixed model, and expressed as a rate per 10,000 neonates. The meta-analysis involved 116 studies, which analyzed 330,210,785 neonates, among whom 174,543 were diagnosed with CH. The pooled global prevalence of CH from 1969 to 2020 was 4.25 (95% confidence interval (CI) 3.96-4.57). The geographic region with highest prevalence was the Eastern Mediterranean (7.91, 95% CI 6.09-10.26), where the prevalence was 2.48-fold (95% CI 2.04-3.01) that in Europe. The national income level with the highest prevalence was upper-middle (6.76, 95% CI 5.66-8.06), which was 1.91-fold (95% CI 1.65-2.22) that in high-income countries. Global prevalence of CH was 52% (95% CI 4-122%) higher in 2011-2020 than in 1969-1980, after adjusting for geographic region, national income level, and screening strategy.  Conclusion: The global prevalence of CH increased from 1969 to 2020, which may reflect the implementation of national neonatal screening, neonatal testing for thyroid-stimulating hormone, and a lowering of the diagnostic level of this hormone. Additional factors are likely to be driving the increase, which should be identified in future research. What is Known: • Cumulated evidence had suggested that the occurrences of congenital hypothyroidism (CH) among newborns were varied in different countries.. • Up-trends of the birth prevalence of CH were observed in many European and American countries. What is New: • This is the first meta-analysis to estimate global and regional prevalence of CH among newborns. • The global prevalence of CH has increased by 127% since 1969. The Eastern Mediterranean has the highest prevalence and stands out with the most pronounced escalation in the prevalence of CH.

A structural equation model linking health literacy, self-efficacy, and quality of life in patients with polycystic ovary syndrome.

BACKGROUND: Health literacy is a crucial factor that affects health outcomes. Understanding the current status of health literacy among patients with polycystic ovary syndrome (PCOS) is the basis for helping patients better manage risk factors and improve their health outcomes. This study aimed to explore the status of and factors influencing health literacy in patients with PCOS, and to validate the pathway between health literacy, quality of life, and self-efficacy for these patients. METHODS: A cross-sectional study was conducted using a convenience sample of 300 patients with PCOS in the gynecology outpatient clinic of a tertiary hospital in Zunyi from March to September 2022. Data on health literacy, demographic features, quality of life, and self-efficacy were collected. Multiple stepwise linear regression was conducted to assess the risk factors associated with health literacy for the study participants. A structural equation model was used to construct and validate the pathways. RESULTS: Most participants exhibited low health literacy (3.61 ± 0.72), and only 25.70% had adequate health literacy. Multiple regression analysis revealed that the main factors associated with health literacy among participants included Body Mass Index (BMI) (B = -0.95, p < 0.01), education (B = 3.44, p < 0.01), duration of PCOS (B = 4.66, p < 0.01), quality of life (B = 0.25, p < 0.01), and self-efficacy (B = 0.76, p < 0.01). Multiple fit values indicated that the model fit the data effectively. The direct effect of health literacy on self-efficacy and quality of life was 0.06 and 0.32, respectively. The indirect effect of health literacy on quality of life was -0.053, and the total effect of health literacy on quality of life was 0.265. CONCLUSIONS: Health literacy was low among patients with PCOS. Healthcare providers should pay more attention to health literacy and to developing the corresponding intervention strategies urgently needed to improve the quality of life and health behavior of patients with PCOS.

Inherent single-cell bioelectrical parameters of thousands of neutrophils, eosinophils and basophils derived from impedance flow cytometry.

