Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations.

Background: Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients. Methods: We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug. Results: Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91±7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07±19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM's AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙µg/mL) compared to oral free-GEM (19.04 hr∙µg/mL) after oral administration (p<0.01), highlighting NGs' efficacy in impeding rapid drug metabolism and enhancing retention. Conclusion: In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.

Pediatric palliative care utilization by decedent children: A nationwide population-based study, 2002-2017.

PURPOSE: This study aimed (1) to describe how trends in pediatric palliative care (PPC) utilization changed from 2002 to 2017, and (2) to examine factors predicting PPC utilization among decedent children in Taiwan. DESIGN: This retrospective, correlational study retrieved 2002-2017 data from three national claims databases in Taiwan. METHODS: Children aged 1 through 18 years who died between January 2002 and December 2017 were included. Pediatric palliative care utilization was defined as PPC enrollment and PPC duration, with enrollment described by frequency (n) and percentage (%) and duration described by mean and standard deviation (SD). Logistic regression was used to examine the associations of various demographic characteristics with PPC enrollment; generalized linear regression was used to examine associations of the demographic characteristics with PPC duration. FINDINGS: Across the 16-year study period, PPC enrollment increased sharply (15.49 times), while PPC duration decreased smoothly (by 29.41%). Cause of death was a continuous predictor of both PPC enrollment and PPC duration. The children less likely to be enrolled in PPC services were those aged 1 to 6 years, boys, living in poverty, living in rural areas, and diagnosed with life-threatening noncancer diseases. CONCLUSION: This study used nationwide databases to investigate PPC enrollment and PPC duration among a large sample of deceased children from 2002 to 2017. The findings not only delineate trends and predictors of PPC enrollment and PPC duration but also highlight great progress in PPC as well as the areas still understudied and underserved. This information could help the pediatric healthcare system achieve the core value of family-centered care for children with life-threatening diseases and their families. CLINICAL RELEVANCE: Pediatric palliative care should be widely and continuously implemented in routine pediatric clinical practice to enhance quality of life for children and their families at the end of life.

Differential cellular responses to FDA-approved nanomedicines: an exploration of albumin-based nanocarriers and liposomes in protein corona formation.

Albumin nanoparticles (NPs) and PEGylated liposomes have garnered tremendous interest as therapeutic drug carriers due to their unique physicochemical properties. These unique properties also have significant effects on the composition and structure of the protein corona formed around these NPs in a biological environment. Herein, protein corona formation on albumin NPs and liposomes was simultaneously evaluated through in vitro and simulation studies. The sizes of both types of NPs increased with more negatively charged interfaces upon being introduced into fetal bovine serum. Gel electrophoresis and label-free quantitative proteomics were performed to identify proteins recruited to the hard corona, and fewer proteins were found in albumin NPs than in liposomes, which is in accordance with isothermal titration calorimetry. The cellular uptake efficiency of the two NPs significantly differed in different serum concentrations, which was further scrutinized by loading an anticancer compound into albumin NPs. The presence of the hard protein corona increased the cellular uptake of albumin NPs in comparison with liposomes. In our simulation study, a specific receptor present in the membrane was greatly attracted to the albumin-apolipoprotein E complex. Overall, this study not only evaluated protein corona formation on albumin NPs, but also made promising advancements toward albumin- and liposome-based therapeutic systems.

A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment.

Doxorubicin is a widely-used chemotherapeutic drug, however its high toxicity poses a significant challenge for its clinical use. To address this issue, a physiologically-based pharmacokinetic (PBPK) model was implemented to quantitatively assess doxorubicin toxicity at cellular scale. Due to its unique pharmacokinetic behavior (e.g. high volume of distribution and affinity to extra-plasma tissue compartments), we proposed a modified PBPK model structure and developed the model with multispecies extrapolation to compensate for the limitation of obtaining clinical tissue data. Our model predicted the disposition of doxorubicin in multiple tissues including clinical tissue data with an overall absolute average fold error (AAFE) of 2.12. The model's performance was further validated with 8 clinical datasets in combined with intracellular doxorubicin concentration with an average AAFE of 1.98. To assess the potential cellular toxicity, toxicity levels and area under curve (AUC) were defined for different dosing regimens in toxic and non-toxic scenarios. The cellular concentrations of doxorubicin in multiple organ sites associated with commonly observed adverse effects (AEs) were simulated and calculated the AUC for quantitative assessments. Our findings supported the clinical dosing regimen of 75 mg/m2 with a 21-day interval and suggest that slow infusion and separated single high doses may lower the risk of developing AEs from a cellular level, providing valuable insights for the risk assessment of doxorubicin chemotherapy. In conclusion, our work highlights the potential of PBPK modelling to provide quantitative assessments of cellular toxicity and supports the use of clinical dosing regimens to mitigate the risk of adverse effects.

