Distribution and co-occurrence of microplastics and co-existing pollutants in bottom water and sediment of the East China Sea.

Microplastics (MPs) contamination in marine environment has been an emerging issue worldwide, notably due to the potential ecological risks of MPs with co-existing environmental contaminants and released toxic plastic additives. To verify the co-occurrence characteristics of MPs and co-existing pollutants in the benthic boundary layer (BBL), the distribution characteristics of MPs, and selected heavy metals (HMs) and halogenated flame retardants (Polybrominated diphenyl ethers, PBDEs, and Dechlorane Plus) in the bottom water and sediment were comprehensively investigated in the East China Sea (ECS). The sampling sites were selected along the coast of ECS, where might be significantly affected by terrigenous inputs and anthropogenic sources. MPs were abundant in the bottom water (62.8-480.2 items/L) and sediment (80.1-1346.7 items/kg d.w.) with polyester, polyethylene, and polypropylene being as the most abundant types and characterized as fiber/line, particle size 200-500 µm, and transparent/white. The abundance and characteristics of MPs demonstrated strong correlations within the bottom water and sediment, which might be due to the frequent exchange of materials. In addition, the abundance of MPs was significantly positively correlated with HMs (Cd, Cr, Pb) in the bottom water and PBDEs in sediment, respectively. According to the scanning electron microscopy/energy dispersive X-ray spectrometry analysis, MPs might act as carriers to transport and co-sediment the co-existing pollutants in water, and physically adsorb or chemically bind with pollutants in sediment. These results could help to elucidate the sources, migration, and fate, and verify the occurrence and potential risks of MPs and their co-existing pollutants in BBL, thus realize the management and control of MPs contamination in marine.

Pyrolysis-induced migration and transformation of heavy metals in sewage sludge containing microplastics.

Stabilizing heavy metals (HMs) in sewage sludge is urgently needed to facilitate its recycling and reuse. Pyrolysis stands out as a promising method for not only stabilizing these metals but also producing biochar. Our research delves into the migration and transformation of specific HMs (Cr, Mn, Ni, Cu, Zn, As, and Pb) during co-pyrolysis under various conditions, including the presence and absence of microplastics (PVC and PET). We examined different concentrations of these plastics (1 %, 5 %, 10 %, and 15 %) and temperatures (300 °C, 500 °C, and 700 °C). Findings reveal that microplastics, particularly PVC, enhance the migration of Zn and Mn, leading to significant volatilization of Zn and Pb at higher temperatures, peaking at 700 °C. The increase in temperature also markedly influences HM migration, with As showcasing notable loss rates that climbed by 18.0 % and 16.3 % in systems with PET and PVC, respectively, as temperatures soared from 300 °C to 700 °C. Moreover, our speciation analysis indicates that microplastics aid in transforming certain HMs from unstable to more stable forms, suggesting their beneficial role in HM stabilization during pyrolysis. This study significantly enriches our understanding of microplastics' impact on HM behavior in sewage sludge pyrolysis, offering new avenues for pollution control and environmental management strategies.

Antifungal heteroresistance causes prophylaxis failure and facilitates breakthrough Candida parapsilosis infections.

Breakthrough fungal infections in patients on antimicrobial prophylaxis during allogeneic hematopoietic cell transplantation (allo-HCT) represent a major and often unexplained cause of morbidity and mortality. Candida parapsilosis is a common cause of invasive candidiasis and has been classified as a high-priority fungal pathogen by the World Health Organization. In high-risk allo-HCT recipients on micafungin prophylaxis, we show that heteroresistance (the presence of a phenotypically unstable, low-frequency subpopulation of resistant cells (~1 in 10,000)) underlies breakthrough bloodstream infections by C. parapsilosis. By analyzing 219 clinical isolates from North America, Europe and Asia, we demonstrate widespread micafungin heteroresistance in C. parapsilosis. Standard antimicrobial susceptibility tests, such as broth microdilution or gradient diffusion assays, which guide drug selection for invasive infections, fail to detect micafungin heteroresistance in C. parapsilosis. To facilitate rapid detection of micafungin heteroresistance in C. parapsilosis, we constructed a predictive machine learning framework that classifies isolates as heteroresistant or susceptible using a maximum of ten genomic features. These results connect heteroresistance to unexplained antifungal prophylaxis failure in allo-HCT recipients and demonstrate a proof-of-principle diagnostic approach with the potential to guide clinical decisions and improve patient care.

