Adaptive designs were primarily used but inadequately reported in early phase drug trials.

BACKGROUND: Faced with the high cost and limited efficiency of classical randomized controlled trials, researchers are increasingly applying adaptive designs to speed up the development of new drugs. However, the application of adaptive design to drug randomized controlled trials (RCTs) and whether the reporting is adequate are unclear. Thus, this study aimed to summarize the epidemiological characteristics of the relevant trials and assess their reporting quality by the Adaptive designs CONSORT Extension (ACE) checklist. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception to January 2020. We included drug RCTs that explicitly claimed to be adaptive trials or used any type of adaptative design. We extracted the epidemiological characteristics of included studies to summarize their adaptive design application. We assessed the reporting quality of the trials by Adaptive designs CONSORT Extension (ACE) checklist. Univariable and multivariable linear regression models were used to the association of four prespecified factors with the quality of reporting. RESULTS: Our survey included 108 adaptive trials. We found that adaptive design has been increasingly applied over the years, and was commonly used in phase II trials (n = 45, 41.7%). The primary reasons for using adaptive design were to speed the trial and facilitate decision-making (n = 24, 22.2%), maximize the benefit of participants (n = 21, 19.4%), and reduce the total sample size (n = 15, 13.9%). Group sequential design (n = 63, 58.3%) was the most frequently applied method, followed by adaptive randomization design (n = 26, 24.1%), and adaptive dose-finding design (n = 24, 22.2%). The proportion of adherence to the ACE checklist of 26 topics ranged from 7.4 to 99.1%, with eight topics being adequately reported (i.e., level of adherence ≥ 80%), and eight others being poorly reported (i.e., level of adherence ≤ 30%). In addition, among the seven items specific for adaptive trials, three were poorly reported: accessibility to statistical analysis plan (n = 8, 7.4%), measures for confidentiality (n = 14, 13.0%), and assessments of similarity between interim stages (n = 25, 23.1%). The mean score of the ACE checklist was 13.9 (standard deviation [SD], 3.5) out of 26. According to our multivariable regression analysis, later published trials (estimated ß = 0.14, p < 0.01) and the multicenter trials (estimated ß = 2.22, p < 0.01) were associated with better reporting. CONCLUSION: Adaptive design has shown an increasing use over the years, and was primarily applied to early phase drug trials. However, the reporting quality of adaptive trials is suboptimal, and substantial efforts are needed to improve the reporting.

The Polysaccharides from Pinellia ternata and Their Derivatives: Preparation, Structure Characteristics, and Activities in Vitro.

Three polysaccharides, PTC, PTH, and PTB, were extracted from Pinellia ternata using three different extraction conditions: room temperature water, hot water, and 2 % Na2CO3 solution. PTC and PTH were composed of rhamnose, glucose, galactose, mannose, glucuronic acid, galacturonic acid, and arabinose, which combine to form complex structures. PTB was composed solely of glucose and rhamnose. Further analysis indicated that PTC and PTB exhibited triple-helix structures. PTC showed the highest scavenging capacity against DPPH, superoxide anion, and hydroxyl radicals, with half maximal inhibitory concentrations (IC50) of 1004.1, 1584.1, and 1584.1 µg/mL, respectively. Additionally, PTC, PTH, and PTB were subjected to sulfation, phosphorylation, and selenization, resulting in the production of nine derivates. The distinctive absorptive bands of these derivates were determined through infrared spectroscopy. Selenized and sulfated derivates have shown significant antitumor and immunoenhancing properties. Our findings revealed that at 400 µg/mL, the inhibition rate of selenated PTB on HeLa cells was 54.2 % and that on HepG2 cells was 43.1 %. Additionally, selenized PTC displayed significant immunoenhancing activity, with a proliferation rate of 63.7 % at 400 µg/mL in RAW264.7 cells. These results provide valuable evidence supporting the consideration of polysaccharides from Pinellia ternata as a potential candidate for the development of antineoplastic drugs.

