Cross-sectional study of the association between burnout and work overload and work-life imbalance among medical personnel in Liaoning, China: role of specialty.

OBJECTIVES: Burnout is common among medical personnel in China and may be related to excessive and persistent work-related stressors by different specialties. The aims of this study were to assess the prevalence of burnout, work overload and work-life imbalance according to different specialties and to explore the effect of specialty, work overload and work-life imbalance on burnout among medical personnel. DESIGN: A cross-sectional study. SETTING: This study was conducted in 1 tertiary general public hospital, 2 secondary general hospitals and 10 community health service stations in Liaoning, China. PARTICIPANTS: A total of 3299 medical personnel participated in the study. METHODS: We used the 15-item Chinese version of the Maslach Burnout Inventory General Survey (MBI-GS) to measure burnout. Multivariable logistic regression models were used to explore the association between medical specialty, work overload, work-life imbalance and burnout. RESULTS: 3299 medical personnel were included in this study. The prevalence of burnout, severe burnout, work overload and work-life imbalance were 88.7%, 13.6%, 23.4% and 23.2%, respectively. Compared with medical personnel in internal medicine, working in obstetrics and gynaecology (OR=0.61, 95% CI 0.38, 0.99) and management (OR=0.45, 95% CI 0.28, 0.72) was significantly associated with burnout, and working in ICU （Intensive Care Unit）(OR=2.48, 95% CI 1.07, 5.73), surgery (OR=1.66, 95% CI 1.18, 2.35) and paediatrics (OR=0.24, 95% CI 0.07, 0.81) was significantly associated with severe burnout. Work overload and work-life imbalance were associated with higher ORs for burnout (OR=1.64, 95% CI 1.16, 2.32; OR=2.79, 95% CI 1.84, 4.24) and severe burnout (OR=4.33, 95% CI 3.43, 5.46; OR=3.35, 95% CI 2.64, 4.24). CONCLUSIONS: Burnout, work overload and work-life imbalance were prevalent among Chinese medical personnel but varied considerably by clinical specialty. Burnout may be reduced by decreasing work overload and promoting work-life balance across different specialties.

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect.

Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

Subtle Structural Changes across the Boundary between A2AR/A2BR Dual Antagonism and A2BR Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives.

Aberrantly elevated adenosine in the tumor microenvironment exerts its immunosuppressive functions through adenosine receptors A2AR and A2BR. Antagonism of A2AR and A2BR has the potential to suppress tumor growth. Herein, we report a systemic assessment of the effects of an indole modification at position 4, 5, 6, or 7 on both A2AR/A2BR activity and selectivity of novel 2-aminopyrimidine compounds. Substituting indole at the 4-/5-position produced potent A2AR/A2BR dual antagonism, whereas the 6-position of indole substitution gave highly selective A2BR antagonism. Molecular dynamics simulation showed that the 5-cyano compound 7ai had a lower binding free energy than the 6-cyano compound 7aj due to water-bridged hydrogen bond interactions with E169 or F168 in A2AR. Of note, dual A2AR/A2BR antagonism by compound 7ai can profoundly promote the activation and cytotoxic function of T cells. This work provided a strategy for obtaining novel dual A2AR/A2BR or A2BR antagonists by fine-tuning structural modification.

Two-step reconstruction framework of fluorescence molecular tomography based on energy statistical probability.

Fluorescence molecular tomography (FMT), as a promising technique for early tumor detection, can non-invasively visualize the distribution of fluorescent marker probe three-dimensionally. However, FMT reconstruction is a severely ill-posed problem, which remains an obstacle to wider application of FMT. In this paper, a two-step reconstruction framework was proposed for FMT based on the energy statistical probability. First, the tissue structural information obtained from computed tomography (CT) is employed to associate the tissue optical parameters for rough solution in the global region. Then, according to the global-region reconstruction results, the probability that the target belongs to each region can be calculated. The region with the highest probability is delineated as region of interest to realize accurate and fast source reconstruction. Numerical simulations and in vivo experiments were carried out to evaluate the effectiveness of the proposed framework. The encouraging results demonstrate the significant effectiveness and potential of our method for practical FMT applications.

Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A2 receptors.

The adenosine subfamily G protein-coupled receptors A2AR and A2BR have been identified as promising cancer immunotherapy candidates. One of the A2AR/A2BR dual antagonists, AB928, has progressed to a phase II clinical trial to treat rectal cancer. However, the precise mechanism underlying its dual-antagonistic properties remains elusive. Herein, we report crystal structures of the A2AR complexed with AB928 and a selective A2AR antagonist 2-118. The structures revealed a common binding mode on A2AR, wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets. In contrast, the cAMP assay and A2AR and A2BR molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A2BR. Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A2BR pocket, while 2-118 did not due to intrinsic differences. This disparity potentially accounted for the difference in inhibitory efficacy between A2BR and A2AR. This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A2AR/A2BR for cancer therapy.

[Common Problems and Improvement Suggestions for the Special Review Application of Shanghai's Class â ¡ Innovative Medical Device].

This study conducted statistics on the special review applications for Class Ⅱ innovative medical devices in Shanghai from April 2020 to April 2023. It summarized and analyzed common problems in the innovation review application stage, and gave suggestions for applicants and reviewers in order to further improve the quality of innovation application and improve the pass rate of innovation applications.

Nanoscale investigations of femtosecond laser induced nanogratings in optical glasses.

Femtosecond (fs) laser irradiation inside transparent materials has drawn considerable interest over the past two decades. More specifically, self-assembled nanogratings, induced by fs laser direct writing (FLDW) inside glass, enable a broad range of potential applications in optics, photonics, or microfluidics. In this work, a comprehensive study of nanogratings formed inside fused silica by FLDW is presented based on high-resolution electron microscopy imaging techniques. These nanoscale investigations reveal that the intrinsic structure of nanogratings is composed of oblate nanopores, shaped into nanoplanes, regularly spaced and oriented perpendicularly to the laser polarization. These nanoporous layers are forced-organized by light, resulting in a pseudo-organized spacing at the sub-wavelength scale, and observed in a wide range of optical glasses. In light of the current state of the art, we discuss the imprinting of nanoporous layers under thermomechanical effects induced by a plasma-mediated nanocavitation process.

Discovery of Biaryl Amide Derivatives as Potent, Selective, and Orally Bioavailable RORγt Agonists for Cancer Immunotherapy.

The master transcription factor receptor retinoic acid receptor-related orphan receptor γt (RORγt) regulates the differentiation of T-helper 17 (Th17) cells and the production of interleukin-17 (IL-17). Activation of RORγt+ T cells in the tumor microenvironment promotes immune infiltration to more effectively inhibit tumor growth. Therefore, RORγt agonists provide a reachable approach to cancer immunotherapy. Herein, a series of biaryl amide derivatives as novel RORγt agonists were designed, synthesized, and evaluated. Starting from the reported RORγt inverse agonist GSK805 (1), "functionality switching" and structure-based drug optimization led to the discovery of a promising RORγt agonist lead compound 14, which displayed potent and selective RORγt agonist activity and significantly improved metabolic stability. With excellent in vivo pharmacokinetic profiles, compound 14 demonstrated robust efficacy in preclinical tumor models of mouse B16F10 melanoma and LLC lung adenocarcinoma. Taken together, current studies indicate that 14 deserves further investigation as a potential lead RORγt agonist for cancer immunotherapy.

Therapeutic and Safety Promise of Mesenchymal Stem Cells for Liver Failure: from Preclinical Experiment to Clinical Application.

