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Atherosclerosis (AS) is a chronic inflammatory disease with thickening or hardening of the arteries, which led to the built-up of plaques in the inner lining of an artery. Among all the clarified pathogenesis, the over-activation of inflammatory reaction is one of the most acknowledged one. The nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome, as a vital and special form of inflammation and innate immunity, has been widely revealed to participate in the onset and development of AS. This review will introduce the process of the pathogenesis and progression of AS, and will describe the biological features of the NLRP3 inflammasome. Furthermore, the role of the NLRP3 inflammasome in AS and the possible mechanisms will be discussed. In addition, several kinds of agents with the effect of anti-atherosclerotic taking advantage of the NLRP3 inflammasome intervention will be described and discussed in detail, including natural compounds (baicalin, dihydromyricetin, luteolin, 5-deoxy-rutaecarpine (R3) and Salvianolic acid A, etc.), microRNAs (microRNA-30c-5p, microRNA-9, microRNA-146a-5p, microRNA-16-5p and microRNA-181a, etc.), and autophagy regulators (melatonin, dietary PUFA and arglabin, etc.). We aim to provide novel insights in the exploration of the specific mechanisms of AS and the development of new treatments of AS.

De novo missense mutations in SCN8A gene encoding voltage-gated sodium channel Na

OBJECTIVES: To assess the correlation between triglyceride glucose (TyG) index and in-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 2190 patients with STEMI who underwent primary angiography within 12 h from symptom onset were selected from the prospective, nationwide, multicenter CAMI registry. TyG index was calculated with the formula: Ln [fasting triglycerides (mmol/L) × fasting glucose (mmol/L)/2]. Patients were divided into three groups according to the tertiles of TyG index. The primary endpoint was in-hospital mortality. RESULTS: Overall, 46 patients died during hospitalization, in-hospital mortality was 1.5%, 2.2%, 2.6% for tertile 1, tertile 2, and tertile 3, respectively. However, TyG index was not significantly correlated with in-hospital mortality in single-variable logistic regression analysis. Nonetheless, after adjusting for age and sex, TyG index was significantly associated with higher mortality when regarded as a continuous variable (adjusted OR = 1.75, 95% CI: 1.16-2.63) or categorical variable (tertile 3 vs. tertile 1: adjusted OR = 2.50, 95% CI: 1.14-5.49). Furthermore, TyG index, either as a continuous variable (adjusted OR = 2.54, 95% CI: 1.42-4.54) or categorical variable (tertile 3 vs. tertile 1: adjusted OR = 3.57, 95% CI: 1.24-10.29), was an independent predictor of in-hospital mortality after adjusting for multiple confounders in multivariable logistic regression analysis. In subgroup analysis, the prognostic effect of high TyG index was more significant in patients with body mass index < 18.5 kg/m(2) (P(interaction) = 0.006). CONCLUSIONS: This study showed that TyG index was positively correlated with in-hospital mortality in STEMI patients who underwent primary angiography, especially in underweight patients.

BACKGROUND: Dacomitinib is a first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on NSCLC with complex EGFR mutations is limited. METHODS: Patients harboring complex (common mutations co-existing with uncommon mutations), or common (comparison cohort) EGFR mutations, who were treated with dacomitinib, were retrospectively evaluated in the Chinese National Cancer Center and the China PLA hospital between August 2019 and August 2021. RESULTS: In total, 72 patients with NSCLC harboring complex (C+U group, n=18) or common (C group, n=54) EGFR mutations and being treated with dacomitinib were enrolled. In the C+U group, 16 cases (88.9%) harbored L858R mutations co-existing with uncommon mutations located from exon 18 to exon 25 of EGFR (mostly E709X), and two cases harbored exon 19 deletion co-existing with G724S or K754E. Among the 15 evaluable patients, the objective response rate (ORR) was 40% (6/15), and the disease control rate (DCR) was 73.3% (11/15). The median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI), 4.4–10.6 months]. Except for the application line of dacomitinib (P=0.039), no significant statistical differences were found in other characteristics and adverse events between the two groups. The Kaplan-Meier method revealed no significant differences in PFS (P=0.889) and overall survival (OS) (P=0.703). However, the stratified analysis found worse PFS in the C+U group than that observed in the C group when receiving 1(st) and ≥3(rd) line dacomitinib treatment, while its OS was worse than that of group C when receiving ≥3(rd) line treatment. Furthermore, in a multivariate analysis, complex mutation status was an independent prognostic factor for OS (P=0.038) in the entire cohort. CONCLUSIONS: This study indicated a worse response and prognosis of patients with NSCLC harboring complex EGFR mutations than those harboring common EGFR mutations when treated with dacomitinib. Further studies and data are needed to confirm this conclusion.

To observe the effect of electroacupuncture (EA) at back-A total of 72 patients with CFS were randomized into an EA group (36 cases, 4 cases dropped off) and a sham EA group (36 cases, 3 cases dropped off). In the EA group, EA at Ganshu (BL 18), Xinshu (BL 15), Pishu (BL 20), Feishu (BL 13) and Shenshu (BL 23) was adopted, with continuous wave, 2 Hz in frequency. In the sham EA group, sham EA at non-acupoints (1.5-2.0 cm lateral to back-After treatment, the physical fatigue score, mental fatigue score and total score of FS-14, as well as RMT of motor cortex in the EA group were decreased compared with those before treatment (EA at back

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (

Urotensin II (UII) could increase blood pressure and heart rate via increased central reactive oxygen species (ROS) levels. We reported previously that hydrogen sulfide (H2S) exerts an antihypertensive effect by suppressing ROS production. The aim of the current study is to further examine the effects of endogenous and exogenous H2S on UII-induced cardiovascular effects by using an integrated physiology approach. We also use cell culture and molecular biological techniques to explore the inhibitory role of H2S on UII-induced cardiovascular effects. In this study, we found that cystathionine-β-synthase (CBS), the main H2S synthesizing enzyme in CNS, was expressed in neuronal cells of the rostral ventrolateral medulla (RVLM) area. Cellular distribution of CBS and urotensin II receptor (UT) in SH-SY5Y cells that are confirmed as glutamatergic were identified by immunofluorescent and Western blots assay. In Sprague–Dawley rats, administration of UII into the RVLM resulted in an increase in mean arterial pressure (MAP), heart rate (HR), ROS production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and phosphorylation of p47phox, extracellular signal-regulated protein kinase (ERK)1/2 and p38MAPK, but not stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK). These effects of UII were attenuated by application into the RVLM of endogenous (L-cysteine, SAM) or exogenous (NaHS) H2S. These results were confirmed in SH-SY5Y cells. UII-induced cardiovascular effects were also significantly abolished by pretreatment with microinjection of Tempol, Apocynin, SB203580, or PD98059 into the RVLM. Preincubated SH-SY5Y cells with Apocynin before administration of UII followed by Western blots assay showed that ROS is in the upstream of p38MAPK/ERK1/2. Gao activation assay in SH-SY5Y cells suggested that H2S may exert an inhibitory role on UII-induced cardiovascular effects by inhibiting the activity of Gαo. These results suggest that both endogenous and exogenous H2S attenuate UII-induced cardiovascular effects via Gαo-ROS-p38MAPK/ERK1/2 pathway.