Evaluation of the safety and potential lipid-lowering effects of oral hydrogen-rich coral calcium (HRCC) capsules in patients with metabolic syndrome: a prospective case series study.

Background: Metabolic syndrome is characterized by a cluster-like occurrence of conditions such as hypertension, hyperglycaemia, elevated low-density lipoprotein (LDL) cholesterol or triglycerides (TG) and high visceral fat. Metabolic syndrome is linked to the build-up of plaque within the artery, which leads to disorders of the circulatory, nervous and immune systems. A variety of treatments target the regulation of these conditions; nevertheless, they remain dominant risk factors for the development of type 2 diabetes (T2DM) and cardiovascular disease (CVD), which affect 26.9% of the US population. Management and intervention strategies for improving cholesterol and/or TG are worthwhile, and recent studies on hydrogen treatment are promising, particularly as molecular hydrogen is easily ingested. This study aimed to investigate the lipid-lowering effects and quality of life (QOL) improvement of hydrogen-rich coral calcium (HRCC) in patients with metabolic syndrome. Methods: The patients, all Taiwanese, were randomly assigned to 3 different doses (low, medium, and high) of HRCC capsules. The primary outcome was the adverse effects/symptoms during this 4-week use of HRCC capsules. The secondary outcome was lipid profile changes. Complete blood count, inflammatory biomarkers, and QOL were also measured before and after the course of HRCC. Results: Sixteen patients with metabolic syndrome completed this study (7 males, 9 females; mean age: 62 years; range: 32-80). No obvious adverse effects were recorded. Only changes in blood TG reached significance. The baseline TG value was 193.19 µL (SD = 107.44), which decreased to 151.75 µL (SD = 45.27) after 4 weeks of HRCC (p = 0.04). QOL showed no significant changes. Conclusion: This study is the first human clinical trial evaluating HRCC capsules in patients with metabolic syndrome. Based on the safety and potential TG-lowering effects of short-term HRCC, further long-term investigations of HRCC are warranted. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT05196295].

DUS testing guidelines for new varieties of Chinese medicinal plants / 中国中药杂志

A rich diversity of wild medicinal plant resources is distributed in China, but the breeding of new plant varieties of Chinese medicinal plants started late and the breeding level is relatively weak. Chinese medicinal plant resources are the foundation for new varieties breeding, and the plant variety rights(PVP) are of great significance for the protection and development of germplasm resources. However, most Chinese medicinal plants do not have a distinctness, uniformity, and stability(DUS) testing guideline. The Ministry of Agriculture and Rural Affairs has put 191 plant species(genera) on protection lists, of which only 30 are medicinal species(genera). At the same time, only 29 of 293 species(genera) plants in the Protection List of New Plant Varieties of the People's Republic of China(Forest and Grass) belong to Chinese medicinal plants. The number of PVP applications and authorization of Chinese medicinal plants is rare, and the composition of variety is unreasonable. Up to now, 29 species(genera) of DUS test guidelines for Chinese medicinal plants have been developed. Some basic problems in the breeding of new varieties of Chinese medicinal plants have appeared, such as the small number of new varieties and insufficient utilization of Chinese medicinal plant resources. This paper reviewed the current situation of breeding of new varieties of Chinese medicinal plants and the research progress of DUS test guidelines in China and discussed the application of biotechnology in the field of Chinese medicinal plant breeding and the existing problems in DUS testing. This paper guides the further application of DUS to protect and utilize the germplasm resources of Chinese medicinal plants.

