Insulin-like growth factor 1 knockdown attenuates high glucose-induced podocyte injury by promoting the JAK2/STAT signalling-mediated autophagy.

PURPOSE: Podocyte injury plays a crucial role in the development of diabetic nephropathy (DN). A high serum level of insulin-like growth factor 1 (IGF-1) has been observed in patients with DN. This paper is to study the role and mechanism of IGF-1 in high glucose (HG)-induced podocyte injury. METHODS: Mouse podocytes MPC-5 were treated with HG to establish a DN model in vitro. db/db diabetic mice and db/m nondiabetic mice were used to evaluate the IGF-1 role in vivo. Western blotting was used for measuring protein levels of IGF-1 receptor, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway-related markers, podocyte markers podocin and nephrin, apoptosis- and autophagy-related markers in MPC-5 cells. Immunofluorescence staining was implemented for measuring the expression of nephrin and the autophagy marker LC3. Flow cytometry was used for detecting podocyte apoptosis. RESULTS: IGF-1 expression was increased in HG-stimulated MPC-5 cells and the kidney of db/db diabetic mice compared with corresponding controls. Knocking down IGF-1 downregulated IGF-1R and inhibited JAK2/STAT signalling pathway in HG-treated MPC-5 cells and db/db diabetic mice. IGF-1 silencing attenuated HG-induced podocyte injury, apoptosis and reduction in autophagy. Activating the JAK2/STAT signalling pathway or inhibiting autophagy reversed the effects of IGF-1 silencing on HG-treated MPC-5 cells. CONCLUSION: Knocking down IGF-1 alleviates HG-induced podocyte injury and apoptosis by inactivating the JAK2/STAT signalling pathway and enhancing autophagy.

Multifunctional fish-skin collagen-based hydrogel sealant with dual-dynamic-bond cross-linked for rapid hemostasis and accelerated wound healing.

Collagen (COL) is the most widespread functional protein. Designing and developing dual-dynamic-bond cross-linked COL adhesive hydrogel sealants with multifunctional is highly advantageous for achieving a superior wound closure effect and hemostasis. In this study, we developed hybrid hydrogels consisting of fish-skin COL, oxidized sodium alginate (OSA), borax and polyvinyl alcohol (PVA) to enhance full-thickness wound healing. The hydrogels were furnished with first-rate self-healing capabilities through the dual-dynamic-bond cross-linking of dynamic Schiff base bonds (COL-OSA) and diol boric acid bonds (OSA-borax) with reversible breakage and re-formation. Moreover, the incorporation of PVA stimulated the formation of hydrogen bonds in the system, bolstering the stability of the hydrogel framework. The prepared hydrogel manifests self-healing, injectability, multifunctional adhesiveness and biodegradability. In vivo assessment of the hemostatic capacity of COSP20 hydrogel was superior to gauze both in the mice liver injury model and mice tail amputation model. In addition, a full-thickness skin wound model in mice revealed that the COSP20 hydrogel facilitated faster wound closure by accelerating reepithelialization, COL deposition and angiogenesis. These findings illustrate the potential of hybrid fish-skin COL-based hydrogels to enhance wound healing and promote rapid tissue repair, and provide new possibilities for the effective utilization of marine fishery resources.

Aurantio-obtusin exerts an anti-inflammatory effect on acute kidney injury by inhibiting NF-κB pathway.

Acute kidney injury (AKI) is one of the major complications of sepsis. Aurantio-obtusin (AO) is an anthraquinone compound with antioxidant and anti-inflammatory activities. This study was developed to concentrate on the role and mechanism of AO in sepsis-induced AKI. Lipopolysaccharide (LPS)-stimulated human renal proximal tubular epithelial cells (HK-2) and BALB/c mice receiving cecal ligation and puncture (CLP) surgery were used to establish in vitro cell model and in vivo mouse model. HK-2 cell viability was measured using MTT assays. Histological alterations of mouse renal tissues were analyzed via hematoxylin and eosin staining. Renal function of mice was assessed by measuring the levels of serum creatinine (SCr) and blood urea nitrogen (BUN). The concentrations of pro-inflammatory cytokines in HK-2 cells and serum samples of mice were detected using corresponding ELISA kits. Protein levels of factors associated with nuclear factor kappa-B (NF-κB) pathway were measured in HK-2 cells and renal tissues by Western blotting. AO exerted no cytotoxic effect on HK-2 cells and AO dose-dependently rescued LPS-induced decrease in HK-2 cell viability. The concentrations of pro-inflammatory cytokines were increased in response to LPS or CLP treatment, and the alterations were reversed by AO treatment. For in vivo experiments, AO markedly ameliorated renal injury and reduced high levels of SCr and BUN in mice underwent CLP operation. In addition, AO administration inhibited the activation of NF-κB signaling pathway in vitro and in vivo. In conclusion, AO alleviates septic AKI by suppressing inflammatory responses through inhibiting the NF-κB pathway.

