Discovery of baicalein derivatives as novel inhibitors against human pancreatic lipase: Structure-activity relationships and inhibitory mechanisms.

Human pancreatic lipase (hPL) is a vital digestive enzyme responsible for breaking down dietary fats in humans, inhibiting hPL is a feasible strategy for preventing and treating obesity. This study aims to investigate the structure-activity relationships (SARs) of flavonoids as hPL inhibitors, and to find potent hPL inhibitors from natural and synthetic flavonoids. In this work, the anti-hPL effects of forty-nine structurally diverse naturally occurring flavonoids were assessed and the SARs were summarized. The results demonstrated that the pyrogallol group on the A ring was a key moiety for hPL inhibition. Subsequently, a series of baicalein derivatives were synthesized, while 4'-amino baicalein (ABA) and 4'-pyrrolidine baicalein (PBA) were identified as novel potent hPL inhibitors (IC50 < 1 µM). Further investigations showed that scutellarein, ABA and PBA potently inhibited hPL in a non-competitive manner (Ki < 1 µM). Among all tested flavonoids, PBA showed the most potent anti-hPL effect in vitro, while this agent also exhibited favorable safety profiles, unique tissue distribution (high exposure level to intestinal system but low exposure levels to deep organs) and impressive in vivo effects for lowering blood triglyceride levels in mice. Collectively, this work uncovers the SARs of flavonoids against hPL, while a newly synthetic flavonoid (PBA) emerges as a potent hPL inhibitor with favorable safety profiles and impressive anti-hPL effects in vivo.

Using a systematic and quantitative approach to generate new insights into drug loading of PLGA nanoparticles using nanoprecipitation.

The synthesis of drug-loaded PLGA nanoparticles through nanoprecipitation in solvent/antisolvent mixtures is well reported but lacks clarity in explaining drug loading mechanisms and the prediction of efficiency of drug entrapment. Various methods using physical parameters such as log P and solid-state drug-polymer solubility aim to predict the intensity of drug-polymer interactions but lack precision. In particular, the zero-enthalpy method for drug/polymer solubility may be intrinsically inaccurate, as we demonstrate. Conventional measurement of loading capacity (LC), expressed in weight ratios, can be misleading for comparing different drugs and we stress the importance of using molar units. This research aims to provide new insights and critically evaluate the established methodologies for drug loading of PLGA nanoparticles. The study employs four model drugs with varying solubilities in solvent/antisolvent mixtures, log P values, and solid-state solubility in PLGA: ketoprofen (KPN), indomethacin (IND), sorafenib (SFN), and clofazimine (CFZ). This study highlights that drug loading efficiency is primarily influenced by the drug's solubilities within the solvent system. We emphasise that both kinetic and thermodynamic factors play a role in the behaviour of the system by considering the changes in drug solubility during mixing. The study introduces a pseudo-constant K* to characterise drug-polymer interactions, with CFZ and SFN showing the highest K* values. Interestingly, while IND and KPN have lower K* values, they achieve higher loading capacities due to their greater solubilities, indicating the key role of solubility in determining LC.

Dimethyl fumarate ameliorates chronic stress-induced anxiety-like behaviors by decreasing neuroinflammation and neuronal activity in the amygdala.

BACKGROUND: Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate (DMF), an effective therapeutic agent approved for the treatment of multiple sclerosis, has been widely reported to display anti-inflammatory and anti-oxidative effects. However, the impact of DMF on chronic stress-induced anxiety disorders and the exact underlying mechanisms remain largely unknown. METHODS: We established a mouse model of chronic social defeat stress (CSDS). DMF was administered orally 1 h before daily stress session for 10 days in CSDS + DMF group. qRT-PCR and western blotting were used to analyze mRNA and protein expression of NLRP3, Caspase-1 and IL-1ß. Immunofluorescence staining was carried out to detect the expression of Iba 1 and c-fos positive cells as well as morphological change of Iba 1+ microglia. Whole-cell patch-clamp recording was applied to evaluate synaptic transmission and intrinsic excitability of neurons. RESULTS: DMF treatment significantly alleviated CSDS-induced anxiety-like behaviors in mice. Mechanistically, DMF treatment prevented CSDS-induced neuroinflammation by inhibiting the activation of microglia and NLRP3/Caspase-1/IL-1ß signaling pathway in basolateral amygdala (BLA), a brain region important for emotional processing. Furthermore, DMF treatment effectively reversed the CSDS-caused disruption of excitatory and inhibitory synaptic transmission balance, as well as the increased intrinsic excitability of BLA neurons. CONCLUSIONS: Our findings provide new evidence that DMF may exert anxiolytic effect by preventing CSDS-induced activation of NLRP3/Caspase-1/IL-1ß signaling pathway and alleviating hyperactivity of BLA neurons.