The number of TIGIT+CD8+ T cells increases but their cytokine secretion decreases in the lungs of Plasmodium yoelii infected mice / 细胞与分子免疫学杂志

Objective To investigate the effect of T cell immunoreceptor with Ig and ITIM domains (TIGIT) on the function of CD8+ T cells in the lungs of Plasmodium infected mice. Methods The lungs of the mice infected with Plasmodium yoelii were isolated, weighed and photographed after 12 days' infection. After dissolution, lung lymphocytes were isolated, counted and stained, and then the contents of CD8+ and TIGIT+CD8+ T cells were detected by flow cytometry. The expressions of L selectin (CD62L), CD69, programmed death 1 (PD-1), CD25, and C-X3-C motif chemokine receptor 1 (CX3CR1) on TIGIT+CD8+ T cells were detected by flow cytometry. After stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, the ability of TIGIT+CD8+T cells to secrete interferon γ(IFN-γ), interleukin 21 (IL-21), IL-4, IL-17, and IL-10 was detected. Results The body mass of mice with Plasmodium infection was reduced. The lungs became darker, and the ratio of the lung mass to body mass was significantly increased. Compared with the normal mice, the percentages and absolute quantity of CD8+ and TIGIT+CD8+ T cells in the lungs of the infected mice were significantly increased. The percentage of TIGIT+CD8+ T cells expressing CD62L in the infected group was significantly lower, while the percentage of the CD69, PD-1, and CX3CR1 cells were significantly higher than that of TIGIT+CD8+ T cells from the normal mice. The percentages of TIGIT+CD8+ T cells secreting IL-21, IL-4, IL-17 and IL-10 cells in the infected group were significantly lower. Conclusion The lung lesions from mice with Plasmodium infection are obvious, the numbers of TIGIT+CD8+ T cells increase, and these cells express a variety of activation-related molecules, but the ability to secrete cytokines is reduced.

Implication practice of “Internet Plus” new technology in chronic diseases management in community / 公共卫生与预防医学

Objective  To introduce and evaluate the practice of “Internet Plus” new technology for health management of chronic diseases in community in Yichang, and to provide reference for chronic disease patients' health management in community. Methods  Data of hypertensive patients were collected from the national basic public health service system, the big data intelligent sorting system for chronic disease patients in Yichang City, and the basic public health service system in urban areas in Yichang from 2016 to 2020. Data on the discovery, sorting and filing, standardized management rate and blood pressure control of urban hypertension patients were analyzed. The application effect of “Internet Plus” new technology in chronic disease community health management was evaluated. Results  From 2016 to 2020, 15 934 patients with hypertension were found and their health records were established through big and intelligent data in Yichang City, accounting for 93.54% (15 934 / 17 035) of the total. The rate of standardized management in each district increased year by year, with an increase of 8.71% in 2020 compared with 2016, and the difference was statistically significant (χ2=1273.30, P2=867.14, P<0.001). Conclusion  Data exchange and sharing among medical institutions at all levels can strengthen the health management of chronic diseases in the community. The “Internet Plus” new technology, integrating the Internet, big data, cloud computing and intelligent terminal technology, can effectively improve the detection, management and treatment rate of chronic diseases, and provide a new direction for the health management of chronic diseases.

Artificial intelligence cell image analysis technology can improve the accuracy of bone marrow cells / 中华检验医学杂志

Objective:To evaluate the screening efficacy of AI for bone marrow cell morphology.Method:Bone marrow specimens of patients attending the Second Hospital of Hebei Medical University from December 1,2019 to December 21,2020;(1) Selected from one hundred bone marrow specimens, The cases included chronic myeloid cell leukemia ( n=23), myelodysplastic syndrome ( n=4), chronic lymphocytic leukemia ( n=4), multiple myeloma ( n=5), 7 acute leukemia ( n=7), chronic anemia ( n=32), infection ( n=6) and healthy control ( n=15). Including 45 males and 55 females, with age 52(37,66)years old.The bone marrow smear prepared with Wright-Giemsa, The AI analysis system and manual audit were applied to classify 13 types of bone marrow nucleated cell, taking the results of manual audit as the gold standard, comparing the difference between the results of the two methods, using statistical software to draw the confusion matrix, The compliance between the manual audit results and the pre-classification results of the AI analysis system was calculated by the Kappa consistency test method; The consistency analysis between the pre-classification results of AI and those of the manual microscopic examination was performed by the Pearson test; (2)Statistics analyzed the blast cell differential count differences of AI and manual microscopy, to evaluate the clinical application value of AI analysis system, which soured from thirty bone marrow samples of patients diagnosed with MDS and AML. Results:76 630 images of 13 nucleated cells were obtained by AI analysis system; the weighted average experimental diagnostic efficiency parameters of 13 types of bone marrow nucleated cells, are as follows: sensitivity(%)=95.82, specificity(%)=99.19, accuracy(%)=98.89, false positive rate(%)=0.81, false negative rate (%)=4.18; the correlation results, between the pre-classification results of AI and manual microscopic classification results,showed that blast cell, promyelocytes, neutrophilic myelocyte, neutrophilic metamyelocyte, band neutrophil, segmented neutrophi,eosinophil, basophil, polychromatic erythroblast, orthochromatic erythroblast, and lymphocytes have good positive correlation ( r>0.70,all P<0.001), while basophilic erythroblast and monocytes have no obvious correlation ( r=0.32,0.30, all P> 0.001); the count results of the blast cells in bone marrow smears of MDS and AML, got by AI and manual microscopy respectively, showed that the average percentage of blast cells was 8.19% by AI and 8.68% by manual microscopy in MDS, there was no significant difference between the two methods ( P>0.05); the average percentage of blast cells was 48.52% by AI analysis system and 53.77% by manual microscopy in AML, and although there was a significant difference in blast cell count ( P<0.01), coincidence the classification diagnostic criteria for AML (blast cells ≥ 20%). Conclusion:The AI analysis system performed good sensitivity, specificity and accuracy for 13 types of bone marrow nucleated cells, which showed potential application value for the rapid classification and diagnosis of MDS and AML.

