Protein vicinal thiols as intrinsic probes of brain redox states in health, aging, and ischemia.

The nature of brain redox metabolism in health, aging, and disease remains to be fully established. Reversible oxidations, to disulfide bonds, of closely spaced (vicinal) protein thiols underlie the catalytic maintenance of redox homeostasis by redoxin enzymes, including thioredoxin peroxidases (peroxiredoxins), and have been implicated in redox buffering and regulation. We propose that non-peroxidase proteins containing vicinal thiols that are responsive to physiological redox perturbations may serve as intrinsic probes of brain redox metabolism. Using redox phenylarsine oxide (PAO)-affinity chromatography, we report that PAO-binding vicinal thiols on creatine kinase B and alpha-enolase from healthy rat brains were preferentially oxidized compared to other selected proteins, including neuron-specific (gamma) enolase, under conditions designed to trap in vivo protein thiol redox states. Moreover, measures of the extents of oxidations of vicinal thiols on total protein, and on creatine kinase B and alpha-enolase, showed that vicinal thiol-linked redox states were stable over the lifespan of rats and revealed a transient reductive shift in these redox couples following decapitation-induced global ischemia. Finally, formation of disulfide-linked complexes between peroxiredoxin-2 and brain proteins was demonstrated on redox blots, supporting a link between protein vicinal thiol redox states and the peroxidase activities of peroxiredoxins. The implications of these findings with respect to underappreciated aspects of brain redox metabolism in health, aging, and ischemia are discussed.

[Relationship between blood glucose variation, collateral circulation and Batman score and prognosis after mechanical thrombectomy with Solitaire stent in acute posterior vascular occlusive stroke].

Objective: To explore the relationship between blood glucose variability, collateral circulation and basilar artery computed scan angiography score (Batman) and prognosis of mechanical thrombectomy with Solitaire stent in patients with large vascular occlusive APCI. Methods: A retrospective study was conducted on 113 patients with large vessel occlusive APCI who underwent Solitaire stent mechanical thrombectomy in the Department of Neurology of Nanyang Central Hospital from March 2021 to July 2022. According to the prognosis, they were divided into outcome group (46 cases) and adverse group (67 cases). Evaluate the prognosis based on the Modified Rankin Scale three months after the surgery. The differences in collateral circulation, GV and Batman score between the two groups were compared, and the related factors affecting the prognosis of large vessel occlusive APCI patients treated with Solitaire stent mechanical thrombectomy were analyzed by multivariate logistic regression model. Results: The age of 113 patients with acute large vessel occlusive APCI was (65.3±8.9) years old. The proportion of female was 34.5% (39 cases). Compared with the outcome group, the adverse group had a lower proportion of collateral circulation [40 cases (87.0%) vs 47 cases (70.2%)], higher GV score [(25.19±3.54) vs (30.36±4.11) points], lower Batman score [(7.49±1.52) vs (6.65±1.33) points], higher proportion of atrial fibrillation history [16 cases (23.9%) vs 4 cases (8.7%)], higher National Institutes of Health Stroke Scale (NIHSS) score at admission [(8.33±0.74) vs (7.25±0.92) points], larger core infarct volume [(32.57±4.87) vs (29.54±5.14) ml], and longer time from admission to vascular recanalization [(123.52±31.17) vs (102.47±29.54) min] (all P<0.05). Atrial fibrillation history, core infarct volume, NIHSS score at admission, time from admission to vascular recanalization, glycemic variability, collateral circulation, and Batman score were related factors for the prognosis of large vessel occlusive APCI patients treated with Solitaire stent mechanical thrombectomy, with ORvalues (95%CI) of 1.383 (1.124-1.641), 1.166 (1.007-1.350), 4.777 (1.856-12.297), 3.068 (2.379-3.757), 1.477 (1.209-1.806), 0.742 (0.654-0.831), and 0.717 (0.214-1.221), respectively (all P<0.05). Conclusion: Blood glucose variation is a risk factor for prognosis of mechanical thrombectomy with Solitaire stent in patients with large vascular occlusive APCI, and collateral circulation and Batman score are protective factors.

[Study on primary screening technique for children with autism spectrum disorder].

