Data Set and Benchmark (MedGPTEval) to Evaluate Responses From Large Language Models in Medicine: Evaluation Development and Validation.

Background: Large language models (LLMs) have achieved great progress in natural language processing tasks and demonstrated the potential for use in clinical applications. Despite their capabilities, LLMs in the medical domain are prone to generating hallucinations (not fully reliable responses). Hallucinations in LLMs' responses create substantial risks, potentially threatening patients' physical safety. Thus, to perceive and prevent this safety risk, it is essential to evaluate LLMs in the medical domain and build a systematic evaluation. Objective: We developed a comprehensive evaluation system, MedGPTEval, composed of criteria, medical data sets in Chinese, and publicly available benchmarks. Methods: First, a set of evaluation criteria was designed based on a comprehensive literature review. Second, existing candidate criteria were optimized by using a Delphi method with 5 experts in medicine and engineering. Third, 3 clinical experts designed medical data sets to interact with LLMs. Finally, benchmarking experiments were conducted on the data sets. The responses generated by chatbots based on LLMs were recorded for blind evaluations by 5 licensed medical experts. The evaluation criteria that were obtained covered medical professional capabilities, social comprehensive capabilities, contextual capabilities, and computational robustness, with 16 detailed indicators. The medical data sets include 27 medical dialogues and 7 case reports in Chinese. Three chatbots were evaluated: ChatGPT by OpenAI; ERNIE Bot by Baidu, Inc; and Doctor PuJiang (Dr PJ) by Shanghai Artificial Intelligence Laboratory. Results: Dr PJ outperformed ChatGPT and ERNIE Bot in the multiple-turn medical dialogues and case report scenarios. Dr PJ also outperformed ChatGPT in the semantic consistency rate and complete error rate category, indicating better robustness. However, Dr PJ had slightly lower scores in medical professional capabilities compared with ChatGPT in the multiple-turn dialogue scenario. Conclusions: MedGPTEval provides comprehensive criteria to evaluate chatbots by LLMs in the medical domain, open-source data sets, and benchmarks assessing 3 LLMs. Experimental results demonstrate that Dr PJ outperforms ChatGPT and ERNIE Bot in social and professional contexts. Therefore, such an assessment system can be easily adopted by researchers in this community to augment an open-source data set.

Sm-like 5 knockdown inhibits proliferation and promotes apoptosis of colon cancer cells by upregulating p53, CDKN1A and TNFRSF10B.

BACKGROUND: The role of Sm-like 5 (LSM5) in colon cancer has not been determined. In this study, we investigated the role of LSM5 in progression of colon cancer and the potential underlying mechanism involved. AIM: To determine the role of LSM5 in the progression of colon cancer and the potential underlying mechanism involved. METHODS: The Gene Expression Profiling Interactive Analysis database and the Human Protein Atlas website were used for LSM5 expression analysis and prognosis analysis. Real-time quantitative polymerase chain reaction and Western blotting were utilized to detect the expression of mRNAs and proteins. A lentivirus targeting LSM5 was constructed and transfected into colon cancer cells to silence LSM5 expression. Proliferation and apoptosis assays were also conducted to evaluate the growth of the colon cancer cells. Human GeneChip assay and bioinformatics analysis were performed to identify the potential underlying mechanism of LSM5 in colon cancer. RESULTS: LSM5 was highly expressed in tumor tissue and colon cancer cells. A high expression level of LSM5 was related to poor prognosis in patients with colon cancer. Knockdown of LSM5 suppressed proliferation and promoted apoptosis in colon cancer cells. Silencing of LSM5 also facilitates the expression of p53, cyclin-dependent kinase inhibitor 1A (CDKN1A) and tumor necrosis factor receptor superfamily 10B (TNFRSF10B). The inhibitory effect of LSM5 knockdown on the growth of colon cancer cells was associated with the upregulation of p53, CDKN1A and TNFRSF10B. CONCLUSION: LSM5 knockdown inhibited the proliferation and facilitated the apoptosis of colon cancer cells by upregulating p53, CDKN1A and TNFRSF10B.

Recurrence of Hepatocellular Carcinoma in Patients with Low Albumin-Bilirubin Grade in TACE Combined with Ablation: A Random Forest Cox Predictive Model.