Application of artificial intelligence assists bone marrow cytomorphology analysis in the diagnosis and treatment of acute myeloid leukemia / 中华检验医学杂志

Objective:To investigate the value of artificial intelligence (AI) cytomorphologic analysis system in the cytomorphological diagnosis and therapeutic evaluation of acute myeloid leukemia (AML).Methods:Bone marrow smear samples were collected from 150 patients with newly diagnosed and treated acute myeloid leukemia who were inpatients and outpatients at the Department of Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from June 1, 2021 to July 31, 2022 for retrospective analysis. Among them, there were 50 patients in the newly diagnosed group, including 28 males and 22 females, with the onset age of 43.5(32.3,58.8)years. There were 100 patients in the post-treatment group, including 36 males and 64 females, with the onset age of 34.5(23.0,47.0)years. The results from cytomorphology expert were used as the gold standard and the Python 3.6.7 was used for analysis to evaluate the accuracy, sensitivity, and specificity of the AI cytomorphologic analysis system for blast cell recognition in AML diagnosis and treatment.Results:The proportion of blasts in AI analysis of 50 samples in the newly diagnosed group was≥20%, which met the diagnostic criteria of AML. AI analysis of blasts had an accuracy of 90.3%, sensitivity of 85.5%, and specificity of 98.0%. The correlation coefficient between AI and the proportion of blasts analyzed by experts was positively correlated( r=0.882, P<0.001). Meanwhile, in the post-treatment group, the sensitivity and specificity of AI analysis of blasts were 89.7% and 99.2%, respectively. The correlation coefficient between AI and the proportion of blasts analyzed by experts was positively correlated( r=0.957, P<0.001). According to AI analysis data, there are 8 samples in this group whose AI efficacy evaluation results on AML are inconsistent with expert analysis. Conclusion:AI cytomorphologic analysis system has high accuracy, sensitivity and specificity for blast cell recognition in AML morphological diagnosis and therapeutic evaluation.

A clinical comparative study on the Laennec’s approach versus the two-step separation stylized approach in laparoscopic left lateral sectionectomy / 中华肝胆外科杂志

Objective:To compare the clinical outcomes of the Laennec’s approach versus the two-step separation stylized approach in laparoscopic left lateral sectionectomy (LLLS).Methods:A total of 60 patients who underwent LLLS at the Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University from March 2019 to April 2022 were prospectively entered into this study. There were 40 males and 20 females, aged (49.1±9.3) years, with 31 patients suffering from liver cancer, 14 patients hepatic hemangioma and 15 patients hepatolithiasis. A randomized number table was used to assign the patients into two groups: the Laennec’s approach group ( n=30) and the two-step separation stylized approach group ( n=30). The age, gender, liver function, operation time, intraoperative blood loss, abdominal drainage amount, drainage tube retention time, postoperative hospital stay, total hospital costs and postoperative complications were compared between the two groups. Results:There were no significant differences between the two groups in gender, age and Child-Pugh grading of liver function (all P>0.05). Comparison of intraoperative bleeding, postoperative hospital stay, postoperative complications, postoperative recurrence between the two groups showed there were no significant differences between the two groups (all P>0.05). The operative time [(85.6±24.5) min vs (99.1±30.7) min, P<0.05] was significantly less in the stylized group than the Laennec’s group, while the Laennec’s group were superior to the stylized group in the amount of draining [(144.1±38.3) ml vs (290.9±59.5) ml], drainage tube retention time [(2.7±1.5) d vs (4.3±1.9) d] and total hospital costs [(35 100.7±13 200.6) yuan vs (44 700.1±11 800.8) yuan](all P<0.05). Conclusions:Both the Laennec’s and stylized approaches for LLLS were safe and feasible. The stylized approach for LLLS could be performed more quickly, while the Laennec’s approach could more accurately dissect and handle intrahepatic and extrahepatic ducts, thus resulting in decreased postoperative exudation and treatment costs.