Specific Activation of Dopamine Receptor D1 Expressing Neurons in the PrL Alleviates CSDS-Induced Anxiety-Like Behavior Comorbidity with Postoperative Hyperalgesia in Male Mice.

Postoperative pain is a type of pain that occurs in clinical patients after surgery. Among the factors influencing the transition from acute postoperative pain to chronic postoperative pain, chronic stress has received much attention in recent years. Here, we investigated the role of dopamine receptor D1/D2 expressing pyramidal neurons in the prelimbic cortex (PrL) in modulating chronic social defeat stress (CSDS)-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice. Our results showed that preoperative CSDS induced anxiety-like behavior and significantly prolonged postoperative pain caused by plantar incision, but did not affect plantar wound recovery and inflammation. Reduced activation of dopamine receptor D1 or D2 expressing neurons in the PrL is a remarkable feature of male mice after CSDS, and chronic inhibition of dopamine receptor D1 or D2 expressing neurons in the PrL induced anxiety-like behavior and persistent postoperative pain. Further studies found that activation of D1 expressing but not D2 expressing neurons in the PrL ameliorated CSDS-induced anxiety-like behavior and postoperative hyperalgesia. Our results suggest that dopamine receptor D1 expressing neurons in the PrL play a crucial role in CSDS-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice.

Targeting dysregulated intracellular immunometabolism within synovial microenvironment in rheumatoid arthritis with natural products.

Immunometabolism has been an emerging hotspot in the fields of tumors, obesity, and atherosclerosis in recent decades, yet few studies have investigated its connection with rheumatoid arthritis (RA). In principle, intracellular metabolic pathways upstream regulated by nutrients and growth factors control the effector functions of immune cells. Dynamic communication and hypermetabolic lesions of immune cells within the inflammatory synovial microenvironment contributes to the development and progression of RA. Hence, targeting metabolic pathways within immune subpopulations and pathological cells may represent novel therapeutic strategies for RA. Natural products constitute a great potential treasury for the research and development of novel drugs targeting RA. Here, we aimed to delineate an atlas of glycolysis, lipid metabolism, amino acid biosynthesis, and nucleotide metabolism in the synovial microenvironment of RA that affect the pathological processes of synovial cells. Meanwhile, therapeutic potentials and pharmacological mechanisms of natural products that are demonstrated to inhibit related key enzymes in the metabolic pathways or reverse the metabolic microenvironment and communication signals were discussed and highlighted.

Discovery of molecular ferroelectric catalytic annulation for quinolines.

Ferroelectrics as emerging and attractive catalysts have shown tremendous potential for applications including wastewater treatment, hydrogen production, nitrogen fixation, and organic synthesis, etc. In this study, we demonstrate that molecular ferroelectric crystal TMCM-CdCl3 (TMCM = trimethylchloromethylammonium) with multiaxial ferroelectricity and superior piezoelectricity has an effective catalytic activity on the direct construction of the pharmacologically important substituted quinoline derivatives via one-pot [3 + 2 + 1] annulation of anilines and terminal alkynes by using N,N-dimethylformamide (DMF) as the carbon source. The recrystallized TMCM-CdCl3 crystals from DMF remain well ferroelectricity and piezoelectricity. Upon ultrasonic condition, periodic changes in polarization contribute to the release of free charges from the surface of the ferroelectric domains in nano size, which then quickly interacts with the substrates in the solution to trigger the pivotal redox process. Our work advances the molecular ferroelectric crystal as a catalytic route to organic synthesis, not only providing valuable direction for molecular ferroelectrics but also further enriching the executable range of ferroelectric catalysis.

Graphene oxide quantum dots-loaded sinomenine hydrochloride nanocomplexes for effective treatment of rheumatoid arthritis via inducing macrophage repolarization and arresting abnormal proliferation of fibroblast-like synoviocytes.

The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.

Immune myocarditis induced by sintilimab therapy: A case report.

Immunotherapy is a potent tool used in cancer treatment, but the occurrence of immune-related adverse events induced by immune checkpoint inhibitors (ICIs) cannot be overlooked. This is particularly true for rare but potentially fatal cardiovascular complications, such as myocarditis; heart muscle inflammation may lead to heart dysfunction and arrhythmia. The present case is a 68-year-old female breast cancer patient who developed palpitations and elevated cardiac enzyme levels after 1 day of ICI therapy, and the patient was eventually diagnosed with immune myocarditis. After receiving hormonal shock therapy, Ctn I, CK, CK-MB and other cardiac enzyme-related markers improved significantly, and electrocardiogram test returned to normal, and the patient recovered during hospitalization without any major adverse cardiac events. Furthermore, the present study reviewed the mechanism of immune myocarditis induced by ICI therapy, with the aim of providing a clinical foundation for the prevention and diagnosis of cardiovascular adverse events in ICI therapy.