To explore screening tools for children with autism spectrum disorder (ASD), which are convenient for primary hospitals, it can provide basic data for formulating ASD prevention policies. This was a cross-sectional study by cluster sampling. Huyi District and Xincheng District were extracted for investigation in Xi'an City. From July 2021 to September 2022, all children aged from 3 months to 36 months who live in the two districts were subjected to primary screening. The child care physician used the routine screening tool "warning signs checklist for screening psychological, behavioral and developmental problems of children" and cartoon pictures of "early high-risk warning signs of autism", the children who were positive in the initial screening were referred to the district level maternal and child health hospital for re-screening, and those who were positive in the re-screening were referred to Xi 'an Children's Hospital for diagnosis. The results showed that a total of 17 905 children aged from 3 months to 36 months were initially screened in the two districts, including 10 588 children aged from 18 months to 36 months, 50 children who were positive in the initial screening and 50 children who were re-screened. 23 children (18 boys and 5 girls) were diagnosed with ASD. The prevalence rate of ASD in children was 2.17‰ (95% confidence interval:1.29‰-3.06‰). 42 children were positive for "warning signs checklist" at the preliminary screening, and 19 were confirmed as ASD. 27 children were positive for "cartoon pictures" in the preliminary screening, and 23 were confirmed with ASD. The "cartoon pictures" in the preliminary screening and diagnosis of consistent rate was higher than the "warning signs checklist", two kinds of screening methods comparison were statistically significant difference in the odds of consistent (χ2=11.01, P=0.001). In conclusion, relying on the three-level network of maternal and child health care, it is conducive to the whole process management of screening and diagnosis of children with ASD, and to guide the formulation of prevention policies. The cartoon pictures of "early high-risk warning signs of autism" can assist the identification of children with ASD based on the "warning signs checklist", which is simple, effective and suitable for promotion in the community health care.

Metal-insulator crossover in monolayer MoS2.

We report on transport measurements in monolayer MoS2devices, close to the bottom of the conduction band edge. These devices were annealedin situbefore electrical measurements. This allows us to obtain good ohmic contacts at low temperatures, and to measure precisely the conductivity and mobility via four-probe measurements. The measured effective mobility up toµeff= 180 cm2V-1s-1is among the largest obtained in CVD-grown MoS2monolayer devices. These measurements show that electronic transport is of the insulating type forσ≤ 1.4e2/handn≤ 1.7 × 1012cm-2, and a crossover to a metallic regime is observed above those values. In the insulating regime, thermally activated transport dominates at high temperature (T> 120 K). At lower temperatures, conductivity is driven by Efros-Schklovkii variable range hopping in all measured devices, with a universal and constant hopping prefactor, that is a clear indication that hopping is not phonon-mediated. At higher carrier density, and high temperature, the conductivity is well modeled by the Boltzmann equation for a non-interacting Fermi gas, taking into account both phonon and impurity scatterings. Finally, even if this apparent metal-insulator transition can be explained by phonon-related phenomena at high temperature, the possibility of a genuine 2D MIT cannot be ruled out, as we can observe a clear power-law diverging localization length close to the transition, and a one-parameter scaling can be realized.

[Advances in clinical significance and detection methods research of high density lipoprotein subfractions].

High density lipoprotein (HDL) is an important biochemical index of clinical cardiovascular disease. Many new studies have demonstrated abnormalities of plasma HDL subfractions in patients with this disease,and their clinical significance is greater than the overall abnormalities of HDL. Therefore,the HDL subfraction as an important factor in cardiovascular disease has attracted extensive research and attention. This article summarizes current research on HDL subfractions,their measurements and their relationships with atherosclerosis and coronary artery disease.

Self-Assembled, Hierarchical Structured Surfaces for Applications in (Super)hydrophobic Antiviral Coatings.

A versatile method for the creation of multitier hierarchical structured surfaces is reported, which optimizes both antiviral and hydrophobic (easy-clean) properties. The methodology exploits the availability of surface-active chemical groups while also manipulating both the surface micro- and nanostructure to control the way the surface coating interacts with virus particles within a liquid droplet. This methodology has significant advantages over single-tier structured surfaces, including the ability to overcome the droplet-pinning effect and in delivering surfaces with high static contact angles (>130°) and good antiviral efficacy (log kill >2). In addition, the methodology highlights a valuable approach for the creation of mechanically robust, nanostructured surfaces which can be prepared by spray application using nonspecialized equipment.

[Effect of dyslipidemia on clinical outcome of infertility patients receiving donor eggs].