Efficacy of perinatal pharmacotherapeutic actions for survival of very preterm newborn rabbits at 26-day gestation.

Investigation of the pathophysiology of lung impairment and protection in very preterm neonates at birth requires adequate experimental models. This study aimed to elucidate the efficacy and mechanism of perinatal pharmacotherapeutic action in postnatal survival of very preterm rabbits. Pregnant New Zealand White rabbits on 25-day gestation (term 31 days) were given dexamethasone (D), or sham injection as control (C), and cesarean delivered 24 hours later on day 26. Newborns were anesthetized, intratracheally intubated, randomly received either saline or porcine surfactant (S), allocated to four groups (C, S, D, and DS), and ventilated with low tidal volume. Under the identical protocol, another four groups were added with nitric oxide (N) inhalation (CN, SN, DN, and DSN). Survival length, lung mechanics, histopathology, and pathobiology of lung tissue were measured for benefits and injury patterns. DSN had the longest median survival time (ST50, 10.3 h), whereas C had the shortest (3.5 h), with remaining groups in-between. The survival was mainly benefited by S, when additive effects with D and/or N were discernible, by improved lung mechanics and alveolar aeration, ameliorated lung injury severity and pneumothorax, and augmented lung phospholipid pools, with DSN being the most optimal. Variable mRNA expression profiles of alveolar epithelia-associated cytokines and inflammatory mediators further characterized injury and response patterns as phenotyping conditioned in pharmacotherapeutic actions. In conclusion, the combined regimens of perinatal medications achieved remarkable survival in very preterm rabbits with lung protective ventilation strategy, offering a unique model in investigation of very preterm birth-associated respiratory physiology and morbidities.NEW & NOTEWORTHY By establishing a very preterm rabbit model with 26-day gestation (term 31 days), optimal survival length for 50% of animals in groups was achieved by comparing regimens of combined antenatal glucocorticoids, postnatal surfactant and inhaled nitric oxide, with a low tidal volume ventilation strategy. The efficacies of pharmacotherapeutic action were associated with significantly improved lung mechanics, ameliorated lung injury and pneumothorax, and enhanced surfactant phospholipid metabolism, along with variable mRNA expression profiles characterizing the response patterns.

Efficacy of synthetic surfactant (CHF5633) bolus and/or lavage in meconium-induced lung injury in ventilated newborn rabbits.

BACKGROUND: The pathogenesis of neonatal meconium aspiration syndrome (MAS) involves meconium-induced lung inflammation and surfactant inactivation. Bronchoalveolar lavage (BAL) with diluted surfactant facilitates the removal of meconium. CHF5633, one of the most promising synthetic surfactants, is effective in neonatal respiratory distress syndrome. Here we investigated its efficacy via BAL in an experimental MAS model. METHODS: Experimental MAS was induced at birth in near-term newborn rabbits by intratracheal instillation of reconstituted human meconium. First, undiluted CHF5633 was compared with a porcine-derived surfactant (Poractant alfa) via intratracheal bolus (200 mg/kg). Second, the efficacy of BAL with diluted CHF5633 (5 mg/mL, 20 ml/kg) alone, or followed by undiluted boluses (100 or 300 mg/kg), was investigated. RESULTS: Meconium instillation caused severe lung injury, reduced endogenous surfactant pool, and poor survival. CHF5633 had similar benefits in improving survival and alleviating lung injury as Poractant alfa. CHF5633 BAL plus higher boluses exerted better effects than BAL or bolus alone in lung injury alleviation by reversing phospholipid pools and mitigating proinflammatory cytokine mRNA expression, without fluid retention and function deterioration. CONCLUSIONS: CHF5633 improved survival and alleviated meconium-induced lung injury, the same as Poractant alfa. CHF5633 BAL plus boluses was the optimal modality, which warrants further clinical investigation. IMPACT: To explore the efficacy of a synthetic surfactant, CHF5633, in neonatal lung protection comparing with Poractant alfa in a near-term newborn rabbit model with meconium-induced lung injury. Similar effects on improving survival and alleviating lung injury were found between CHF5633 and Poractant alfa. Optimal therapeutic effects were identified from the diluted CHF5633 bronchoalveolar lavage followed by its undiluted bolus instillation compared to the lavage or bolus alone regimens. Animals with CHF5633 lavage plus bolus regimen exerted neither substantial lung fluid retention nor lung mechanics deterioration but a trend of higher pulmonary surfactant-associated phospholipid pools.

