Copper-Catalyzed Oxidative α-Double Bond Construction in α-Amino Carbonyl Compounds via Homocoupling with Arylamine Release.

Herein, we present a copper-catalyzed method for oxidative α-double bond formation in α-amino ketone compounds using DTBP as the oxidant. This process, involving homocoupling of α-amino radicals and arylamine release, efficiently produces a series of enaminone skeletons. The strategy has a broad substrate scope and functional group tolerance. In particular, arylamines bearing electron-rich substituents exhibit a pronounced reactivity. This approach facilitates the synthesis of diverse enaminones, enabling the efficient construction of nitrogen-containing heterocycles.

The promotion of cell proliferation and invasion in cutaneous squamous cell carcinomas after ARNT downregulation is associated with CXCL3.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor associated with adaptive responses to cellular stress. Its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. The aim of this study was to investigate the role of ARNT in cSCC. Immunohistochemistry revealed downregulation of ARNT in cSCC, precancerous lesions (actinic keratosis), and cells. Knockdown of ARNT in A431 and SCL-1 cells significantly enhanced cell growth and metastasis. Microarray analysis and Ingenuity Pathway Analysis confirmed that loss of ARNT in A431 cells was highly correlated with cell growth and movement and upregulated CXCL3 expression. Cellular and xenograft experiments further confirmed that ARNT regulates cSCC proliferation and invasiveness in a CXCL3-dependent manner. ARNT may regulate CXCL3 expression through ROS-STAT3 pathway. In conclusion, this study demonstrates that ARNT plays a critical role in the development of cSCC and significantly affects the proliferation and metastatic ability of cSCC cells. It has the potential to serve as an ideal treatment target for cSCC.

Development and validation of a nomogram to estimate fatigue probability in hemodialysis patients.

OBJECTIVE: This study aims to investigate the factors that influence fatigue in hemodialysis (HD) patients and to develop and validate a nomogram to estimate the probability of fatigue in this population. METHODS: This cross-sectional study collected 453 patients who underwent HD at the tertiary hospital in Hubei, China, from April to December 2023. They were randomly divided into a 70% training group (n = 316) and a 30% validation group (n = 137). In the training set, factors influencing fatigue were screened using multivariate logistic regression analysis, and a nomogram was developed to estimate fatigue probability in HD patients. The discrimination and calibration of the nomogram were validated in both the training and validation sets through the area under the receiver operating characteristic (ROC) curve (AUC) and the Hosmer-Lemeshow (H-L) test. RESULTS: In the training group, logistic regression showed that age, dialysis vintage, inter-dialysis weight gain, hemoglobin, depression, insomnia, and social support were variables associated with fatigue in HD patients. Based on these factors, a nomogram for assessing fatigue probability in HD patients was developed. The AUC was 0.955 (95% CI: 0.932-0.977) and 0.979 (95% CI: 0.961-0.997) in the training and validation sets. The results from the H-L test indicated a good fit. CONCLUSION: The nomogram can evaluate fatigue probability in HD patients and may serve as a convenient clinical tool.

Clinician Insights into Effective Components, Delivery Characteristics and Implementation Strategies of Ambulatory Palliative Care for People with Heart Failure: A Qualitative Analysis.