Objective: To explore the effect of dyslipidemia on the clinical outcome of intracytoplasmic sperm injection-embryo transfer (ICSI-ET) in infertility patients receiving donor eggs. Methods: A total of 118 patients were selected to receive egg donors and ICSI-ET at the First Affiliated Hospital of Nanjing Medical University between April 2007 and December 2020. According to the levels of triacylglycerol, serum cholesterol, high density lipoprotein (HDL), and low density lipoprotein, they were divided into dyslipidemia group (35 cases) and normal blood lipids group (83 cases). The influence of body mass index (BMI) and age was adjusted by 1∶1 propensity score matching, and the general condition and clinical outcome of the two groups were analyzed retrospectively. Finally, the relationship between lipid composition and clinical outcome was analyzed according to patients' age and BMI. Results: (1) Comparing the pre-matching dyslipidemia group with the normal blood lipids group, the BMI of the dyslipidemia group was significantly higher than that of the normal blood lipids group [(23.5±2.4) vs (22.4±2.7) kg/m2], and the embryo implantation rate was significantly lower than that of the normal blood lipids group [13.6% (8/59) vs 27.3% (36/132)], the differences were statistically significant (both P<0.05). (2) There were no significant differences in years of infertility, number of pregnancies, number of abortions, number of transplanted embryos, protocol of endometrial preparation, endometrial thickness on transplantation day and high quality embryo rate between the two groups, through propensity score matching (all P>0.05). The biochemical pregnancy rate [28.6% (10/35)], embryo implantation rate [13.6% (8/59)] and live birth rate [20.0% (7/35)] in dyslipidemia group were significantly lower than those in the normal blood lipids group (P<0.05). The clinical pregnancy rate was lower than that of the normal blood lipids group (P>0.05). (3) The results of stratified analysis showed that the level of HDL in the clinically non-pregnant group was significantly lower than that in the pregnant group in patients ≤ 35 years old [(1.5±0.3) vs (1.8±0.5) mmol/L; P<0.05]. In the overweight recipient patients, the level of HDL of the clinically non-pregnant group was lower than that of the pregnant group (P>0.05). Conclusions: Dyslipidemia significantly reduces the biochemical pregnancy rate, embryo implantation rate and live birth rate in patients with receiving donor eggs. Especially in patients aged ≤35 years old, the reduction of HDL is closely related to adverse pregnancy outcomes.

The cholinergic system in joint health and osteoarthritis: a narrative-review.

Osteoarthritis (OA) poses a major health and economic burden worldwide due to an increasing number of patients and the unavailability of disease-modifying drugs. In this review, the latest understanding of the involvement of the cholinergic system in joint homeostasis and OA will be outlined. First of all, the current evidence on the presence of the cholinergic system in the normal and OA joint will be described. Cholinergic innervation as well as the non-neuronal cholinergic system are detected. In a variety of inflammatory diseases, the classic cholinergic anti-inflammatory pathway lately received a lot of attention as via this pathway cholinergic agonists can reduce inflammation. The role of this cholinergic anti-inflammatory pathway in the context of OA will be discussed. Activation of this pathway improved the progression of the disease. Secondly, chondrocyte hypertrophy plays a pivotal role in osteophyte formation and OA development; the impact of the cholinergic system on hypertrophic chondroblasts and endochondral ossification will be evaluated. Cholinergic stimulation increased chondrocyte proliferation, delayed chondrocyte differentiation and caused early mineralisation. Moreover, acetylcholinesterase and butyrylcholinesterase affect the endochondral ossification via an acetylcholine-independent pathway. Thirdly, subchondral bone is critical for cartilage homeostasis and metabolism; the cholinergic system in subchondral bone homeostasis and disorders will be explored. An increase in osteoblast proliferation and osteoclast apoptosis is observed. Lastly, current therapeutic strategies for OA are limited to symptom relief; here the impact of smoking on disease progression and the potential of acetylcholinesterase inhibitors as candidate disease-modifying drug for OA will be discussed.

Distinct Kondo Screening Behaviors in Heavy Fermion Filled Skutterudites with 4f

CeOs_{4}Sb_{12} (COS) and PrOs_{4}Sb_{12} (POS) are two representative compounds that provide the ideal vantage point to systematically study the physics of multi-f-electron systems. COS with Ce 4f^{1}, and POS with Pr 4f^{2} configurations show distinct properties of Kondo insulating and heavy fermion superconductivity, respectively. We unveiled the underlying microscopic origin by angle-resolved photoemission spectroscopy studies. Their eV-scale band structure matches well, representing the common characters of conduction electrons in ROs_{4}Sb_{12} systems (R=rare earth). However, f electrons interact differently with conduction electrons in COS and POS. Strong hybridization between conduction electrons and f electrons is observed in COS with band dependent hybridization gaps, and the development of a Kondo insulating state is directly revealed. Although the ground state of POS is a singlet, finite but incoherent hybridization exists, which can be explained by the Kondo scattering with the thermally excited triplet crystalline electric field state. Our results help us to understand the intriguing properties in COS and POS, and provide a clean demonstration of the microscopic differences in heavy fermion systems with 4f^{1} and 4f^{2} configurations.