Electrophysiological and behavioral responses of Tamarixia radiata (Hymenoptera: Eulophidae) to volatiles of nymphal Diaphorina citri (Hemiptera: Liviidae).

Huanglongbing (HLB), a devastating citrus disease caused by Candidatus Liberibacter asiaticus, is efficiently vectored by the Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae). Tamarixia radiata (Waterston) plays a crucial role as an ectoparasitoid, preying on D. citri nymphs. By collecting and identifying headspace volatiles from fifth instar nymphs of D. citri using a gas chromatograph-mass spectrometer (GC-MS), we obtained a collection of 9 volatile compounds. These compounds were subsequently chosen to investigate the electrophysiological and behavioral responses of female T. radiata. At a concentration of 10 µg/µl, 9 compounds were compared with cis-3-hexen-1-ol (control), resulting in trans-2-nonenal inducing the highest relative electroantennogram (EAG) value, followed by hexanal, heptanal, n-heptadecane, tetradecanal, n-tetradecane, n-pentadecane, 1-tetradecanol, and 1-dodecanol. The top 5 EAG responses of female T. radiata to these compounds were further investigated through EAG dose-response experiments. The results showed positive dose-responses as concentrations increased from 0.01 to 10 µg/µl. In Y-tube olfactometer bioassays, female T. radiata exhibited a preference for specific compounds. They were significantly attracted to tetradecanal at a concentration of 10 µg/µl and trans-2-nonenal at 0.01 µg/µl, while no significant attraction was observed toward hexanal, heptanal, or n-heptadecane. Our report is the first to demonstrate that volatiles produced by D. citri nymphs attract T. radiata, which suggests that this parasitoid may utilize nymph volatiles to locate its host.

Joint toxicity of cadmium (II) and microplastic leachates on wheat seed germination and seedling growth.

Cadmium (Cd) pollution ranks first in soils (7.0%) and microplastics usually have a significant adsorption capacity for it, which could pose potential threats to agricultural production and human health. However, the joint toxicity of Cd and microplastics on crop growth remains largely unknown. In this study, the toxic effects of Cd2+ and two kinds of microplastic leachates, polyvinyl chloride (PVC) and low-density polyethylene (LDPE), on wheat seed germination and seedlings' growth were explored under single and combined conditions. The results showed that Cd2+ solution and two kinds of microplastic leachates stimulated the wheat seed germination process but inhibited the germination rate by 0-8.6%. The combined treatments promoted wheat seed germination but inhibited the seedlings' growth to different degrees. Specifically, the combination of 2.0 mg L-1 Cd2+ and 1.0 mgC L-1 PVC promoted both seed germination and seedlings' growth, but they synergistically increased the antioxidant enzyme activity of seedlings. The toxicity of the PVC leachate to wheat seedlings was stronger than LDPE leachate. The addition of Cd2+ could alleviate the toxicity of PVC leachate on seedlings, and reduce the toxicity of LDPE leachate on seedlings under the same concentration class combinations but aggravated stress under different concentration classes, consistent with the effect on seedlings' growth. Overall, Cd2+, PVC, and LDPE leachates have toxic effects on wheat growth, whether treated under single or combined treatments. This study has important implications for the joint toxicity of Cd2+ solution and microplastic leachates in agriculture.

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) Promoted N-Alkylation of Quinazolinones through Nucleophilic Substitution of Benzyl Alcohols.

We describe here a protocol for alkylation of quinazolinones with a series of primary or secondary alcohols under metal-free conditions. A class of quinazolinone derivatives were obtained in 31%-97% yield with good functional group tolerance. This protocol provides chemists a direct and effective way to obtain bioactive quinazolinone derivatives.

Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension.

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 µCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.

Individualized estimates of intensity-modulated radiotherapy plans after breast conservation surgery for left-sided breast cancer.