Background: The florets of Carthamus tinctorius L. (Safflower) is an important traditional medicine for promoting blood circulation and removing blood stasis. However, its bioactive compounds and mechanism of action need further clarification.Objective: This study aims to investigate the effect and possible mechanism of 6-hydroxykaempferol 3,6-di-O-glucoside-7-O-glucuronide (HGG) from Safflower on endothelial injury in vitro, and to verify its anti-thrombotic activity in vivo.Methods: The endothelial injury on human umbilical vein endothelial cells (HUVECs) was induced by oxygen-glucose deprivation followed by reoxygenation (OGD/R). The effect of HGG on the proliferation of HUVECs under OGD/R was evaluated by MTT, LDH release, Hoechst-33342 staining, and Annexin V-FITC apoptosis assay. RNA-seq, RT-qPCR, Enzyme-linked immunosorbent assay and Western blot experiments were performed to uncover the molecular mechanism. The anti-thrombotic effect of HGG in vivo was evaluated using phenylhydrazine (PHZ)-induced zebrafish thrombosis model.Results: HGG significantly protected OGD/R induced endothelial injury, and decreased HUVECs apoptosis by regulating expressions of hypoxia inducible factor-1 alpha (HIF-1α) and nuclear factor kappa B (NF-κB) at both transcriptome and protein levels. Moreover, HGG reversed the mRNA expression of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, and reduced the release of IL-6 after OGD/R. In addition, HGG exhibited protective effects against PHZ-induced zebrafish thrombosis and improved blood circulation.Conclusion: HGG regulates the expression of HIF-1α and NF-κB, protects OGD/R induced endothelial dysfunction in vitro and has anti-thrombotic activity in PHZ-induced thrombosis in vivo.

Objective to explore the differences in the central response after acupuncture and moxibusbution at Zusānlĭ (足三里ST36) in treatment of functional dyspepsia (FD) based on the analysis of fractional amplitude of low frequency fluctuation (fALFF) of resting-state functional magnetic resonance imaging (rfMRI). Methods a total of 60 patients with FD were randomized into an acupuncture group and a moxibustion group, 30 cases in each one. In the acupuncture group, acupuncture was applied to bilateral ST36. In the moxibustion group, moxibustion was exerted at bilateral ST36. The treatment was given once a day, 5 times a week, totally for 4 weeks in each group, including 20 treatments with acupuncture or moxibustion. Separately, before and at the end of treatment, rfMRI scanning was conducted in two groups. Using data processing assistant for resting-state fMRI (DPARSF) software and MATLAB data platform, rfMRI data were collected for preprocessing and fALFF analysis. Results compared with the data before treatment, after treated with acupuncture at ST36 in FD patients, fALFF value was reduced in the right superior frontal gyrus, left superior frontal gyrus, left inferior frontal gyrus, right cuneus, left precuneus, right middle occipital gyrus, left middle occipital gyrus, etc., and it was increased in the left parahippocampus, right parahippocampus, left cerebellum, etc (all P Conclusion the differences in central function responses are induced in treamtent with acupuncture and moxibustion, which is probably related to the resting-state default network associated with targeted regulation and ventral attention of brain areas in functional dyspepsia.

The microbiota plays important roles for polyphenols exerting bioactivity, which needs support to calculate the accumulated polyphenols in the gastrointestinal tract. Taking phlorizin as an example, fecal excretion kinetics was suggested to be ingenious for achieving it. No phlorizin was excreted with feces, implying almost 100 % total availability. Combined with its 0-5 % bioavailability, more than 95 % of phlorizin quantitatively accumulated in the gastrointestinal tract. Instead, trace phloretin was excreted, and the acquired kinetic parameters were influenced by physical conditions and dietary patterns. Dosage-total-availability curves indicated different relationships among normal-diet and obese mice, resulting in critical dosages of ∼ 159 and ∼ 196 mg/kg when taking 95 % total availability by phloretin. The dietary matrix affects the intake, digestion, metabolism and absorption of polyphenols, and may alter its total availability, and fecal excretion kinetics can provide further support for polyphenol dietary supplements targeting microbiota.

Study Objectives Examine how different trajectories of reported sleep duration associate with early childhood cognition. Methods Caregiver-reported sleep duration data (n = 330) were collected using the Brief Infant Sleep Questionnaire at 3, 6, 9, 12, 18, and 24 months and Children’s Sleep Habits Questionnaire at 54 months. Multiple group-based day-, night-, and/or total sleep trajectories were derived—each differing in duration and variability. Bayley Scales of Infant and Toddler Development-III (Bayley-III) and the Kaufman Brief Intelligence Test- 2 (KBIT-2) were used to assess cognition at 24 and 54 months, respectively. Results Compared to short variable night sleep trajectory, long consistent night sleep trajectory was associated with higher scores on Bayley-III (cognition and language), while moderate/long consistent night sleep trajectories were associated with higher KBIT-2 (verbal and composite) scores. Children with a long consistent total sleep trajectory had higher Bayley-III (cognition and expressive language) and KBIT-2 (verbal and composite) scores compared to children with a short variable total sleep trajectory. Moderate consistent total sleep trajectory was associated with higher Bayley-III language and KBIT-2 verbal scores relative to the short variable total trajectory. Children with a long variable day sleep had lower Bayley-III (cognition and fine motor) and KBIT-2 (verbal and composite) scores compared to children with a short consistent day sleep trajectory. Conclusions Longer and more consistent night- and total sleep trajectories, and a short day sleep trajectory in early childhood were associated with better cognition at 2 and 4.5 years.