Genotype to phenotype: Diet-by-mitochondrial DNA haplotype interactions drive metabolic flexibility and organismal fitness.

Diet may be modified seasonally or by biogeographic, demographic or cultural shifts. It can differentially influence mitochondrial bioenergetics, retrograde signalling to the nuclear genome, and anterograde signalling to mitochondria. All these interactions have the potential to alter the frequencies of mtDNA haplotypes (mitotypes) in nature and may impact human health. In a model laboratory system, we fed four diets varying in Protein: Carbohydrate (P:C) ratio (1:2, 1:4, 1:8 and 1:16 P:C) to four homoplasmic Drosophila melanogaster mitotypes (nuclear genome standardised) and assayed their frequency in population cages. When fed a high protein 1:2 P:C diet, the frequency of flies harbouring Alstonville mtDNA increased. In contrast, when fed the high carbohydrate 1:16 P:C food the incidence of flies harbouring Dahomey mtDNA increased. This result, driven by differences in larval development, was generalisable to the replacement of the laboratory diet with fruits having high and low P:C ratios, perturbation of the nuclear genome and changes to the microbiome. Structural modelling and cellular assays suggested a V161L mutation in the ND4 subunit of complex I of Dahomey mtDNA was mildly deleterious, reduced mitochondrial functions, increased oxidative stress and resulted in an increase in larval development time on the 1:2 P:C diet. The 1:16 P:C diet triggered a cascade of changes in both mitotypes. In Dahomey larvae, increased feeding fuelled increased ß-oxidation and the partial bypass of the complex I mutation. Conversely, Alstonville larvae upregulated genes involved with oxidative phosphorylation, increased glycogen metabolism and they were more physically active. We hypothesise that the increased physical activity diverted energy from growth and cell division and thereby slowed development. These data further question the use of mtDNA as an assumed neutral marker in evolutionary and population genetic studies. Moreover, if humans respond similarly, we posit that individuals with specific mtDNA variations may differentially metabolise carbohydrates, which has implications for a variety of diseases including cardiovascular disease, obesity, and perhaps Parkinson's Disease.

The root cause analysis on failed patient-specific measurements of pencil beam scanning protons using a 2D detection array with finite size ionization chambers.

The aim of this report is to present the root cause analysis on failed patient-specific quality assurance (QA) measurements of pencil beam scanning (PBS) protons; referred to as PBS-QA measurement. A criterion to fail a PBS-QA measurement is having a <95% passing rate in a 3.0%-3.0 mm gamma index analysis. Clinically, we use a two-dimensional (2D) gamma index analysis to obtain the passing rate. The IBA MatriXX PT 2D detection array with finite size ionization chamber was utilized. A total of 2488 measurements performed in our PBS beamline were cataloged. The percentage of measurements for the sites of head/neck, breast, prostate, and other are 53.3%, 22.7%, 10.5%, and 13.5%, respectively. The measurements with a passing rate of 100 to >94%, 94 to >88%, and <88% were 93.6%, 5.6%, and 0.8%, respectively. The percentage of failed measurements with a <95% passing rate was 10.9%. After removed the user errors of either re-measurement or re-analysis, 8.1% became acceptable. We observed a feature of >3% per mm dose gradient with respect to depth on the failed measurements. We utilized a 2D/three-dimensional (3D) gamma index analysis toolkit to investigate the effect of depth dose gradient. By utilizing this 3D toolkit, 43.1% of the failed measurements were improved. A feature among measurements that remained sub-optimal after re-analysis was a sharp >3% per mm lateral dose gradient that may not be well handled using the detector size of 5.0 mm in-diameter. An analysis of the sampling of finite size detectors using one-dimensional (1D) error function showed a large dose deviation at locations of low-dose areas between two high-dose plateaus. User error, large depth dose gradient, and the effect of detector size are identified as root causes. With the mitigation of the root causes, the goals of patient-specific QA, specifically detecting actual deviation of beam delivery or identifying limitations of the dose calculation algorithm of the treatment planning system, can be directly related to failure of the PBS-QA measurements.

