Li13YGe4O16: A Mid-infrared Rare-Earth Germanate Nonlinear Optical Crystal Featuring a Broad Transmission Range and an Enlarged Band Gap.

Germanate is garnering increasing attention in the field of optoelectronics owing to its competitive optical transparency and robust stability. Herein, a novel lithium-rich rare-earth germanate, Li13YGe4O16, was fabricated for the first time using a high-temperature solution approach. This compound adopts the asymmetric space group Cmc21 (no. 36), characterized by isolated [YO6] and [GeO4] structural motifs with Li+ cations located in the channel. Notably, Li13YGe4O16 presents a short ultraviolet cutoff edge at 240 nm, indicative of an enlarged band gap of 4.96 eV and showcases a wide mid-infrared transmission region exceeding 6.0 µm. Moreover, Li13YGe4O16 features exceptional thermal stability and moderate second harmonic generation (SHG) intensity. Additionally, a theoretical analysis suggests that the distorted [YO6] octahedra. [GeO4] and [LiO4] tetrahedra play a significant role in the optical activities of Li13YGe4O16. These attributes endow Li13YGe4O16 with the potential to serve as a new mid-IR nonlinear optical (NLO) crystal and enrich the structural chemistry of germanates.

Comparative safety assessment of nasogastric versus nasojejunal feeding initiated within 48 hours post-admission versus unrestricted timing in moderate or severe acute pancreatitis: a systematic review and meta-analysis.

BACKGROUND: The primary objective of this study is to comparatively assess the safety of nasogastric (NG) feeding versus nasojejunal (NJ) feeding in patients with acute pancreatitis (AP), with a special focus on the initiation of these feeding methods within the first 48 h of hospital admission. METHODS: Studies were identified through a systematic search in PubMed, EMbase, Cochrane Central Register of Controlled Trials, and Web of Science. Four studies involving 217 patients were included. This systematic review assesses the safety and efficacy of nasogastric versus nasojejunal feeding initiated within 48 h post-admission in moderate/severe acute pancreatitis, with a specific focus on the timing of initiation and patient age as influential factors. RESULTS: The results showed that the mortality rates were similar between NG and NJ feeding groups (RR 0.86, 95% CI 0.42 to 1.77, P = 0.68). Significant differences were observed in the incidence of diarrhea (RR 2.75, 95% CI 1.21 to 6.25, P = 0.02) and pain (RR 2.91, 95% CI 1.50 to 5.64, P = 0.002) in the NG group. The NG group also showed a higher probability of infection (6.67% vs. 3.33%, P = 0.027) and a higher frequency of multiple organ failures. Subgroup analysis for early intervention (within 48 h) showed a higher risk of diarrhea in the NG group (RR 2.80, P = 0.02). No significant differences were found in the need for surgical intervention, parenteral nutrition, or success rates of feeding procedures. CONCLUSION: This meta-analysis highlights the importance of considering the method and timing of nutritional support in acute pancreatitis. While NG feeding within 48 h of admission increases the risk of certain complications such as diarrhea and infection, it does not significantly impact mortality or the need for surgical intervention.

Characteristics and correlation of body fat distribution and brachial-ankle pulse wave velocity in adults aged 20-59 years: a cross-sectional study.

BACKGROUND: Fat distribution is closely related to vascular stiffness. This study aimed to investigate age and sex differences in fat distribution and brachial-ankle pulse wave velocity (baPWV), and the association between fat parameters and baPWV. METHODS: A total of 10,811 participants aged 20-59 years were recruited. Measures included waist and hip circumference, waist-to-hip ratio (WHR), body mass index (BMI), percentage body fat (PBF), subcutaneous fat area (SFA), visceral fat area (VFA), and baPWV. RESULTS: The results confirm that fat accumulates with age and that men tend to carry more abdominal fat than women in the same age group. The findings also indicate that baPWV increases with age and is significantly higher in men than in women in the same age group. In addition, WHR, VFA, and baPWV were more strongly correlated than baPWV and BMI, SFA, and PBF. Finally, the effects of age, PBF, WHR, and VFA on baPWV were greater for the higher quantiles. CONCLUSIONS: There are age and sex differences in fat distribution and baPWV. Abdominal obesity is more closely linked to arterial stiffness than overall obesity, and people with higher baPWV are more affected by obesity parameters.