Risk factor analysis and clinical decision tree model construction for diabetic retinopathy in Western China.

BACKGROUND: Diabetic retinopathy (DR) is the driving force of blindness in patients with type 2 diabetes mellitus (T2DM). DR has a high prevalence and lacks effective therapeutic strategies, underscoring the need for early prevention and treatment. Yunnan province, located in the southwest plateau of China, has a high pre-valence of DR and an underdeveloped economy. AIM: To build a clinical prediction model that will enable early prevention and treatment of DR. METHODS: In this cross-sectional study, 1654 Han population with T2DM were divided into groups without (n = 826) and with DR (n = 828) based on fundus photography. The DR group was further subdivided into non-proliferative DR (n = 403) and proliferative DR (n = 425) groups. A univariate analysis and logistic regression analysis were conducted and a clinical decision tree model was constructed. RESULTS: Diabetes duration ≥ 10 years, female sex, standing- or supine systolic blood pressure (SBP) ≥ 140 mmHg, and cholesterol ≥ 6.22 mmol/L were risk factors for DR in logistic regression analysis (odds ratio = 2.118, 1.520, 1.417, 1.881, and 1.591, respectively). A greater severity of chronic kidney disease (CKD) or hemoglobin A 1c increased the risk of DR in patients with T2DM. In the decision tree model, diabetes duration was the primary risk factor affecting the occurrence of DR in patients with T2DM, followed by CKD stage, supine SBP, standing SBP, and body mass index (BMI). DR classification outcomes were obtained by evaluating standing SBP or BMI according to the CKD stage for diabetes duration < 10 years and by evaluating CKD stage according to the supine SBP for diabetes duration ≥ 10 years. CONCLUSION: Based on the simple and intuitive decision tree model constructed in this study, DR classification outcomes were easily obtained by evaluating diabetes duration, CKD stage, supine or standing SBP, and BMI.

"I don't know what to do or where to go". experiences of accessing healthcare support from the perspectives of people living with Long Covid and healthcare professionals: A qualitative study in Bradford, UK.

BackgroundIn July 2022 it was estimated 2 million people in the UK have self-reported Long Covid (LC).1 Many people have reported not receiving adequate healthcare support. There is a lack of research which provides an in-depth exploration of the barriers faced by people with LC in accessing healthcare support. It is important to understand these barriers to provide better support, care and advice for those experiencing LC. ObjectiveTo understand the barriers faced in accessing primary, secondary and specialist healthcare support for people with LC. Design and participation40 interviews were conducted with people with LC alongside 12 interviews with healthcare professionals (HCPs) providing LC support in Bradford, as part of a UK wide qualitative longitudinal study. ResultsPeople living with LC had a large degree of difficulty in accessing healthcare services for LC support. We categorised the healthcare access experiences of participants into five main types: 1) being unable to access primary care 2) accessing primary care but receiving (perceived) inadequate support 3) extreme persistence 4) alternatives to mainstream healthcare 5) positive experiences. There was a severe lack of access to specialist LC services. Ethnic minority participants faced a further barrier of mistrust and fear of services deterring them from accessing support. HCPs discussed systemic barriers to delivering services. Experiences were embedded in macro structural issues further exacerbated by the pandemic. ConclusionTo better support people with LC the barriers faced in accessing healthcare support must be addressed. Of significance, improvements to GP access are required; especially as GPs are the first line of support for people living with LC. Patient and public involvementA PPI group is engaged at regular intervals in the project. O_TEXTBOXBox 1Patient and Public Contribution Designing an interview schedule for people with LC: The wider CONVALSCENCE research project has a PPI group involved in various work packages. The PPI group is hosted by researchers at University of West of England who have expertise in patient and public involvement. Members of the PPI group all have or had LC. After an extensive literature review4, a draft of the interview schedule was presented to the group via a workshop. It was then revised after incorporating their feedback and piloted by the research team for further refinement. Data interpretation workshop: Following advice of the UWE researchers, the PPI group were presented ahead of time with 4 interview transcripts from the dataset and provided their interpretation of the interviews via a workshop. The theme of barriers to accessing healthcare was also highlighted by attendees, for example they discussed patients being disbelieved (particularly young people) and fragmented services as some points of interest within the transcripts. C_TEXTBOX