Purpose: The aim of our study was to investigate the relationship between albumin-bilirubin (ALBI) grade and recurrence in patients who underwent TACE sequential ablation. We developed and validated a nomogram to predict low levels of ALBI patients' recurrence. Patients and Methods: A total of 880 patients undergoing TACE combined ablation at Beijing Youan Hospital from January 2014 to December 2021 were retrospectively enrolled, including 415 patients with L-ALBI (≤-2.6) and 465 patients with high levels (>-2.6) of ALBI (H-ALBI). L-ALBI patients were randomized in a 7:3 ratio into the training cohort (N=289) and validation cohort (N=126). Multivariate Cox regression followed by random survival forest was carried out to identify independent risk factors for prediction nomogram construction. An examination of nomogram accuracy was performed using the C-index, receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA) curves. According to the nomogram, the patients were divided into low-risk, intermediate-risk, and high-risk groups. Kaplan-Meier (KM) curves were applied to compare the difference in recurrence-free survival (RFS) among the three groups. Results: The median RFS in L-ALBI patients was significantly longer than the H-ALBI patients (40.8m vs 20.1m, HR:1.71, 95% CI:1.44-2.04, P<0.0001). The nomogram was composed of five variables, such as age, Barcelona Clinic Liver Cancer (BCLC) stage, globulin, gamma-glutamyl transferase to lymphocyte ratio (GLR), and international normalized ratio (INR). The C-index (0.722 and 0.731) and 1-, 3-, and 5-year AUCs (0.725, 0.803, 0.870, and 0.764, 0.816, 0.798) of the training and validation cohorts proved the good predictive performance of the nomogram. Calibration curves and DCA curves demonstrated good consistency and good clinical utility. There were significant differences in RFS between the low-risk, intermediate-risk, and high-risk groups (P<0.0001). Conclusion: L-ALBI Patients who underwent TACE combined ablation had better recurrence-free survival than patients with H-ALBI. The nomogram developed and validated in our study had good predictive ability in recurrence for L-ALBI patients.

Synthesis and antiproliferative activity of CBD aromatic ester derivatives.

This study involved the synthesis of a series of novel cannabidiol (CBD) aromatic ester derivatives, including CBD-8,12-diaromaticester derivatives (compounds 2a-2t) and CBD-8,12-diacetyl-21-aromaticester derivatives (compound 5a-5c). The antiproliferative activities of these compounds against human liver cancer cell lines HePG2 and HeP3B as well as human pancreatic cancer cell lines ASPC-1 and BXPC-3 were evaluated in vitro using the CCK-8 assay. The results indicated that compound 2f exhibited an IC50 value of 2.75 µM against HePG2, which is 5.32-fold higher than that of CBD. Additionally, compounds 2b and 5b demonstrated varying degrees of improved anticancer activity (IC50 5.95-9.21 µM) against HePG2.

Efficacy and safety of sintilimab in combination with chemotherapy for recurrent extensive-stage small cell lung cancer: a real-world retrospective study.

Background: Immune checkpoint inhibitors (ICIs) no longer are approved for second-line or later treatment of extensive-stage small cell lung cancer (ES-SCLC), and have not been studied in combination with chemotherapy. Exploring the efficacy and safety of second-line or later immunotherapy for ES-SCLC is an urgent clinical question that needs to be addressed, and combination therapies are an important research direction. This study intended to investigate the efficacy and safety of the sintilimab in combination with chemotherapy as a second-line and beyond treatment option for ES-SCLC. Methods: Medical records of patients who received treatment with sintilimab in combination with chemotherapy or chemotherapy alone as a second-line or beyond therapy were retrospectively analyzed. The study evaluated efficacy and safety. Indicators of efficacy included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety indicators included adverse events (AEs). Results: This cohort comprised of 46 patients: 24 in the sintilimab combination chemotherapy group and 22 in the chemotherapy group. Chemotherapy received by both groups was either albumin-bound paclitaxel or irinotecan. Compared with the chemotherapy group, the sintilimab combination chemotherapy group had higher ORR and DCR (ORR: 37.5% vs. 9.1%, P=0.04; DCR: 75.0% vs. 40.9%, P=0.04), and significantly prolonged PFS and OS [median PFS (mPFS): 5.07 vs. 2.45 months, P=0.006; median OS (mOS): 14.43 vs. 10.34 months, P=0.009]. Also, there was no significant increase in the incidence of AEs in the sintilimab combination chemotherapy group, which was well tolerated by patients. Conclusions: Sintilimab in combination with chemotherapy is superior to single-agent chemotherapeutic treatment as second-line or later therapy in ES-SCLC patients who have not received prior immunotherapy. These results need to be confirmed in future clinical trials.