AIM: To investigate the clinical manifestations, diagnostic approaches, treatments, and outcomes of intraocular lymphoma. METHODS: In this retrospective study, 16 patients (28 eyes) with intraocular lymphoma were recruited in the Department of Ophthalmology, Peking Union Medical College Hospital, from 2004 to 2019. All patients underwent comprehensive ophthalmic examinations. Vitreous specimens of 13 patients were sent for cytopathology examination and other adjunctive diagnostic procedures. Three patients were diagnosed with intraocular lymphoma according to analysis of the histopathological results of systemic lymphoma by one clinician. Twenty-three eyes were treated with intravitreal administration of methotrexate, 4 eyes could not receive ocular treatment due to life-threatening lymphoma, and 1 eye did not require ocular treatment because the fundus lesions regressed after systematic chemotherapy. RESULTS: In 28 eyes, 25 eyes were diagnosed with vitreoretinal lymphoma, and 3 eyes were diagnosed with ciliary body lymphoma, all of which were non-Hodgkin diffuse large B cell lymphomas. The final visual acuity improved in 15 eyes (54%), remained unchanged in 5 eyes (18%), and decreased in 8 eyes (29%). Anterior segment inflammation disappeared or reduced in 8 and 5 eyes, respectively; and 15 eyes had no anterior segment reaction. Twenty eyes had mild vitreous opacity, 1 eye had mild vitritis, and 7 eyes had pars plana vitrectomy combined with silicone oil tamponade. Fundus lesions disappeared in 9 eyes and were relieved in 5 eyes; 4 eyes showed no changes, and the remaining 10 eyes' fundus were normal. CONCLUSION: The clinical manifestations of intraocular lymphoma are diverse, and the misdiagnosis rate is high. Cytopathological analysis of vitreous is one of the gold standards for the diagnosis. Immunohistochemistry, gene rearrangement and flow cytometric immunophenotypic analysis can improve the diagnostic rate. Ocular chemotherapy or radiotherapy regimens may preserve visual acuity, and a multidisciplinary team can provide individualized treatment for the patients.

Objective This study investigates variations in night, day, and total sleep trajectories across infancy and childhood in Asian children. Participants Participants consisted of a subset of 901 children, within the Growing Up in Singapore Towards healthy Outcomes cohort, which recruited 1247 pregnant women between June 2009 and September 2010. Design We used a novel conditional probabilistic trajectory model: a probabilistic model for mixture distribution, allowing different trajectory curves and model variances among groups to cluster longitudinal observations. Longitudinal sleep duration data for the trajectory analyses were collected from caregiver-reported questionnaires at 3, 6, 9, 12, 18, 24, and 54 months. Results We found 3 patterns of night sleep trajectories (n = 356): long consistent (31%), moderate consistent (41%), and short variable (28%); and 4 patterns of day sleep trajectories (n = 347): long variable (21%), long consistent (20%), moderate consistent (34%), and short consistent (25%). We also identified 4 patterns of total sleep trajectories (n = 345): long variable (19%), long consistent (26%), moderate consistent (28%), and short variable (27%). Short, moderate, and long trajectories differed significantly in duration. Children with consistent trajectories also displayed sleep patterns that were significantly more representative of typical developmental sleep patterns than children with variable trajectories. Conclusions This is the first study to describe multiple sleep trajectories in Singaporean children and identify between-individual variability within the trajectory groups. Compared to predominantly Caucasian samples, night/total sleep trajectories were generally shorter, while day sleep trajectories were longer. Future studies should investigate how these variations are linked to different developmental outcomes.

Mammalian lignans are phytoestrogens with important bioactivities, and their concentrations in livestock milk may influence the health of consumers. This research aimed to establish a method to quantify multiple mammalian lignans in the biofluids of dairy sheep using ultra-HPLC-triple quadropole mass spectrometry with multiple-reaction monitoring. Secoisolariciresinol, 2-[(4-hydroxy-3-methoxyphenyl)methyl]-3-[(3-hydroxyphenyl)methyl]-1,4-butanediol, enterodiol (ED), enterolactone (EL), ED-sulfate (ED-S), and EL-sulfate (EL-S) were purified from the urine of flaxseed cake-fed dairy sheep. The structures of these lignans were identified by a combination of mass and nuclear magnetic resonance spectra. These purified lignans were used as standards to optimize their quantification conditions in urine, milk, and plasma of dairy sheep. On this basis, the lignan metabolites in biofluids were quantified. To improve analysis sensitivity, plasma and milk were pretreated with acetonitrile containing 1% formic acid and passed through a HybridSPE-PL 55261-U column (Supelco, Bellefonte, PA). The limit of quantification of the lignans ranged from 1.43 to 18.3 ng/mL in plasma, and from 1.01 to 18.7 ng/mL in milk. The linearity of the calibration curves ranged from their limit of quantification to at least 217 ng/mL in plasma, and 217 ng/mL in milk. Regression coefficient of the calibration curves were above 0.99 for secoisolariciresinol, 2-[(4-hydroxy-3-methoxyphenyl)methyl]-3-[(3-hydroxyphenyl)methyl]-1,4-butanediol, ED, EL, ED-S, and EL-S, indicating satisfactory relationships between the peak areas and concentrations in the quantification range. The relative concentrations of ED-glucuronide and EL-glucuronide (EL-G) in different biofluids were compared based on their chromatogram peak areas. The sheep plasma contained all forms of mammalian lignans (i.e., ED, EL, ED-S, EL-S, ED-glucuronide, and EL-G.); the urine contained ED, EL, ED-S, and EL-S; and the milk contained ED, EL, ED-S, EL-S, and EL-G. Milk-to-plasma concentration ratios of the mammalian lignans indicated that the free forms were more permeable than the sulfated conjugates. Mammalian lignans found in sheep plasma and milk may provide health benefits to the sheep and sheep-product consumers. The analytical method established in this work could be used to quantify mammalian lignans in livestock products.

Accumulating study indicated that microRNA (miRNA) played critical role in the osteosarcoma (OS). The role and mechanisms of miR-193b in OS cell lines were still unknown. We resolved the miR-193b expression in OS cell line and normal cell by RT-PCR assay. The effects of upregulated miR-193b on OS cell proliferation, migration, invasion and apoptosis were evaluated using CCK-8 assay, transwell assay, would-healing assay and flow cytometric analysis in vitro, respectively. We investigated the effect of upregulated miR-193b on the mRNA level of cell cycle protein CCND1 and CCNE1 using RT-PCR assay and the protein level of epithelial to mesenchymal transition (EMT)-related protein E-cadherin, vimentin, and N-cadherin by western blotting assay in MG-63 and U2SO cells. Furthermore, luciferase reporter assays were employed to identify the candidate target gene RAB7A of miR-193b. The expression of miR-193b was downregulated in OS cells. In MG-63 and U2SO cells, ectopic miR-193b expression inhibited cell proliferation, migration, invasion, and induced apoptosis. We found that miR-193b reduced the mRNA expression of CCND1 and CCNE1, and regulated the associated proteins of EMT including E-cadherin, vimentin and N-cadherin in MG-63and U2SO cell lines. Moreover, the candidate target gene RAB7A was negatively regulated by miR-193b. In addition, upregulated RAB7A rescued the inhibitory effect of miR-193b mimics on the development of OS cell. In conclusion, this study suggested that miR-193b overexpression inhibited cell proliferation, migration, invasion, and induced cell apoptosis by down-regulating RAB7A in OS cell lines.

Hainan Island had experienced several cold-warm and dry-humid fluctuations since the Late Pleistocene period, resulting in separating and connecting from the mainland several times with the cyclic rise and fall of sea level. The fluctuations can change the biota and ecological environment in the island.

Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited.Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1–2 months. Adverse events were assessed by CTCAE 5.0.Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1–14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4–5 adverse events (AEs) occurred, but all patients had grade 1–2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs.Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

BackgroundSynergistic anti-tumor effects were observed in vivo and in vitro when immune checkpoint inhibitors (ICIs) were combined with denosumab. However, the clinical benefit and safety of this synergy have not been adequately evaluated in non-small cell lung cancer (NSCLC).MethodsConsecutive charts of NSCLC patients with bone metastases between December 2020 and December 2021 in the Chinese National Cancer Center were reviewed. The entire cohort was divided into one experimental group (denosumab + ICIs [DI]) and three control groups (denosumab + non-ICIs [DnI], phosphates + ICIs [PI], phosphates + non-ICIs [PnI]). Real-world objective response rates (ORRs), median progression-free survival (mPFS), skeletal-related events (SREs), and adverse events (AEs) were compared between groups.ResultsA total of 171/410 (41.7%) patients with advanced or recurrent NSCLC carrying bone metastases who received bone-targeted therapy were eligible for analysis. Although the DI group showed a better benefit trend, differences were not statistically significant concerning the therapeutic efficacy among the DI group (n = 40), PI group (n = 74), DnI group (n = 15), and PnI group (n = 42) (ORRs: 47.5%, 43.2%, 33.3%, and 40.5%, respectively, p = 0.799; and mPFS: 378, 190, 170, and 172 days, respectively, p = 0.115; SREs: 5%, 10.8%, 13.3%, and 11.9%, respectively, p = 0.733). Nevertheless, further analysis in the NON-DRIVER cohort revealed a greater benefit for the DI group (p = 0.045). Additionally, the AEs of the DI group were not significantly different from those of the PI, DnI, and PnI groups (AEs: 27.5%, 39.2%, 26.7%, and 28.6%, respectively, p = 0.742). Furthermore, the multivariate analysis revealed the independent prognostic role of DI treatment for PFS in the overall cohort. Within the DI group, we did not observe differences in benefit among different mutational subgroups (p = 0.814), but patients with single-site bone metastasis (p = 0.319) and high PD-L1 expression (p = 0.100) appeared to benefit more, though no significant differences were observed.ConclusionsDenosumab exhibited synergistic antitumor efficacy without increasing toxicity when used concomitantly with ICIs in patients with advanced non-small cell lung cancer carrying bone metastases.

(−)-Naringenin 4′,7-dimethyl ether ((−)-NRG-DM) was isolated for the first time by our lab from Nardostachys jatamansi DC, a traditional medicinal plant frequently used to attenuate pain in Asia. As a natural derivative of analgesic, the current study was designed to test the potential analgesic activity of (−)-NRG-DM and its implicated mechanism. The analgesic activity of (−)-NRG-DM was assessed in a formalin-induced mouse inflammatory pain model and mustard oil-induced mouse colorectal pain model, in which the mice were intraperitoneally administrated with vehicle or (−)-NRG-DM (30 or 50 mg/kg) (n = 10 for each group). Our data showed that (−)-NRG-DM can dose dependently (30~50 mg/kg) relieve the pain behaviors. Notably, (−)-NRG-DM did not affect motor coordination in mice evaluated by the rotarod test, in which the animals were intraperitoneally injected with vehicle or (−)-NRG-DM (100, 200, or 400 mg/kg) (n = 10 for each group). In acutely isolated mouse dorsal root ganglion neurons, (−)-NRG-DM (1~30 μM) potently dampened the stimulated firing, reduced the action potential threshold and amplitude. In addition, the neuronal delayed rectifier potassium currents (IK) and voltage-gated sodium currents (INa) were significantly suppressed. Consistently, (−)-NRG-DM dramatically inhibited heterologously expressed Kv2.1 and Nav1.8 channels which represent the major components of the endogenous IK and INa. A pharmacokinetic study revealed the plasma concentration of (−)-NRG-DM is around 7 µM, which was higher than the effective concentrations for the IK and INa. Taken together, our study showed that (−)-NRG-DM is a potential analgesic candidate with inhibition of multiple neuronal channels (mediating IK and INa).

Meropenem is increasingly used to treat neonatal sepsis. There are several guidelines recommending different dosing regimens of meropenem in neonates. Furthermore, deviations from these guidelines regularly occur in daily clinical practice. Therefore, the current study aimed to evaluate the variations of meropenem dosing guidelines and compare the difference between guideline and clinical practice in terms of the probability of target attainment.This study is based on a population pharmacokinetic model. After defining the predictive performance of the model, Monte Carlo simulations were used to calculate the probability of target attainment of the currently existing dosing guidelines of meropenem and their use in daily clinical practice.Two guidelines and two labels were included in the Monte Carlo simulations. For 70% fTThis model-based population pharmacokinetics simulation showed that improper guidelines and/or clinical practice deviations will result in low probability of target attainment for patients infected with resistant bacteria and critically ill patients. It is important to develop and adhere to evidence-based and clinically pragmatic guidelines.

Purpose Members in a supply chain account for corporate social responsibility (CSR) in different ways. This paper considers a socially responsible supply chain in which the manufacturer innovates in a sustainable product while the retailer exhibits CSR concerns. This paper aims to investigate how socially responsible behavior, namely, sustainable innovations or CSR concerns, affects the pure profit, environmental impact and social welfare, in such a socially responsible supply chain. Design/methodology/approach This paper first constructs an integrated case as a benchmark and then develops a Manufacturer-Stackelberg game in a decentralized scenario. The pure profit, environmental impact and social welfare are confirmed and analyzed in centralized and decentralized cases. Moreover, two unique coordinating contracts, i.e. wholesale price discount contract and revenue-sharing contract, are used in this socially responsible supply chain. Findings Analytical analysis shows that, under certain conditions, the optimal CSR strategies hold for maximizing pure channel profit, minimizing environmental impact and maximizing social welfare. Whether the performance in a centralized case outnumbers that in a decentralized case depends on the CSR concerns level and environment-friendly degree of the product. In addition, it is found that a wholesale price discount contract is better for the retailer whereas a revenue-sharing contract is better for the manufacturer in pure profit to improve coordinating efficiency. Practical implications These results can offer managerial implications to the socially responsible supply chain in terms of pricing decisions, CSR strategies and sustainability innovations. Specifically, under certain conditions, placing more CSR concerns level increases pure channel profit and the social welfare. A balance between the pure profit and the social welfare is hereby achieved for the two socially responsible individuals by designing a proper contract. Originality/value To the best of the authors’ knowledge, this paper is among the first studies so far to combine the CSR concerns strategy and sustainability innovation into a socially responsible supply chain.

This paper aims to find operational decisions and financing strategies in a closed-loop supply chain (CLSC) consisting of a financially constrained manufacturer and a retailer. Based on a benchmark...