Unmixing the coupling influence from driving factors on vegetation changes considering spatio-temporal heterogeneity in mining areas: a case study in Xilinhot, Inner Mongolia, China.

Considering the spatio-temporal heterogeneity, this study resolved the coupling influence of a variety of driving factors on vegetation changes in mining areas and discovered the influencing characteristics of the respective driving factors, especially mining activities. First, the spatio-temporal characteristics of FVC (fractional vegetation cover) variation were analyzed in the Sheng-Li mining area. Second, the quantitative relationships among the natural factors (temperature, precipitation, and elevation), artificial factors (mining activities, urban activities), and FVC were constructed by GTWR (geographically and temporally weighted regression) to quantify the contribution of each factor to the change in FVC. Third, the influencing characteristics of the respective driving factors, especially mining activities, were analyzed and summarized. The results show that (1) the FVC change was mainly influenced by natural factors in the areas far from mines and towns and artificial factors in the areas close to mines and towns. (2) The contribution of mining activities to vegetation change (C-Mine) was spatially characterized by two features: (a) distance attenuation characteristics: C-Mine showed logarithmic decrement with distance; (b) directional heterogeneity: C-Mine varied significantly in different directions. In particular, there was a high C-Mine area located near multiple mining areas, and the range of this area shifted to include the mine with more production over time. Overall, unmixing the coupling influence from driving factors with spatio-temporal heterogeneity and achieving a quantitative description of the influencing characteristics in mining areas were the main contributions of this study. The quantification methods and results in this paper provide important support for decision-making on ecological protection and restoration in mining areas.

[Analysis of risk factors of major adverse kidney events within 30 days in patients with acute pancreatitis].

OBJECTIVE: To analyze the risk factors of major adverse kidney events within 30 days (MAKE30) in patients with acute pancreatitis (AP). METHODS: A retrospective cohort study was conducted. A total of 162 patients who were first diagnosed with AP in the First Affiliated Hospital of Soochow University from June 2019 to June 2021 and the onset time was less than 72 hours were enrolled. Patients were divided into MAKE30 group and non-MAKE30 group according to the occurrence of MAKE30 after hospitalization. MAKE30 was defined as death from any cause, new renal replacement therapy (RRT), and persistent renal insufficiency (PRD). The clinical data of the two groups at admission were compared. The independent risk factors of MAKE30 were analyzed by multivariate Logistic regression method, and a regression equation was established as a quantitative prediction model of MAKE30. Receiver operator characteristic curve (ROC curve) was drawn to analyze the prediction of the quantitative prediction model value. RESULTS: All 162 patients were included in the final analysis, including 32 in the MAKE30 group and 130 in the non-MAKE30 group. Univariate analysis showed that compared with the non-MAKE30 group, the body mass index (BMI), the proportion of severe AP, and the acute physiology and chronic health evaluation II (APACHE II) score, the sequential organ failure assessment (SOFA) score, blood urea nitrogen (BUN), serum creatinine (SCr), C-reactive protein (CRP), HCO3-, Cl- levels and the proportion of hyperchloremia at admission in the MAKE30 group were significantly increased. Multivariate Logistic regression analysis showed that APACHE II score at admission [odds ratio (OR) = 1.659, 95% confidence interval (95%CI) was 1.426-1.956, P = 0.009], SOFA score (OR = 1.501, 95%CI was 1.236-1.840, P = 0.014) and hyperchloremia (OR = 1.858, 95%CI was 1.564-2.231, P = 0.004) were independent risk factors for MAKE30 in AP patients. The MAKE30 regression equation was established by the above risk factors [Logit(P) = 0.063+0.525×APACHE II score+0.328×SOFA score+0.895×hyperchloremia], which was used as the MAKE30 quantitative prediction model. ROC curve analysis showed that the area under the ROC curve (AUC) of the model for predicting MAKE30 was 0.846 (95%CI was 0.774-0.923, P = 0.001). The patients were divided into two subgroups with hyperchloremia (Cl- ≥ 110 mmol/L, n = 19) and non-hyperchloremia (Cl- < 110 mmol/L, n = 143) according to the blood Cl- level at admission. The incidence of MAKE30 and acute kidney injury (AKI) in the hyperchloremia group was significantly increased (MAKE30: 68.4% vs. 13.3%, AKI: 89.5% vs. 43.4%), and the levels of BUN and SCr at admission were significantly increased [BUN (mmol/L): 9.3±2.5 vs. 5.9±1.1, SCr (µmol/L): 162.3±26.4 vs. 78.6±9.2], the total length of hospital stay and length of intensive care unit (ICU) stay were significantly longer [total length of hospital stay (days): 10.2±1.6 vs. 5.6±1.2, length of ICU stay (days): 6.2±1.0 vs. 3.1±0.6], the cumulative intravenous infusion volume increased significantly at 48 hours and 72 hours (mL: 7 235.9±1 025.3 vs. 5 659.6±956.7 at 48 hours, 11 052.6±1 659.8 vs. 7 156.9±1 052.4 at 72 hours), differences were statistically significant (all P < 0.01). CONCLUSIONS: MAKE30 can be used as an important indicator to evaluate the short-term clinical prognosis of AP patients. APACHE II score, SOFA score and hyperchloremia at admission are the main risk factors. The risk model of MAKE30 based on these three indicators has good predictive performance. AP patients with hyperchloremia are at high risk of developing MAKE30, which should be highly regarded in clinical practice.