The structure of the archaeal nuclease RecJ2 implicates its catalytic mechanism and inability to interact with GINS.

Bacterial RecJ exhibits 5'→3' exonuclease activity that is specific to ssDNA; however, archaeal RecJs show 5' or 3' exonuclease activity. The hyperthermophilic archaea Methanocaldococcus jannaschii encodes the 5'-exonuclease MjRecJ1 and the 3'-exonuclease MjRecJ2. In addition to nuclease activity, archaeal RecJ interacts with GINS, a structural subcomplex of the replicative DNA helicase complex. However, MjRecJ1 and MjRecJ2 do not interact with MjGINS. Here, we report the structural basis for the inability of the MjRecJ2 homologous dimer to interact with MjGINS and its efficient 3' hydrolysis polarity for short dinucleotides. Based on the crystal structure of MjRecJ2, we propose that the interaction surface of the MjRecJ2 dimer overlaps the potential interaction surface for MjGINS and blocks the formation of the MjRecJ2-GINS complex. Exposing the interaction surface of the MjRecJ2 dimer restores its interaction with MjGINS. The cocrystal structures of MjRecJ2 with substrate dideoxynucleotides or product dCMP/CMP show that MjRecJ2 has a short substrate binding patch, which is perpendicular to the longer patch of bacterial RecJ. Our results provide new insights into the function and diversification of archaeal RecJ/Cdc45 proteins.

Multifunctional role of oral bacteria in the progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders of varying severity, ultimately leading to fibrosis. This spectrum primarily consists of NAFL and non-alcoholic steatohepatitis. The pathogenesis of NAFLD is closely associated with disturbances in the gut microbiota and impairment of the intestinal barrier. Non-gut commensal flora, particularly bacteria, play a pivotal role in the progression of NAFLD. Notably, Porphyromonas gingivalis, a principal bacterium involved in periodontitis, is known to facilitate lipid accumulation, augment immune responses, and induce insulin resistance, thereby exacerbating fibrosis in cases of periodontitis-associated NAFLD. The influence of oral microbiota on NAFLD via the "oral-gut-liver" axis is gaining recognition, offering a novel perspective for NAFLD management through microbial imbalance correction. This review endeavors to encapsulate the intricate roles of oral bacteria in NAFLD and explore underlying mechanisms, emphasizing microbial control strategies as a viable therapeutic avenue for NAFLD.

Mechanically Robust, Durable, and Multifunctional Hyper-Crosslinked Elastomer Based on Metal-Organic-Cluster Crosslinker: The Role of Topological Structure.

Polymer materials formed by conventional metal-ligand bonds have very low branch functionality, the crosslinker of such polymer usually consists of 2-4 polymer chains and a single metal ion. Thus, these materials are weak, soft, humidity-sensitive, and unable to withstand their shape under long-term service. In this work, a new hyperbranched metal-organic cluster (MOC) crosslinker containing up to 16 vinyl groups is prepared by a straightforward coordination reaction. Compared with the current typical synthesis of metal-organic cages (MOCs) or metal-organic-polyhedra (MOP) crosslinkers with complex operations and low yield, the preparation of the MOC is simple and gram-scale. Thus, MOC can serve as a high-connectivity crosslinker to construct hyper-crosslinked polymer networks. The as-prepared elastomer exhibits mechanical robustness, creep-resistance, and humidity-stability. Besides, the elastomer possesses self-healing and recyclability at mild condition as well as fluorescence stability. These impressive comprehensive properties are proven to originate from the hyper-crosslinked topological structure and microphase-separated morphology. The MOC-driven hyper-crosslinked elastomers provide a new solution for the construction of mechanically robust, durable, and multifunctional polymers.