Introduction The protective effect of catalpol on diabetic osteoporosis (DOP) and its mechanism remain unclear. This study aimed to explore whether catalpol enhanced the proliferation and differentiation of MC3T3 cells induced by high glucose by inhibiting the expression of KDM7A. Methods MC3T3 cells were induced by high glucose (HG) and treated with different concentrations of catalpol. The proliferation and mineralization abilities of MC3T3-E1 cells were determined by CCK-8 assay and Alizarin Red Staining, respectively. The expression of differentiation-related osteogenic proteins, KDM7A and related proteins of Wnt/β-catenin signaling pathway was analyzed by Western blot analysis. The alkaline phosphatase (ALP) activity was detected by ALP assay kits. Results MC3T3-E1 cells induced by high glucose showed decreased proliferation and mineralization abilities and decreased ALP activity, which were all reversed by the treatment of catalpol. High glucose induction inhibited the expression of KDM7A, Total-β-catenin, Nuclear-β-catenin and p-GSK3β, which was reversed by the treatment of catalpol. And KDM7A interference up-regulated the expression of Total-β-catenin, Nuclear-β-catenin and p-GSK3β, which was down-regulated by KDM7A overexpression. Furthermore, the proliferation and mineralization abilities and ALP activity were improved when treated with KDM7A interference and decreased when treated with KDM7A overexpression. However, SKL2001 could improve the proliferation and mineralization abilities and ALP activity of MC3T3-E1 cells. Discussion Catalpol promotes the proliferation and differentiation of osteoblasts induced by high glucose by regulating the Wnt/β-catenin signaling pathway through KDM7A.

At present, there are a lot of researches on the metric about static source code. However, there are few studies about automatic code generation. Based on the quality and efficiency of automatic code generation, this paper proposes the metric model including six metric characteristics. Then, three automatic code generation tools are used to measure the experimental source code. Finally, the experimental results showed that the metric of automatic code generation is effective.

Our previous studies have demonstrated that the total triterpenes from the fruits of Chaenomeles speciosa (CSTT) exhibit effective therapeutic effects on gastric ulcer patients and animals. The present aim is to further investigate the mechanisms involved. The results indicated that CSTT could ameliorate IND-induced gastric injury, which was related to promoting IND-damaged GES-1 cell proliferation and migration, improving the IND-damaged rat GBF, ulcer area, inhibition rate and pathologic changes of gastric mucous tissue, increasing the amount of adhered gastric mucus, attenuating the volume and total acidity of the gastric effluents, and augmenting the gastric pH; further studies showed that CSTT obviously downregulated miR-423-5p mRNA, NAG-1 mRNA and protein expression, Bax, Bad, cytosol cytochrome C, Apaf-1, cleaved-caspase-3, and cleaved-caspase-9 protein expression and cytosol cytochrome C concentration, and upregulated TFF1, TFF2 and TFF3 mRNA and protein expression, Bcl-2, Bcl-xl, pro-caspase-3, and pro-caspase-9 protein expression, mitochondrial viability, mitochondrial cytochrome C concentration and Bcl-2/Bax, Bcl-xl/Bad ratios. These findings demonstrated that CSTT protected against IND-induced gastric damage by depressing miR-423-5p expression and modulating the TFF/NAG-1 pathway, which in turn restrained mitochondrion-mediated apoptosis.

(-)-Naringenin 4',7-dimethyl ether ((-)-NRG-DM) was isolated for the first time by our lab from

Introduction: Chronic severe aortic regurgitation (AR) has a poor long-term prognosis, especially among old-age patients. Considering their advancing age, the surgical approach of aortic valve replacement may not always be the best alternative modality of treatment in such patients. Therefore, this study’s primary goal was to provide an initial summary of the medium- and short-term clinical effectiveness of transcatheter aortic valve replacement (TAVR) guided by accurate multi-detector computed tomography (MDCT) measurements in patients with severe and chronic AR, especially in elderly patients. Methods: The study enrolled retrospectively and prospectively patients diagnosed with severe AR who eventually underwent TAVR procedure from January 2019 to September 2022 at Fuwai cardiovascular Hospital, Beijing. Baseline information, MDCT measurements, anatomical classification, perioperative, and 1-year follow-up outcomes were collected and analyzed. Based on a novel anatomical categorization and dual anchoring theory, patients were divided into four categories according to the level of anchoring area. Type 1, 2, and 3 patients (with at least two anchoring regions) will receive TAVR with a transcatheter heart valve (THV), but Type 4 patients (with zero or one anchoring location) will be deemed unsuitable for TAVR and will instead receive medical care (retrospectively enrolled patients who already underwent TAVR are an exception). Results: The mean age of the 37 patients with severe chronic AR was 73.1 ± 8.7 years, and 23 patients (62.2%) were male. The American Association of Thoracic Surgeons’ score was 8.6 ± 2.1%. The MDCT anatomical classification included 17 cases of type 1 (45.9%), 3 cases of type 2 (8.1%), 13 cases of type 3 (35.1%), and 4 cases of Type 4 (10.8%). The VitaFlow valve (MicroPort, Shanghai, China) was implanted in 19 patients (51.3%), while the Venus A valve (Venus MedTech, Hangzhou, China) was implanted in 18 patients (48.6%). Immediate TAVR procedural and device success rates were 86.5% and 67.6%, respectively, while eight cases (21.6%) required THV-in-THV implantation, and nine cases (24.3%) required permanent pacemaker implantation. Univariate regression analysis revealed that the major factors affecting TAVR device failure were sinotubular junction diameter, THV type, and MDCT anatomical classification (p < 0.05). Compared with the baseline, the left ventricular ejection fraction gradually increased, while the left ventricular end-diastolic diameter remained small, and the N-terminal-pro hormone B-type natriuretic peptide level significantly decreased within one year. Conclusion: According to the results of our study, TAVR with a self-expanding THV is safe and feasible for patients with chronic severe AR, particularly for those who meet the criteria for the appropriate MDCT anatomical classification with intact dual aortic anchors, and it has a significant clinical effect for at least a year.