ADAMDEC1 induces EMT and promotes colorectal cancer cells metastasis by enhancing Wnt/ß-catenin signaling via negative modulation of GSK-3ß.

Colorectal cancer (CRC) is a highly invasive malignant tumor with pronounced proliferation capacity and is prone to epithelial-mesenchymal transition (EMT) and subsequent metastasis. A disintegrin and metalloproteinase domain-like decysin 1 (ADAMDEC1) is a proteolytically active metzincin metalloprotease that is involved in extracellular matrix remodeling, cell adhesion, invasion, and migration. However, the effects of ADAMDEC1 on CRC are unclear. This study was conducted to investigate the expression and biological role of ADAMDEC1 in CRC. We found that ADAMDEC1 was differentially expressed in CRC. Further, ADAMDEC1 was found to enhance CRC proliferation, migration, and invasion while inhibiting apoptosis. Exogenous ADAMDEC1 overexpression elicited EMT in CRC cells, as evidenced by alterations in E-cadherin, N-cadherin, and vimentin expression. In ADAMDEC1 knockdown or ADAMDEC1 overexpressed CRC cells, the western blotting analysis revealed that Wnt/ß-catenin signaling pathway-related proteins were down-regulated or up-regulated. Furthermore, an inhibitor of the Wnt/ß-catenin pathway (FH535) partially negated the effect of ADAMDEC1 overexpression on EMT and CRC cell proliferation. Further mechanistic research suggested that ADAMDEC1 knockdown may upregulate GSK-3ß and inactivate the Wnt/ß-catenin pathway, accompanied by suppressing the expression of ß-catenin. Additionally, the blocker of GSK-3ß (CHIR-99021) markedly abolished the inhibitory effect of ADAMDEC1 knockdown on Wnt/ß-catenin signaling. Our results indicate that ADAMDEC1 promotes CRC metastasis by negatively regulating GSK-3ß, activating the Wnt/ß-catenin signaling pathway, and inducing EMT, presenting its potential as a therapeutic target for the treatment of metastatic CRC.

Genome-wide identification and molecular characterization of the AP2/ERF superfamily members in sand pear (Pyrus pyrifolia).

BACKGROUND: 'Whangkeumbae' (Pyrus pyrifolia) is a typical climacteric fruit variety of sand pear with excellent taste. However, the rapid postharvest ethylene production limits the shelf life of 'Whangkeumbae' fruit. AP2/ERF superfamily is a large family of transcription factors involved in plant growth and development, including fruit ripening and senescence through the ethylene signaling pathway. The numbers and functions of AP2/ERF superfamily members in sand pear remain largely unknown. RESULTS: In this study, a total of 234 AP2/ERF family members were identified through the transcriptome of Pyrus pyrifolia 'Whangkeumbae' (17 genes) and Pyrus pyrifolia genome (223 genes) analyses. Six genes (Accession: EVM0023062.1, EVM0034833.1, EVM0027049.1, EVM0034047.1, EVM0028755.1, EVM0015862.1) identified via genome analysis shared 100% identity with PpERF14-L, PpERF5-L, PpERF3a, PpERF3, PpERF017 and PpERF098, respectively, which were identified from transcriptome sequencing. Further, the AP2/ERF superfamily members were divided into AP2, ERF, and RAV subfamilies, each comprising 38, 188, and 8 members, respectively. Tissue-specific expression analysis showed that PpERF061, PpERF113, PpERF51L-B, PpERF5-L, and PpERF017 were predominantly expressed in fruits than in other tissues. Additionally, PpERF5-L and PpERF017 showed higher expressions at the early stage of fruit development. While, PpERF51B-L exhibited higher expression during the fruit ripening stage. Besides, PpERF061 and PpERF113 had pronounced expressions during fruit senescence. CONCLUSION: These results indicate that PpERF061, PpERF113, PpERF51L-B, PpERF5-L, and PpERF017 could play crucial roles in sand pear fruit development, ripening, and senescence. Overall, this study provides valuable information for further functional analysis of the AP2/ERF genes during fruit ripening and senescence in sand pear.