Ameliorating effects of the HIF-2α inhibitor PT2385 on high-altitude polycythemia.

High-altitude polycythemia (HAPC) is a common chronic altitude disease caused by living in low-pressure and low-oxygen environment. At present, there is still no effective cure for HAPC. HIF-2α may play an important role in the development of HAPC in regulating the increased red blood cell excessively induced by HIF-EPO and the blood vessel formation induced by VEGF-VEGFR. Here, we established a rat HAPC model and treated it with the HIF-2α inhibitor PT2385. We mainly evaluated the therapeutic effect of PT2385 on HAPC rats by observing the changes in rat phenotype, tissue and organ damage, red blood cell and hemoglobin content, angiogenesis, lipid peroxidation reaction, and inflammatory factors. The results showed that PT2385 treatment improved the congestion phenotype characteristics, inhibited increased erythrocytes and hemoglobin, reduced blood vessel formation, lipid peroxidation, and inflammation, and reduced tissue and organ damage in HAPC rats. This study preliminarly explains the physiological, pathological, and immunological effects of PT2385 treatment for HAPC. It provides a new idea, a reliable experimental basis, and theoretical support for the clinical prevention and treatment of HAPC.

A Facile One-Step Self-Assembly Strategy for Novel Carbon Dots Supramolecular Crystals with Ultralong Phosphorescence Controlled by NH4.

A new methodological design is proposed for carbon dots (CDs)-based crystallization-induced phosphorescence (CIP) materials via one-step self-assembled packaging controlled by NH4 +. O-phenylenediamine (o-PD) as a nitrogen/carbon source and the ammonium salts as oxidants are used to obtain CDs supramolecular crystals with a well-defined staircase-like morphology, pink fluorescence and ultralong green room-temperature phosphorescence (RTP) (733.56 ms) that is the first highest value for CDs-based CIP materials using pure nitrogen/carbon source by one-step packaging. Wherein, NH4 + and o-PD-derived oxidative polymers are prerequisites for self-assembled crystallization so as to receive the ultralong RTP. Density functional theory calculation indicates that NH4 + tends to anchor to the dimer on the surface state of CDs and guides CDs to cross-arrange in an X-type stacking mode, leading to the spatially separated frontier orbitals and the through-space charge transfer (TSCT) excited state in turn. Such a self-assembled mode contributes to both the small singlet-triplet energy gap (ΔEST) and the fast inter-system crossing (ISC) process that is directly related to ultralong RTP. This work not only proposes a new strategy to prepare CDs-based CIP materials in one step but also reveals the potential for the self-assembled behavior controlled by NH4 +.

The TAK1/JNK axis participates in adaptive immunity by promoting lymphocyte activation in Nile tilapia.

The transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) axis is an essential MAPK upstream mediator and regulates immune signaling pathways. However, whether the TAK1/JNK axis harnesses the strength in regulation of signal transduction in early vertebrate adaptive immunity is unclear. In this study, by modeling on Nile tilapia (Oreochromis niloticus), we investigated the potential regulatory function of TAK1/JNK axis on lymphocyte-mediated adaptive immune response. Both OnTAK1 and OnJNK exhibited highly conserved sequences and structures relative to their counterparts in other vertebrates. Their mRNA was widely expressed in the immune-associated tissues, while phosphorylation levels in splenic lymphocytes were significantly enhanced on the 4th day post-infection by Edwardsiella piscicida. In addition, OnTAK1 and OnJNK were significantly up-regulated in transcriptional level after activation of lymphocytes in vitro by phorbol 12-myristate 13-acetate plus ionomycin (P + I) or PHA, accompanied by a predominant increase in phosphorylation level. More importantly, inhibition of OnTAK1 activity by specific inhibitor NG25 led to a significant decrease in the phosphorylation level of OnJNK. Furthermore, blocking the activity of OnJNK with specific inhibitor SP600125 resulted in a marked reduction in the expression of T-cell activation markers including IFN-γ, CD122, IL-2, and CD44 during PHA-induced T-cell activation. In summary, these findings indicated that the conserved TAK1/JNK axis in Nile tilapia was involved in adaptive immune responses by regulating the activation of lymphocytes. This study enriched the current knowledge of adaptive immunity in teleost and provided a new perspective for understanding the regulatory mechanism of fish immunity.

SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer.

Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.

The impact of CYP3A4 genetic polymorphism on crizotinib metabolism and drug-drug interactions.

To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC50 values were 24.53 ± 0.32 µM in rat liver microsomes and 18.24 ± 0.12 µM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC(0-t), Cmax of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism.

Implicit 3D Human Reconstruction Guided by Parametric Models and Normal Maps.

Accurate and robust 3D human modeling from a single image presents significant challenges. Existing methods have shown potential, but they often fail to generate reconstructions that match the level of detail in the input image. These methods particularly struggle with loose clothing. They typically employ parameterized human models to constrain the reconstruction process, ensuring the results do not deviate too far from the model and produce anomalies. However, this also limits the recovery of loose clothing. To address this issue, we propose an end-to-end method called IHRPN for reconstructing clothed humans from a single 2D human image. This method includes a feature extraction module for semantic extraction of image features. We propose an image semantic feature extraction aimed at achieving pixel model space consistency and enhancing the robustness of loose clothing. We extract features from the input image to infer and recover the SMPL-X mesh, and then combine it with a normal map to guide the implicit function to reconstruct the complete clothed human. Unlike traditional methods, we use local features for implicit surface regression. Our experimental results show that our IHRPN method performs excellently on the CAPE and AGORA datasets, achieving good performance, and the reconstruction of loose clothing is noticeably more accurate and robust.

Structure of cryptophyte photosystem II-light-harvesting antennae supercomplex.

Cryptophytes are ancestral photosynthetic organisms evolved from red algae through secondary endosymbiosis. They have developed alloxanthin-chlorophyll a/c2-binding proteins (ACPs) as light-harvesting complexes (LHCs). The distinctive properties of cryptophytes contribute to efficient oxygenic photosynthesis and underscore the evolutionary relationships of red-lineage plastids. Here we present the cryo-electron microscopy structure of the Photosystem II (PSII)-ACPII supercomplex from the cryptophyte Chroomonas placoidea. The structure includes a PSII dimer and twelve ACPII monomers forming four linear trimers. These trimers structurally resemble red algae LHCs and cryptophyte ACPI trimers that associate with Photosystem I (PSI), suggesting their close evolutionary links. We also determine a Chl a-binding subunit, Psb-γ, essential for stabilizing PSII-ACPII association. Furthermore, computational calculation provides insights into the excitation energy transfer pathways. Our study lays a solid structural foundation for understanding the light-energy capture and transfer in cryptophyte PSII-ACPII, evolutionary variations in PSII-LHCII, and the origin of red-lineage LHCIIs.

Experimental study of the influence of variable external optical feedback on visible laser diode speckle.

This study employs an experimental setup with a variable feedback fraction (fext), external cavity length (ECL), and pump current (J) to investigate their relationships with optical linewidth and external optical feedback-induced speckle contrast (SC) reduction in a visible laser diode. In total, speckle contrast and optical linewidth data for seven feedback fractions, two pump currents, and three external cavity lengths were collected. Achieving optical linewidths up to 3.90 nm (1/e2 width) and a reduction in speckle contrast of up to 41.6%, we also revealed negative correlations between speckle contrast and optical linewidth, and speckle contrast and feedback fraction, and a positive correlation between optical linewidth and feedback fraction.

A multifactor hybrid model for carbon price interval prediction based on decomposition-integration framework.