OBJECTIVES: To elicit perspectives from specialist palliative care (SPC) and cardiology clinicians concerning the necessary components, delivery characteristics and implementation strategies of successful ambulatory SPC for people with heart failure (HF). BACKGROUND: Palliative care is a recommended component of guideline-directed care for people with HF. However, optimal strategies to implement SPC within ambulatory settings are unknown. METHODS: We conducted a qualitative descriptive study composed of semistructured interviews with SPC and cardiology clinicians at Veterans Affairs Medical Centers (VAMCs) with the highest number of ambulatory SPC consultations within the VA system among people with HF between 2021 and 2022. Clinicians were asked how they provided ambulatory SPC and what they felt were the necessary components, delivery characteristics and implementation strategies of care delivery. Interviews were analyzed using directed content analysis. RESULTS: We interviewed 14 SPC clinicians and 9 cardiology clinicians at 7 national VAMCs; 43% were physicians, and 48% were advanced-practice registered nurses/physician associates. Essential components of ambulatory SPC encompassed discussion of goals of care (eg, prognosis, advance directives) and connecting patients/caregivers to resources (eg, home care). Preferred delivery characteristics included integrated (ie, embedded) approaches to SPC delivery, standardized patient selection and referral procedures, and formalized procedures for handoffs to and from SPC. Strategies that addressed SPC implementation included deploying palliative champions, educating non-SPC clinicians on the value of ambulatory SPC for people with HF and developing ambulatory models through leadership support. CONCLUSIONS/IMPLICATIONS: Facilitating the broader adoption of ambulatory SPC among people with HF may be achieved by prioritizing these mutually valued and necessary features of SPC delivery.

TGM1/3-mediated transamidation of Exo70 promotes tumor metastasis upon LKB1 inactivation.

Exo70, a key exocyst complex component, is crucial for cell motility and extracellular matrix (ECM) remodeling in cancer metastasis. Despite its potential as a drug target, Exo70's post-translational modifications (PTMs) are poorly characterized. Here, we report that Exo70 is transamidated on Gln5 with Lys56 of cystatin A by transglutaminases TGM1 and TGM3, promoting tumor metastasis. This modification enhances Exo70's association with other exocyst subunits, essential for secreting matrix metalloproteinases, forming invadopodia, and delivering integrins to the leading edge. Tumor suppressor liver kinase B1 (LKB1), whose inactivation accelerates metastasis, phosphorylates TGM1 and TGM3 at Thr386 and Thr282, respectively, to inhibit their interaction with Exo70 and the following transamidation. Cantharidin, a US Food and Drug Administration (FDA)-approved drug, inhibits Exo70 transamidation to restrain tumor cell migration and invasion. Together, our findings highlight Exo70 transamidation as a key molecular mechanism and target and propose cantharidin as a therapeutic strategy with direct clinical translational value for metastatic cancers, especially those with LKB1 loss.

Photoinduced copper catalyzed nitrogen-to-alkyl radical relay Sonogashira-type coupling of o-alkylbenzamides with alkynes.

This report describes a copper-catalyzed, photoinduced N-to-alkyl radical relay Sonogashira-type reactions at benzylic sites in o-alkylbenzamides with alkynes. The process employs an N-to-alkyl radical mechanism, initiated through the copper-catalyzed reductive generation of nitrogen radicals. Radical translocation is facilitated by a 1,5-hydrogen atom transfer (1,5-HAT), leading to the formation of translocated carbon radicals. These radicals are then subjected to copper-catalyzed alkynylation. The methodology exhibits broad sub-strate scope and applicability to the synthesis of complex natural products.

Variation in Specialist Palliative Care Reach and Associated Factors Among People With Advanced Heart Failure in the Department of Veterans Affairs.

CONTEXT: Clinical practice guidelines recommend palliative care for people with advanced heart failure (aHF), yet it remains underutilized. OBJECTIVES: We examined medical center variation in specialist palliative care (SPC) and identified factors associated with variation among people with aHF. METHODS: We conducted a retrospective cohort study of 21,654 people with aHF who received healthcare in 83 Veterans Affairs Medical Centers (VAMCs) from 2018-2020. We defined aHF with ICD-9/10 codes and hospitalizations. We used random intercept multilevel logistic regression to derive SPC reach (i.e., predicted probability) for each VAMC adjusting for demographic and clinical characteristics. We then examined VAMC-level SPC delivery characteristics associated with predicted SPC reach including the availability of outpatient SPC (proportion of outpatient consultations), cardiology involvement (number of outpatient cardiology-initiated referrals), and earlier SPC (days from aHF identification to consultation). RESULTS: Of the sample the mean age = 72.9+/-10.9 years, 97.9% were male, 61.6% were White, and 32.2% were Black. The predicted SPC reach varied substantially across VAMCs from 9% to 57% (mean: 28% [95% Confidence Interval: 25%-30%]). Only the availability of outpatient SPC was independently associated with higher SPC reach. VAMCs, in which outpatient delivery made up the greatest share of SPC consultations (9% or higher) had 11% higher rates of SPC reach relative to VAMCs with a lower proportion of outpatient SPC. CONCLUSION: SPC reach varies widely across VAMCs for people with aHF. Outpatient palliative is common among high-reach VAMCs but its role in reach warrants further investigation. Strategies used by high-reach VAMCs may be potential targets to test for implementation and dissemination.