Ultra-compact and ultra-broadband arbitrary-order silicon photonic multi-mode converter designed by an intelligent algorithm.

Multi-mode converters, which can achieve spatial mode conversion in multimode waveguide, play a key role in multi-mode photonics and mode-division multiplexing (MDM). However, rapid design of high-performance mode converters with ultra-compact footprint and ultra-broadband operation bandwidth is still a challenge. In this work, through combining adaptive genetic algorithm (AGA) and finite element simulations, we present an intelligent inverse design algorithm and successfully designed a set of arbitrary-order mode converters with low excess losses (ELs) and low crosstalk (CT). At the communication wavelength of 1550 nm, the footprint of designed TE0-n (n = 1, 2, 3, 4) and TE2-n (n = 0, 1, 3, 4) mode converters are only 1.8 × 2.2 µm2. The maximum and minimum conversion efficiency (CE) is 94.5% and 64.2%, and the maximum and minimum ELs/CT are 1.92/-10.9 dB and 0.24/-20 dB, respectively. Theoretically, the smallest bandwidth for simultaneously achieving ELs ≤ 3 dB and CT ≤ -10 dB exceeds 70 nm, which can be as large as 400 nm for the case of low-order mode conversion. Moreover, the mode converter in conjunction with a waveguide bend allows for mode-conversion in ultra-sharp waveguide bends, significantly increasing the density of on-chip photonic integration. This work provides a general platform for the realization of mode converters and has good prospect in application of multimode silicon photonics and MDM.

All-silicon polarization-independent broadband achromatic metalens designed for the mid-wave and long-wave infrared.

Metasurfaces demonstrate excellent capabilities in manipulating the phase, amplitude and polarization of light. Metalens, as a typical kind of metasurface devices, shows great prospect in simplifying imaging systems. However, like diffractive optical elements, intrinsic dispersion of metasurfaces is high. Thus, significant chromatic aberration is present in common metalenses, deteriorating imaging quality under broadband illumination condition and limiting their applications. To tackle this problem, broadband achromatic metalenses have been proposed and demonstrated in the visible and near-infrared wavelength regions so far. However, broadband achromatic metalens working in the mid-wave and long-wave infrared is still rare. In this paper, thanks to the ingenious design of meta-units that provide the required local phase and phase dispersion, several all-silicon broadband achromatic metalenses working in the mid-wave infrared (3-5 µm) or long-wave infrared (8-14 µm) wavelengths are proposed. Numerical simulation results demonstrate that the designed broadband achromatic metalenses can provide a near-constant focal length with small deviations and an average focusing efficiency of about 70% over the whole operation bandwidths. In addition, these metalenses hold near diffraction-limited focusing capability and polarization-independent focusing features. The achromatic metalenses proposed here are beneficial for improving imaging quality under broadband illumination and increasing detection efficiency of mid-wave and long-wave infrared detection systems.

Bow Hunter's syndrome combined with ipsilateral vertebral artery dissection/pseudoaneurysm: case study and literature review.