Heterogeneity in Systematic Reviews of Medical Imaging Diagnostic Test Accuracy Studies: A Systematic Review.

Importance: Systematic reviews of medical imaging diagnostic test accuracy (DTA) studies are affected by between-study heterogeneity due to a range of factors. Failure to appropriately assess the extent and causes of heterogeneity compromises the interpretability of systematic review findings. Objective: To assess how heterogeneity has been examined in medical imaging DTA studies. Evidence Review: The PubMed database was searched for systematic reviews of medical imaging DTA studies that performed a meta-analysis. The search was limited to the 40 journals with highest impact factor in the radiology, nuclear medicine, and medical imaging category in the InCites Journal Citation Reports of 2021 to reach a sample size of 200 to 300 included studies. Descriptive analysis was performed to characterize the imaging modality, target condition, type of meta-analysis model used, strategies for evaluating heterogeneity, and sources of heterogeneity identified. Multivariable logistic regression was performed to assess whether any factors were associated with at least 1 source of heterogeneity being identified in the included meta-analyses. Methodological quality evaluation was not performed. Data analysis occurred from October to December 2022. Findings: A total of 242 meta-analyses involving a median (range) of 987 (119-441 510) patients across a diverse range of disease categories and imaging modalities were included. The extent of heterogeneity was adequately described (ie, whether it was absent, low, moderate, or high) in 220 studies (91%) and was most commonly assessed using the I2 statistic (185 studies [76%]) and forest plots (181 studies [75%]). Heterogeneity was rated as moderate to high in 191 studies (79%). Of all included meta-analyses, 122 (50%) performed subgroup analysis and 87 (36%) performed meta-regression. Of the 242 studies assessed, 189 (78%) included 10 or more primary studies. Of these 189 studies, 60 (32%) did not perform meta-regression or subgroup analysis. Reasons for being unable to investigate sources of heterogeneity included inadequate reporting of primary study characteristics and a low number of included primary studies. Use of meta-regression was associated with identification of at least 1 source of variability (odds ratio, 1.90; 95% CI, 1.11-3.23; P = .02). Conclusions and Relevance: In this systematic review of assessment of heterogeneity in medical imaging DTA meta-analyses, most meta-analyses were impacted by a moderate to high level of heterogeneity, presenting interpretive challenges. These findings suggest that, despite the development and availability of more rigorous statistical models, heterogeneity appeared to be incomplete, inconsistently evaluated, or methodologically questionable in many cases, which lessened the interpretability of the analyses performed; comprehensive heterogeneity assessment should be addressed at the author level by improving personal familiarity with appropriate statistical methodology for assessing heterogeneity and involving biostatisticians and epidemiologists in study design, as well as at the editorial level, by mandating adherence to methodologic standards in primary DTA studies and DTA meta-analyses.

Selectively coated contact lenses by nanoelectrospray (nES) to fabricate drug-eluting contact lenses for treating ocular diseases.

Drug-eluting contact lenses (DECLs) incorporated with poly(lactic-co-glycolic acid) (PLGA) and various model drugs (ketotifen fumarate, bimatoprost and latanoprost) were fabricated using nanoelectrospray (nES) approach. The resulting DECLs demonstrated outstanding optical transmittance within the optical zone, indicating that the employed coating procedure did not compromise visual acuity under the prescribed spraying parameters. In vitro drug release assessments of the model drugs (ketotifen fumarate (KF), bimatoprost (BIM), and latanoprost (LN)) revealed a strong correlation between the model drug's hydrophobicity and the duration of drug release. Changing the drug loading of the more hydrophilic model drugs, BIM and KF, showed no impact on the drug release kinetics of DECLs loaded with BIM and KF. However, for the hydrophobic model drug, LN, the highest LN loading led to the most extended drug release. The conventional steam sterilisation method was found to damage the PLGA coating on the DECLs fabricated by nES. An alternative sterilisation strategy, such as radiation sterilisation may need to be investigated in the future study to minimise potential harm to the coating.