Analysis of risk factors related to the progression rate of hemifacial spasm.

Introduction: Although there have been many researches on the etiology and risk factors with the onset of hemifacial spasm, researches on the risk factors related to progression rate are limited. This study aims to analyze the risk factors related to the progression rate of hemifacial spasm. Methods: The study enrolled 142 patients who underwent microvascular decompression for hemifacial spasm. Based on the duration and severity of symptoms, patients were classified into rapid progression group and slow progression group. To analyze risk factors, univariate and multivariate logistic regression analyses were conducted. Of 142 patients with hemifacial spasm, 90(63.3%) were classified as rapid progression group, 52(36.7%) were classified as slow progression group. Results: In the univariate analysis, there were significant statistical differences between the two groups in terms of age of onset (P = 0.021), facial nerve angle (P < 0.01), hypertension (P = 0.01), presence of APOE ε4 expression (P < 0.01) and different degrees of brainstem compression in the Root Entry Zone (P < 0.01). In the multivariable analyses, there were significant statistical differences between the two groups in terms of age of symptom onset (P < 0.01 OR = 6.591), APOE ε4 (P < 0.01 OR = 5.691), brainstem compression (P = 0.006 OR = 5.620), and facial nerve angle (P < 0.01 OR = 5.758). Furthermore, we found no significant correlation between the severity of facial spasms and the progression rate of the disease (t = 2.47, P = 0.12>0.05). Conclusion: According to our study, patients with facial nerve angle ≤ 96.5°, severer compression of the brainstem by offending vessels, an onset age > 45 years and positive expression of APOE ε4, may experience faster progression of hemifacial spasm.

Simultaneous determination of BGT-002 and its acyl glucuronide metabolite ZM326E-M2 in human plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

BGT-002, a new type of ATP-citrate lyase inhibitor, is a promising therapeutic for treatment of hypercholesterolemia. After an oral administration of BGT-002 to subjects, it underwent extensive metabolism and an acyl monoglucuronide (ZM326E-M2) on 1- carboxylic acid group was the major circulating metabolite. In this study, an LC-MS/MS method was developed and validated for the simultaneous determination of BGT-002 and ZM326E-M2 in plasma and the evaluation of their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes were separated on a Waters ACQUITY UPLC® BEH C18 column using acetonitrile and 2 mM ammonium acetate containing 0.1% formic acid as the mobile phase for gradient elution. Negative electrospray ionization was performed using multiple reaction monitoring (MRM) of m/z 501.3→325.4 for ZM326E-M2 and m/z 507.3→331.2 for D6-ZM326E-M2, and pseudo-MRM of m/z 325.3→325.3 for BGT-002 and m/z 331.3→331.3 for D6-ZM326E, respectively. The method was validated with respect to accuracy, precision, linearity, stability, selectivity, matrix effect, and recovery. The analytical range in human plasma was linear over a concentration range of 0.0500-50.0 µg/mL for BGT-002 and 0.0100-10.0 µg/mL for ZM326E-M2. The pharmacokinetic results showed that after a single oral administration of 100 mg BGT-002, the parent drug was rapidly absorbed with a mean time to peak concentration (tmax) of 1.13 h, compared with BGT-002, the tmax (4.00 h) of ZM326E-M2 was significantly delayed. The peak concentration and plasma exposure of ZM326E-M2 were about 14.1% and 19.5% of the parent drug, suggesting that attention should be paid to the safety and efficacy of ZM326E-M2 in clinical research.