Single-cell bioelectrical properties are commonly used for blood cell phenotyping in a label-free manner. However, previously reported inherent single-cell bioelectrical parameters (e.g., diameter Dc , specific membrane capacitance Csm and cytoplasmic conductivity σcy ) of neutrophils, eosinophils and basophils were obtained from only tens of individual cells with limited statistical significance. In this study, granulocytes were separated into neutrophils, eosinophils and basophils based on fluorescent flow cytometry, which were further aspirated through a constriction-microchannel impedance flow cytometry for electrical property characterization. Based on this microfluidic impedance flow cytometry, single-cell values of Dc , Csm and σcy were measured as 10.25 ± 0.66 µm, 2.17 ± 0.30 µF/cm2 , and 0.37 ± 0.05 S/m for neutrophils (ncell  = 9442); 9.73 ± 0.51 µm, 2.07 ± 0.19 µF/cm2 , and 0.30 ± 0.04 S/m for eosinophils (ncell  = 2982); 9.75 ± 0.49 µm, 2.06 ± 0.17 µF/cm2 , and 0.31 ± 0.04 S/m for basophils (ncell  = 5377). Based on these inherent single-cell bioelectrical parameters, neural pattern recognition was conducted, producing classification rates of 80.8% (neutrophil vs. eosinophil), 77.7% (neutrophil vs. basophil) and 59.3% (neutrophil vs. basophil). These results indicate that as inherent single-cell bioelectrical parameters, Dc , Csm and σcy can be used to classify neutrophils from eosinophils or basophils to some extent while they cannot be used to effectively distinguish eosinophils from basophils.

Inherent bioelectrical parameters of hundreds of thousands of single leukocytes based on impedance flow cytometry.

As label-free biomarkers, bioelectrical properties of single cells have been widely used in hematology analyzers for 3-part differential of leukocytes, in which, however, instrument dependent bioelectrical parameters (e.g., DC/AC impedance values) rather than inherent bioelectrical parameters (e.g., diameter Dc , specific membrane capacitance Csm and cytoplasmic conductivity σcy ) were used, leading to poor comparisons among different instruments. In order to address this issue, this study collected inherent bioelectrical parameters from hundreds of thousands of white blood cells based on a home-developed impedance flow cytometry with corresponding 3-part differential of leukocytes realized. More specifically, leukocytes were separated into three major subtypes of granulocytes, monocytes and lymphocytes based on density gradient centrifugation. Then these separated cells were aspirated through a constriction-microchannel based impedance flow cytometry where inherent bioelectrical parameters of Dc , Csm and σcy were quantified as 9.8 ± 0.7 µm, 2.06 ± 0.26 µF/cm2 , and 0.34 ± 0.05 S/m for granulocytes (ncell  = 134,829); 10.4 ± 1.0 µm, 2.45 ± 0.48 µF/cm2 , and 0.42 ± 0.08 S/m for monocytes (ncell  = 40,226); 8.0 ± 0.5 µm, 2.23 ± 0.34 µF/cm2 , and 0.35 ± 0.08 S/m for lymphocytes (ncell  = 129,193). Based on these inherent bioelectrical parameters, neural pattern recognition was conducted, producing a high "classification accuracy" of 93.5% in classifying these three subtypes of leukocytes. These results indicate that as inherent bioelectrical parameters, Dc , Csm , and σcy can be used to electrically phenotype white blood cells in a label-free manner.

Lactucin & Lactucopicrin ameliorates FFA-induced steatosis in HepG2 cells via modulating lipid metabolism.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, and there are no effective drugs available so far. Lactucin and Lactucopicrin belong to sesquiterpene lactones and are extracted from Cichorium glandulosum Boiss. et Huet (CG) possesses multiple biopharmacological activities. However, the therapeutic effects of both Lactucin and Lactucopicrin on many diseases and their underlying mechanisms remain largely unknown. Here, we analyzed the both natural compounds hypolipidemic effects on FFA-induced HepG2 cells and their potential mechanisms based on transcriptomics and experimental tests. Our results indicated that Lactucin (10 µM) and Lactucopicrin (20 µM) remarkably reduced TG accumulation. Transcriptomics analysis identified 1960, 1645, and 1791 differentially expressed genes (DEGs) and obtained 611 and 635 specific genes in different comparisons, respectively. The enrichment analysis and experimental validations (RT-qPCR and Western Blot) showed that their hypolipidemic activities were most probably exerted via regulating numerous key DEGs involved in lipid metabolism. Taken together, both Lactucin and Lactucopicrin may represent potent hepatoprotective agents. Both of them exhibited therapeutic effects against liver diseases such as NAFLD by regulating multi-gene and proteins like HADHA, ADAM17, SQSTM1, and GBA and modulating multi-pathways like fatty acid oxidation metabolic signaling.