[Effects of different doses of glucocorticoids on minimally invasive procedures in pain patients with type 2 diabetes].

Objective: To investigate the effects of different doses of glucocorticoids on minimally invasive procedures in patients with type 2 diabetes mellitus (T2DM), and optimize the clinical pathways of minimally invasive procedures. Methods: The clinical data of 284 patients with T2DM who received minially invasive procedures from the Department of Pain Medicine, West China Hospital, Sichuan University from May 2017 to May 2020 were retrospectively reviewed. The patients were divided into two groups according to the main diagnostic types: spine-related group (n=148) and herpes zoster group (n=136). According to the cumulative dose of glucocorticoids (GCs) per unit body surface area during the hospitalization, patients were further divided into three subgroups: low-dose group (GCs<3.5 mg/m2), medium-dose group (3.5 mg/m2 ≤GCs<7 mg/m2), and high-dose group (GCs≥7 mg/m2). The clinical characteristics of the patients in different subgroups of the two diseases groups were compared. The effects of the glucocorticoids on the pain intensity, blood glucose, length of hospital stay (LOS) and total hospitalization cost were compared among the 3 subgroups of the two diseases groups. Results: There were no significant differences in the age, gender, height, weight, visual analog scale (VAS) and fasting blood glucose before procedures between the two groups (all P>0.05). The VAS score of the low-dose group from the spine-related group was 4.5±1.6, which was higher than that of the medium-dose group (3.5±1.3) (P=0.004). VAS score was 4.3±1.3 in the medium-dose group and 4.4±1.6 in the high-dose group from the herpes zoster group, which were higher than that in the low-dose group (3.5±0.9) (P=0.006). In terms of blood glucose, the impact on the fasting blood glucose before and after the procedures in the low-dose group from the spine-related group was less than that in the medium dose group (P=0.013). In the herpes zoster group, the blood glucose of the low-dose group was (11±5) mmol/L, which had less influence on the blood glucose fluctuation during the hospitalization than that in the high-dose group [(15±5) mmol/L] (P<0.05). The LOS and hospitalization cost in the low-dose group from the spine-related group were (9±4) d and (10 583±4 851) yuan, respectively, which were less than those in the medium-dose group [(11±3) d and (15 202±7 418) yuan] and high-dose group [(13±6) d and (18 100±4 138) yuan] (all P<0.05); however, there was no significant difference among different subgroups in the herpes zoster group (all P>0.05). Conclusion: When used in the patients with T2DM undergoing minimally invasive procedures for spine-related diseases, low-dose glucocorticoids can obtain more clinical benefit than high dose, and high dose can lead to raised blood glucose, prolong the LOS, and increase the hospitalization cost.

[Analysis of epidemiological characteristics of human coronavirus in hospitalized children with respiratory tract infection in Hebei region].