Subacute thyroiditis during early pregnancy: a case report and literature review.

BACKGROUND: Subacute thyroiditis (SAT) is rarely diagnosed in pregnant women, and only 7 cases have been reported to date. Thyroid dysfunction, especially hyperthyroidism, during pregnancy has been associated with both maternal and neonatal complications. Thus, the early diagnosis and treatment of SAT during pregnancy may be beneficial. We present a case report and literature review to complement the diagnostic evaluation and management of SAT during pregnancy. CASE PRESENTATION: A 27-year-old woman presented in gestational week 17 of her first pregnancy and had a negative prior medical history. She presented to the Endocrinology Department complaining of neck pain for one month that had intensified in the last five days. Physical examination revealed a diffusely enlarged thyroid gland that was firm and tender on palpation. The patient also had an elevated temperature and heart rate. The increasing and long-lasting pain coupled with a decreased level of thyroid-stimulating hormone indicated hyperthyroidism. Ultrasound findings were indicative of SAT. Importantly, the pain was so severe that 10 mg of oral prednisone per day was administered in gestational week 18, which was increased to 15 mg/d after 10 days that was discontinued in week 28. Levothyroxine was started in gestational week 24 and administered throughout the pregnancy. The patient responded well to the treatments, and her neck pain disappeared in gestational week 21. She gave birth to a healthy male in gestational week 41. CONCLUSION: SAT can be diagnosed and effectively managed during pregnancy, thus benefiting mothers and infants.

Betaine Attenuates Osteoarthritis by Inhibiting Osteoclastogenesis and Angiogenesis in Subchondral Bone.

Osteoarthritis (OA) is the most common type of arthritis with no effective therapy. Subchondral bone and overlying articular cartilage are closely associated and function as "osteo-chondral unit" in the joint. Abnormal mechanical load leads to activated osteoclast activity and increased bone resorption in the subchondral bone, which is implicated in the onset of OA pathogenesis. Thus, inhibiting subchondral bone osteoclast activation could prevent OA onset. Betaine, isolated from the Lycii Radicis Cortex (LRC), has been demonstrated to exert anti-inflammatory, antifibrotic and antiangiogenic properties. Here, we evaluated the effects of betaine on anterior cruciate ligament transection (ACLT)-induced OA mice. We observed that betaine decreased the number of matrix metalloproteinase 13 (MMP-13)-positive and collagen X (Col X)-positive cells, prevented articular cartilage proteoglycan loss and lowered the OARSI score. Betaine decreased the thickness of calcified cartilage and increased the expression level of lubricin. Moreover, betaine normalized uncoupled subchondral bone remodeling as defined by lowered trabecular pattern factor (Tb.pf) and increased subchondral bone plate thickness (SBP). Additionally, aberrant angiogenesis in subchondral bone was blunted by betaine treatment. Mechanistically, we demonstrated that betaine suppressed osteoclastogenesis in vitro by inhibiting reactive oxygen species (ROS) production and subsequent mitogen-activated protein kinase (MAPK) signaling. These data demonstrated that betaine attenuated OA progression by inhibiting hyperactivated osteoclastogenesis and maintaining microarchitecture in subchondral bone.

One-pot fabrication of sacchachitin for production of TEMPO-oxidized sacchachitin nanofibers (TOSCNFs) utilized as scaffolds to enhance bone regeneration.