Influencing factors of particle deposition in the human nasal cavity.

Objective: To review the existing literature on the application of computational fluid dynamics methods to study nasal particle deposition and to summarize and analyze the factors affecting nasal particle deposition in order to provide theoretical references for the development of future transnasal drug delivery devices and the prevention of respiratory-related diseases. Data Source: PubMed and CNKI databases. Methods: A search of all current literature (up to and including February 2023) was conducted. Search terms related to the topic of factors influencing nasal particle deposition were identified, and queries were conducted to identify relevant articles. Results: Both the properties of the particles themselves and the environmental conditions external to the particles can affect particle deposition in the nasal cavity, with particle deposition showing a positive correlation with particle size, particle density, and airflow velocity, with increasing subject age leading to a decrease in deposition, and with the relationship between airflow temperature and humidity still requiring more research to further explore. Conclusions: With the popularity of computational fluid dynamics, more and more scholars have applied computational fluid dynamics technology to explore the influence of different parameters on particle deposition. By summarizing and analyzing the influence law of various factors on deposition, it can provide a theoretical basis for the future development and application of transnasal drug delivery devices and the prevention of respiratory-related diseases, which makes a significant contribution to the optimization of clinical disease prevention and treatment. Level of Evidence: NA.

Coupling the Isopentenol Utilization Pathway and Prenyltransferase for the Biosynthesis of Licoflavanone in Recombinant Escherichia coli.

Prenylflavonoids are promising candidates for food additives and functional foods due to their diverse biological activities and potential health benefits. However, natural prenylflavonoids are generally present in low abundance and are limited to specific plant species. Here, we report the biosynthesis of licoflavanone from naringenin and prenol by recombinant Escherichia coli. By investigating the activities of seven different sources of prenyltransferases overexpressed in E. coli toward various flavonoid substrates, the prenyltransferase AnaPT exhibits substrate preference when naringenin serves as the prenyl acceptor. Furthermore, licoflavanone production was successfully achieved by coupling the isopentenol utilization pathway and AnaPT in recombinant E. coli. In addition, the effects of fermentation temperatures, induction temperatures, naringenin concentrations, and substrate feeding strategies were investigated on the biosynthesis of licoflavanone in recombinant E. coli. Consequently, the recombinant E. coli strain capable of improved dimethylallyl diphosphate (DMAPP) supply and suitable for prenylflavonoid biosynthesis increased licoflavanone titers to 142.1 mg/L in a shake flask and to 537.8 mg/L in a 1.3 L fermentor, which is the highest yield for any prenylflavonoids reported to date. These strategies proposed in this study provide a reference for initiating the production of high-value prenylflavonoids.

Biodegradable Ferroelectric Molecular Plastic Crystal HOCH2(CF2)7CH2OH Structurally Inspired by Polyvinylidene Fluoride.

Ferroelectric materials, traditionally comprising inorganic ceramics and polymers, are commonly used in medical implantable devices. However, their nondegradable nature often necessitates secondary surgeries for removal. In contrast, ferroelectric molecular crystals have the advantages of easy solution processing, lightweight, and good biocompatibility, which are promising candidates for transient (short-term) implantable devices. Despite these benefits, the discovered biodegradable ferroelectric materials remain limited due to the absence of efficient design strategies. Here, inspired by the polar structure of polyvinylidene fluoride (PVDF), a ferroelectric molecular crystal 1H,1H,9H,9H-perfluoro-1,9-nonanediol (PFND), which undergoes a cubic-to-monoclinic ferroelectric plastic phase transition at 339 K, is discovered. This transition is facilitated by a 2D hydrogen bond network formed through O-H···O interactions among the oriented PFND molecules, which is crucial for the manifestation of ferroelectric properties. In this sense, by reducing the number of -CF2- groups from ≈5 000 in PVDF to seven in PFND, it is demonstrated that this ferroelectric compound only needs simple solution processing while maintaining excellent biosafety, biocompatibility, and biodegradability. This work illuminates the path toward the development of new biodegradable ferroelectric molecular crystals, offering promising avenues for biomedical applications.