[Risk factors for ketoacidosis in children/adolescents with type 1 diabetes mellitus and establishment of a predictive model]. / 儿童青少年1åž‹ç³–å°¿ç— æ‚£å„¿å‘ç”Ÿé ®ç—‡é ¸ä¸­æ¯’çš„å±é™©å› ç´ åˆ†æžåŠé¢„æµ‹æ¨¡åž‹çš„å»ºç«‹.

OBJECTIVES: To investigate the risk factors for diabetic ketoacidosis (DKA) in children/adolescents with type 1 diabetes mellitus (T1DM) and to establish a model for predicting the risk of DKA. METHODS: A retrospective analysis was performed on 217 children/adolescents with T1DM who were admitted to General Hospital of Ningxia Medical University from January 2018 to December 2021. Among the 217 children/adolescents,169 cases with DKA were included as the DKA group and 48 cases without DKA were included as the non-DKA group. The risk factors for DKA in the children/adolescents with T1DM were analyzed, and a nomogram model was established for predicting the risk of DKA in children/adolescents with T1DM. RESULTS: For the 217 children/adolescents with T1DM, the incidence rate of DKA was 77.9% (169/217). The multivariate logistic regression analysis showed that high levels of random blood glucose, hemoglobin A1c (HbA1c), blood ketone body, and triglyceride on admission were closely associated with the development of DKA in the children/adolescents with T1DM (OR=1.156, 3.2031015, 20.131, and 9.519 respectively; P<0.05). The nomogram prediction model had a C-statistic of 0.95, with a mean absolute error of 0.004 between the risk of DKA predicted by the nomogram model and the actual risk of DKA, indicating that the model had a good overall prediction ability. CONCLUSIONS: High levels of random blood glucose, HbA1c, blood ketone body, and triglyceride on admission are closely associated with the development of DKA in children/adolescents with T1DM, and targeted intervention measures should be developed to reduce the risk of DKA.

Enriched environment ameliorates fear memory impairments induced by sleep deprivation via inhibiting PIEZO1/calpain/autophagy signaling pathway in the basal forebrain.

AIMS: To verify the hypothesis that an enriched environment (EE) alleviates sleep deprivation-induced fear memory impairment by modulating the basal forebrain (BF) PIEZO1/calpain/autophagy pathway. METHODS: Eight-week-old male mice were housed in a closed, isolated environment (CE) or an EE, before 6-h total sleep deprivation. Changes in fear memory after sleep deprivation were observed using an inhibitory avoidance test. Alterations in BF PIEZO1/calpain/autophagy signaling were detected. The PIEZO1 agonist Yoda1 or inhibitor GsMTx4, the calpain inhibitor PD151746, and the autophagy inducer rapamycin or inhibitor 3-MA were injected into the bilateral BF to investigate the pathways involved in the memory-maintaining role of EE in sleep-deprived mice. RESULTS: Mice housed in EE performed better than CE mice in short- and long-term fear memory tests after sleep deprivation. Sleep deprivation resulted in increased PIEZO1 expression, full-length tropomyosin receptor kinase B (TrkB-FL) degradation, and autophagy, as reflected by increased LC3 II/I ratio, enhanced p62 degradation, increased TFEB expression and nuclear translocation, and decreased TFEB phosphorylation. These molecular changes were partially reversed by EE treatment. Microinjection of Yoda1 or rapamycin into the bilateral basal forebrain induced excessive autophagy and eliminated the cognition-protective effects of EE. Bilateral basal forebrain microinjection of GsMTx4, PD151746, or 3-MA mimicked the cognitive protective and autophagy inhibitory effects of EE in sleep-deprived mice. CONCLUSIONS: EE combats sleep deprivation-induced fear memory impairments by inhibiting the BF PIEZO1/calpain/autophagy pathway.