Liver failure (LF) is serious liver damage caused by multiple factors, resulting in severe impairment or decompensation of liver synthesis, detoxification, metabolism, and biotransformation. The general prognosis of LF is poor with high mortality in non-transplant patients. The clinical treatments for LF are mainly internal medicine comprehensive care, an artificial liver support system, and liver transplantation. However, none of the above treatment strategies can solve the problems of all liver failure patients and has its own limitations. Mesenchymal stem cells (MSCs) are a kind of stem cells with multidirectional differentiation potential and paracrine function, which play an important role in immune regulation and tissue regeneration. In recent years, MSCs have shown multiple advantages in the treatment of LF in pre-clinical experiments and clinical trials. In this work, we reviewed the biological characteristics of MSCs, the possible molecular mechanisms of MSCs in the treatment of liver failure, animal experiments, and clinical application, and also discussed the existing problems of MSCs in the treatment of liver failure.

Upper temperature limit for nanograting survival in oxide glasses: publisher's note.

This publisher's note contains corrections to Appl. Opt.62, 6794 (2023)APOPAI0003-693510.1364/AO.496351.

Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia.

The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and transient clinical benefit of FLT3 kinase inhibitors (FLT3i) emphasizes the need for alternative therapeutic options for this subset of myeloid malignancies. Herein, we showed that FLT3-ITD mutant (FLT3-ITD+) AML cells were susceptible toward inhibitors of DHODH, a rate-limiting enzyme of de novo pyrimidine biosynthesis. Genetic and pharmacological blockade of DHODH triggered downregulation of FLT3-ITD protein, subsequently suppressed activation of downstream ERK and STAT5, and promoted cell death of FLT3-ITD+ AML cells. Mechanistically, DHODH blockade triggered autophagy-mediated FLT3-ITD degradation via inactivating mTOR, a potent autophagy repressor. Notably, blockade of DHODH synergized with an FDA-approved FLT3i quizartinib in significantly impairing the growth of FLT3-ITD+ AML cells and improving tumor-bearing mice survival. We further demonstrated that DHODH blockade exhibited profound anti-proliferation effect on quizartinib-resistant cells in vitro and in vivo. In summary, this study demonstrates that the induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.

Upper temperature limit for nanograting survival in oxide glasses.

The thermal stability of self-assembled porous nanogratings inscribed by an infrared femtosecond (fs) laser in five commercial glasses (BK7, soda lime, 7059, AF32, and Eagle XG) is monitored using step isochronal annealing experiments. Their erasure, ascertained by retardance measurements and attributed to the collapse of nanopores, is well predicted from the Rayleigh-Plesset (R-P) equation. This finding is thus employed to theoretically predict the erasure of nanogratings in the context of any time-temperature process (e.g., thermal annealing, laser irradiation process). For example, in silica glass (Suprasil CG) and using a simplified form of the R-P equation, nanogratings composed of 50 nm will erase within ∼30m i n, ∼1µs, and ∼30n s at temperatures of ∼1250∘ C, 2675°C, and 3100°C, respectively. Such conclusions are expected to provide guidelines to imprint nanogratings in oxide glasses (for instance, in the choice of laser parameters) or to design appropriate thermal annealing protocols for temperature sensing.

Drug design education in China.

With the emergence of innovative technologies, including combinatorial chemistry, high-throughput screening, computer-aided drug design (CADD), artificial intelligence (AI) and big data, the importance of drug design in the field of drug discovery and development is increasing. Additionally, education in drug design plays an important role in the training of pharmaceutical talent. Starting with undergraduates, cultivating pharmaceutical design thinking, developing innovation and creativity, and establishing an interdisciplinary knowledge system will not only provide students with a solid knowledge basis but also promote the development of the pharmaceutical industry in China. This article presents the current status of pharmaceutical education and the distribution of drug design courses in China and summarizes the employment prospects of graduates, thus providing valuable references and evidence for global pharmaceutical design education.