Hypoparathyroidism and late-onset hypogonadism in an adult male with familial 22q11.2 deletion syndrome: a case report with 3-year follow-up and review of the literature.

BACKGROUND: 22q11.2 deletion syndrome (DiGeorge syndrome) is associated with multiple organ dysfunctions such as cardiac defects, immunodeficiency, and hypoplasia of parathyroid glands. Moreover, the phenotype of 22q11.2 DS has clinical variability and heterogeneity. CASE PRESENTATION: In this report, we present the case of a 35-year-old patient with a past medical history that included recurrent infections, mild learning difficulties in childhood, pediatric obesity, and cataract. He was admitted to the endocrinology department for the management of hypogonadism and hypocalcemia. During the 3-year follow-up, the patient gradually developed primary hypoparathyroidism, hypogonadism, chronic renal failure, and heart failure, and his medical condition deteriorated. Meanwhile, in order to improve clinicians' awareness of the endocrine manifestations of adult 22q11.2 DS and reduce missed diagnoses, we reviewed 28 case reports of adult 22q11.2 DS to analyze the clinical characteristics. DISCUSSION: Here, we report the case of a young man diagnosed with 22q11.2 DS presented a rare combination of multiple endocrine disorders. This is the first time that a patient with 22q11.2DS had late-onset hypogonadism caused by primary testicular failure combined with decreased pituitary gonadotropin reserve in a patient with 22q11.2DS.

Value of the triglyceride glucose index combined with body mass index in identifying non-alcoholic fatty liver disease in patients with type 2 diabetes.

BACKGROUND: The triglyceride glucose index combined with body mass index is a new index that reflects the degree of insulin resistance. In this cross-sectional study, we aimed to explore the predictive value of the triglyceride glucose-body mass index (TyG-BMI) in relation to the occurrence of non-alcoholic fatty liver disease (NAFLD) in the Chinese population with type 2 diabetes (T2D). METHODS: We selected 826 patients with T2D who were hospitalized at the Department of Endocrinology and Metabolism of Karamay People's Hospital from September 2016 to October 2018 for this research. The height, weight, fasting blood glucose, serum insulin, and lipid profiles of the subjects were collected. The liver ultrasound showed any degree of echogenic enhancement of liver tissue and the liver appeared brighter than the renal cortex on ultrasound were considered to be NAFLD. The logistic regression analysis was performed to estimate associations between the triglyceride glucose index (TyG), TyG-BMI index, insulin resistance index (HOMA-IR) and the ratio of the triglycerides to high-density lipoprotein-cholesterol with a diagnosis of NAFLD. The receiver operating characteristic curve method was used to analyze its predictive value for NAFLD. RESULTS: Results of the logistic regression analysis showed that the odds ratios of NAFLD were 6.535 (3.70-11.53) and 4.868 (2.576-9.200) for the TyG-BMI before and after correction,respectively(P < 0.001). The area under the curve (AUC) for TyG-BMI was 0.727 (0.691-0.764), which was the highest among all the other parameters studied. CONCLUSION: Compared with the TyG index, the TG/HDL-C and HOMA-IR, the TyG-BMI was a more effective predictor of NAFLD in T2D.

Transtheoretical model-based mobile health application for PCOS.

BACKGROUND: Lifestyle modification (diet, exercise, and behavioral interventions) is the first-line treatment for polycystic ovary syndrome (PCOS). The benefits of face-to-face lifestyle modification intervention in a short time have been demonstrated. However, few studies have investigated the mobile technology effects on lifestyle modification in PCOS. Therefore, we examined the effect of transtheoretical model-based mobile health application intervention program for PCOS. METHODS: A randomised controlled, single-blind trial, was carried out from October 2018 to March 2019, which included 122 participants recruited from gynecology outpatient clinics of affiliated Hospital of Zunyi Medical University in Guizhou. The study participants were randomised into intervention (n = 61) and control groups (n = 61). Participants in the intervention group undertook a TTM-based mobile health application program in addition to routine care, and participants in the control group received only routine care. RESULTS: Fifty-one participants in the intervention group and 49 in the control group completed the study. Compared to the control group, participants in the intervention group showed statistically significant decrease for BMI (P < 0.05), WC (P < 0.05), SAS (P < 0.05), and SDS (P < 0.05) scores at 6-month and 12-month, respectively. Behavior stage change of exercise and diet among paticipants with PCOS was significant at 6 months (c2 = 43.032, P < 0.05) and 12th months (c2 = 49.574, P < 0.05) between the intervention and control groups. CONCLUSIONS: This study showed that the TTM-based mobile health application program can decrease BMI, WC, anxiety, and depression, and improve exercise and diet adherence in patients with PCOS in the long term. The TTM-based mobile health application program can be applied for lifestyle modification in women with PCOS. Trial registration This study was approved by the ethics committee NO.[2019]1-028 in March 2018 and was registered at the Chinese Clinical Trial Registry (website: www.chictr.org.cn , registry number: ChiCTR2000034572).