BACKGROUND: Bow hunter's syndrome (BHS), also known as rotational vertebral artery occlusion syndrome, is rare. Occasionally, it combines with dissection/pseudoaneurysm of the ipsilateral VA. METHODS: We report a case of BHS combined with ipsilateral VA dissection/pseudoaneurysm and review eight similar cases reported in the literature. Their aetiology, clinical and imaging features, treatment, and prognosis were analysed. RESULTS: Nine patients (seven male, two female; average age 22.0 ± 4.5 years) were enrolled. Visual symptoms comprised the most common clinical finding (66.7%, 7/9). Clinical symptoms were not related to neck rotation in seven patients (77.8%). Eight patients (88.9%) had multiple, scattered, new and old infarctions of the posterior circulation revealed on computed tomography/magnetic resonance imaging (CT/MRI) scans. Dissection/pseudoaneurysm was found in the ipsilateral VA - usually subtle and localised in the atlas, axis, and occipital bone - in all nine patients. Seven patients (66.7%) had special causes for the syndrome (i.e. congenital bone dysplasia). Altogether, 87.5% (7/8) experienced recurrence with cerebral infarction after antithrombotic therapy alone. Aetiologically targeted treatment, including surgical decompression or vertebral fixation, was performed in seven patients (77.8%). CONCLUSION: Young patients presenting with cryptogenic stroke in the posterior circulation and localised, subtle dissection/pseudoaneurysm of the ipsilateral VA around the atlanto-axial joint should undergo carotid ultrasonography with a neck rotation test or dynamic CT angiography/MR angiography/digital subtraction angiography, if necessary, to rule out/diagnose BHS.

Screening of Active Ingredients from Wendan Decoction in Alleviating Palmitic Acid-Induced Endothelial Cell Injury.

(1) Objective: Traditional Chinese medicine (TCM) plays an important role in the treatment of numerous illnesses. As a classic Chinese medicine, Wendan Decoction (WDD) encompasses a marvelous impact on the remedy of hyperlipidemia. It is known that hyperlipidemia leads to cardiovascular injury, therefore anti-vascular endothelial cell injury (AVECI) may be an underlying molecular mechanism of WDD in the cure of hyperlipidemia. However, there is no relevant research on the effect of WDD on vascular endothelial cells and its pharmacodynamic substances. Therefore, the purpose of this study was to investigate the protective effect of WDD on vascular endothelial cells. (2) Methods: The chemical constituents of WDD were determined by LC-MS/MS technology. The protective effects of 16 batches of WDD on samples from human umbilical vein endothelial cells (HUVECs) were evaluated. Finally, gray relation analysis (GRA) and partial least squares regression (PLSR) were used to analyze the potential correlation between chemical ingredients and AVECI. (3) Results: The results indicated that WDD had apparent protective effect on endothelial cells, and pharmacological properties in 16 batches of WDD tests were apparently discrepant. The GRA and PLSR showed that trigonelline, liquiritin, hesperidin, hesperetin, scopoletin, morin, quercetin, isoliquiritigenin, liquiritigenin and formononetin may be the active ingredients of AVECI in WDD. (4) Conclusions: WDD has a protective effect on endothelial cell injury induced by palmitic acid, which may be related to its component content. This method was suitable for the search of active components in classical TCM.

Factors associated with lack of tracheal sealing by a cuff inflated to more than 30 cmH2O during mechanical ventilation: A cross-sectional study.

Objectives: The cuff pressures > 30 cmH2O may create a seal in the trachea. The objective of this study was to identify risk factors associated with lack of tracheal sealing by an endotracheal cuff inflated to > 30 cmH2O in patients undergoing mechanical ventilation. Methods: This prospective cross-sectional study was conducted from 2019 to 2020 in the cardiothoracic intensive care unit and respiratory medical care unit of a Hospital in Nantong, China. Patients aged >16 years undergoing cardiothoracic surgery with mechanical ventilation using endotracheal intubation were included. Patient characteristics and ventilator parameters were analyzed. Cuff pressure was maintained with the minimum leak technique (MLT) and measured with a cuff pressure gauge. Cuff pressure was measured for 30 seconds when ventilation was accompanied by no leak, simultaneously detected by the ventilator or auscultation with a stethoscope. Result: Of 352 patients undergoing mechanical ventilation, 51 patients (14.5%) had a cuff pressure of >30 cmH2O. Multivariable analysis showed that cuff manufacturer (Guangzhou Weili) and nasal endotracheal intubation significantly increased the risk of an unsealed trachea. Peak inspiratory pressure, cuff diameter and male sex had a strong inverse association with an unsealed trachea. Conclusions: These findings suggest that an endotracheal cuff pressure of 20 to 30 cmH2O is adequate for most patients, but lack of a tracheal seal still occurs in a small number of people. An unsealed trachea is most likely because cuff and tracheal diameters do not match. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx Unique identifier: ChiCTR-COC-15006459.