Objective: To investigate the epidemiological characteristics of human coronavirus (HCoV) in hospitalized children with respiratory tract infection in Hebei region, providing evidence for the diagnosis and prevention of children with respiratory tract infection. Methods: A retrospective study was conducted on 1 062 HCoV positive children hospitalized for respiratory tract infection in Children's Hospital of Hebei Province from January 2015 to December 2020, aged from 33 days to 14 years, with a median age of 2 years. 27 932 (60.9%) were males and 17 944(39.1%) were females. And the gender, ages, seasonal distribution, HCoV-positive rates, co-detection distribution and clinical diagnosis of HCoV positive cases were analyzed by SPSS 25.0. Enumeration data were expressed by frequency and percentage; categorical variable were compared by the Pearson χ2test. Results: The overall HCoV-positive rate was 2.31% (1 062/45 876), which was 2.37% (662/27 932) in male children and 2.23% (400/17 944) in female children. There was no statistically significant difference between genders (χ²=0.916, P=0.339). Children at age groups<1 years (2.44%) and 1-<3 years (2.63%) had higher HCoV-positive rates than those at age groups 3-<5 years (1.97%) and ≥5 years (1.38%) (χ²=27.332,P<0.01). The HCoV-positive rates from 2015 to 2018 were 2.13%, 2.45%, 2.28% and 2.23%. The HCoV-positive rate of 2019 (1.71%) was significantly lower than in 2016 (χ²=12.05, P<0.01), 2017 (χ²=7.34, P=0.01) and 2018 (χ²=6.78, P=0.01), but there was no significant difference compared with 2015 (χ²=2.84, P=0.09). The HCoV-positive rate of 2020 (3.37%) was significantly higher than in 2015 (χ²=13.636, P<0.01), 2016 (χ²=11.099, P<0.01), 2017 (χ²=15.482, P<0.01), 2018(χ²=18.601, P<0.01) and 2019(χ²=45.580, P<0.01). The positive rate was highest in spring (March to May) in 2015 and 2017 to 2018. February to April and July to September of 2016 were the peak periods of positive detection. No obvious seasonal change was observed in 2019 and the HCoV-positive rate of 2020 was extremely low from January to July, following significantly increased from August to December. 26.37% (280/1 062) of HCoV were co-detected with other respiratory pathogens and the most frequently identified mixed detection was RSV. Three or more pathogens were detected in 7.34% (78/1 062) of the HCoV-positive samples. Bronchopneumonia and bronchiolitis were more frequently observed in the single HCoV positive (61.89% and 16.75%) children compared to co-detected children(34.29% and 9.64%)(χ²=63.394 and 8.228, P<0.01). However, compared to those with HCoV mono-detection, co-detected children were more likely to have severe pneumonia (4.6% and 47.14%) (χ²=280.171, P<0.01). Conclusions: HCoV is one of the respiratory pathogens in children in Hebei region and more prevalent in spring. The susceptible population of HCoV is mainly children under the age of 3 years old. HCoV often co-detects with other respiratory pathogens, and the co-infection is one of the risk factors of severe pneumonia in children with respiratory infection.

[Hepatitis B virus antigen peptide presentation by Epstein-Barr virus-transformed peripheral blood B cells].

Objective: To establish an Epstein-Barr virus-transformed peripheral blood B cell line (BCL), and explore its phenotypic characteristics, the ability to secrete antibodies and cytokines, and the ability to present hepatitis B virus (HBV) antigen peptide. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with HBV infection. Epstein-Barr virus supernatant was incubated to construct BCL. The expression of CD19, CD138, CD38, CD27 and the production levels of IFN - γ, IL-10, IL-6 were detected by flow cytometry. BCL loaded with HBV antigen peptide was incubated with in vitro-expanded autologous T cells. Intracellular staining was used to detect the level of interferon-gamma produced by T cells. Results: Compared with untransformed peripheral blood B cells, BCL had high expression levels of CD138, CD38 and CD27, and the difference was statistically significant (P < 0.05), while the level of IL-6 production was decreased, and the difference was statistically significant (P < 0.01). BCL loaded with HBV antigen peptide had significantly enhanced the production of interferon-gamma by in vitro-expanded autologous T cells, and the difference was statistically significant (P < 0.01). Conclusion: BCL highly expresses CD138, CD38 and CD27, but its ability to produce IL-6 decreases. BCL can improve the immune response efficiency of HBV-specific T cells to HBV antigen peptide, and serve as a new tool for hepatitis B immune research.

[Long-term therapeutic effects and liver fibrosis changes with direct-antiviral therapy in HIV/HCV co-infected patients].

Objective: To investigate the long-term characteristic changes of virus, immune status, and liver fibrosis markers in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients after receiving direct-antiviral agents (DAAs). Methods: HIV/HCV co-infected patients who visited the Guangzhou Eighth People's Hospital, Guangzhou Medical University from May 2014 to December 2019 were selected as the research subjects. The changes of virological response rate, peripheral blood CD4(+)T lymphocyte level and serological markers of liver fibrosis (APRI score and FIB-4 index) were observed during 144 weeks of follow-up course after the end of DAAs treatment. Kruskal-Wallis test was used for statistical approach. Results: A total of 103 cases were included in the study. There were 87 males (87.5%), with a median age of 44 years. Sustained virological response rate at 12 weeks (SVR12) after DAAs treatment was 97.6%, and the SVR during the entire follow-up period was at least 95.9%. Compared with baseline, CD4(+)T lymphocyte count were significantly increased equally at 12 weeks (Z = -2.283, P = 0.022), 24 weeks (Z = -3.538, P < 0.001), 48 weeks (Z = -3.297, P = 0.001), 96 weeks (Z = -3.562, P < 0.001), and 144 weeks (Z = -2.842, P = 0.004). APRI score (Z = -6.394, P < 0.001) and FIB-4 index (Z = -2.528, P = 0.011) were significantly lower than baseline at week 4 of DAAs treatment, and thereafter remained at a low level, without further declination. Conclusion: HIV/HCV co-infected patients can maintain high SVR for a long time, acquire good immune reconstitution, and significantly improve liver fibrosis after DAAs treatment.