Dielectric and Magnetic Composites of Fe3O4@APNs for Superior Microwave Thermal Effect.

As for the deep tissue infections of chronic osteomyelitis, antibiotics are hard to deliver into the infected bone tissue, which makes it difficult to be cured completely in clinic. Microwave has strong penetration, and the medium can produce a good bactericidal effect through the microwave thermal effect (MTE). Here, a new microwave sensitizer (Fe3O4@APNs) was prepared and evaluated. Black phosphorus nanosheets modified with phytic acid dodecasodium (APNs) were fabricated by a liquid-phase exfoliation method that exhibited good water oxygen stability. A complex with Fe3O4 compound and APNs (Fe3O4@APNs) was formed by an ultrasonic mixing process, which showed excellent MTE (quickly increased to 53.5 °C in 5 min at 2.45 GHz, 10 W/cm2) via dielectric versus magnetic loss (reflect loss value of -5.94 dB at 2.45 GHz). The Fe3O4@APNs microwave sensitizer developed in this study has an outstanding in vitro antibacterial effect and might show promise for the treatment of chronic osteomyelitis enabled by local tissue heating via the MTE.

Effects of health education during public health emergencies on the health literacy, emotion and coping style of Chinese junior middle school students: a randomized controlled trial.

BACKGROUND: Schools are high incidence places for public health emergencies. Good health literacy helps students cope with public health emergencies. Overall, the health literacy of young students is relatively low. Health education can promote health literacy, but the health education related to public health emergencies for Chinese junior middle school students needs to be improved. To design and implement health education courses related to public health emergencies for junior middle school students and examine the impact on their health literacy, emotions, and coping styles. METHODS: From March to December 2022, 724 students in Grade 7 and Grade 8 of two junior middle schools in Changzhou were randomly divided into a course group (n = 359) and a control group (n = 365). The course group received an age-appropriate health education course that addressed public health emergencies; there were 12 classes, one per week. The control group received general health education. One week before and after the courses, the two groups of students were assessed with the Adolescent Health Literacy Evaluation Scale under Public Health Emergencies (AHLES-PHE), the Depression Self-Rating Scale for Children (DSRSC), the Generalized Anxiety Disorder 7-item scale (GAD-7), and the Simplified Coping Style Questionnaire (SCSQ). RESULTS: After the courses were completed, the scores of AHLES-PHE [156.0 (45.0,180.0) vs. 165.0 (54.0,180.0), P < 0. 05] in the course group increased significantly. The positive rate of DSRSC [81 (22.6%) vs. 57 (15.9%), P < 0.05] and GAD-7 [45 (12.5%) vs. 29 (8.1), P < 0.05]in the course group were significantly lower than those before courses. There was no significant difference in the above indices before and after courses in the control group (P > 0.05). CONCLUSION: This suggests that the health education courses related to public health emergencies designed in this study has an effect on improving health literacy, depression and anxiety in junior middle school students.

Analyzing EFL learners' demotivating factors in blended learning context.

In second language and foreign language learning, demotivation in learning is a common occurrence. Almost all previous studies on learners' demotivation focused on traditional classroom learning environment rather than blended learning setting. This paper investigates learner perceptions of demotivating factors for Chinese EFL college students in blended learning context. 272 college sophomores with varied majors from a university in Mid-East China took part in a questionnaire survey. The questionnaire, consisted of 34 4-point Likert type items about learners' demotivation in a blended EFL learning environment, was adapted from Kikuchi's demotivation questionnaire and Xie's LPDS (Learner Perceptions of Demotivator Scale). An exploratory factor analysis was performed to explore the factor structure of the questionnaire items. Then mean scores of items loading on each factor were calculated and independent samples t-test analysis was adopted to examine the differences of demotivating factors between different groups of participants. Five demotivating factors from the questionnaire were extracted. The findings reveal a newly discovered factor: learners' lack of self-discipline in online learning. The paper indicates that there is no significant difference of these five demotivating factors between male and female learners, and between rural and urban learners. Whereas less motivated learners perceive four among the five factors to be more demotivating than more motivated learners.