Effect of Artificial Liver Support Systems on Gut Microbiota in Patients with HBV-Related Acute-on-Chronic Liver Failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a rare and severe form of end-stage liver disease with high mortality; gut microbes are strongly associated with the development of this severe liver disease but the exact association is unclear. Artificial liver support systems (ALSS) are clinically important in prolonging the waiting time for liver transplantation and in aiding drug therapy to achieve remission. The aim of this study was to investigate the effect of ALSS on the abundance and diversity of microorganisms in the gut of HBV-ACLF patients. In this study, 109 stool samples were collected from patients with hepatitis B virus-associated acute chronic liver failure (HBV-ACLF) for 16S rRNA sequencing. Among them, 44 samples were from patients treated with ALSS therapy as an adjunct to standard medical treatment (SMT) and 65 were from patients receiving SMT only. Analysis of the sequencing results suggested that there were significant differences in the abundance and diversity of gut microbiota between the with-ALSS and without-ALSS groups (p < 0.05). The operational taxonomic units and Shannon indexes indicated that the diversity and abundance of the gut microbiome, while decreasing after the first ALSS treatment, gradually increased after an increase in the number of ALSS therapies. The overall proportion of HBV-ACLF patients with coinfection was 27.59%; the coinfection can reduce the abundance of the Bacteroidetes phylum in the microbiome significantly whereas Proteobacteria were highly enriched. After ALSS therapy, HBV-ACLF patients had a decrease in potentially harmful bacteria, an increase in potentially beneficial bacteria, an increase in the diversity of the intestinal microbiota, and the intestinal microecological disorders were corrected to a certain extent. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) levels, as well as the international normalized ratio (INR), showed a decreasing trend whereas plasminogen activity (PTA) increased and the condition of patients with HBV-ACLF progressed in a favorable direction. In addition, the abundance of Blautia and Coprococcus was negatively correlated with TBIL and INR, positively correlated with PTA, and positively correlated with disease recovery. Our study shows that ALSS can alter the composition of the gut microbiota and have an ameliorating effect on the gut microecological imbalance in HBV-ACLF patients. It is worth mentioning that Blautia and Coprococcus may have great potential as biomarkers.

Identification of tau-tubulin kinase 1 inhibitors by microfluidics-based mobility shift assay from a kinase inhibitor library.

Tau tubulin kinase 1 (TTBK1) is a serine/threonine/tyrosine kinase that phosphorylates multiple residues in tau protein. Hyperphosphorylated tau is the main cause of tauopathy, such as Alzheimer's disease (AD). Therefore, preventing tau phosphorylation by inhibiting TTBK1 has been proposed as a therapeutic strategy for AD. However, few substrates of TTBK1 are reported for a biochemical assay and few inhibitors targeting TTBK1 have been reported so far. In this study, we identified a fluorescein amidite (FAM)-labeled peptide 15 from a small peptide library as the optimal peptide substrate for human TTBK1 (hTTBK1). We then developed and validated a microfluidics-based mobility shift assay (MMSA) with peptide 15. We further confirmed that peptide 15 could also be used in the ADP-Glo kinase assay. The established MMSA was applied for screening of a 427-compound kinase inhibitor library, yielding five compounds with IC50s of several micro molars against hTTBK1. Among them, three compounds, AZD5363, A-674,563 and GSK690693 inhibited hTTBK1 in an ATP competitive manner and molecular docking simulations revealed that they enter the ATP pocket and form one or two hydrogen bonds to the hinge region with hTTBK1. Another hit compound, piceatannol, showed non-ATP competitive inhibitory effect on hTTBK1 and may serve as a starting point to develop highly selective hTTBK1 inhibitors. Altogether, this study provided a new in vitro platform for the development of novel hTTBK1 inhibitors that might have potential applications in AD prevention.

Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone.