Objective Dacomitinib has been approved for the first‐line treatment of non‐small cell lung cancer (NSCLC) carrying classical epidermal growth factor receptor (EGFR) mutations; however, real‐world data on its later‐line application are lacking. Materials and methods Patients’ data were retrospectively collected from the Chinese National Cancer Center and the PLA hospital between August 2019 and August 2021. Kaplan‐Meier method and Log‐rank test were utilized to assess progression‐free survival (PFS) and overall survival (OS). Univariate and multivariate Cox regression analysis was conducted to determine prognostic indicators. Results In total, 56 NSCLC patients harboring EGFR mutations treated with later‐line single dacomitinib or combinatory dacomitinib were enrolled. A total of 53 patients (94.6%) had treatment‐related adverse events; eight patients (14.3%) had grade 3 or 4 events. Among 49 evaluable patients, 26.5% (13 patients) had a confirmed partial response and 73.5% (36 patients) had disease control; the median duration of follow‐up was 9.6 months (95% confidence interval [CI], 8.4–10.8 months), the median progression‐free survival was 5.4 months (95% CI, 3.5–7.3 months), and the half‐year, 1‐year, and 2‐year OS rate were 79.2%, 70.6%, and 64.1%, respectively. Univariate analysis suggested that smoking, line of dacomitinib, and interval between last EGFR‐tyrosine kinase inhibitor (TKI) and dacomitinib were associated with PFS and OS; chemotherapy between last EGFR‐TKI and dacomitinib, and EGFR‐TKI generation followed by dacomitinib were respectively associated with PFS and OS; multivariate analysis indicated chemotherapy between last EGFR‐TKI and dacomitinib negatively affect PFS, and smoking and third‐generation EGFR‐TKI followed by dacomitinib negatively affect OS. Conclusions This real‐world study has shown that dacomitinib is active and well‐tolerated in NSCLC patients harboring different EGFR mutations in later‐line settings, even for those with brain metastases. Patients who benefited more from the first TKI were more likely to benefit from dacomitinib, and earlier application of dacomitinib after front‐line TKI resistance may be considered.

Background: Admission hypothermia (AH, Methods: The study used sequential Plan - Do - Study - Act (PDSA) approach. Clinical data were collected prospectively with 5 NICUs from Sino-Northern Neonatal Network (SNN) in China. Bundle come into practice since January 1, 2019. The clinical data in pre-QI phase (January 1, 2018– December 31, 2018) were compared with post-QI phase (January 1, 2019–December 31, 2020). Clinical characteristics and outcomes data were analysed.Results: A total of 750 in-born VLBW infants were enrolled in the study, 270 in pre-QI period and 480 in post- QI period, respectively. There had no significant differences in clinical characteristics in two phases. Compared with pre-QI period, the percentage of AH decreased in the QI period (95.9 %vs 71.3%, P < 0.01). Admission mod-severe hypothermia (AMSH) was improved significantly, reduced by 38.5% after QI (68.5 %vs 30%, P < 0.01). Average admission temperature improved after QI [36.0 ˚C（35.8˚C，36.5˚C）vs 35.5 ˚C（35.2 ˚C，36.0 ˚C）, P < 0.01 ]. No significant increase in AH rate and thermal burns (0.4%VS 0%). Risks of mortality and late-onset neonatal sepsis (LOS) were significantly lower in post-QI period as compared to pre-QI period (aRR 0.19, 95% CI 0.09–0.39; aRR 0.55, 95% CI 0.41–0.80) whether adjusting for birth weight (BW), gestational age (GA)，small for gestational age (SGA), Apgar score at 5 min < 7.Conclusion：Implementation of multicenter thermoregulatory QI help in significant reduction of AH and AMSH of VLBW neonates within a certain area, which in turn can help to improve reginal neonatal outcomes. We gained a lot from QI, learned and explored a suitable method to continuous QI, this may provide reference for similar developing countries.

Background Admission hypothermia (AH, Methods The study used a sequential Plan—Do—Study—Act (PDSA) approach. Clinical data were collected prospectively from 5 NICUs within the Sino-Northern Neonatal Network (SNN) in China. The hypothermia prevention bundle came into practice on January 1, 2019. The clinical characteristics and outcomes data in the pre-QI phase (January 1, 2018– December 31, 2018) were compared with that from the post-QI phase (January 1, 2019–December 31, 2020). Clinical characteristics and outcomes data were analyzed. Results A total of 750 in-born VLBW infants were enrolled in the study, 270 in the pre-QI period and 480 in the post- QI period, respectively. There were no significant differences in clinical characteristics of infants between these two phases. Compared with pre-QI period, the incidence of AH was decreased significantly after the QI initiative implementation in the post-QI period (95.9% vs. 71.3%, P P $$\pm$$ ± 0.7℃ vs. 36.0 $$\pm$$ ± 0.6℃, P 37.5 °C or thermal burns between the two groups. The risk ratio of mortality in infants during the post-QI period was significantly lower in the post-QI period as compared to the pre-QI period [adjusted risk ratio (aRR): 0.26, 95% confidence interval (CI): 0.13–0.50]. The risk ratio of late-onset neonatal sepsis (LOS) also significantly lowered in the post-QI period (aRR: 0.66, 95% CI: 0.50–0.87). Conclusion Implementation of multicentric thermoregulatory QI resulted in a significant reduction in AH and AMSH in VLBW neonates with associated reduction in mortality. We gained a lot from the QI, and successfully aroused the attention of perinatal medical staff to neonatal AH. This provided a premise for continuous quality improvement of AH in the future, and might provide a reference for implementation of similar interventions in developing countries. Trial registration Trial registration number: ChiCTR1900020861. Date of registration: 21 January 2019(21/01/2019). Prospectively registered.

Tetraena mongolica Maxim, a relict originating from the Tertiary Period, is an endemic species of Zygophyllaceae in China. Three new monoterpenoids (1-3), two new phenols (4, 5) with unusual O-sulfoglucosyl groups, a new flavonoid (6), and nine known compounds were isolated from the leaves of T. mongolica. The structures of these compounds were determined by interpretation of NMR, MS, and ECD data. Some of the isolated compounds showed protective effects on HEK 293t cells damaged by CdCl2, with IC50 values being 55.7 and 80.3 μM for compounds 7 and 8, respectively, at the time point of 48 h after treatment.

Glycyrrhiza uralensis is the major plant source of licorice. This study was to identify bioactive compounds from the plant's leaves in order to make better use of its aerial part. An ethanol extract of the leaves was subjected to repeated chromatography to yield 15 compounds. The structures were determined to be three novel dihydrostilbenes, based on their various spectroscopic data-glycypytilbene A (1), glycydipytilbene (2), and glycypytilbene B (3)-and 12 known compounds, α,α'-dihydro-3,5,4'-trihydroxy-4,3'-diisopentenylstilbene (4), α,α'-dihydro-3,5,3',4'-tetrahydroxy-2,5'-diisopentenylstilbene (5), 6-prenyleriodictyol (6), 5'-prenyleriodictyol (7), 6-prenylquercetin-3-Me ether (8), 5'-prenylquercetin (9), 6-prenylquercetin (10), 6-prenylnaringenin (11), 3'-prenylnaringenin (12), sigmoidin C (13), 8-[(E)-3-hydroxymethyl-2- butenyl]-eriodictyol (14), and quercetin-3-Me ether (15). Most of these chemical constituents inhibited α-glucosidase activity, with the two prenylated quercetin derivatives (9 to 10) being the greatest active (IC50 < 4.0 µg/mL). Compounds 1, 3 to 4, 6 to 7, 9 to 12 impeded the growth of human hepatic stellate cells, with the prenylated flavonoids (6 to 7, 9 to 12) being more robust than their unprenylated counterparts. PRACTICAL APPLICATIONS: This study found that Glycyrrhiza uralensis leaves contain prenylated dihydrostilbenes and flavonoids with inhibiting effects on α-glucosidase and on the proliferation of human hepatic stellate cells, which should prompt the development of G. uralensis leaves for healthy products with anti-diabetic or liver fibrosis-preventing effects.