OBJECTIVES: The purpose of this study was to explore the influence of individual patient factors, such as volume of the planning target volume (PTV) (VPTV), cardiothoracic ratio (CTR), central lung distance (CLD), and maximal heart distance (MHD), on the design of treatment plans in terms of target dose coverage, integral dose, and dose to organs at risk (OAR) in early breast cancer. METHODS: Ninety-six patients were selected for this study. Radiation doses of 50 Gy and a simultaneous dose of 60 Gy in 25 fractions were administered to the whole breast and tumor bed, respectively. The intensity modulation plan (IMRT) of each patient uses both physical parameters and an equivalent uniform dose (EUD) to optimize the target function. Univariate and multivariate linear regression were used to analyze the relationship between predictive impact factors and OAR percent dose volume, conformity index (CI), and homogeneity index (HI). RESULTS: The average CI and HI values of the left breast cancer plan were 0.595 ± 0.071 (0.3-0.72) and 1.095 ± 0.023 (1.06-1.18), respectively. The CTR (B = 0.21, P = 0.045), VPTV (B = 0.63, P = 0.000), volume of the lung (Vlung) (B = - 0.29, P = 0.005), and MHD (B = 0.22, P = 0.041) were identified as factors influencing the CI index of the left breast cancer intensity modulation plan. VPTV (B = 1.087, P = 0.022) was identified as the influencing factor of the HI index of the left breast cancer intensity modulation plan. volume of the heart (Vheart) (B = - 0.43, P = 0.001) and CLD (B = 0.28, P = 0.008) were influencing factors of the volume of lung (Vlung20) of the lung. The prediction formulas for left-sided breast cancer are noted as follows: CI = 0.459 + 0.19CTR-0.16CLD, Vlung10 = 35.5-0.02Vheart; and Vlung20 = 21.48 + 2.8CLD-0.018Vheart. CONCLUSIONS: CTR, CLD, and MHD can predict the rationality of the parameters of the left breast cancer IMRT. The calculation formula generated based on this information can help the physicist choose the optimal radiation field setting method and improve the quality of the treatment plan.

DBP exposure induces thyroid inflammatory impairment through activating AKT/NF-κB/NLRP3 signaling.

Previous studies exhibited reproductive and neurodevelopmental toxicity in rats exposed to Di-n-butyl phthalate (DBP). However, the effects of DBP exposure on the other endocrine organ are still unclear. This study aimed to assess the impact of DBP exposure on the thyroid of male rats and the associated mechanisms. Here, rats were respectively treated with DBP at 0 (control), 50 (low dose), 250 (medium dose), or 500 (high dose) mg/kg/day dissolved in 1 ml quantity of corn oil by intragastrical administration for two weeks. The results demonstrated that the proliferation and inflammatory response changes were significantly different compared to the control. In vivo DBP is mainly converted to mono-n-butyl phthalate (MBP), an active form producing untoward reactions of DBP exposure. Therefore, for in vitro experiments, we treated the thyroid follicular epithelial cell line (Nthy-ori 3-1) in a temporal gradient using 1 mM MBP. Further in vitro studies showed that MBP exposure upregulated tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), as well as interleukin-1ß (IL-1ß) by activating AKT/NF-κB/NLRP3 signaling. Meanwhile, we detected that Pellino2 (Peli2) played an essential role in promoting the activation of NLRP3 inflammasome. Briefly speaking, this study confirmed that DBP exposure caused impaired thyroid structure and thyroid inflammation in male rats, which offered new views into the harm of DBP exposure on the endocrine organ.

Embryonic 6:2 FTOH exposure causes reproductive toxicity by disrupting the formation of the blood-testis barrier in offspring mice.