Grading of endocervical adenocarcinoma: a novel prognostic system based on tumor budding and cell cluster size.

A novel 3-tiered grading system based on tumor budding activity and cell nest size has been validated to be highly prognostic in organ-wide squamous cell carcinomas. In this study, we applied a similar grading system with slight modification to assess the prognostic value in an institutional cohort of well annotated endocervical adenocarcinomas (EAC) consisting of 398 consecutive cases with surgical resection, no neoadjuvant chemotherapy, and higher than stage pT1a. Each case was reviewed by the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and Silva pattern classification, and scored on tumor budding activity and cell cluster size to form the basis of a novel grading system. High budding activity, small tumor cell cluster size, and novel grade 3 were more frequently associated with a decreased overall survival time and tumor recurrence time (p < 0.001), and several other clinicopathologic factors including HPV-independent adenocarcinoma, lymphovascular invasion, lymph node metastasis, advanced FIGO stage, and Silva pattern C (p < 0.05). Moreover, the novel grading system was helpful in stratifying overall survival in HPV-associated adenocarcinoma (p = 0.036) and gastric-type adenocarcinoma (p = 0.033). On multivariate analysis, novel grade 3 was an adverse indicator for overall survival and tumor recurrence independently of age and FIGO stage (p < 0.05). By comparison, Silva pattern C was only associated with tumor relapse (p = 0.020) in HPV-associated adenocarcinomas whereas the conventional FIGO system was not associated with overall survival and tumor recurrence in EAC (p > 0.05). In conclusion, our study demonstrates that the grading system based on tumor budding activity and cell cluster size is robust in prognostic assessment that outperforms the conventional FIGO grading and Silva pattern classification in EAC. The novel grading system, if further validated, could be applicable in routine pathologic descriptions of EAC by providing useful information in clinical decision-making.

Optimal dose of meropenem for the treatment of neonatal sepsis: Dosing guideline variations and clinical practice deviations.

AIMS: 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. METHODS: 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. RESULTS: Two guidelines and two labels were included in the Monte Carlo simulations. For 70% fT>MIC (fraction of time when the free meropenem concentration exceeded the minimum inhibitory concentration during the dosing interval), the probability of target attainment of four recommended doses ranged from 59% to 88% (MIC = 2 mg·L-1 ) and from 17% to 47% (MIC = 8 mg·L-1 ). At the clinical practice evaluation, only 20% of patients attained target exposure for the MIC of 8 mg·L-1 with 70% fT>MIC , which was much less than those found in the Food and Drug Administration labels (40%). CONCLUSION: This 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.

Clinical utiliy of a model-based piperacillin dose in neonates with early-onset sepsis.

AIMS: Early-onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for EOS treatment without clinically validated dosing regimens, although the population pharmacokinetics (PPK) of piperacillin in neonates has been reported. Therefore, we wanted to study the effectiveness and tolerance of a PPK model-based dosing regimen of piperacillin/tazobactam in EOS patients. METHODS: A prospective, single-centre, phase II clinical study of piperacillin/tazobactam in neonates with EOS was conducted. The dosing regimen (90 mg·kg-1 , q8h) was determined based on a previous piperacillin PPK model in young infants using NONMEM v7.4. The pharmacodynamics (PD) target (70%fT > MIC, free drug concentration above MIC during 70% of the dosing interval) attainment was calculated using NONMEM combined with an opportunistic sampling design. The clinical treatment data were collected. RESULTS: A total of 52 neonates were screened and 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis. The median (range) values of postmenstrual age were 33.57 (range 26.14-41.29) weeks. Forty-seven (96%) neonates reached their PD target. Eight (16%) neonates experienced treatment failure clinically. The mean (SD, range) duration of treatment and length of hospitalization were 100.1 (62.2, 36.2-305.8) hours and 31 (30, 5-123) days. There were no obvious adverse events and no infection-related deaths occurred in the first month of life. CONCLUSIONS: A model-based dosing regimen of piperacillin/tazobactam was evaluated clinically, was tolerated well and was determined to be effective for EOS treatment.