An investigation into the effects of ink formulations of semi-solid extrusion 3D printing on the performance of printed solid dosage forms.

Semi-solid extrusion (SSE) 3D printing has recently attracted increased attention for its pharmaceutical application as a potential method for small-batch manufacturing of personalised solid dosage forms. It has the advantage of allowing ambient temperature printing, which is especially beneficial for the 3D printing of thermosensitive drugs. In this study, the effects of polymeric compositions (single hydroxypropyl methylcellulose (HPMC) system and binary HPMC + polyvinylpyrrolidone (PVP) system), disintegrant (silicon oxide (SiO2)), and active pharmaceutical ingredients (tranexamic acid (TXA) and paracetamol (PAC)) on the printability of semisolid inks and the qualities of SSE printed drug-loaded tablets were investigated. Printability is defined by the suitability of the material for the process in terms of its physical properties during extrusions and post-extrusion, including rheology, solidification time, avoiding slumping, etc. The rheological properties of the inks were investigated as a function of polymeric compositions and drug concentrations and further correlated with the printability of the inks. The SSE 3D printed tablets were subjected to a series of physicochemical properties characterisations and in vitro drug release performance evaluations. The results indicated that an addition of SiO2 would improve 3D printing shape fidelity (e.g., pore area and porosity) by altering the ink rheology. The pores of HPMC + PVP + 5PAC prints completely disappeared after 12 hours of drying (pore area = 0 mm2). An addition of SiO2 significantly improved the pore area of the prints which are 3.5 ± 0.1 mm2. It was noted that the drug release profile of PAC significantly increased (p < 0.05) when additive SiO2 was incorporated in the formulation. This could be due to a significantly higher porosity of HPMC + PVP + SiO2 + PAC (70.3 ± 0.2%) compared to HPMC + PVP + PAC (47.6 ± 2.1%). It was also likely that SiO2 acted as a disintegrant speeding up the drug release process. Besides, the incorporation of APIs with different aqueous solubilities, as well as levels of interaction with the polymeric system showed significant impacts on the structural fidelity and subsequently the drug release performance of 3D printed tablets.

Thickness-variation-insensitive near-infrared quantum dot LEDs.

In terms of tunable luminescence and high quantum efficiency, colloidal quantum dots (CQDs) are promising semiconductors for constructing near-infrared light-emitting diodes (NIR-LEDs). However, currently available NIR-LEDs are susceptible to variations in the emission layer thickness (EMLT), the highest external quantum efficiency (EQE) decreases to below 50% (relative to peak EQE) when the EMLT varies out of a narrow range of (±30 nm). This is due to the thickness-dependent carrier recombination rate and current density variation, resulting in batch-to-batch EQE fluctuations that limit LED reproducibility. Here we report efficient NIR-LEDs that exhibit EQE variations of less than 15% (relative to the champion EQE) over an EMLT range of 40-220 nm; the highest achievable EQE of ∼11.5% was obtained by encapsulating a 212 nm-thick CQD within a type-I inorganic shell to enhance the radiative recombination in the dots, resulting in a high photoluminescence quantum yield of 80%, and by post-treating the films with a bifunctional linking agent to improve and balance the hole and electron mobilities in the entire film (electron mobility: 8.23 × 10-3 cm2 V-1 s-1; hole mobility: 7.0 × 10-3 cm2 V-1 s-1). This work presents the first NIR-LEDs that exhibit EMLT-invariant EQE over an EMLT range of 40-220 nm, which represents the highest EQE among reported CQD NIR-LEDs with a QD thickness exceeding 100 nm.

Non-overlapping epitopes on the gHgL-gp42 complex for the rational design of a triple-antibody cocktail against EBV infection.