One-pot fabrication of sacchachitin (SC) for mass-production was developed and optimized by selecting KOH as alkaline agent in depigmentation step and utilizing NaClO2 as bleaching agent in subsequent step in the same pot. Overall yield of one-pot-fabricated SC was up to 35 %w/w of initial weight with a fibrous texture soft enough for mechanical disintegration into SC nanofibers (SCNFs) and better dispersion for producing TEMPO-oxidized SCNFs (T033SC). Both SCNFs and T033SC could form a 3D gelatinous scaffold into which MC3T3-E1 cells were attracted. Higher calcium-trapping ability of T033SC resulting from a greater extent of carboxylate groups provided an excellent bone regeneration environment that resulted in better outcomes of bone regeneration in a femur defect rat model compared to those with SCNFs possessed fewer carboxylate groups. In conclusion, biomaterial scaffolds based on TEMPO-oxidized SCNFs produced from one-pot fabricated SC showed great potential for bone regeneration due to unique physical and chemical properties.

Impact of inflammatory reaction levels and culprit plaque characteristics on preprocedural thrombolysis in myocardial infarction flow grade in patients with ST-segment elevation myocardial infarction / 中华心血管病杂志

Objective: To determine the impact of inflammatory reaction levels and the culprit plaque characteristics on preprocedural Thrombolysis in Myocardial Infarction (TIMI) flow grade in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods: The is a retrospective study. A total of 1 268 STEMI patients who underwent pre-intervention optical coherence tomography (OCT) examination of culprit lesion during emergency PCI were divided into 2 groups by preprocedural TIMI flow grade (TIMI 0-1 group (n =964, 76.0%) and TIMI 2-3 group (n =304, 24.0%)). Baseline clinical data of the 2 groups were collected; blood samples were collected for the detection of inflammatory markers such as high sensitivity C-reactive protein (hsCRP), myocardial injury marker, blood lipid, etc.; echocardiography was used to determine left ventricular ejection fraction; coronary angiography and OCT were performed to define the lesion length, diameter stenosis degree of the infarct-related arteries, presence or absence of complex lesions, culprit lesion type, area stenosis degree and vulnerability of culprit plaques. Multivariable logistic regression analysis was performed to identify independent correlation factors. The receiver operating characteristic (ROC) curve of continuous independent correlation factors was analyzed, and the best cut-off value of TIMI 0-1 was respectively determined according to the maximum value of Youden index. Results: The mean age of 1 268 STEMI patients were (57.6±11.4) years old and 923 cases were males (72.8%). Compared with TIMI 2-3 group, the patients in TIMI 0-1 group were older and had higher N-terminal-pro-B-type natriuretic peptide level, lower cardiac troponin I (cTnI) level, lower left ventricular ejection fraction, and higher hsCRP level (5.16(2.06, 11.78) mg/L vs. 3.73(1.51, 10.46) mg/L). Moreover, the hsCRP level of patients in TIMI 0-1 group was higher in the plaque rupture subgroup (all P<0.05). Coronary angiography results showed that compared with TIMI 2-3 group, the proportion of right coronary artery (RCA) as the infarct-related artery was higher, the angiographical lesion length was longer, minimal lumen diameter was smaller, and diameter stenosis was larger in TIMI 0-1 group (all P<0.05). The prevalence of plaque rupture was higher (75.8% vs. 61.2%) in TIMI 0-1 group. Plaque vulnerability was significantly higher in TIMI 0-1 group than that in TIMI 2-3 group with larger mean lipid arc (241.27°±46.78° vs. 228.30°±46.32°), more thin-cap fibroatheroma (TCFA, 72.4% vs. 57.9%), more frequent appearance of macrophage accumulation (84.4% vs. 70.7%) and cholesterol crystals (39.1% vs. 25.7%). Minimal flow area was smaller [1.3(1.1-1.7)mm2 vs. 1.4(1.1-1.9)mm2, all P<0.05] and flow area stenosis was higher (78.2%±10.6% vs. 76.3%±12.3%) in TIMI 0-1 group. Multivariable analysis showed that mean lipid arc>255.55°, cholesterol crystals, angiographical lesion length>16.14 mm, and hsCRP>3.29 mg/L were the independent correlation factors of reduced preprocedural TIMI flow grade in STEMI patients. Conclusions: Plaque vulnerability and inflammation are closely related to reduced preprocedural TIMI flow grade in STEMI patients.