Poor adherence of life management in patients with PCOS and many then go on to adherence poor health outcomes as a result. There is an urgent need for new approach to enhance to life management compliance for patients with PCOS. TTM is a common behavior change model, which can effectively promote the behavior change of patients, but it has not been used in the life management of PCOS patients. Meanwhile, the traditional life management of PCOS is mainly face-to-face intervention, few studies have investigated the mobile technology effects on lifestyle modification in PCOS. This study aimed to evaluate the long-term effects of TTM-based mobile technology (for lifestyle modification) on the maintenance of health-related behavior changes among women with PCOS. This study confirmed that the TTM-based mobile health application program can decrease BMI, WC, anxiety, and depression, and improve exercise and diet adherence in patients with PCOS in the long term. Our study conducted TTM-based mobile health application program can provide a reference for other researchers or research organizations.

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. METHODS: In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 µg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. RESULTS: We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 µg, 150 µg and 200 µg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were -7.76 mmol/mol (95% CI -9.23, -4.63, p < 0.001) (-0.72%, 95% CI -1.01, -0.43), -12.89 mmol/mol (95% CI -16.05, -9.72, p < 0.001) (-1.18%, 95% CI -1.47, -0.89) and -11.14 mmol/mol (95% CI -14.19, -7.97, p <0 .001) (-1.02%, 95% CI -1.30, -0.73) in the 75 µg, 150 µg and 200 µg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. CONCLUSIONS/INTERPRETATION: All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03520972 FUNDING: The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.

The usefulness of the combined high-dose dexamethasone suppression test and desmopressin stimulation test in establishing the source of ACTH secretion in ACTH-dependent Cushing's syndrome.

Bilateral inferior petrosal sinus sampling (BIPSS) is the current gold standard test for differentially diagnosing ACTH-dependent Cushing's syndrome (CS). However, BIPSS is an invasive procedure, and its availability is limited. We retrospectively analysed the 24-hour urinary free cortisol (UFC) level during the high-dose dexamethasone suppression test (HDDST) and plasma ACTH/cortisol levels after the desmopressin stimulation test (DDAVP test) in subjects with confirmed Cushing's disease (CD) (n = 92) and ectopic ACTH-dependent CS (EAS) (n = 16), and evaluated the positive predictive value (PPV) of the two combined-tests in the aetiological diagnosis of ACTH-dependent CS. The percent changes in UFC levels after the HDDST and in ACTH/cortisol levels after DDAVP administration relative to the corresponding basal levels and the area under the receiver operating characteristic (ROC) curve (AUC) were analysed. UFC suppression below 62.7% suggested a pituitary origin with a sensitivity (SE) of 80% (95% CI: 70-88) and a specificity (SP) of 80% (95% CI: 52-96). A threshold increase in the ACTH level after DDAVP stimulation of 44.6% identified CD with an SE of 91% (95% CI: 83-97) and an SP of 75% (95% CI: 48-93). The combination of both tests yielded an SE of 95.5% and PPV of 98.4% for CD, and significantly improved the efficiency of the differential diagnosis between CD and EAS. These dual non-invasive endocrine tests may substantially reduce the need for BIPSS in the etiological investigation of ACTH-dependent CS.

Efficacy and safety of bempedoic acid for prevention of cardiovascular events and diabetes: a systematic review and meta-analysis.