Epstein-Barr virus (EBV) is closely associated with cancer, multiple sclerosis, and post-acute coronavirus disease 2019 (COVID-19) sequelae. There are currently no approved therapeutics or vaccines against EBV. It is noteworthy that combining multiple EBV glycoproteins can elicit potent neutralizing antibodies (nAbs) against viral infection, suggesting possible synergistic effects. Here, we characterize three nAbs (anti-gp42 5E3, anti-gHgL 6H2, and anti-gHgL 10E4) targeting different glycoproteins of the gHgL-gp42 complex. Two antibody cocktails synergistically neutralize infection in B cells (5E3+6H2+10E4) and epithelial cells (6H2+10E4) in vitro. Moreover, 5E3 alone and the 5E3+6H2+10E4 cocktail confer potent in vivo protection against lethal EBV challenge in humanized mice. The cryo-EM structure of a heptatomic gHgL-gp42 immune complex reveals non-overlapping epitopes of 5E3, 6H2, and 10E4 on the gHgL-gp42 complex. Structural and functional analyses highlight different neutralization mechanisms for each of the three nAbs. In summary, our results provide insight for the rational design of therapeutics or vaccines against EBV infection.

Cascading effects of hypobaric hypoxia on the testis: insights from a single-cell RNA sequencing analysis.

Most mammals tolerate exposure to hypobaric hypoxia poorly as it may affect multiple regulatory mechanisms and inhibit cell proliferation, promote apoptosis, limit tissue vascularization, and disrupt the acid-base equilibrium. Here, we quantified the functional state of germ cell development and demonstrated the interaction between the germ and somatic cells via single-cell RNA sequencing (scRNA-seq). The present study elucidated the regulatory effects of hypobaric hypoxia exposure on germ cell formation and sperm differentiation by applying enrichment analysis to genomic regions. Hypobaric hypoxia downregulates the genes controlling granule secretion and organic matter biosynthesis, upregulates tektin 1 (TEKT1) and kinesin family member 2C (KIF2C), and downregulates 60S ribosomal protein 11 (RPL11) and cilia- and flagella-associated protein 206 (CFAP206). Our research indicated that prosaposin-G protein-coupled receptor 37 (PSAP-GPR37) ligands mediate the damage to supporting cells caused by hypobaric hypoxic exposure. The present work revealed that hypoxia injures peritubular myoid (PTM) cells and spermatocytes in the S phase. It also showed that elongating spermatids promote maturation toward the G2 phase and increase their functional reserve for sperm-egg binding. The results of this study provide a theoretical basis for future investigations on prophylactic and therapeutic approaches toward protecting the reproductive system against the harmful effects of hypobaric hypoxic exposure.

Double-modified oncolytic adenovirus armed with a recombinant interferon-like gene enhanced abscopal effects against malignant glioma.

Background: The development of new therapies for malignant gliomas has been stagnant for decades. Through the promising outcomes in clinical trials of oncolytic virotherapy, there is now a glimmer of hope in addressing this situation. To further enhance the antitumor immune response of oncolytic viruses, we have equipped a modified oncolytic adenovirus (oAds) with a recombinant interferon-like gene (YSCH-01) and conducted a comprehensive evaluation of the safety and efficacy of this modification compared to existing treatments. Methods: To assess the safety of YSCH-01, we administered the oAds intracranially to Syrian hamsters, which are susceptible to adenovirus. The efficacy of YSCH-01 in targeting glioma was evaluated through in vitro and in vivo experiments utilizing various human glioma cell lines. Furthermore, we employed a patient-derived xenograft model of recurrent glioblastoma to test the effectiveness of YSCH-01 against temozolomide. Results: By modifying the E1A and adding survivin promoter, the oAds have demonstrated remarkable safety and an impressive ability to selectively target tumor cells. In animal models, YSCH-01 exhibited potent therapeutic efficacy, particularly in terms of its distant effects. Additionally, YSCH-01 remains effective in inhibiting the recurrent GBM patient-derived xenograft model. Conclusions: Our initial findings confirm that a double-modified oncolytic adenovirus armed with a recombinant interferon-like gene is both safe and effective in the treatment of malignant glioma. Furthermore, when utilized in combination with a targeted therapy gene strategy, these oAds exhibit a more profound effect in tumor therapy and an enhanced ability to inhibit tumor growth at remote sites.