Clinical epidemiology and outcome of HIV-associated talaromycosis in Guangdong, China, during 2011-2017.

OBJECTIVES: Talaromycosis is an invasive mycosis endemic to Southeast Asia. This study aimed to investigate the epidemiology, clinical features and prognostic factors of HIV-associated talaromycosis in Guangdong, China. METHODS: We retrospectively evaluated HIV patients hospitalized with histopathology- or culture-confirmed talaromycosis between 2011 and 2017. Factors associated with poor prognosis were identified using logistic regression. RESULTS: Overall, 1079 patients with HIV-associated talaromycosis were evaluated. Both the number and prevalence of talaromycosis among HIV admissions increased from 125 and 15.7% in 2011 to 253 and 18.8% in 2017, respectively, reflecting the increase in HIV admissions. Annual admissions peaked during the rainy season between March and August. Common clinical manifestations included fever (85.6%), peripheral lymphadenopathy (72.3%), respiratory symptoms (60.8%), weight loss (49.8%), skin lesions (44.5%) and gastrointestinal symptoms (44.3%). Common laboratory abnormalities were hypoalbuminaemia (98.6%), anaemia (95.6%), elevated aspartate aminotransferase level (AST) (76.9%), elevated alkaline phosphatase level (55.8%) and thrombocytopenia (53.7%). The median CD4 count was 9 cells/µL. Talaromyces marneffei was isolated from blood and bone marrow cultures of 66.6% and 74.5% of patients, respectively. The rate increased to 86.6% when both cultures were performed concurrently. At discharge, 14% of patients showed worsening conditions or died. Leucocytosis, thrombocytopenia, elevated AST, total bilirubin, creatinine and azole monotherapy independently predicted poor prognosis. CONCLUSIONS: The incidence of HIV-associated talaromycosis has increased in Guangdong with the high HIV burden in China. Skin lesions were seen in less than half of patients. Induction therapy with azole alone is associated with higher mortality. Findings from this study should help to improve treatment of the disease.

Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model.

OBJECTIVES: This study aimed to investigate the role of endothelin-1 (ET-1), originally known as the potent vasoconstrictor, and its receptors in chondrocyte senescence and osteoarthritis (OA) development. METHOD: Temporal changes of ET-1 and its receptors with OA development were characterized in a posttraumatic OA (PTOA) mouse model at time zero, 1-month and 4-month after surgical induction via destabilization of medial meniscus (DMM). A transgenic ET-1 overexpression (TET-1) mouse model was deployed to assess the impact of upregulated ET-1 on chondrocyte senescence and cartilage degradation. Effects of endothelin receptor blockade on chondrocyte senescence and OA development were further examined both in vitro and in vivo. RESULTS: Local expression of ET-1 in subchondral bone and synovium upregulated after DMM with an increase of plasma ET-1 level from 3.18 ± 0.21 pg/ml at time zero to 6.47 ± 0.34 pg/ml at 4-month post-surgery. Meanwhile, endothelin type B receptor (ETBR) (53.31 ± 2.42% to 83.8 ± 2.65%) and p16INK4a (10.91 ± 1.07% to 28.2 ± 1.0%) positve chondrocytes accumulated in articular cartilage since 1-month prior to cartilage loss at 4-month post-surgery. Overexpressed ET-1 promoted p16INK4a-positive senescent chondrocytes accumulation and cartilage degradation in TET-1 mice. Selective blockade of ETBR, but not ETAR, lowered the expression of p16INK4a in ET-1 or H2O2-induced chondrocyte senescence model, and mitigated the severity of murine PTOA. Intriguingly, reactive oxygen species (ROS) scavenger, Vitamin C, could rescue ET-1-induced chondrocyte senescence in vitro associated with restoration of mitochondrial dynamics. CONCLUSION: ET-1 could induce chondrocytes senescence and cartilage damages via ETBR in PTOA.

Molecular and structural imaging in surgically induced murine osteoarthritis.