Previous studies have revealed nephrotoxicity, hepatotoxicity, subchronic developmental and reproductive toxicity in rats exposed to fluorotelomer alcohol (FTOH). However, the effects of embryonic 6:2 FTOH exposure on the reproductive system of offspring mice remain unclear. The purpose of this study is to explore the reproductive toxic effects of embryonic 6:2 FTOH exposure on offspring male mice and the related molecular mechanisms. Therefore, the pregnant mice were given corn oil or 6:2 FTOH by gavage from gestational days 12.5-21.5. The results demonstrated that embryonic 6:2 FTOH exposure resulted in disrupted testicular structure, low expression of tight junction protein between Sertoli cells (SCs), impaired blood-testis barrier (BTB) formation and maturation, reduced sperm viability and increased malformation, and induced testicular inflammation in the offspring of mice. Further in vitro studies showed that 6:2 FTOH treatment upregulated MMP-8 expression by activating AKT/NF-κB signaling pathway, which in turn enhanced occludin cleavage leading to the disruption of SCs barrier integrity. In summary, this study demonstrated that 6:2 FTOH exposure caused reproductive dysfunction in male offspring through disruption of BTB, which provided new insights into the effects of 6:2 FTOH exposure on the offspring.

Biofilm-developed biomass residues as novel bulking agents and microbial carriers for synergistically enhanced bioevaporation: Degradation potential and contribution to metabolic heat.

Economical and easily prepared bulking agents and microbial carriers are essential in the practical application of bioevaporation process. Biofilm-developed biomass residues not only provide structural support and microbial sources but also may contribute metabolic heat to the bioevaporation process, achieving the enhanced water evaporation and synergistic treatment of biomass residues. In this study, biofilm was cultivated on the rice straw, wheat straw, sawdust, corncob, luffa cylindrica and palm first, then those biofilm-developed biomass residues were successfully used as the bulking agents and microbial carriers in food waste bioevaporation. The degradation potential (volatile solid degradation ratio) of those biomass residues was in the order of corncob (23.96%), wheat straw (21.12%), rice straw (14.57%), luffa cylindrica (11.02%), sawdust (-2.87%) and palm (-9.24%). It's primarily the degradation of the major components, cellulose and hemicellulose, in corncob and wheat straw governed the metabolic heat contribution (91.73 and 79.61%) to the bioevaporation process. While the high lignin content in sawdust (14.57%) and palm (28.62%) caused negligible degradation of cellulose and hemicellulose, hence made them only function as structural supporter and did not contribute any metabolic heat. Moreover, though the metabolic heat contribution of rice straw and luffa cylindrica reached 58.19 and 37.84%, their lowest lignocellulose content (62.99 and 65.95%) and their lower density, as well as the dominated Xanthomonas (bacteria) and Mycothermus (fungi) led to their rapid collapse during the repeated cycles of bioevaporation. The greatest abundance of thermophilic bacteria (22.3-88.0%) and thermophilic fungi (82.0-99.3%) was observed in the corncob pile. Furthermore, considering the Staphylococcus (pathogenic bacteria) and Candida (animal pathogen) was effectively inhibited, the biofilm-developed corncob was the most favorable bulking agents and microbial carrier for the synergistic bioevaporation of highly concentrated organic wastewater and biomass residues.

Uniformly Dispersed Sb-Nanodot Constructed by In Situ Confined Polymerization of Ionic Liquids for High-Performance Potassium-Ion Batteries.

Antimony (Sb) is a potential candidate anode for potassium-ion batteries (PIBs) owing to its high theoretical capacity. However; in the process of potassium alloying reaction; the huge volume expansion (about 407%) leads to pulverization of active substance as well as loss of electrical contact resulting in rapidly declining capacity. Herein; uniformly dispersed Sb-Nanodot in carbon frameworks (Sb-ND@C) were constructed by in situ confined polymerization of ionic liquids. Attributed to the uniformly dispersed Sb-ND and confinement effect of carbon frameworks; as anode for PIBs; Sb-ND@C delivered a superior rate capability (320.1 mA h g-1 at 5 A g-1) and an outstanding cycling stability (486 mA h g-1 after 1000 cycles; achieving 89.8% capacity retention). This work offers a facile route to prepare highly dispersed metal-Nanodot via the in situ polymerization of ionic liquid for high-performance metal-ion batteries.

Dynamic molecular choreography of circadian rhythm disorders (DMCRD): a prospective cohort study protocol.