BACKGROUND: Bempedoic acid is an oral, once-daily, first-in-class drug being developed for the treatment of hyperlipidemia. However, evidence of bempedoic acid use for the prevention of cardiovascular events and diabetes is lacking. Thus, we aim to evaluate the benefit and safety of bempedoic acid use for the prevention of cardiovascular events and diabetes. METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials with no language restriction from inception until March 3, 2020. Pairs of reviewers independently identified randomized controlled trials comparing the use of bempedoic acid with placebo or no treatment for primary prevention of cardiovascular events in statin-intolerant patients with hypercholesterolemia. The primary outcomes were major adverse cardiac events, and percent change in LDL-C. RESULTS: We identified 11 trials including a total of 4391 participants. Bempedoic acid use was associated with a reduction in composite cardiovascular outcome (RR 0.75, 95% CI 0.56-0.99; I2 = 0%). Bempedoic acid reduced LDL-C levels (MD - 22.91, 95% CI - 27.35 to - 18.47; I2 = 99%), and similarly reduced CRP levels (MD -24.70, 95% CI - 32.10 to - 17.30; I2 = 53%). Bempedoic acid was associated with a reduction in rates of new-onset or worsening diabetes (RR 0.65, 95% CI 0.44-0.96; I2 = 23%). CONCLUSIONS: Bempedoic acid in patients with hypercholesterolemia was associated with a lower risk of cardiovascular events and diabetes.

Microplastics Reduce Lipid Digestion in Simulated Human Gastrointestinal System.

Microplastics (MPs) are unavoidably ingested by humans, and their gastrointestinal processes and impact on lipid digestion are unknown. In the present work, all five MP types used, including polystyrene (PS), polyethylene terephthalate, polyethylene, polyvinyl chloride, and poly(lactic-co-glycolic acid) (80 mg/L in small intestine), significantly reduced lipid digestion in the in vitro gastrointestinal system. PS MPs exhibited the highest inhibition (12.7%) among the five MPs. Lipid digestion decreased with increasing PS concentration, but independent of PS size (50 nm, 1 µm, 10 µm). PS MPs after photoaging by simulated sunlight also significantly decreased lipid digestion. Confocal imaging shows that PS MPs could interact with both lipid droplets and lipases. Two mechanisms underlying the PS-induced digestion inhibition were revealed using both experimental and molecular dynamics simulation approaches: (1) PS MPs decreased the bioavailability of lipid droplets via forming large lipid-MPs heteroaggregates due to the high MP hydrophobicity; and (2) PS MPs adsorbed lipase, and reduced its activity by changing the secondary structure and disturbing the essential open conformation. The first mechanism (MP-lipid interaction) played a more important role in lipid digestion reduction based on interaction energy calculation. These findings reveal potential risk of MPs to human digestion health and nutrient assimilation.

Unusual ectopic ACTH syndrome in a patient with orbital neuroendocrine tumor, resulted false-positive outcome of BIPSS:a case report.

BACKGROUND: Cushing's syndrome has been described as a complex endocrine disorder characterized with high cortisol concentration. Correct and early diagnosis of Cushing's syndrome is challenging. According to the latest guideline, bilateral inferior petrosal sinus sampling (BIPSS) is considered to be the gold standard for the differential diagnosis. However, in some unusual cases, this method may be false positive. Here, we presented a rare case of orbital neuroendocrine tumor secreting adrenocorticotrophic hormone with false positive inferior petrosal sinus sampling. CASE PRESENTATION: A 48-year-old woman was admitted to West China Hospital of Sichuan University, presenting with fatigue, whole body edema for 1 year, alopecia and skin pigmentation for 5 months. Hormonal profiles including plasma cortisol and adrenocorticotrophic hormone (ACTH) measurements and low-dose dexamethasone inhibition test suggested that the patient had Cushing's syndrome. However, during tumor location phase, the results of high-dose dexamethasone inhibition test (HDDST) contradicted desmopressin (DDAVP) stimulation test. Thus, BIPSS was employed, and its results indicated a pituitary origin. Interestingly, MRI of sellar region showed an innocent pituitary but caught a serendipitous lesion in the lateral rectus muscle of left eye, which was later proved to be an orbital neuroendocrine tumor secreting ACTH by pathological and immunohistochemical results. ACTH level of the patients was < 0.1 ng/L and cortisol level was 51.61 nmol/L 1 week after surgery. At 24 months follow-up, the patient appeared stable with no complaints nor any symptoms of Cushing's syndrome, including moon face, purple striate and central obesity. The patient's life quality also improved significantly. CONCLUSION: We reported a rare case of endogenous Cushing's syndrome due to ectopic ACTH secreting from an orbital neuroendocrine tumor. This unique case of orbital EAS suggests that orbital venous blood backflow, owning to abnormal anatomic structures, may possibly lead to false positive BIPSS results.