Preclinical imaging in osteoarthritis is a rapidly growing area with three principal objectives: to provide rapid, sensitive tools to monitor the course of experimental OA longitudinally; to describe the temporal relationship between tissue-specific pathologies over the course of disease; and to use molecular probes to measure disease activity in vivo. Research in this area can be broadly divided into those techniques that monitor structural changes in tissues (microCT, microMRI, ultrasound) and those that detect molecular disease activity (positron emission tomography (PET), optical and optoacoustic imaging). The former techniques have largely evolved from experience in human joint imaging and have been refined for small animal use. Some of the latter tools, such as optical imaging, have been developed in preclinical models and may have translational benefit in the future for patient stratification and for monitoring disease progression and response to treatment. In this narrative review we describe these methodologies and discuss the benefits to animal research, understanding OA pathogenesis, and in the development of human biomarkers.

Clinical utility of 2-D anatomic measurements in predicting cough-associated headache in Chiari I malformation.

PURPOSE: Cough-associated headache (CAH) is the most distinctive symptom of patients with Chiari I malformation (CMI) and indicates clinically significant disease. We determined the clinical utility of simple 2D anatomic measurements performed on a PACS workstation by assessing their diagnostic accuracy in predicting CAH in CMI patients. METHODS: Seventy-two consecutive CMI patients (cerebellar tonsillar herniation > 5 mm) with headache seen by neurosurgeons over 6 years were included. Sagittal T1 images were used by two readers to measure: extent of tonsillar herniation, lengths of the clivus and supra-occiput, McRae and pB-C2 lines, as well as clivus-canal, odontoid retroversion, and skull base angles. Neurosurgery notes were reviewed to determine presence of CAH. Mann-Whitney test was used to compare measurements between patients with and without CAH. Predictive accuracy was assessed by receiver operating characteristic (ROC) curve. RESULTS: 47/72 (65.3%) CMI patients reported CAH. Tonsillar herniation with CAH (10.2 mm, 7-14 mm; median, interquartile range) was significantly greater than those without CAH (7.9 mm, 6.3-10.9 mm; p = 0.02). Tonsillar herniation ≥ 10 mm showed sensitivity and specificity of 51% and 68%, and tonsillar herniation > 14 mm showed sensitivity and specificity of 30% and 100%, respectively, for predicting CAH. Other 2D measurements showed no statistically significant differences. CONCLUSIONS: Among the 2D measurements used, only the extent of tonsillar herniation is different between CMI patients with and without CAH. Although CMI is diagnosed with tonsillar herniation of only 5 mm, we found that a much higher extent of herniation is needed to be predictive of CAH.

[The efficacy and safety of lopinavir/ritonavir and arbidol in patients with coronavirus disease 2019].

Objective: To evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) and arbidol in treating patients with coronavirus disease 2019 (COVID-19) in the real world. Methods: The clinical data of 178 patients diagnosed with COVID-19 admitted to Guangzhou Eighth People's Hospital from January 20 to February 10, 2020 were retrospectively analyzed. According to patient's antiviral treatment regimens, 178 patients were divided into 4 groups including LPV/r group (59 patients), arbidol group (36 patients), LPV/r plus arbidol combination group (25 patients) and the supportive care group without any antiviral treatment (58 patients). The primary end point was the negative conversion time of nucleic acid of 2019 novel coronavirus (2019-nCoV) by pharyngeal swab. Results: The baseline parameters of 4 groups before treatment was comparable. The negative conversion time of viral nucleic acid was (10.20±3.49), (10.11±4.68), (10.86±4.74), (8.44±3.51) days in LPV/r group, arbidol group, combination group, and supportive care group respectively (F=2.556, P=0.058). There was also no significant difference in negative conversion rate of 2019-nCoV nucleic acid, the improvement of clinical symptoms, and the improvement of pulmonary infections by CT scan (P>0.05). However, a statistically significant difference was found in the changing rates from mild/moderate to severe/critical type at day 7 (χ(2)=9.311, P=0.017), which were 24%(6/25) in combination group, 16.7%(6/36) in arbidol group, 5.4%(3/56) in LPV/r group and 5.2%(3/58) in supportive care group. Moreover, the incidence of adverse reactions in three antiviral groups was significantly higher than that in supportive care group (χ(2)=14.875, P=0.002). Conclusions: Antiviral treatment including LPV/r or arbidol or combination does not shorten the negative conversion time of 2019-nCoV nucleic acid nor improve clinical symptoms. Moreover, these antiviral drugs cause more adverse reactions which should be paid careful attention during the treatment.