Early versus delayed laparoscopic cholecystectomy after endoscopic retrograde cholangiopancreatography: A meta-analysis.

PURPOSES: Patients with cholecysto- and choledocholithiasis usually undergo endoscopic retrograde cholangiopancreatography (ERCP)/-endoscopic sphincterotomy followed by laparoscopic cholecystectomy (LC). However, differences in the timing of LC after the ERCP may alter the post-operative outcomes. The aim of this study was to compare the effect of early (≤3 days) or delayed LC (>3 days) following ERCP on the post-operative outcomes. METHODS: A comprehensive search of the 3 databases PubMed, EMBASE and the Cochrane Library was performed. Articles related to LC at different time-points after ERCP were retrieved. Dichotomous and continuous outcomes were analyzed by risk ratio (RR) and mean difference, and RevMan was used to analyze each group. RESULTS: A total of 7 studies, including 5 randomized controlled studies and 2 retrospective studies, involved a total of 711 patients. There were 332 patients in early LC group and 379 in delayed LC group. The conversion rate was lower in the early LC group compared to the delayed LC group (RR 0.38, 95% confident interval 0.19 to 0.74, P = .005, I2 = 0%). Early LC resulted in a shorter operation time (RR -6.2, 95% CI -27.2 to -5.2, P = .004, I2 = 97%) and fewer complications (RR 0.48, 95% CI 0.29 to 0.79, P = .004, I2 = 17%). Subgroup analysis found that there were no significant differences in the conversion rate (RR 0.61, 95% CI 0.25 to 1.45, P = .26, I2 = 0%) or complications between the early LC group and the delayed group who underwent LC after 1 month. CONCLUSION: Early LC after ERCP is the preferred treatment for patients with concurrent cholecysto- and choledocholithiasis due to improved clinical outcomes as compared to those who undergo delayed LC.

Sector-Based Regression Strategies to Reduce Refractive Error-Associated Glaucoma Diagnostic Bias When Using OCT and OCT Angiography.

Purpose: This cross-sectional study aimed to investigate the sectoral variance of optical coherence tomography (OCT) and OCT angiography (OCTA) glaucoma diagnostic parameters across eyes with varying degrees of refractive error. Methods: Healthy participants, including individuals with axial ametropia, enrolled in the Hong Kong FAMILY cohort were imaged using the Avanti/AngioVue OCT/OCTA system. The OCT and OCTA parameters obtained include peripapillary nerve fiber layer thickness (NFLT), peripapillary nerve fiber layer plexus capillary density (NFLP-CD), and macular ganglion cell complex thickness (GCCT). Sectoral measurements of NFLT, NFLP-CD, and GCCT were based on sectors and hemispheres. Results: A total of 1339 eyes from 791 participants were stratified based on spherical equivalent refraction: high myopia (<-6 D), low myopia (-6 D to -1 D), emmetropia (-1 D to 1 D), and hyperopia (>1 D). Multivariable broken stick regression models, accounting for age, sex, and signal strength, showed that all NFLT sectors except temporally, the inferior GCCT hemisphere, and half of the NFLP-CD sectors were more affected by ametropia-related covariates than the corresponding global parameters. As expected, the false-positive rates in those sectors were elevated. Finally, sector-specific axial length (AL) and spherical equivalent (SE) adjustments helped reduce the elevated false-positive rates. Conclusions: The effect of optical magnification is even more prominent among sectors than the global parameters. AL- and SE-based adjustments should be individualized to each sector to mitigate this magnification bias effectively. Translational Relevance: Identifying sectoral differences among diagnostic parameters and adopting these sector-based adjustments into commercial OCT systems will hopefully reduce false-positive rates related to refractive error.

Systematic review of adherence to the standards for reporting of diagnostic accuracy studies (STARD) 2015 reporting guideline in cerebral aneurysm imaging diagnostic accuracy studies.