[The Pharmacokinetics, Pharmacodynamics and Bioequivalence of Insulin Aspart Produced by the United Laboratories Evaluated by Euglycemic Clamp Study].

OBJECTIVE: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of a rapid-acting insulin analog-insulin aspart (the tested formulation) which was manufactured by The United Laboratories and to evaluate the bioequiavailability to the reference formulation (NovoRapid ®) produced by Novo Nordisk in Chinese healthy volunteers. METHODS: A total of 24 male healthy volunteers were recruited from February to April 2016 to participant in this before-after, single dose, and randomized crossover study. And the experimental observation was conducted on 2 test days respectively with a between-period from 7 to10 d. According to a random number table, the volunteers were divided into group A or B, group A was administrated with tested insulin aspart (IAsp) for the first time and reference NovoRapid ® for the second time and group B had the revered order differed from group A. The PK/PD of these insulin analogs were estimated by euglycemic clamp study. RESULTS: The relative biological effectiveness (reflecting gloucose-lowing effect) and bioavailability on behalf of plasma-drug concentration were 98.3±18.8% and 97.3%±8.3% respectively. For PK parameters, the 90% confidence interval ( CI) of peak plasma insulin concentration ( C max) and area under the curve of insulin aspart concentration from 0 to 10 hours ( AUC IAsp, 0-10 h) of IAsp were 88.8%-106% (equivalent range 70%-143%) and 94.0%-100% (equivalent range 80%-125%) respectively; for PD parameters, the 90% CI of the maximum glucose infusion rate ( GIR max) and AUC GIR, 0-10 h were 95.5%-113% (equivalent range 70%-143%) and 89.9%-104% (equivalent range 80%-125%) respectively, which indicated that IAsp and NovoRapid® was bioequivalent. One of the subjects discovered hyperuricemia without clinical symptoms and the rest had no clinically significant abnormalities in the safety indexes before and after the tests. No hypoglycemic events, allergic reactions, or local injection adverse reaction occurred in this trial. CONCLUSION: The tested IAsp has comparable relative bioavailability to the reference NovoRapid ®.

[Risk Factors Associated with Thyroid Nodules in Patients with Acromegaly].

OBJECTIVE: To identify risk factors associated with thyroid nodular lesions in patients with acromegaly. METHODS: Clinical and thyroid ultrasonography data of patients with acromegaly diagnosed in the West China Hospital of Sichuan University from May 2009 to January 2018 were reviewed and analyzed. Multivariate linear regression models were established to identify factors associated with thyroid volumes and size of thyroid nodules. Multivariate binary logistic regression models were established to determine risk factors associated with thyroid nodules in patients with acromegaly. RESULTS: Of the 240 acromegaly patients, 70 received thyroid ultrasonography and 56 had thyroid nodules (56/70, 80%). The patients with thyroid nodules had a longer median duration of acromegaly than 14 patients who without thyroid nodules (8.0 years vs. 3.0 years, P＜0.05), but had a similar mean age and female to male ratio with the latter. The risk of thyroid nodules increased with the duration of acromegaly (odds ratio=1.306, 95% confidence interval (1.010, 1.688), P=0.042). The level of random growth hormone was linearly correlated with thyroid volumes. Gender, age, and serum growth hormone were not predictors of thyroid nodules in patients with acromegaly. CONCLUSION: Duration of acromegaly is an independent predictor of thyroid nodules.