Soil moisture alters the responses of alpine ecosystem productivity to environmental factors, especially VPD, on the Qinghai-Tibetan Plateau.

Water availability, which can be represented by soil water content (SWC), plays a crucial role in plant growth and productivity across the cold and arid Qinghai-Tibetan Plateau. However, the indirect effects of SWC are less well understood, and a more comprehensive understanding of its regulating effects may enhance the recognition of its importance, as this factor is pivotal for accurately predicting the future response of alpine ecosystems to climate change. In this study, in situ eddy covariance observation data from typical alpine ecosystems and satellite data covering the Qinghai-Tibetan region were used to comprehensively reveal the effects of SWC on ecosystem productivity. The results indicated that SWC played an important role in regulating the responses of gross primary productivity (GPP) to other environmental factors over both time and space, especially in terms of the responses of GPP to vapor pressure deficit (VPD). The regulating effect can be summarized as follows: there was a specific SWC value (SWC = 0.24 m3 m-3 on the Qinghai-Tibetan Plateau) above which SWC was no longer the primary limiting factor. The responses of GPP to certain environmental factors shifted from negative to positive when the SWC increased above this value. The responses of GPP to VPD exhibited the highest sensitivity to the regulating effects of SWC, with a general response pattern found across different temporal and spatial scales. The findings revealed divergent responses of GPP to environmental factors under different SWC conditions and between arid and humid regions, emphasizing the importance of soil water conditions. These findings suggest that water conditions should be given primary consideration in global change studies.

The effect of aromatherapy on patients with acute coronary syndrome: A systematic review and meta-analysis.

OBJECTIVE: To systematically investigate the efficacy of aromatherapy in patients with acute coronary syndrome (ACS). METHODS: We conducted a comprehensive search for papers published until November 2023 using the following databases: PubMed, Embase, and Cochrane Library. This study was conducted following the PRISMA and Cochrane Guidelines. The inclusion criteria were randomized controlled trials (RCTs) performed to assess the comparative effectiveness of inhalation aromatherapy versus controls in individuals diagnosed with ACS. The Jadad rating method was used to assess the quality of the included studies, and a meta-analysis was performed using the RevMan 5.4 software. Heterogeneity was quantified using the Higgins I2 (%) test. RESULTS: A total of 12 RCTs with 476 patients with ACS were included. Aromatherapy has been shown to reduce anxiety scores significantly (standard mean difference [SMD]: -1.18, 95 % confidence interval [CI]: -1.33 to -1.03; P < 0.00001) along with reduction in systolic blood pressure (MD = -8.78, 95 % CI [-13.92, -3.65], P = 0.008); diastolic blood pressure (MD = -7.76, 95 % CI [-11.39, -4.12], P < 0.001); mean artery pressure MD = -9.68, 95 % CI [-13.93.-5.44]; P < 0.0001). However, no significant effects were reported on the heart rate (MD = -6.98, 95 % CI [-15.46, 1.50], P = 0.11) and respiratory rate (MD = -0.67, 95 % CI [-2.52, 1.19], P = 0.48). A greater frequency of aromatherapy was associated greater anxiety -1.80 incidence, with 95 % CI [-2.04, -1.56]. Citrus essential oils exhibited the strongest effect (SMD = -1.97, 95 % CI [-3.34, -0.60], P = 0.005) in reducing anxiety levels. CONCLUSION: Aromatherapy appears to be an effective non-pharmacological intervention for reducing blood pressure and anxiety in individuals with ACS. This suggests that aromatherapy more than twice a day is effective in reducing anxiety levels. However, aromatherapy had no statistically significant impact on the heart or respiratory rates. Moreover, additional high-quality RCTs should be conducted to verify these results and explore the efficacy and mechanism of aromatherapy in patients with ACS.

Unraveling the relationship between gut microbiota and site-specific endometriosis: a Mendelian randomization analysis.