BACKGROUND: Diagnostic neuroimaging plays an essential role in guiding clinical decision-making in the management of patients with cerebral aneurysms. Imaging technologies for investigating cerebral aneurysms constantly evolve, and clinicians rely on the published literature to remain up to date. Reporting guidelines have been developed to standardise and strengthen the reporting of clinical evidence. Therefore, it is essential that radiological diagnostic accuracy studies adhere to such guidelines to ensure completeness of reporting. Incomplete reporting hampers the reader's ability to detect bias, determine generalisability of study results or replicate investigation parameters, detracting from the credibility and reliability of studies. OBJECTIVE: The purpose of this systematic review was to evaluate adherence to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) 2015 reporting guideline amongst imaging diagnostic accuracy studies for cerebral aneurysms. METHODS: A systematic search for cerebral aneurysm imaging diagnostic accuracy studies was conducted. Journals were cross examined against the STARD 2015 checklist and their compliance with item numbers was recorded. RESULTS: The search yielded 66 articles. The mean number of STARD items reported was 24.2 ± 2.7 (71.2% ± 7.9%), with a range of 19 to 30 out of a maximum number of 34 items. CONCLUSION: Taken together, these results indicate that adherence to the STARD 2015 guideline in cerebral aneurysm imaging diagnostic accuracy studies was moderate. Measures to improve compliance include mandating STARD 2015 adherence in instructions to authors issued by journals.

Protective effects and regulatory mechanisms of Shen-shuai-yi recipe on renal fibrosis in unilateral ureteral obstruction-induced mice.

Renal fibrosis (RF) is a common pathological feature of chronic kidney disease (CKD), which remains a major public health problem. As now, there is still lack of chemical or biological drugs to reverse RF. Shen-shuai-yi Recipe (SSYR) is a classical Chinese herbal formula for the treatment of CKD. However, the effects and mechanisms of SSYR in treating RF are still not clear. In this study, the active constituents SSYR for treating RF were explored by UHPLC-Q-Orbitrap HRMS. Bioinformatics analyses were employed to analyze the key pharmacological targets and the core active constituents of SSYR in the treatment of RF. In experimental validation, vehicle or SSYR at doses of 2.12 g/kg/d and 4.25 g/kg/d were given by orally to unilateral ureteric obstruction (UUO) mice. 13 days after treatment, we detected the severity of renal fibrosis, extracellular collagen deposition and pre-fibrotic signaling pathways. Bioinformatics analysis suggested that signal transducer and activator of transcription 3 (STAT3) was the core target and lenticin, luteolin-7-O-rutinoside, hesperidin, kaempferol-3-O-rutinoside, and 3,5,6,7,8,3',4'-heptamethoxyflavone were the key constituents in SSYR for treating RF. SSYR significantly reduced the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), collagen-I and alleviated renal interstitial collagen deposition in UUO kidneys. In mechanism, SSYR potently blocked the phosphorylation of STAT3 and Smad3 and suppressed the expression of connective tissue growth factor (CTGF). Collectively, SSYR can ameliorate RF via inhibiting the phosphorylation of STAT3 and its downstream and reducing the collagen deposition, suggesting that SSYR can be developed as a novel medicine for treating RF.

A New Temperature Correction Method for NaI(Tl) Detectors Based on Pulse Deconvolution.

To overcome the temperature effect of NaI(Tl) detectors for energy spectrometry without additional hardware, a new correction method was put forward based on pulse deconvolution, trapezoidal shaping and amplitude correction, named DTSAC. To verify this method, actual pulses from a NaI(Tl)-PMT detector were measured at various temperatures from -20 °C to 50 °C. Pulse processing and spectrum synthesis showed that the position drift of the 137Cs 662 keV peak was less than 3 keV, and the corresponding resolution at 662 keV of the sum spectra ranged from 6.91% to 10.60% with the trapezoidal width set from 1000 ns to 100 ns. The DTSAC method corrects the temperature effect via pulse processing, and needs no reference peak, reference spectrum or additional circuits. The method solves the problem of correction of pulse shape and pulse amplitude at the same time, and can be used even at a high counting rate.