BACKGROUND: Circadian rhythm disorders (CRDs) are closely associated with the occurrence and development of various diseases, such as inflammatory and cardiovascular diseases, as well as tumors. The impact of a CRD on bodily health is a complex and comprehensive process, and its molecular mechanisms and signaling pathways are still unclear. We therefore aimed to investigate the molecular mechanism variation and adverse outcomes associated with CRDs in a prospective cohort of CRD cases and controls at term using multiomics data. The study has been tasked with developing a precise health promotion model for the prevention and management of CRDs. METHODS: This will be a 5-year prospective cohort study centered on the health management of individuals with CRDs. One hundred volunteers were recruited and had undergone baseline specimen collection, health examination, and health assessment. All of them will be followed up every year using the same protocol, and their biological specimens will be subjected to multiomics analysis after standardized processing. DISCUSSION: Longitudinal health examination, health assessment, and multiomics data will be analyzed to study the impact of CRDs on the volunteers' health status. The results of this study will promote the development of targeted health management programs based on precision medicine. TRIAL REGISTRATION: The clinical study registration has been completed (Trial Registration No. ChiCTR2100047242 ).

Comparison Between Hemodialysis and Peritoneal Dialysis in the Risks for Disease Activity in LN-ESRD Patients: A Systematic Review and Meta-analysis.

Context: End-stage renal disease (ESRD) is the advanced stage of a progressive loss of kidney function. About 10% of all patients with lupus nephritis (LN) eventually progress to ESRD, which may necessitate renal replacement therapy (RRT), such as hemodialysis (HD), peritoneal dialysis (PD), and/or kidney transplant. Research hasn't confirmed which dialysis options, prior to kidney transplantation, are beneficial to patients' prognoses. Objective: The study intended to compare the risks-related to disease activity, exercise, all-cause infection, all-cause cardiovascular events, and mortality-of the use of HD and PD for LN-ESRD adults, as the initial alternative treatment before renal transplantation. Design: The research team performed a narrative review and analyzed the data obtained about clinical outcomes for HD and peritoneal dialysis. For the review, the research team searched the PubMed, EMBASE, and SCOPUS databases. The search used the keywords: end-stage renal disease, renal replacement therapy, hemodialysis and peritoneal dialysis. Setting: The study made in Affiliated Hospital of Hebei University, China. Participants: The studies included 15 636 patients who had been diagnosed with LN-ESRD prior to renal transplantation. Outcome Measures: For the data analysis, the research team divided the data into two groups, one of which included the data on the clinical outcomes for HD patientsand one of which included the data on the clinical outcomes for PD patients. The study evaluated four types of risks: lupus-flare risks, all-cause infection risks, all-cause cardiovascular events risk, and risk of mortality. Results: The 16 studies found in the review reported one or more outcomes of interest for the two dialysis modalities, HD and PD. The analysis of the data from the 16 studies showed that HD was associated with a higher risk than PD: (1) of lupus flares, with RR = 1.23 (confidence interval: 0.82, 1.85), but the difference didn't reach statistical significance (P = .31); (2) of all-cause infection risk, with RR = 1.02 (confidence interval: 0.66, 1.59), but the difference didn't reach statistical significance (P = .92); (3) of all-cause cardiovascular events, with RR = 1.44 (confidence interval: 1.02, 2.04), and the difference reached statistical significance (P = .04); and (4) of mortality risk, with RR = 1.29 (confidence interval: 0.95, 1.75), but the difference didn't reach statistical significance (P = .10). Conclusions: The current study may have reference significance for clinical treatment of ESRD. Except for all-cause cardiovascular events in which PD was superior to HD, offering better outcomes, both treatment modalities provide more or less similar clinical outcomes as effective initial choices for RRT in LN-ESRD patients prior to renal transplant. The current research team, however, encourages further research on the question, addressing better the possible sources of biases encountered in the current study.

Transcriptomic and physiological analyses unravel the effect and mechanism of halosulfuron-methyl on the symbiosis between rhizobium and soybean.