Background: Although numerous studies have illustrated the connection between gut microbiota and endometriosis, a conspicuous gap exists in research focusing on the pathogenesis of endometriosis at various sites and its linkage with infertility. Methods: In this study, we used a two-sample Mendelian randomization analysis to investigate the effect of gut microbiota on the development of endometriosis in different regions, including the uterus, ovary, fallopian tube, pelvic peritoneum, vagina, and rectovaginal septum, as well as the intestine. Additionally, we explored the correlation between gut microbiota and endometriosis-induced infertility. Genetic associations with gut microbes were obtained from genome-wide association study (GWAS) datasets provided by the MiBioGen consortium, whereas endometriosis-related GWAS data were sourced from the FinnGen dataset. In our analysis, single-nucleotide polymorphisms were used as instrumental variables, with the primary estimation of the causal effect performed via the inverse variance weighting method. Our sensitivity analyses incorporated heterogeneity tests, pleiotropy tests, and the leave-one-out method. Results: We identified associations at the genus level between four bacterial communities and endometriosis. Subsequently, several associations between the gut microbiota and various subtypes of endometriosis at different anatomical sites were recognized. Specifically, three genera were linked with ovarian endometriosis, six genera were associated with tubal endometriosis, four genera showed links with pelvic peritoneum endometriosis, five genera were connected with vaginal and rectovaginal septum endometriosis, and seven genera demonstrated linkages with intestinal endometriosis. Additionally, one genus was associated with adenomyosis, and three genera exhibited associations with endometriosis-induced infertility. Conclusion: Our study elucidates associations between gut microbiota and site-specific endometriosis, thereby augmenting our understanding of the pathophysiology of endometriosis. Moreover, our findings pave the way for potential therapeutic strategies targeting gut microbiota for individuals grappling with endometriosis-related infertility.

Left Atrial Strain for Prediction of Left Ventricular Reverse Remodeling After ST-segment Elevation Myocardial Infarction by Cardiac Magnetic Resonance Feature Tracking.

PURPOSE: The study aimed to investigate the potential utility of left atrial (LA) strain by using cardiac magnetic resonance feature-tracking (CMR-FT) to predict left ventricular reverse remodeling (LVRR) following ST-segment elevation myocardial infarction (STEMI). MATERIALS AND METHODS: Patients with a first STEMI treated by primary percutaneous coronary intervention were consecutively enrolled in the prospective study and underwent CMR scans at 5 days and 4 months. LA global longitudinal strain (reservoir strain [εs], conduit strain [εe], booster strain [εa]) and corresponding strain rate were assessed by CMR-FT using cine images. LVRR was defined as a reduction in the LV end-systolic volume index of >10% from baseline to follow-up. Logistic regression analyses were performed to determine the predictors of LVRR. RESULTS: Of 90 patients analyzed, patients with LVRR (n=35, 39%) showed higher values of LA strain and strain rate and less extensive infarct size (IS) compared with patients without LVRR (n=55, 61%) at initial and second CMR. The LVRR group demonstrated significant improvements in LV and LA cardiac function over time, especially the obvious increase in LA strain and strain rate. In multivariate logistic regression analyses, εs and εe, together with IS, were independent predictors of LVRR. The combination of εs and IS could optimally predict the LVRR with the highest area under the curve of 0.743. CONCLUSIONS: Post-STEMI patients with LVRR presented better recovery from cardiac function and LA deformation compared with patients without LVRR. Assessment of εs and εe by using CMR-FT after STEMI enabled prediction of LVRR.

Implementation and Evaluation of the FLS Model Nursing in the Rehabilitation of Geriatric Patients with Femoral Neck Fractures.

Objective: To evaluate the effectiveness of FLS model nursing in the rehabilitation of elderly patients after femoral neck fracture surgery. Methods: We retrospectively analyzed data from 89 elderly patients treated surgically for femoral neck fractures, comparing outcomes between those receiving routine nursing (control group, n=44) and FLS model nursing interventions (observation group, n=45). Key metrics included rehabilitation process indicators, hip joint function, self-efficacy, perceived burden, limb stability, and adverse reactions. Results: The observation group showed significantly shorter first out-of-bed time, time for pain disappearance, and length of hospital stay compared to the control group. The observation group also exhibited significantly higher scores in pain, gait, functional activities, and deformity/mobility assessments after the intervention compared to the control group. The GSES score was significantly higher and the SPB score was significantly lower in the observation group after the intervention compared to the control group. The observation group demonstrated significantly higher levels of dynamic balance ability, lower limb muscle strength, and mobile walking ability than the control group. The incidence of adverse reactions was significantly lower in the observation group (8.89%) compared to the control group (36.36%). Conclusion: FLS model nursing intervention has a significant positive effect on the rehabilitation of elderly patients undergoing surgery for femoral neck fractures. Compared to routine nursing intervention, the FLS model nursing intervention can further promote postoperative recovery of hip joint function, improve self-efficacy, alleviate the self-perceived burden, shorten the rehabilitation process, and reduce the risk of adverse postoperative reactions. These findings suggest the FLS model nursing approach holds promise for broader clinical adoption and implementation.

Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear. METHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. RESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity. CONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).

Influencing Factors of Generic Prescribing Behavior of Physicians: A Structural Equation Model Based on the Theory of Planned Behavior.

Background: Although affordable generics could probably contribute to the solution of rapidly increasing pharmaceutical expenditure, those drugs are prescribed at a lower rate in China. Physicians' perception and knowledge of generics have a great influence on their prescribing behavior. Objective: This study aimed to identify factors that affect physicians' generic prescribing behavior based on the theory of planned behaviors (TPB). Methods: Data were collected by both electronic and paper-based surveys from 1297 Chinese physicians, and 1047 surveys were retained. The structural equation model (SEM) was employed to investigate the relationship between four behavioral constructs, namely, attitudes, subjective norms, perceived control of behaviors, and intentions. Results: About 50% of Chinese physicians had a positive attitude towards generic drugs that had passed the "Consistency Evaluation of Quality and Efficacy of Generic Drugs" (high-quality generic drugs), but their knowledge of generic drugs was relatively inadequate. The path coefficients for the effect of attitudes, subjective norms, and perceived behavioral control on behavioral intention were 0.285, 0.366, and 0.322 respectively. The path coefficients for the effect of behavioral intention and perceived behavioral control on prescribing behavior were 0.009 and 0.410 respectively. Conclusion: Physicians' attitudes, subjective norms, and perceived behavioral control were significant positive correlation predictors of behavioral intention. Subjective norms and perceived behavior control had a greater impact than attitude on physicians' prescribing intention. However, the generic prescribing behavior is not under the volitional control of Chinese physicians. Physicians' prescribing practice is likely affected by perceived strong control over prescribing generic drugs.

Room-Temperature Phase Transition Material with Switchable Second-Order Nonlinear Optical Properties.

Phase transition materials with switchable second-order nonlinear optical (NLO) properties have attracted extensive attention because of their great application potential in photoelectric switches, sensors, and modulators, while metal-free organics with NLO switchability near room temperature remain scarce. Herein, we report a hydrogen-bonded metal-free organic crystal, 2-methylpropan-2-aminium 2,2-dimethylpropanoate (1), exhibiting a room-temperature phase transition and favorable NLO switchability. Through investigations on its thermal anomalies, dielectric properties, and crystal structures, we uncover that 1 holds a near-room-temperature phase transition at 303 K from noncentrosymmetric point group C2v to centrosymmetric one D2h, which is attributed to the order-disorder transformations of both tert-butylamine cations and dimethylpropionic acid anions. Accompanied by symmetry change during the phase transition, 1 exhibits reversible and repeatable NLO "on-off" switchability with a desirable switching contrast ratio of ca. 19 between high and low NLO states. This discovery demonstrates a metal-free organic crystal with NLO switching behavior near room temperature, serving as a promising candidate in smart and ecofriendly photoelectric functional materials and devices.

Membrane-Active All-Hydrocarbon-Stapled α-Helical Amphiphilic Tat Peptides: Broad-Spectrum Antibacterial Activity and Low Incidence of Drug Resistance.

Multidrug resistance against conventional antibiotics has dramatically increased the difficulty of treatment and accelerated the need for novel antibacterial agents. The peptide Tat (47-57) is derived from the transactivating transcriptional activator of human immunodeficiency virus 1, which is well-known as a cell-penetrating peptide in mammalian cells. However, it is also reported that the Tat peptide (47-57) has antifungal activity. In this study, a series of membrane-active hydrocarbon-stapled α-helical amphiphilic peptides were synthesized and evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The impact of hydrocarbon staple, the position of aromatic amino acid residue in the hydrophobic face, the various types of aromatic amino acids, and the hydrophobicity on bioactivity were also investigated and discussed in this study. Among those synthesized peptides, analogues P3 and P10 bearing a l-2-naphthylalanine (Φ) residue at the first position and a Tyr residue at the eighth position demonstrated the highest antimicrobial activity and negligible hemolytic toxicity. Notably, P3 and P10 showed obviously enhanced antimicrobial activity against multidrug-resistant bacteria, low drug resistance, high cell selectivity, extended half-life in plasma, and excellent performance against biofilm. The antibacterial mechanisms of P3 and P10 were also preliminarily investigated in this effort. In conclusion, P3 and P10 are promising antimicrobial alternatives for the treatment of the antimicrobial-resistance crisis.