Carbon price is a pivotal element in the carbon trading sector. Accurate estimation of carbon price can offer precise guidance for the carbon market participants. This study introduces a novel prediction model encompassing both point and interval prediction for the carbon price. Firstly, to distill the volatility traits inherent in carbon price, the successive variational mode decomposition is utilized to adaptively decompose the carbon price into regular sequences. Secondly, to obtain the optimal input variables, the partial autocorrelation function and random forest are employed to filter the influencing factors and historical carbon price. Then, to avoid single model constraint, a combination model of categorical boosting and kernel extreme learning machine optimized by the sparrow search algorithm is employed for the point prediction, and the shapley additive explanation is employed to elucidate the model prediction process. Finally, to provide more efficient information, the adaptive bandwidth kernel density estimation is applied to the interval prediction. The data from Hubei carbon market is adopted as a case study, and the results indicate that the mean absolute error, mean absolute percentage error, root mean square error and R2 of the proposed model are 0.1022, 0.0022, 0.1262 and 0.9921, respectively. The historical carbon price, Brent crude oil futures settlement price and European Union allowance futures carbon price have a positive impact on carbon price, and Hushen 300 has a negative impact on carbon price. Compared with the constant kernel density estimation, the proposed model achieves higher interval coverage probability and lower interval width. Thus, the application of the hybrid model can promote the operational efficiency of the carbon market and facilitate the implementation of carbon emission reduction policies.

Dispersion characteristics of arc-axis waveguides.

Ultrasonic single mode excitation methods, mode separation algorithms and damage detection applications all require the calculation of the dispersion characteristics of the waveguide. However, existing dispersion calculation methods are mainly applicable to straight-axis waveguides. Therefore, in this paper, a novel semi-analytical finite element method in cylindrical coordinates (SAFEM-CC) is established and we focus on the dispersion characteristics of arc-axis waveguides. The cross-section of the waveguide can have arbitrary complex shapes, and the correctness of this method is verified by the finite element eigenfrequency method. At the same time, this paper takes the example of an arc-axis structure with a square cross-section and investigates the convergence of SAFEM-CC under different numbers of elements, element types, and element orders. This paper also establishes a finite element simulation model to study the waveform transmission law over a wide frequency range and the wave amplitude distribution law within the cross-section of arc-axis waveguides. The dispersion characteristics of arc-axis waveguides at different radii are also investigated. Finally, the correctness of the proposed method and the dispersion characteristics of arc-axis waveguides are verified by a large number of experiments. The main conclusions are as follows: the waveform transmission laws of the guided wave in arc-axis waveguides at each frequency agree with the dispersion curve; the theoretical wavestructure gives the distribution law of the amplitude within the cross-section; when the axis is arc, the displacement of the wavestructure on the inner and outer sides does not have symmetry, and the difference between the left and right sides gradually increases as the radius decreases.

Invoking Interfacial Engineering Boosts Structural Stability Empowering Exceptional Cyclability of Ni-Rich Cathode.

The cycling stability of LiNi0.8Co0.1Mn0.1O2 under high voltages is hindered by the occurrence of hybrid anion- and cation-redox processes, leading to oxygen escape and uncontrolled phase collapse. In this study, an interfacial engineering strategy involving a straightforward mechanical ball milling and low-temperature calcination, employing a Se-doped and FeSe2&Fe2O3-modified approach is proposed to design a stable Ni-rich cathode. Se2- are selectively adsorbed within oxygen vacancies to form O─TM─Se bond, effectively stabilizing lattice oxygen, and preventing structural distortion. Simultaneously, the Se-NCM811//FeSe2//Fe2O3 self-assembled electric field is activated, improving interfacial charge transfer and coupling. Furthermore, FeSe2 accelerates Li+ diffusion and reacts with oxygen to form Fe2O3 and SeO2. The Fe2O3 coating mitigates hydrofluoric acid erosion and acts as an electrostatic shield layer, limiting the outward migration of oxygen anions. Impressively, the modified materials exhibit significantly improved electrochemical performance, with a capacity retention of 79.7% after 500 cycles at 1C under 4.5 V. Furthermore, it provides an extraordinary capacity retention of 94.6% in 3-4.25 V after 550 cycles in pouch-type full battery. This dual-modification approach demonstrates its feasibility and opens new perspective for the development of stable lithium-ion batteries operating at high voltages.

Development of Vogt-Koyanagi-Harada disease-like uveitis during treatment by anti-programmed death-1 antibody: a case report.