HLA-targeted sequencing reveals the pathogenic role of HLA-B*15:02/HLA-B*13:01 in albendazole-induced liver failure: a case report and a review of the literature.

Drug-induced liver injury (DILI) is one of the serious adverse drug reactions (ADRs), which belongs to immune-mediated adverse drug reactions (IM-ADRs). As an essential health drug, albendazole has rarely been reported to cause serious liver damage. A young man in his 30 s developed severe jaundice, abnormal transaminases, and poor blood coagulation mechanism after taking albendazole, and eventually developed into severe liver failure. The patient was found heterozygous of HLA-B*15:02 and HLA-B*13:01 through HLA-targeted sequencing, which may have a pathogenic role in the disease. This case report summarizes his presentation, treatment, and prognosis. A useful summary of the diagnosis and associated genetic variant information is provided.

ITGB4 Serves as an Identification and Prognosis Marker Associated with Immune Infiltration in Small Cell Lung Carcinoma.

Integrin beta 4 (ITGB4) is a vital factor for numerous cancers. However, no reports regarding ITGB4 in small cell lung carcinoma (SCLC) have been found in the existing literature. This study systematically investigated the expression and clinical value of ITGB4 in SCLC using multi-center and large-sample (n = 963) data. The ITGB4 expression levels between SCLC and control tissues were compared using standardized mean difference and Wilcoxon rank-sum test. The clinical significance of the gene in SCLC was observed using Cox regression and Kaplan-Meier curves. ITGB4 is overexpressed in multiple cancers and represents significant value in distinguishing among cancer samples (AUC = 0.91) and predicting the prognoses (p < 0.05) of patients with different cancers. In contrast, decreased ITGB4 mRNA expression was determined in SCLC (SMD < 0), and this finding was further confirmed at protein levels using in-house specimens (p < 0.05). This decrease in expression may be attributed to the regulatory role of estrogen receptor 1. ITGB4 may participate in the progression of SCLC by affecting several signaling pathways (e.g., tumor necrosis factor signaling pathway) and a series of immune cells (e.g., dendritic cells) (p < 0.05). The gene may serve as a potential marker for predicting the disease status (AUC = 0.97) and prognoses (p < 0.05) of patients with SCLC. Collectively, ITGB4 was identified as an identification and prognosis marker associated with immune infiltration in SCLC.

The binding profile of SARS-CoV-2 with human leukocyte antigen polymorphisms reveals critical alleles involved in immune evasion.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), astonished the world and led to millions of deaths. Due to viral new mutations and immune evasion, SARS-CoV-2 ranked first in transmission and influence. The binding affinity of human leukocyte antigen (HLA) polymorphisms to SARS-CoV-2 might be related to immune escape, but the mechanisms remained unclear. In this study, we obtained the binding affinity of SARS-CoV-2 strains with different HLA proteins and identified 31 risk alleles. Subsequent structural predictions identified 10 active binding sites in these HLA proteins that may promote immune evasion. Particularly, we also found that the weak binding ability with HLA class I polymorphisms could contribute to the immune evasion of Omicron. These findings suggest important implications for preventing the immune evasion of SARS-CoV-2 and providing new insights for the vaccine design.

Xenon inhalation attenuates neuronal injury and prevents epilepsy in febrile seizure Sprague-Dawley pups.