Background: Approximately 70% patients with acute myocardial infarction (AMI) presented without ST-segment elevation on electrocardiogram. Patients with non-ST segment elevation myocardial infarction (NSTEMI) often presented with atypical symptoms, which may be related to pre-hospital delay and increased risk of mortality. However, up to date few studies reported detailed symptomatology of NSTEMI, particularly among Asian patients. The objective of this study was to describe and compare symptoms and presenting characteristics of NSTEMI vs. STEMI patients. Methods: We enrolled 21,994 patients diagnosed with AMI from China Acute Myocardial Infarction (CAMI) Registry between January 2013 and September 2014. Patients were divided into 2 groups according to ST-segment elevation: ST-segment elevation (STEMI) group and NSTEMI group. We extracted data on patients’ characteristics and detailed symptomatology and compared these variables between two groups. Results: Compared with patients with STEMI (N= 16,315), those with NSTEMI (N= 5679) were older, more often females and more often have comorbidities. Patients with NSTEMI were less likely to present with persistent chest pain (54.3% vs. 71.4%), diaphoresis (48.6% vs. 70.0%), radiation pain (26.4% vs. 33.8%), and more likely to have chest distress (42.4% vs. 38.3%) than STEMI patients (all P < 0.0001). Patients with NSTEMI were also had longer time to hospital. In multivariable analysis, NSTEMI was independent predictor of presentation without chest pain (odds ratio: 1.974, 95% confidence interval: 1.849–2.107). Conclusions: Patients with NSTEMI were more likely to present with chest distress and pre-hospital patient delay compared with patients with STEMI. It is necessary for both clinicians and patients to learn more about atypical symptoms of NSTEMI in order to rapidly recognize myocardial infarction. Trial Registration: www.clinicaltrials.gov (No. NCT01874691). Key words: Non-ST segment elevation myocardial infarction; Symptom assessment; Time to treatment

Quantitative magnetic resonance image (MRI) in individual muscles may be useful for monitoring disease progression in Duchenne muscular dystrophy (DMD). The purpose of this study was to measure T2 relaxation time of thigh muscles in children with DMD and healthy boys, and to correlate the T2 relaxation time of muscles with the fat fraction (FF) at quantitative magnetic resonance and results of clinical assessment. Thirty-two boys with DMD and 18 healthy boys were evaluated with T2 mapping and three-point Dixon MRI. Age, body mass index (BMI), muscle strength assessment, timed functional tests (time to walk or run 10 metres, rise from the floor and ascend four stairs), and the North Star Ambulatory Assessment (NSAA) were evaluated. Spearman's correlation was used to assess the relationships between FF and clinical assessments and T2 relaxation time. The mean T2 relaxation time of thigh muscles in DMD was significantly longer than that in the control group (P

International audience; Background Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data. Objective The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates. Methods Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods. Results The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods. Conclusion A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data. Bo-Hao Tang and Zheng Guan contributed equally to this work.

BackgroundHypothermia is a common problem that is associated with increased mortality and morbidity among preterm infants, especially in China. The objective of this study was to evaluate the efficacy of a targeted quality improvement (QI) project that applied hypothermia prevention measures for very-low-birth-weight (VLBW) infants in three tertiary neonatal intensive care units (NICUs) in China.ProblemBetween January 2018 and December 2018, we conducted a prospective analysis and found that the incidence of AH was 88.2% among VLBW infants.MethodsThe study enrolled preterm infants born at less than 32 weeks’ gestation with a VLBW of less than 1500 g who were delivered at three academic tertiary-care hospitals between January 2018 and December 2019. The primary outcome measure was the incidence of hypothermia. The outcomes of the pre-QI group (1 January–31 December 2018) were compared with those of the post-QI group (1 January–31 December 2019).InterventionsBased on the literature, our preliminary findings and the needs of each unit, a temperature bundle that included a transport incubator, prewarmed hats, polyethylene wrap, team training and education, and temperature documentation and workflows were implemented in consecutive plan–do–study–act cycles.ResultsOf the 530 VLBW infants, 235 infants (36.9%) belonged to the pre-QI group, and 295 infants (46.4%) belonged to the post-QI group. The incidence of hypothermia decreased significantly, from 92.3% to 62% (pConclusionsTargeted interventions can dramatically reduce admission hypothermia and improve the outcome of VLBW infants in China.Trial registration numberChi CTR 1900020861.

Bacillus velezensis is widely used for agricultural biocontrol, due to its ability to enhance plant growth while suppressing the growth of microbial pathogens. However, there are few reports on its application in fermented feed. Here, a two-stage solid-state fermentation process using Bacillus velezensis followed by Lactobacillus plantarum was developed to degrade antinutritional factors (ANFs) and improve soybean meal (SBM) nutrition for animal feed. The process was evaluated for performance in degrading SBM antinutritional factors, dynamic changes in physicochemical characteristics, microorganisms and metabolites. After two-stage fermentation, degradation rates of glycinin and β-conglycinin contents reached 78.60% and 72.89%, respectively. The pH of fermented SBM (FSBM) decreased to 4.78 ± 0.04 and lactic acid content reached 183.38 ± 4.86 mmol/kg. NSP-degrading enzymes (Non-starch polysaccharide, NSPases) and protease were detected from the fermented product, which caused the changed microstructure of SBM. Compared to uninoculated SBM, FSBM exhibited increased proportions of crude protein (51.97 ± 0.44% vs. 47.28 ± 0.34%), Ca, total phosphorus (P), and trichloroacetic acid-soluble protein (11.79 ± 0.13% vs. 5.07 ± 0.06%). Additionally, cellulose and hemicellulose proportions declined by 22.10% and 39.15%, respectively. Total amino acid content increased by 5.05%, while the difference of AA content between the 24 h, 48 h and 72 h of fermentation was not significant (P > 0.05). Furthermore, FSBM also showed antibacterial activity against Staphylococcus aureus and Escherichia coli. These results demonstrated that two-stage SBM fermentation process based on Bacillus velezensis 157 and Lactobacillus plantarum BLCC2-0015 is an effective approach to reduce ANFs content and improve the quality of SBM feed.