BACKGROUND: Several immune checkpoint inhibitors (ICIs) have been linked to the occurrence of Vogt-Koyanagi-Harada disease (VKHD)-like uveitis. Among the ICIs, there has been no report of immune-related adverse events (irAEs) caused by a new programmed death protein-1(PD-1) monoclonal antibody (Toripalimab). CASE PRESENTATION: This paper presents a case of VKHD-like uveitis that arose following Toripalimab therapy for urothelial cancer of the bladder, and the patient experienced symptoms 10 days after the final dosage of 20 months of medication treatment. This patient with bladder uroepithelial carcinoma had severe binocular acute panuveitis with exudative retinal detachment after receiving Toripalimab therapy. Binocular VKHD-like uveitis was suggested as a diagnosis. Both eyes recovered after discontinuing immune checkpoint inhibitors and local and systemic corticosteroid treatment. CONCLUSIONS: This report suggests that VKHD-like uveitis can also occur in patients receiving novel PD-1 antibodies and the importance of paying attention to eye complications in patients receiving treatment over a long period.

Association of depressive symptoms and sleep disturbances with survival among US adult cancer survivors.

BACKGROUND: Depression and sleep disturbances are associated with increased risks of various diseases and mortality, but their impacts on mortality in cancer survivors remain unclear. The objective of this study was to characterize the independent and joint associations of depressive symptoms and sleep disturbances with mortality outcomes in cancer survivors. METHODS: This population-based prospective cohort study included cancer survivors aged ≥ 20 years (n = 2947; weighted population, 21,003,811) from the National Health and Nutrition Examination Survey (NHANES) 2007-2018 cycles. Depressive symptoms and sleep disturbances were self-reported. Depressive symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9). Death outcomes were determined by correlation with National Death Index records through December 31, 2019. Primary outcomes included all-cause, cancer-specific, and noncancer mortality. RESULTS: During the median follow-up of 69 months (interquartile range, 37-109 months), 686 deaths occurred: 240 participants died from cancer, 146 from heart disease, and 300 from other causes. Separate analyses revealed that compared with a PHQ-9 score (0-4), a PHQ-9 score (5-9) was associated with a greater risk of all-cause mortality (hazard ratio [HR], 1.28; 95% CI, 1.03-1.59), and a PHQ-9 score (≥ 10) was associated with greater risk of all-cause mortality (HR, 1.37; 95% CI, 1.04-1.80) and noncancer mortality (HR, 1.45; 95% CI, 1.01-2.10). Single sleep disturbances were not associated with mortality risk. In joint analyses, the combination of a PHQ-9 score ≥ 5 and no sleep disturbances, but not sleep disturbances, was associated with increased risks of all-cause mortality, cancer-specific mortality, and noncancer mortality. Specifically, compared with individuals with a PHQ-9 score of 0-4 and no sleep disturbances, HRs for all-cause mortality and noncancer mortality in individuals with a PHQ-9 score of 5-9 and no sleep disturbances were 1.72 (1.21-2.44) and 1.69 (1.10-2.61), respectively, and 2.61 (1.43-4.78) and 2.77 (1.27-6.07), respectively, in individuals with a PHQ-9 score ≥ 10 and no sleep disturbances; HRs for cancer-specific mortality in individuals with a PHQ-9 score ≥ 5 and no sleep disturbances were 1.95 (1.16-3.27). CONCLUSIONS: Depressive symptoms were linked to a high risk of mortality in cancer survivors. The combination of a PHQ-9 score (≥ 5) and an absence of self-perceived sleep disturbances was associated with greater all-cause mortality, cancer-specific mortality, and noncancer mortality risks, particularly in individuals with a PHQ-9 score (≥ 10).

Total Synthesis of Brevitaxin.

Brevitaxin was prepared in nine steps from commercially available carnosic acid. The construction of the 1,4-benzodioxin moiety involved an unique stepwise ortho-quinone-engaged [4+2] cycloaddition. Two strategic stages were employed to prepare the highly unsaturated cycloaddition precursor 3: (1) synthesizing the diene moiety (C1-C2 and C10-C20 double bonds) by regioselective ortho-quinone tautomerization, and (2) installing four sp2-hybridized carbon atoms (C3, C5, C6 and C7) in one step using a SeO2-promoted chemo- and regioselective oxidation reaction.