The discovery and development of novel µ-opioid receptor (MOR) antagonists is a significant area to combat Opioid Use Disorder (OUD). In this work, a series of para-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized and pharmacologically assayed. Compound 6a was identified as a selective MOR antagonist both in vitro and in vivo. Its molecular basis was elucidated using molecular docking and MD simulations. A subpocket on the extracellular side of the TM2 domain of MOR, in particular the residue Y2.64, was proposed to be responsible for the reversal of subtype selectivity and functional reversal of this compound.

Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists.

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to treat inflammatory and autoimmune diseases via modulating the interleukin-17 (IL-17) production by T helper 17 (Th17) cells. Herein, we reported a series of triazine-based derivatives as novel RORγt inverse agonists. By screening of our in-house compound library, the hit compound 1 was identified with weak RORγt inhibitory activity. Subsequently, we engineered detailed structural modifications to explore the structure-activity relationships (SARs) of triazines derivatives, which led to discovery of a number of potent RORγt inverse agonists with IC50 values in the range of 7 nM-50 nM in RORγt dual FRET assay. Among them, compound 14g displayed potent RORγt inverse agonistic activity with an IC50 value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC50 value of 0.428 µM and maximum inhibition rate of 108.9%. Compound 14g also exhibited good metabolic stability and a decent pharmacokinetic profile with a low clearance (CL = 0.229 L/h/kg) and a reasonable oral exposure (AUC0-Last = 5058 ng/mL*h). Most importantly, 14g alleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazine-based derivatives represent a new chemical class of RORγt inverse agonists as potential therapeutic agents against autoimmune diseases.

Volume nanogratings inscribed by ultrafast IR laser in alumino-borosilicate glasses.

Self-assembled nanogratings, inscribed by femtosecond laser writing in volume, are demonstrated in multicomponent alkali and alkaline earth containing alumino-borosilicate glasses. The laser beam pulse duration, pulse energy, and polarization, were varied to probe the nanogratings existence as a function of laser parameters. Moreover, laser-polarization dependent form birefringence, characteristic of nanogratings, was monitored through retardance measurements using polarized light microscopy. Glass composition was found to drastically impact the formation of nanogratings. For a sodium alumino-borosilicate glass, a maximum retardance of 168 nm (at 800 fs and 1000 nJ) could be measured. The effect of composition is discussed based on SiO2 content, B2O3/Al2O3 ratio, and the Type II processing window is found to decrease as both (Na2O + CaO)/Al2O3 and B2O3/Al2O3 ratios increase. Finally, an interpretation in the ability to form nanogratings from a glass viscosity viewpoint, and its dependency with respect to the temperature, is demonstrated. This work is brought into comparison with previously published data on commercial glasses, which further indicates the strong link between nanogratings formation, glass chemistry, and viscosity.

Discovery of novel BTK PROTACs with improved metabolic stability via linker rigidification strategy.

Bruton's Tyrosine Kinase (BTK) functions as a key regulator of B-cell receptor (BCR) signaling pathway, which is frequently hyperactivated in a variety of lymphoma cancers. Using Proteolysis Targeting Chimera (PROTAC) technology, we have recently discovered a highly potent ARQ-531-derived BTK PROTAC 6e, inducing effective degradation of both wild type (WT) and C481S mutant BTK proteins. However, the poor metabolic stability of PROTAC 6e have limited its further in vivo studies. Herein, we present our structure-activity relationship (SAR) studies on modifying PROTAC 6e using linker rigidification strategy to identify a novel cereblon (CRBN)-recruiting compound 3e that induced BTK degradation in a concentration-dependent manner but had no effect on reducing the level of CRBN neo-substrates. Moreover, compound 3e suppressed the cell growth more potently than the small molecule inhibitors ibrutinib and ARQ-531 in several cells. Furthermore, compound 3e with the rigid linker displayed a significantly improved metabolic stability profile with the T1/2 increased to more than 145 min. Overall, we discovered a highly potent and selective BTK PROTAC lead compound 3e, which could be further optimized as potential BTK degradation therapy for BTK-associated human cancers and diseases.