Ovarian Metastasis by Gastric-type Endocervical Adenocarcinoma: A Clinicopathologic Description of 12 Cases.

Cervical gastric-type adenocarcinoma has a propensity for ovarian metastasis, but the clinicopathologic findings and possible routes of tumor spread have not been well characterized to date. To address these points, we reported 12 cervical gastric-type adenocarcinomas with ovarian metastases from a single institution. Seven patients with gastric-type adenocarcinoma had concurrent endometrial fallopian tube involvement, 5 of which showed tumors confined to the fallopian tube mucosa. Two of these 5 patients died of disease at 2 and 16 mo, and 1 recurred at 18 mo. In the remaining 5 patients, 3 had wide pelvic/peritoneal spread while the other 2 showed no evidence of uterine or tubal involvement. Among them, 1 died of disease at 94 mo, and another relapsed at 20 mo. Morphologically, ovarian tumors frequently had surface involvement consistent with metastasis, but also mimicked a primary tumor with a mixture of benign/borderline/intraepithelial carcinoma-like areas, as well as carcinoma with expansile or destructive stromal invasion. The tubal lesions were predominantly in the form of mucosal colonization without invasion of the underlying structures. Block p16 and high-risk human papillomavirus mRNA signals were not detected in cervical gastric-type adenocarcinomas and ovarian metastatic tumors. We conclude that fallopian tube spread may be associated with ovarian metastasis of cervical gastric-type adenocarcinomas that have bad clinical outcomes. Ovarian involvement may be a part of the aggressive nature of these tumors.

Progress of triazole antifungal agent posaconazole in individualized therapy.

WHAT IS KNOWN AND OBJECTIVE: Posaconazole is the second-generation triazole antifungal agent with widespread clinical application. Posaconazole exposure is influenced by various factors such as drug interactions, disease state and diet, resulting in a high interindividual variability in many patients and failure to ensure therapeutic efficacy. Therefore, it is necessary to conduct individualized therapy on posaconazole to ensure the efficacy and safety of treatment. METHODS: Articles were identified through PubMed using the keywords such as "posaconazole," "therapeutic drug monitoring" and "Population pharmacokinetics" from 1 January 2001 to 30 April 2022. RESULTS AND DISCUSSION: In this paper, we review the individualized treatment studies of posaconazole from the three aspects of therapeutic drug monitoring, population pharmacokinetic study and Monte Carlo simulation to provide reference for in-depth individualized posaconazole dosing studies. WHAT IS NEW AND CONCLUSION: This review suggests that therapeutic drug monitoring should be performed in patients taking posaconazole to adjust the dosage and assess the efficacy and cost-effectiveness of posaconazole under different clinical conditions and different dosing regimens through Monte Carlo simulations. In the future, a more detailed delineation and comprehensive examination of posaconazole PPK for specific populations requires further study.

CRISPR-based RNA-binding protein mapping in live cells.

RNA-binding proteins (RBPs) are involved in all aspects of RNA metabolism, and RNA-RBP interactions are important for cell homeostasis and viral replication. The global RNA-binding proteome was recently reported; however, little is known about the proteins that bind to specific RNAs. In this study, we describe a novel CRISPR-based RNA interaction proteomics method in live cells. In brief, dCas13a with an HA tag was expressed in cells and bound to an RNA of interest with the help of gRNA. The RNA-protein complexes physically bound to dCas13a-HA were crosslinked using UV light and captured using anti-HA beads, after which the proteins were purified and identified using mass spectrometry. We optimized this system and subsequently applied it to U1 small nuclear RNA, which revealed 226 proteins.

Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study.

OBJECTIVES: Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS). METHODS: This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval ('70% fT>MIC')] and to investigate the tolerance and safety in neonates. RESULTS: A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7-41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3-41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin. CONCLUSIONS: Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.

miR-335-5p suppresses gastric cancer progression by targeting MAPK10.

BACKGROUND: Recent studies have established the roles of microRNAs (miRNAs) in cancer progression. The aberrant expression of miR-335-5p has been reported in many cancers, including gastric cancer (GC). In this study, the precise roles of miR-335-5p in GC as well as the molecular mechanisms underlying its effects, including the role of its target MAPK10, were evaluated. METHODS: Quantitative real-time PCR was used to evaluate miR-335-5p levels in GC cell lines and tissues. MTT and colony formation assays were used to detect cell proliferation, and Transwell and wound-healing assays were used to evaluate the invasion and migration of GC cells. The correlation between levels of miR-335-5p and the cell cycle-related target gene mitogen-activated protein kinase 10 (MAPK10) in GC was analyzed. In addition, the candidate target was evaluated by a luciferase reporter assay, qRT-PCR, and western blotting. RESULTS: The levels of miR-335-5p were downregulated in GC tissues and cell lines. Furthermore, miR-335-5p inhibited the proliferation and migration of GC cells and induced apoptosis. Additionally, miR-335-5p arrested the cell cycle at the G1/S phase in GC cells in vitro. Levels of miR-335-5p and the cell cycle-related target gene MAPK10 in GC were correlated, and MAPK10 was directly targeted by miR-335-5p. CONCLUSIONS: These data suggest that miR-335-5p is a tumor suppressor and acts via MAPK10 to inhibit GC progression.

Pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor in children with acute leukaemia.

AIMS: This open-label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for the treatment of chemotherapy-induced neutropenia in children with acute leukaemia. METHODS: PEG-rhG-CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG-rhG-CSF. PEG-rhG-CSF serum concentrations were determined by an enzyme-linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed-effects model. Short-term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360). RESULTS: A total of 16 acute leukaemia patients (1.8-13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG-rhG-CSF serum concentrations were obtainable. A one-compartment model with first-order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration-time curve (AUC) were 5.65 (1.49-14.45) mL/h/kg and 16514.75 (6632.45-54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG-rhG-CSF was "possible". CONCLUSIONS: The AUC of PEG-rhG-CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG-rhG-CSF (100 mcg/kg) in children with sarcoma. PEG-rhG-CSF is safe, representing an important therapeutic option for chemotherapy-induced neutropenia in paediatric patients with acute leukaemia.

Stereoselective environmental fate of fosthiazate in soil and water-sediment microcosms.

The stereoselective fates of chiral pesticides in the environment has been reported in many studies. However, there is little data focused on the fate of chiral fosthiazate in the soil and aquatic ecosystems at chiral view. This study investigated the stereoselective fate of fosthiazate in the soil and aquatic ecosystems using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and liquid chromatography tandem time-of-flight mass spectrometry (LC-TOF/MS/MS). Significant stereoselective degradation among four fosthiazate stereoisomers were found in both greenhouse soil and water-sediment microcosms. In greenhouse soil, (1R,3S)-fosthiazate degraded faster than other three stereoisomers with the half-life of 2.7 d. The fosthiazate stereisomers in the seawater-sediment microcosm degraded more rapidly than in the river water-sediment microcosm. However, (1S,3R)-fosthiazate and (1S,3S)-fosthiazate possessed shorter degradation half-lives than their enantiomers in both microcosms, with the half-lives ranging from 3.4 d to 15.8 d. Ten degradation products were identified in the water-sediment microcosms, and, six of them were reported for the first time. Oxidation and hydrolysis were confirmed as the main degradation pathways of fosthiazate in the water-sediment microcosms. Our results revealed that the (1R,3S)-fosthiazate and (1R,3R)-fosthiazate may cause more serious ecotoxicity due to the longer half-lives than the other two stereoisomers in environment.