Resistance, molecular epidemiology and virulence gene of non-A-F group serotype isolates of Salmonella enterica enteric subspecies isolated from children / 中华检验医学杂志

Objective:To analyze the anti-drug resistance, molecular epidemiology and virulence gene distribution of non-A-F group serotype isolates of Salmonella enterica enteric subspecis, so as to provide epidemiological basis for clinical diagnosis and treatment.Methods:Serotyping, antimicrobial susceptibility test and whole genome sequencing were performed on 11 isolates of non-A-F group serotype isolates of Salmonella enterica enteric subspecies that were isolated from The Children′s Hospital, Zhejiang University School of Medicine between 2017 and 2020. The serotype, multilocus sequence typing and virulence gene of the whole genome sequencing results were analyzed. Results:In our hospital, the detection rate of non-A-F group serotype isolates of Salmonella enterica enteric subspecies was low (1.13%). Among the 11 strains, there were 3 strains belong to Jangwani serotype, 2 strains of Hvittingfoss serotype, and Wandsworth, Pomona, Kedougou, Urbana, Poona and Kumasi serotypes have 1 strain each. Except for the two multi-drug resistant strains, the other strains were sensitive to most antibiotics, and the MICs were at low levels. A total of 9 ST types were detected in the 11 strains, the 3 Jangwani serotype strains were ST3918, and the other isolates were of different ST types. The phylogenetic tree shown that the three strains of Jangwani serotype were closely related. A total of 103 virulence genes were detected in the 11 strains, including 78 genes related to secretion system, 21 genes related to adherence, 2 genes related to magnesium uptake, 1 gene related to resistance to antimicrobial peptides and 1 gene related to typhoid toxin. Conclusions:The detection rate of the non-A-F group serotype isolates of Salmonella enterica enteric subspecies was low, and the sensitivity of the isolates to common antibiotics was high. The ST types and genetic relationship showed diversity. Clinical laboratory should pay attention to the detection of the non-A-F group serotype isolates of Salmonella enterica enteric subspecies, and the changes in drug resistance and virulence genes of the isolates should be closely monitored.

Association between neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and diabetic retinopathy among diabetic patients without a related family history.

BACKGROUND: Diabetic retinopathy (DR) is a specific neurovascular complication of diabetes mellitus (DM). Clinically, family history is a widely recognized risk factor for DR, assisting diagnosis and risk strata. However, among a great amount of DR patients without hereditary history like hypertension and diabetes, direct and simple risk factors to assist clinical decisions are still required. Herein, we intend to investigate the associated risk factors for these DR patients based on systemic inflammatory response indexes, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). METHODS: We consecutively enrolled 1030 patients with a definite diagnosis of type 2 diabetes mellitus (T2DM) from the endocrinology department of the Second hospital of People in Yun Nan. Based on funduscopy and family history checking, we excluded patients with a family history of hypertension and diabetes and finally enrolled 264 patients with DR and 206 patients with non-diabetic retinopathy (NDR). Through correlation analysis, univariate and multivariate regression, we further explore the association between NLR, PLR, and DR. On top of that, we investigate the effect of NLR and PLR on risk reclassification of DR. RESULTS: Compared with NDR patients, NLR and PLR levels are significantly higher among DR patients (NLR: 2.36 ± 1.16 in DR group versus 1.97 ± 1.06 in NDR group, p < 0.001; PLR: 11.62 ± 4.55 in DR group versus10.56 ± 4.45 in NDR group, p = 0.012). According to univariate analysis, NLR and PLR add risks to DR. After fully adjusting co-founders, NLR, as both continuous and categorical variate, remains an independent risk factor for DR (OR (95%CI): 1.37 (1.06, 1.78) P = 0.018). And though PLR was not independently associated with DR as a continuous variable (OR (95%CI) 1.05 (0.99, 1.11) p = 0.135), the highest quantile of PLR add two-fold increased risk (OR (95%CI) 2.20 (1.05, 4.59) p = 0.037) in the fully adjusted model for DR. In addition, addition of PLR and NLR to the established factor hemoglobin (Hb) improved the discriminability of the model and assisted the reclassification of DR. After combining PLR and NLR the Area under curve (AUC) of Hb based model raised from 0.76 to 0.78, with a category-free net reclassification improvement (NRI) of 0.532 (p < 0.001) and integrated discrimination improvement (IDI) of 0.029 (p < 0.001). CONCLUSIONS: Systemic inflammatory response indexes NLR and PLR were associated with the presence of DR among patients without associated family history and contributed to improvements in reclassification of DR in addition to Hb.