Halosulfuron-methyl (HSM) is a new and highly effective sulfonylurea herbicide widely used in weed control, but its residue in the environment poses a potential risk to soybean. Soybean-rhizobium symbiotic nitrogen fixation is crucial for sustainable agricultural development and ecological environment health. However, the impact of HSM on the symbiosis between soybean and rhizobium is unclear. In this study, the effects of HSM on the soybean-rhizobium symbiotic process and nitrogen fixation were investigated by means of transcriptomic and physiological analyses. Treatment with a concentration of HSM less than 0.5 mg L-1 had no effect on rhizobium growth, but significantly reduced nodules number, the biomass of soybean nodules, and nitrogenase activity in root nodules (P < 0.05). Transcriptomic analysis showed that differentially expressed genes (DEGs) involved in NH4+ assimilation were significantly downregulated (P < 0.05). In addition, the activities of NH4+ assimilation enzymes were markedly reduced. This result was further confirmed by the accumulation of NH4+ in root nodules, indicating that the inhibition of nitrogen fixation by HSM may be caused by excessive NH4+ accumulation in root nodules. Furthermore, DEGs involved in flavonoid synthesis, phytohormone biosynthesis, and phytohormone signaling transduction were significantly downregulated (P < 0.05), which was consistent with the decrease in flavonoid and phytohormone contents determined in this study. These results suggested that HSM may inhibit soybean nodulation by inhibiting flavonoid synthesis in soybean roots, disrupting the balance of plant endogenous hormones in roots during symbiosis, and blocking the transmission of hormone signals during the symbiosis. Our findings provide new insights into the effects of HSM on the legume-rhizobium nodule symbiotic process.

Identification of differentially expressed proteins and clinicopathological significance of HMGB2 in cervical cancer.

To investigate the complexity of proteomics in cervical cancer tissues, we used isobaric tags for relative and absolute quantitation (iTRAQ)-based mass spectrometry analysis on a panel of normal cervical tissues (N), high-grade squamous intraepithelial lesion tissues (HSIL) and cervical cancer tissues (CC). Total 72 differentially expressed proteins were identified both in CC vs N and CC vs HSIL. The expression of HMGB2 was markedly higher in CC than that in HSIL and N. High HMGB2 expression was significantly correlated with primary tumor size, invasion and tumor stage. The up-regulated HMGB2 was discovered to be associated with human cervical cancer. These findings suggest that HMGB2 may be a potentially prognostic biomarker and a target for the therapy of cervical cancer.

Long Non-Coding RNA CASC2 Overexpression Ameliorates Sepsis-Associated Acute Kidney Injury by Regulating MiR-545-3p/PPARA Axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in the progression of sepsis-induced acute kidney injury (AKI). In this study, we aimed to explore the functions of lncRNA cancer susceptibility candidate 2 (CASC2) in sepsis-induced AKI. METHODS: The sepsis cell models were established by exposing HK2 and HEK293 cells into lipopolysaccharide (LPS). Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to determine the expression of CASC2, miR-545-3p and peroxisome proliferator-activated receptor-α (PPARA) mRNA. Cell Counting Kit-8 (CCK-8) assay, flow cytometry analysis and wound healing assay were employed for cell viability, apoptosis and migration, respectively. Western blot assay was conducted for the protein levels of E-cadherin, α-SMA and PPARA. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by specific kits. The relationship between miR-545-3p and CASC2 or PPARA was verified by dual-luciferase reporter assay. RESULTS: CASC2 level was decreased in sepsis patients' serums and LPS-treated HK2 and HEK293 cells. CASC2 overexpression facilitated cell viability and restrained cell apoptosis, migration, epithelial-mesenchymal transition (EMT) and oxidative stress in LPS-triggered HK2 and HEK293 cells. CASC2 was identified as a sponge for miR-545-3p to regulate PPARA expression. MiR-545-3p overexpression restored the impact of CASC2 on LPS-induced injury in HK2 and HEK293 cells. Moreover, miR-545-3p overexpression aggravated LPS-induced cell injury in HK2 and HEK293 cells by targeting PPARA. CONCLUSION: CASC2 overexpression relieved the damage of HK2 and HEK293 cells mediated by LPS treatment through regulating miR-545-3p/PPARA axis.