Outcome of neonatal hypoxemic respiratory failure: a livebirth population-based retrospective survey.

BACKGROUND: To explore the prevalence, outcome and perinatal risks of neonatal hypoxemic respiratory failure (NRF) in a survey of all livebirths from a regional network of perinatal-neonatal care during the transition period after 5-year universal health insurance implemented in China. METHODS: Clinical data of all neonatal respiratory morbidities in Huai'an were retrospectively collected in the regional perinatal network database of all livebirths as vital statistics in 2015. NRF was defined as hypoxemia requiring continuous positive airway pressure (CPAP) and/or mechanical ventilation (MV) for at least 24 h. Mortality risks of antenatal and perinatal morbidities, major respiratory therapies and complications were analyzed by multivariable logistic regression model. RESULTS: There were 788 NRF cases identified in 9.9% (7960) hospitalized, or 13.3‰ (59056) livebirths, in which 6.7% received intensive care and 93.0% critical care. The major underlying morbidities were respiratory distress syndrome (RDS, 36.4%) and pneumonia/sepsis (35.3%), treated mainly by CPAP, MV and surfactant. Significantly improved outcomes by surfactant in RDS were in patients with birthweight (BW) < 1500 g or gestational age (GA) < 32 weeks. The overall mortality rate in NRF was 18.4% whereas for those of BW < 1000 g and GA < 28 weeks, 70% and 54%, respectively. The multivariable regression analysis showed the highest odds for NRF death among meconium aspiration syndrome, congenital anomalies, BW < 1500 g and necrotizing enterocolitis, whereas born in level III hospitals, cesarean delivery, CPAP and MV were associated with markedly reduced death odds. CONCLUSIONS: The salient findings with associated risk estimates reflected efficiency of respiratory support as critical care in a prefectural regional network infrastructure for annual livebirths in 5.6 million inhabitants. It implicated the representativeness of contemporaneous perinatal-neonatal care standard at medium to medium-high level, in one/fourth of the population of China, aiming at saving more life of very critical and preterm infants for better survival.

The combination of gene hyperamplification and PD-L1 expression as a biomarker for the clinical benefit of tislelizumab in gastric/gastroesophageal junction adenocarcinoma.

BACKGROUND: In solid tumor Phase 1/2 trials (NCT02407990; NCT04068519), tislelizumab demonstrated clinical benefit, including in advanced gastroesophageal adenocarcinoma (GEA). However, the majority of patients with GEA did not respond, highlighting the need to understand mechanisms of resistance and identify predictive biomarkers for response. METHODS: All tislelizumab-treated patients with GEA from the Phase 1/2 trials were included (N = 105). Programmed death-ligand 1 (PD-L1) expression (Tumor Area Positivity [TAP] ≥ 5%), interferon gamma (IFNγ)-related gene signature, gene expression profile, tumor mutational burden (TMB), and gene hyperamplification (HA) were analyzed for correlation with tislelizumab. RESULTS: A moderate association was observed between PD-L1 TAP ≥ 5%, IFNγ gene signature, TMB-high and efficacy. A potential correlation between hyperamplification (HA +) and worse outcomes with programmed cell death protein 1 (PD-1) inhibition was identified. Hyperamplified genes were mainly enriched in cancer progression pathways, including cell cycle and RTK-RAS-PI3K pathways. Joint PD-L1 TAP ≥ 5% and lack of hyperamplification showed the most favorable benefit with an objective response rate of 29.4%, and median progression-free survival and overall survival of 4.1 and 14.7 months, respectively. Tumors with TAP ≥ 5% and HA - had inflamed immune signatures with increased immune cell infiltration, enhanced anti-tumor cytotoxic activity and antigen presentation signatures. Findings were validated in two independent gastric and gastrointestinal cancer cohorts treated with immune checkpoint inhibitors. CONCLUSIONS: In GEA, PD-L1 positivity, IFNγ-related gene signature and TMB-high status were positively associated with tislelizumab clinical benefit, whereas HA was associated with worse clinical outcomes. Combining PD-L1 positivity and HA - may help identify patients more likely to benefit from PD-1 blockade.