The huge volumes of spatial-temporal maritime traffic data that is currently being accumulated from the Automatic Identification System (AIS) can open the path for smart decision-making and facilitate a number of intelligent applications including ship movements tracking, route patterns extraction, operations and next event prediction, trade and cargo flow, etc. However, it is very challenging to store, transfer, and load such large volumes of spatial-temporal data. Pre-analysis is essential before extracting spatial and temporal relationships in maritime traffic data, in which data variability, inconsistent data quality, and computational complexity demanded by various applications can pose additional constraints. In this chapter, we first briefly review maritime traffic surveillance systems for spatial-temporal data collection. Then we present a computational framework to efficiently compress, transfer, and acquire necessary information for the further analysis of large-scale AIS data to empower relevant applications in the maritime sector. The framework is composed of two parts: the first is a lossless compression algorithm that compresses the AIS data into binary form for efficient storage, speedy access, and easy transfer across networks and systems within the organization; the second is an aggregation algorithm which derives movement and activity information of vessels grouped by grid and/or time window from the compressed binary files. The aggregation algorithm compresses and organizes data by vessel identity (ID), thereby improving accessibility and reducing storage demand. Finally, a use case of maritime big data intelligent surveillance is briefly described.

In this study, multi-layer scheduling optimization algorithms are proposed and validated based on historical vessel operation data in maritime terminals. The most relevant KPIs are average wait time, average turnaround time and berth occupancy rate presented in this study. Through the proposed optimization algorithms, the results shown that average wait time and turnaround time are significantly reduced with increasing of randomness threshold, which is a threshold to allow reschedules to buffer terminals. The average wait time and turnaround time are shortened by around 27.30 hrs (by 39.06%) and 39.41 hrs (by 27.18%), respectively. The berth occupancy rate of less utilized buffer terminals is also improved from 21.39% to 38.35%.

Carbapenem-resistant enterobacteriaceae (CRE) bloodstream infections have been rapidly spreading worldwide with a high mortality and pose a challenge to therapeutic decision-making, especially in premature neonates because insufficient empirical antimicrobial therapy is independently associated with high mortality. This case reported that a premature infant with CRE bloodstream infection was treated successfully with high-dose meropenem treatment with model-based therapeutic drug monitoring (TDM). In clinical settings, treatment target attainment of meropenem can be improved by increasing the frequency of administration, prolonging the infusion time, and using a high dose. This case report shows a successful regimen for CRE infection in a premature neonate and emphasizes the utility of model-based TDM of high-dose meropenem treatment. The adequate antimicrobial benefit provided by innovative techniques could ensure the efficacy and safety of high-dose meropenem therapy for CRE infection.

The effects of Liuwei Dihuang pill (LWDH) on diabetic nephropathy-related osteoporosis (DNOP) are unclear. The present study aimed to evaluate the effects of LWDH on KDM7A and Wnt/β-catenin signaling pathway in DNOP rats and the high glucose-induced MC3T3-E1 cells. A DNOP model was prepared by streptozotocin in 9-week-old male Sprague-Dawley (SD) rats to evaluate the effects of LWDH. The cell viability and differentiation capacity of high glucose-induced MC3T3-E1 cells were determined by CCK-8 assay, Alizarin Red staining, and alkaline phosphatase (ALP) staining, respectively. Furthermore, the expressions of KDM7A and Wnt1/β-catenin pathway-related proteins were determined by Western blot analysis. Treatment of DNOP rats with LWDH could significantly ameliorate the general state, degradation of renal function, and renal pathological changes. LWDH decreased the levels of TNF-α, IL-6, IL-8, IL-1β, ALP, and TRAP, and increased the calcium, phosphorus in serum, as well as decreased the level of the calcium and phosphorus in the urine. Besides, LWDH significantly improved bone mineral density (BMD), bone volume (BV), and the bone microstructure of DNOP rats. Moreover, LWDH increased the levels of the elastic modulus, ultimate load, and bending strength in the femurs. In MC3T3-E1 cells, serum-containing LWDH significantly increases in cell viability and osteoblastic differentiation capability. The expression of α-SMA, vimentin, KDM7A, Wnt1 and β-catenin were significantly down-regulated, and the E-cadherin, H3K9-Me2, H3K27-Me2, BMP-4, BMP-7, Runx2, osteocalcin, and Col1a1 were significantly up-regulated with LWDH treatment. The present study shows that LWDH has a therapeutic effect on DNOP, in part, through down-regulation of KDM7A and Wnt/β-catenin pathway.

Background: Diabetic nephropathy-related osteoporosis (DNOP) is the most common comorbid bone metabolic disorder associated with diabetes mellitus (DM). The Liuwei Dihuang Pill (LWD) is a traditional Chinese herbal medicine widely used to treat diabetic complications, including diabetic nephropathy (DN). This study aimed to identify the biomarkers of the mechanisms of DNOP in LWD with systems biology approaches. Methods: Herein, we performed an integrated analysis of the GSE51674 and GSE63446 datasets from the GEO database via weighted gene co-expression network and network pharmacology (WGCNA) analysis. In addition, a network pharmacology approach, including bioactive compounds, was used with oral bioavailability (OB) and drug-likeness (DL) evaluation. Next, target prediction, functional enrichment analysis, network analysis, and virtual docking were used to investigate the mechanisms of LWD in DNOP. Results : WGCNA successfully identified 63 DNOP-related miRNAs. Among them, miR-574 was significantly upregulated in DN and OP samples. A total of 117 targets of 22 components associated with LWD in DNOP were obtained. The cellular response to nitrogen compounds, the AGERAGE signaling pathway in diabetic complications, and the MAPK signaling pathway were related to the main targets. Network analysis showed that kaempferol and quercetin were the most significant components. MAPK1 was identified as a potential target of miR-574 and the hub genes in the protein-protein interaction (PPI) network. The docking models demonstrated that kaempferol and quercetin had a strong binding affinity for Asp 167 of MAPK1. Conclusion: This study demonstrated that miR-574 may play important roles in DNOP, and the therapeutic effects of kaempferol and quercetin on LWD in DNOP might be mediated by miR-574 by targeting MAPK1. Our results provide new perspectives for further studies on the anti-DNOP mechanism of LWD.

Dengue has been as an endemic with year-round presence in Singapore. In the recent years 2013, 2014, and 2016, there were several severe dengue outbreaks, posing serious threat to the public health. To proactively control and mitigate the disease spread, early warnings of dengue outbreaks, at which there are rapid and large-scale spread of dengue incidences, are extremely helpful. In this study, a two-step framework is proposed to predict dengue outbreaks and it is evaluated based on the dengue incidences in Singapore during 2012 to 2017. First, a generalized additive model (GAM) is trained based on the weekly dengue incidence data during 2006 to 2011. The proposed GAM is a one-week-ahead forecasting model, and it inherently accounts for the possible correlation among the historical incidence data, making the residuals approximately normally distributed. Then, an exponentially weighted moving average (EWMA) control chart is proposed to sequentially monitor the weekly residuals during 2012 to 2017. Our investigation shows that the proposed two-step framework is able to give persistent signals at the early stage of the outbreaks in 2013, 2014, and 2016, which provides early alerts of outbreaks and wins time for the early interventions and the preparation of necessary public health resources. In addition, extensive simulations show that the proposed method is comparable to other potential outbreak detection methods and it is robust to the underlying data-generating mechanisms.