Background: Febrile seizures (FS) usually occur in childhood and may cause irreversible neuronal damage, cognitive functional defects, and an increase in the risk of epilepsy later in life. Anti-epileptic drugs (AEDs), currently used to treat FS in children, can relieve seizures. However, their effects in preventing the risk of developing epilepsy in later life are unsatisfactory. Moreover, AEDs may damage child brain development. Here, we evaluated the efficiency of xenon in treating prolonged FS (PFS) and preventing epilepsy in Sprague-Dawley pups. Methods: Prolonged FS was induced by hyperthermic treatment. After 90 min of PFS, the pups in the xenon treatment group were immediately treated with 70% xenon/21% oxygen/9% nitrogen for 60 min. The levels of glutamate, mitochondrial oxidative stress, mitophagy, and neuronal injury, seizures, learning, and memory functions were measured at specific time points. Results: Neonatal period PFS led to spontaneous seizure, learning and memory dysfunction, accompanied by increased levels of glutamate, mitochondrial oxidative stress, mitophagy, and neuronal injury. Xenon treatment alleviated the changes caused by PFS and reduced the risk of PFS developing into epilepsy later. Conclusion: Our results suggest that xenon inhalation could be a potential therapeutic strategy to attenuate neuronal injury and prevent epilepsy in patients with FS.

Competitive Growth of Ge Quantum Dots on a Si Micropillar with Pits for a Precisely Site-Controlled QDs/Microdisk System.

Semiconductor quantum dots (QDs)/microdisks promise a unique system for comprehensive studies on cavity quantum electrodynamics and great potential for on-chip integrated light sources. Here, we report on a strategy for precisely site-controlled Ge QDs in SiGe microdisks via self-assembly growth of QDs on a micropillar with deterministic pits and subsequent etching. The competitive growth of QDs in pits and at the periphery of the micropillar is disclosed. By adjusting the growth temperature and Ge deposition, as well as the pit profiles, QDs can exclusively grow in pits that are exactly located at the field antinodes of the corresponding cavity mode of the microdisk. The inherent mechanism of the mandatory addressability of QDs is revealed in terms of growth kinetics based on the non-uniform surface chemical potential around the top of the micropillar with pits. Our results demonstrate a promising approach to scalable and deterministic QDs/microdisks with strong light-matter interaction desired for fundamental research and technological applications.

Validation of Electronic Health Record-Based Algorithms to Identify Specialist Palliative Care Within the Department of Veterans Affairs.

BACKGROUND: The measurement of specialist palliative care (SPC) across Department of Veterans Affairs (VA) facilities relies on algorithms applied to administrative databases. However, the validity of these algorithms has not been systematically assessed. MEASURES: In a cohort of people with heart failure identified by ICD 9/10 codes, we validated the performance of algorithms to identify SPC consultation in administrative data and differentiate outpatient from inpatient encounters. INTERVENTION: We derived separate samples of people by receipt of SPC using combinations of stop codes signifying specific clinics, current procedural terminology (CPT), a variable representing encounter location, and ICD-9/ICD-10 codes for SPC. We calculated sensitivity, specificity, and positive and negative predictive values (PPV, NPV) for each algorithm using chart review as the reference standard. OUTCOMES: Among 200 people who did and did not receive SPC (mean age = 73.9 years (standard deviation [SD] = 11.5), 98% male, 73% White), the validity of the stop code plus CPT algorithm to identify any SPC consultation was: Sensitivity = 0.89 (95% Confidence Interval [CI] 0.82-0.94), Specificity = 1.0 [0.96-1.0], PPV = 1.0 [0.96-1.0], NPV = 0.93 [0.86-0.97]. The addition of ICD codes increased sensitivity but decreased specificity. Among 200 people who received SPC (mean age = 74.2 years [SD = 11.8], 99% male, 71% White), algorithm performance in differentiating outpatient from inpatient encounters was: Sensitivity = 0.95 (0.88-0.99), Specificity = 0.81 (0.72-0.87), PPV = 0.38 (0.29-0.49), and NPV = 0.99 (0.95-1.0). Adding encounter location improved the sensitivity and specificity of this algorithm. CONCLUSIONS: VA algorithms are highly sensitive and specific in identifying SPC and in differentiating outpatient from inpatient encounters. These algorithms can be used with confidence to measure SPC in quality improvement and research across the VA.