A versatile Y shaped DNA nanostructure for simple, rapid and one-step detection of mycotoxins.

A versatile Y shaped DNA nanostructure has been developed for simple, rapid and one-step simultaneous detection aflatoxin B1 (AFB1) and ochratoxin A (OTA). Y shaped duplex DNA arms was formed with two DNA tweezer at the ends. The aptamer sequence at the third end can bind to its target mycotoxins with strong affinity and then release the two DNA fragments. The released DNA fragments can open the DNA tweezers at the ends of Y shaped DNA arm. The amounts of AFB1 and OTA can be quantitative detection through the recovery of the fluorescent intensities. This strategy is simple and rapid with self-powered DNA hybridization reaction to control the "open" of Y shaped DNA tweezers. Furthermore, it can be finished in 60 min with only one-step of operation. The linear range of AFB1 was from 0.5 to 200 ng/mL (R2 = 0.995) and linear relationship of OTA was obtained from 4 to 300 ng/mL (R2 = 0.990). It also has been successfully applied for mycotoxins detection in real food samples. Importantly, the target mycotoxins can be extended to others by simply replacing the corresponding aptamer sequences.

Comparative study on characteristics of mandarin peel extracts by biological processing.

Mandarin peel is a by-product from mandarin canning industry containing multiple functional substances with useful properties such as antibacterial and antioxidant activities. To evaluate the effect of bioprocessing, fresh mandarin peels were fermented by Rhizopus stolonifer JP13 for 4 days and then the peels' antioxidant and antimicrobial activities were tested. The flavonoiuds, hesperidin and VC contents in dry peels were also determined. The data showed that the fermented mandarin peels had promoted antibacterial activity against Escherichia coli, Staphylococcus aureus, Aspergillus flavus, and Candida albicans. An increased scavenging effect on free radicals, with 73.0% of·OH scavenging activities were obtained when compared with fresh mandarin peels. We also observed a significant increase on content of flavonoid (334%) and hesperindin (253.7%), a reduced scavenging effect on O2- free radicals (13.94%), and a decrease content of VC (13.7%). The presaging of mandarin peels by Rhizopus stolonifer JP13 strain will promote the functional activities of mandarin peels and accelerate the process of manufacture Citri Reticulatae Pericarpium.

Factors associated with glycemic variability in children with type 1 diabetes mellitus based on flash glucose monitoring system. / 基于扫描式葡萄糖监测系统的儿童1åž‹ç³–å°¿ç— æ‚£è€ è¡€ç³–æ³¢åŠ¨çš„å½±å“å› ç´ .

OBJECTIVES: Patients with classical type 1 diabetes mellitus (T1DM) require lifelong dependence on exogenous insulin therapy due to pancreatic beta-cell destruction and absolute insulin deficiency. T1DM accounts for about 90% of children with diabetes in China, with a rapid increase in incidence and a younger-age trend. Epidemiological studies have shown that the overall glycated haemoglobin (HbA1c) and compliance rate are low in Chinese children with T1DM. Optimal glucose control is the key for diabetes treatment, and maintaining blood glucose within the target range can prevent or delay chronic vascular complications in patients with T1DM. Therefore, this study aims to investigate the glycemic control of children with T1DM from Hunan and Henan Province with flash glucose monitoring system (FGMS), and to explore factors associated with glycemic variability. METHODS: A total of 215 children with T1DM under 14 years old were enrolled continuously in 16 hospitals from August 2017 to August 2020. All subjects wore a FGMS device to collect glucose data. Correlation of HbA1c, duration of diabetes, or glucose scan rates with glycemic variability was analyzed. Glucose variability was compared according to the duration of diabetes, HbA1c, glucose scan rates and insulin schema. RESULTS: HbA1c and duration of diabetes were positively correlated with mean blood glucose, standard deviation of glucose, mean amplitude of glucose excursions (MAGE), and coefficient of variation (CV) of glucose (all P<0.01). The glucose scan rates during FGMS wearing was significantly positively correlated with time in range (TIR) (P=0.001) and negatively correlated with MAGE and mean duration of hypoglycemia (all P<0.01). Children with duration ≤1 year had lower time below range (TBR) and MAGE when compared with those with duration >1 year (all P<0.05). TIR and TBR in patients with HbA1c ≤7.5% were higher (TIR: 65% vs 45%, TBR: 5% vs 4%, P<0.05), MAGE was lower (7.0 mmol/L vs 9.4 mmol/L, P<0.001) than those in HbA1c >7.5% group. Compared to the multiple daily insulin injections group, TIR was higher (60% vs 52%, P=0.006), MAGE was lower (P=0.006) in the continuous subcutaneous insulin infusion group. HbA1c was lower in the high scan rates (≥14 times/d) group (7.4% vs 8.0%, P=0.046), TIR was significantly higher (58% vs 47%, P<0.001), and MAGE was lower (P<0.001) than those in the low scan rate (<14 times/d) group. CONCLUSIONS: The overall glycemic control of T1DM patients under 14 years old in Hunan and Henan Province is under a high risk of hypoglycemia and great glycemic variability. Shorter duration of diabetes, targeted HbA1c, higher glucose scan rates, and CSII are associated with less glycemic variability.