Blood Glucose Levels and Mortality in Patients With Sepsis: Dose-Response Analysis of Observational Studies.

BACKGROUND: We undertook a systematic review and meta-analysis to investigate the relationship between blood glucose levels and mortality in patients with sepsis. METHODS: Medline and EMBASE were searched from inception to April 8, 2018. Cohort studies or case-control studies reported the association between blood glucose and mortality in patients with sepsis were selected. Study characteristics, baseline characteristics, definition of hyperglycemia, and outcomes of interest were extracted. We performed a dose-response meta-analysis to assess the effect of blood glucose level on mortality. We also conducted meta-analysis for patients with or without diabetes separately. RESULTS: Ten cohort studies involving 26 429 patients were included, of which 5 were prospective studies and 5 retrospective studies. Dose-response analysis showed that the effect of blood glucose on mortality may differ in patients with versus without diabetes. There was a U-shaped relationship for patients with diabetes and a J-shaped relationship for patients without diabetes, with blood glucose at 145 to 155 mg/dL corresponding to lowest mortality both in patients with and without diabetes. CONCLUSIONS: Current evidence suggested U-shaped relationship between blood glucose and mortality in all patients irrespective of their diabetes status. Diabetic patients with blood glucose below 145 mg/dL may have poorer prognosis compared to patients without established diabetes.

Outcomes of icotinib combined with concurrent chemoradiotherapy in locally advanced cervical cancer.

Concurrent chemoradiotherapy (CRT) based on cisplatin is recognized as the current standard treatment for locally advanced cervical cancer. The treatment of cervical cancer has reached a plateau in the last 20 years. Previous studies have proven that the epidermal growth factor receptor is correlated with chemo- and radioresistance and treatment failure. Hence, the purpose of this study was to investigate the efficacy and safety of icotinib combined with CRT in the treatment of locally advanced cervical cancer. Eligibility criteria included patients treated in the radiotherapy department of Taizhou Central Hospital of Zhejiang Province for stage IIB to IIIB cervical cancers who had not received anti-tumor treatment before and a performance status of 0 to 2. Patients were given icotinib 125 mg three times a day for 6 weeks, which was one week before the start of radiotherapy (500 centigrays in 28 fractions) and chemotherapy (40 mg/m2 administered weekly for 3-5 cycles). There were 29 patients who completed the I+CRT treatment, and it was tolerated well. The median follow-up time was 50 months and 27 patients (93.10%) achieved complete responses. The 5-year cumulative overall survival rate and disease-free survival rate were 58.4% and 60.9%, respectively. The treatment with I+CRT is safe and effective for locally advanced cervical cancer. As far as we know, this is the first study to report the 5-year survival rate of locally advanced cervical cancer with targeted therapy combined with chemoradiotherapy.

What is the impact of knee morphology on posterior cruciate ligament avulsion fracture in men and women: a case control study.