Perinatal Risks of Neonatal and Infant Mortalities in a Sub-provincial Region of China: A Livebirth Population-based Cohort Study.

BACKGROUND: Current vital statistics of birth population and neonatal outcome in China lacked information and definition of deaths at delivery and during hospitalization, especially for extreme preterm (EPT) birth. This study aims to delineate the prevalence of neonatal hospitalization, neonatal and infant mortality rates (NMR, IMR) and associated perinatal risks based on all livebirths in Huai'an, an evolving sub-provincial region in eastern China. METHODS: This retrospective cohort study established a comprehensive database linking information of whole regional livebirths and neonatal hospitalization in 2015, including deaths at delivery and EPT livebirths. The primary outcomes were NMR and IMR stratified by gestational age (GA) and birthweight (BW) with 95% confidence intervals. Causes of the neonatal and infant deaths were categorized according to the International Statistical Classification of Diseases 10th version, and population attributable fractions of GA and BW strata were analyzed. Perinatal risks of infant mortalities in continuum periods were estimated by Cox regression models. RESULTS: Among the whole livebirth population (59056), 7960 were hospitalized (prevalence 13.5%), with 168 (2.8‰) in-hospital deaths. The NMR was 3.6 (3.2, 4.1)‰ and IMR 4.9 (1.4, 4.5)‰, with additionally 35 (0.6‰) deaths at delivery. The major causes of infant deaths were perinatal conditions (2.6‰, mainly preterm-related), congenital anomalies (1.5‰), sudden unexpected death in infancy (0.6‰) and other causes (0.2‰). The deaths caused by preterm and low BW (LBW) accounted for 50% and 40% of NMR and IMR, with 20-30% contributed by EPT or extremely LBW, respectively. Multivariable Cox regression analysis revealed that peripartum factors and LBW strata had strong association with early- and late-neonatal deaths, whereas those of GA < 28 weeks were highly associated with postneonatal deaths. Congenital anomalies and neonatal hospitalization remained high death risks over the entire infancy, whereas maternal co-morbidities/complications were modestly associated with neonatal but not postneonatal infant mortality. CONCLUSIONS: The NMR, IMR, major causes of deaths and associated perinatal risks in continuum periods of infancy, denote the status and quality improvement of the regional perinatal-neonatal care associated with socioeconomic development. The study concept, applicability and representativeness may be validated in other evolving regions or countries for genuine comparison and better maternal-infant healthcare.

Prevalence of major morbidities and outcome of all hospitalized neonates. A retrospective cohort study of Huai'an neonatal survivals.

BACKGROUND: Reliable data for causal implication of neonatal survival in China are lacking. We assumed that by analyzing surviving data of in-hospital neonatal care based on all livebirths in Huai'an, prevalence of neonatal morbidity, mortality and causal relations may be derived comprehensively. MATERIALS AND METHODS: Data of all regionally hospitalized neonates were retrospectively linked with corresponding whole livebirths (59,056) in 2015 as a cohort. Diagnoses of diseases and causes of deaths were redefined and categorized. Disease patterns, prevalence of morbidities, case-fatality rate (CFR), and cause-specific mortality rate (CSMR) referring to livebirths were presented. Perinatal and disease-specific risks of death were estimated by multivariable logistic regression. RESULTS: In 7,960 (134.8‰) hospitalized patients, 168 (2.1%) died in hospital (2.85‰ of livebirths). Prevalence of major morbidities were 76.8‰ hyperbilirubinemia, 57.4‰ pneumonia, 32.7‰ intraventricular hemorrhage, 20.7‰ sepsis, 20.2‰ birth asphyxia, 9.69‰ congenital anomalies (CA), and 5.30‰ respiratory distress syndrome (RDS). The CFR (CSMR) of major diseases were 30.4% (0.12‰) meconium aspiration syndrome, 17.6% (0.22‰) necrotizing enterocolitis, 14.1% (0.75‰) RDS, 9.09% (0.88‰) CA, 5.26% (0.07‰) bronchopulmonary dysplasia, 1.71% (0.36‰) sepsis and 1.51% (0.31‰) asphyxia. Overall mortality rates were 4.6% and 6.8% in the preterm and low birthweight, and >50% in those of <28 week gestation or <1000 g birthweight, respectively. Mortality risks associated with the perinatal and neonatal morbidities were markedly declined with variable magnitude by multivariable regression models. CONCLUSIONS: The in-hospital neonatal survival datafile, depicted as the prevalence of major morbidities and CSMR of livebirth population in Huai'an, denoted overall and specific quality and efficiency of the perinatal-neonatal care system. Its concept and methodology should be relevant, and outcome extrapolated, to other countries or domestic regions, with similar socioeconomic development.

Impact of flash glucose monitoring on glycemic control varies with the age and residual ß-cell function of patients with type 1 diabetes mellitus.

AIMS/INTRODUCTION: We aimed to explore the clinical factors associated with glycemic variability (GV) assessed with flash glucose monitoring (FGM), and investigate the impact of FGM on glycemic control among Chinese type 1 diabetes mellitus patients in a real-life clinical setting. MATERIALS AND METHODS: A total of 171 patients were included. GV was assessed from FGM data. A total of 110 patients wore FGM continuously for 6 months (longitudinal cohort). Hemoglobin A1c (HbA1c), fasting and 2-h postprandial C-peptide, and glucose profiles were collected. Changes in HbA1c and glycemic parameters were assessed during a 6-month FGM period. RESULTS: Individuals with high residual C-peptide (HRCP; 2-h postprandial C-peptide >200 pmol/L) had less GV than patients with low residual C-peptide ( 2-h postprandial C-peptide ≤200 pmol/L; P < 0.001). In the longitudinal cohort (n = 110), HbA1c and mean glucose decreased, time in range (TIR) increased during the follow-up period (P < 0.05). The 110 patients were further divided into age and residual C-peptide subgroups: (i) HbA1c and mean glucose were reduced significantly only in the subgroup aged ≤14 years during the follow-up period, whereas time below range also increased in this subgroup at 3 months (P = 0.047); and (ii) HbA1c improved in the HRCP subgroup at 3 and 6 months (P < 0.05). The mean glucose decreased and TIR improved significantly in the low residual C-peptide subgroup; however, TIR was still lower and time below range was higher than those of the HRCP subgroup at all time points (P < 0.05). CONCLUSIONS: HRCP was associated with less GV. FGM wearing significantly reduced HbA1c, especially in pediatric patients and those with HRCP. Additionally, the mean glucose and TIR were also found to improve.

Comparison of survival of preterm newborn rabbits at 25-28 days of gestation with perinatal therapies at birth transition.

Eligibility of ventilated preterm rabbit model to investigate extreme pulmonary immaturity at birth transition is unknown. By extending this model to early saccular stage of fetal lung development, we evaluated efficacy in survival, lung maturation, and underlying mechanisms of contemporary perinatal therapies. Pregnant New Zealand White rabbit does were given dexamethasone (DEX), or sham injection as control (NDEX), 48 and 24 h before delivery at gestational age (GA) of 25-28 days. At birth, newborn rabbits were anesthetized and randomly allocated to four groups receiving either surfactant or nonsurfactant for both DEX and NDEX, and mechanically ventilated within low tidal volumes. Ranges of time to maintain survival rate ≥ 50% in GA 25-28 days were 59-136, 138-259, 173-288, and 437 to ≥600 min, respectively, each across the four groups. The benefits of DEX and/or surfactant for survival were more obvious in GA 25-26 days, as judged by improved lung mechanics, lower lung injury scores, higher lung surfactant phospholipid pools, and surfactant protein mRNA expression, with DEX-surfactant combination being the most optimal for the outcome. In contrast, those of GA 27-28 days had variable but meaningful responses to the treatment. Cox regression analysis revealed GA, DEX, and surfactant being independently protective factors whereas pneumothorax was a risk factor. The extremely preterm rabbits at GA 25-26 days markedly responded to the perinatal therapies for longer survival, lung maturation and injury alleviation, and were relevant for study of preterm birth transition-associated morbidities and underlying mechanisms.NEW & NOTEWORTHY An extremely preterm rabbit model with gestational age of 25-26 (term 31) days was established by mechanical ventilation with individually adjusted tidal volume at lower ranges. The administration of antenatal glucocorticoids and/or postnatal surfactant achieved significantly longer duration to maintain 50% survival and facilitated lung maturation and protection at early saccular stage. The usefulness of this model should be validated in future investigation of perinatal and neonatal morbidity and mortality at extremely preterm birth transition.

Haloamines as Bifunctional Reagents for Oxidative Aminohalogenation of Maleimides.