BACKGROUND: Several studies on the relationship between morphological parameters and traumatic diseases of the knee have already been conducted. However, few studies focused on the association between knee morphology and posterior cruciate ligament (PCL) avulsion fracture in adults. The objective of this study was to evaluate the impact of knee morphology on PCL avulsion fracture. METHODS: 76 patients (comprised 40 men and 36 women) with PCL avulsion fracture and 76 age- and sex-matched controls without PCL avulsion fracture were studied from 2012 to 2020. MRI measurements of the knee were acquired in the sagittal, coronal, and axial planes. The assessed measurements including intercondylar notch width index, coronal tibial slope, and medial/lateral posterior tibial slopes were compared between men and women, and between case and control groups respectively using independent sample t-tests. In addition, binary logistic regression analyses were used to identify independent risk factors of PCL avulsion fracture. RESULTS: Except notch width index (coronal) (p = 0.003) in the case groups, there was no statistical difference in the assessed measurements including notch width index (axial), coronal tibial slope, medial posterior tibial slope, and lateral posterior tibial slope between men and women in the case and control groups (p > 0.05). When female patients were analyzed, the notch width index (coronal) was significantly smaller (p = 0.0004), the medial posterior tibial slope (p = 0.018) and the lateral posterior tibial slope (p = 0.033) were significantly higher in the case group. The binary logistic regression analysis showed that the notch width index (coronal) (B = -0.347, OR = 0.707, p = 0.003) was found to be an independent factor of PCL avulsion fracture. However, none of the assessed measurements was found to have a statistical difference between the case and control groups in men (p > 0.05). CONCLUSIONS: Notch width index (coronal), medial posterior tibial slope, and lateral posterior tibial slope were found to affect PCL avulsion fracture in women, but no such measurements affected the PCL avulsion fracture in men. Furthermore, a smaller notch width index (coronal) in women was found to be a risk factor in PCL avulsion fracture.

Hospitalization Risk for Adults with Bipolar I Disorder Treated with Oral Atypical Antipsychotics as Adjunctive Therapy with Mood Stabilizers: A Retrospective Analysis of Medicaid Claims Data.

Background: Atypical antipsychotics (AAPs) with mood stabilizers are recommended as a first-line treatment for patients with bipolar disorder. No studies have compared the inpatient health care resource utilization for patients with bipolar disorder treated with lurasidone as adjunctive therapy with mood stabilizers compared with other oral AAPs. Objective: To compare the risk of hospitalization for adult Medicaid beneficiaries with bipolar I disorder when treated with lurasidone compared with other oral AAPs as adjunctive therapy with mood stabilizers. Methods: This retrospective cohort study used the MarketScan Research Databases Multi-State Medicaid Database (IBM, Armonk, NY) claims data to assess patients with bipolar I disorder between January 1, 2014, and June 30, 2019. Adult patients who initiated oral AAP treatment with mood stabilizers (index date) and who were continuously enrolled 12 months before (pre-index) and 24 months after (post-index) the index date were included. Treatment categories assigned by patient-month included lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone with mood stabilizers; no/minimal treatment; AAP monotherapy; and other. Marginal structural models were performed to estimate the all-cause and psychiatric hospitalization rates and hospital length of stay associated with each adjunctive AAP therapy by controlling for both time-invariant and time-varying confounders. Results: Adults with bipolar I disorder (N = 11,426; mean age = 39.4 years; female=73%) treated with an adjunctive oral AAP with mood stabilizers during the index month were categorized into lurasidone (12%), aripiprazole (17%), olanzapine (7%), quetiapine (32%), risperidone (11%), ziprasidone (7%), or other (15%) treatment groups. The adjusted odds of all-cause and psychiatric hospitalization were significantly higher for olanzapine (all causes: adjusted odds ratio [aOR] = 1.59; 95% CI, 1.13-2.25; psychiatric: aOR = 1.61, 95% CI, 1.12-2.32), quetiapine (all-causes: aOR = 1.27, 95% CI, 1.01-1.58; psychiatric: aOR = 1.28, 95% CI, 1.02-1.59), and ziprasidone (all-causes: aOR = 1.68, 95% CI, 1.05-2.66; psychiatric: aOR = 1.55, 95% CI, 1.02-2.35) compared with lurasidone with mood stabilizers. The adjusted odds of all-cause and psychiatric hospitalizations were numerically lower for lurasidone compared with aripiprazole. The all-cause hospital length of stay per 100 patient-months was significantly higher for olanzapine (20.3 days) and quetiapine (16.0 days) compared with lurasidone (12.2 days, both P values < 0.05). Conclusions: In a Medicaid population, adults with bipolar I disorder treated with lurasidone as adjunctive therapy with mood stabilizers had significantly lower all-cause and psychiatric hospitalization rates compared with olanzapine, quetiapine, and ziprasidone. Fewer hospitalizations may reduce the economic burden associated with bipolar disorder. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).