An unprecedented copper-catalyzed oxidative aminohalogenation of electron-deficient maleimides with secondary amines and NXS (X = Cl, Br, I) was developed, in which the N-X bonds generated in situ were used as difunctionalized reagents. The distinctive features of this multicomponent reaction include a simple green catalytic system, a spectral substrate range, and the late-stage modification of drug molecules. Most importantly, this umpolung radical cascade strategy exploits the in situ formation of N-iodoamines that enable efficient alkene aminoiodination.

Lipopolysaccharide-Induced Microglial Neuroinflammation: Attenuation by FK866.

Alleviating microglia-mediated neuroinflammation bears great promise to reduce neurodegeneration. Nicotinamide phosphoribosyltransferase (NAMPT) may exert cytokine-like effect in the brain. However, it remains unclear about role of NAMPT in microglial inflammation. Also, it remains unknown about effect of NAMPT inhibition on microglial inflammation. In the present study, we observed that FK866 (a specific noncompetitive NAMPT inhibitor) dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory mediator (interleukin (IL)-6, IL-1ß, inducible nitric oxide synthase, nitric oxide and reactive species) level increase in BV2 microglia cultures. FK866 also significantly inhibited LPS-induced polarization change in microglia. Furthermore, LPS significantly increased NAMPT expression and nuclear factor kappa B (NF-κB) phosphorylation in microglia. FK866 significantly decreased NAMPT expression and NF-κB phosphorylation in LPS-treated microglia. Finally, conditioned medium from microglia cultures co-treated with FK866 and LPS significantly increased SH-SY5Y and PC12 cell viability compared with conditioned medium from microglia cultures treated with LPS alone. Our study strongly indicates that NAMPT may be a promising target for microglia modulation and NAMPT inhibition may attenuate microglial inflammation.

Aggravated behavioral and neurochemical deficits and redox imbalance in mice with enhanced neonatal iron intake: improvement by biochanin A and role of microglial p38 activation.

Objectives: We aim to investigate the joint effect of iron (enhanced neonatal iron intake), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and biochanin A (BA, oral administration) and possible mechanisms for action on behavioral and neurochemical indicators in the mice. Methods: Rotarod test, pole test and swim test were used to evaluate animal behavior. The neurochemical analysis was conducted by HPLC-ECD. Oxidative stress was determined in this study. Further mechanism was investigated through in vitro experiments. Results: Iron and MPTP co-administration significantly induced behavioral deficits and decreased striatal dopamine content in the male and female mice. The co-administration of iron and MPTP also significantly induced redox imbalance in the substantia nigra (SN) of mice. Furthermore, BA significantly improved behavioral deficits and increased striatal dopamine content in the mice co-treated with iron and MPTP. BA also significantly improved redox imbalance in the SN of mice co-administered with iron and MPTP. Finally, we showed that iron and 1-Methyl-4-phenylpyridinium (MPP+) co-treatment significantly increased superoxide production in microglial cultures by inducing p38 mitogen-activated protein kinase (MAPK) activation. BA also significantly decreased superoxide production and p38 MAPK phosphorylation in the cultures co-treated with iron and MPP+. Conclusion: Iron and MPTP co-treatment may result in worsened behavioral and neurochemical deficits and aggravated redox imbalance through inducing microglial p38 MAPK activation. BA may improve behavioral and neurochemical deficits and redox imbalance through repressing microglial p38 MAPK activation.

Association of histological and clinical chorioamnionitis with perinatal and neonatal outcome.

Objectives: We investigated the incidence and outcome of clinical and histological chorioamnionitis (CA) and the associated risk factors in an emerging provincial perinatal center in 2014-2015.Study design: Based on the suspected and proven clinical infection in the third trimester of pregnancy, placenta and accessories from singleton deliveries were routinely examined histologically. The incidence of CA and associated fetal and neonatal outcome were compared by the total deliveries.Results: Of the 14,166 deliveries in 12 months, infection and inflammation were found in 373 out of 2372 (15.7%) placentas subjected to histological examination and diagnosed as CA (2.6%). These cases were divided into four groups as histological CA only (HCA, n = 335), clinical and histological CA (HCC, n = 20), clinical CA only (CCA, n = 18) and non-CA control (CON, n = 1999). Thus, an incidence of histological CA was 2.5% (355/14 166) in this birth population. Compared to CON, HCA group was more likely to have premature rupture of membrane, antenatal antibiotic use, gestational age <34 weeks, fetal distress, positive bacterial culture from vaginal secretions, and early-onset sepsis in newborns (all p ≤ .01), which were associated with perinatal risk factors of CA. In the very preterm subgroups, more stillbirths and death at delivery and neonatal intensive care unit admissions (p < .001) were found in the CA group.Conclusions: The results suggested that histological CA was associated with early-onset sepsis and combined perinatal comorbidities which are of more diagnostic importance than clinical only CA. The placental histological examination should be routinely performed in very preterm births to better assess perinatal and neonatal outcome.