Low temperature Cu-Cu direct bonding in air ambient by ultrafast surface grain growth.

Fine-grain copper (Cu) films (grain size: 100.36 nm) with a near-atomic-scale surface (0.39 nm) were electroplated. Without advanced post-surface treatment, Cu-Cu direct bonding can be achieved with present-day fine-grain Cu films at 130℃ in air ambient with a minimum pressure of 1 MPa. The instantaneous growth rate on the first day is 164.29 nm d-1. Also, the average growth rate (∆R/∆t) is evaluated by the present experimental results: (i) 218.185 nm d-1 for the first-day period and (ii) 105.58 nm d-1 during the first 14-day period. Ultrafast grain growth and near-atomic-scale surface facilitate grain boundary motion across the bonding interface, which is the key to achieve Cu-Cu direct bonding at 130℃ in air ambient.

Synthesis of alkynyl cyclopropa[c]coumarins via propargyl sulfonium salts as C1 synthons.

Herein, we present a novel approach for the preparation of alkynyl cyclopropa[c]coumarin derivatives with medium to good yields utilizing propargyl sulfonium salts as C1 synthons. Compared with Br-, using ClO4- as the counter anion significantly enhances the yield due to its lesser nucleophilic ability. This method features mild reaction conditions and a broad substrate scope with good diastereoselectivity when the substituted R1 group is at the 5-position of the coumarin scaffold.

Acute and preventive treatment of menstrual migraine: a meta-analysis.

BACKGROUND AND OBJECTIVES: About a quarter of migraine cases among women have menstrual migraine (MM), which is usually more severe, longer lasting, and less responsive to treatment than typical migraine. Randomized controlled trials (RCTs) have evaluated the efficacy of several medication in the acute and preventive treatment of MM; this meta-analysis compared the effectiveness of these treatments. METHODS: We conducted systematic searches in the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases. The primary outcomes of acute treatment trials were pain relief at 2 and 24 h after treatment compared with placebo or another treatment. The three endpoints we checked for studying MM prevention were: no recurrence of headaches each month, a 50% reduction in monthly migraine days from baseline, and a decrease in the mean number of headache days per month. RESULTS: Out of 342 studies, 26 RCTs met the criteria. Triptans, combined with or without other analgesics, were superior to placebo in providing pain relief in the acute treatment and prevention of MM. Among the treatments, sumatriptan and lasmiditan demonstrated superior pain relief at 2 h (OR: 4.62) and 24 h (OR: 4.81). Frovatriptan exhibited effectiveness in preventing headache recurrence, whereas galcanezumab and erenumab displayed significant preventive benefits in reducing headache days per month. CONCLUSION: Sumatriptan and lasmiditan are effective first-line treatments for acute MM. For prevention, frovatriptan may be the more effective of triptans. Compared with triptans, CGRP monoclonal antibodies, here including erenumab and galcanezumab, are more effective in reducing headache days, and therefore, in preventing MM.

Nutraceutical Potential of Djulis (Chenopodium formosanum) Hull: Phytochemicals, Antioxidant Activity, and Liver Protection.

Djulis (Chenopodium formosanum), a traditional Taiwanese crop enriched with phenolic compounds and betalain pigments, is associated with various health benefits, including antioxidant and hepatoprotective effects. This study analysed the phytochemical content and antioxidant capacity of extracts from both the hull and kernel of Djulis. The hull extract, which contained higher levels of flavonoids and exhibited superior antioxidant activity compared to the kernel extract, was selected for further in vivo studies. These experiments showed that oral administration of the Djulis hull crude extract significantly mitigated lipopolysaccharide (LPS)-induced acute liver injury (ALI) in mice by increasing the activity of the antioxidant enzyme glutathione peroxidase (GPx), reducing plasma levels of pro-inflammatory cytokine interferon gamma (IFN-γ), and enhancing liver levels of the anti-inflammatory cytokine interleukin-4 (IL-4). Additionally, the extract demonstrated potential in inhibiting the TLR4/NF-κB pathway, a critical signalling pathway in inflammation and apoptosis, offering insights into its protective mechanisms. These findings underscore Djulis hull's potential as a functional food ingredient for ALI prevention and propose a valuable application for agricultural by-products.

Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment.

A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1H-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.

Health-related Quality of Life of Patients with Rosacea: A Systematic Review and Meta-analysis of Real-world Data.

Patients with rosacea commonly experience stigmatization, which induces stress and thereby exacerbates their symptoms. Given the strong effects of rosacea on health-related quality of life (HRQoL), addressing the physical and psychosocial aspects of rosacea is essential. To examine the effects of rosacea on HRQoL, we conducted a systematic review and meta-analysis involving real-world data. PubMed, EMBASE, and the Cochrane Library were searched, and randomized controlled trials (RCTs), cross-sectional studies, and case series evaluating the HRQoL of patients with rosacea were included. HRQoL assessment tools such as the Dermatology Life Quality Index (DLQI) and Rosacea-Specific Quality-of-Life Questionnaire (RosaQoL) were used. Data on 13,453 patients were retrieved from 52 eligible studies: 4 RCTs, 15 case series, and 33 cross-sectional studies. Compared with healthy controls, patients with rosacea had significantly lower DLQI scores (standardized mean difference [SMD] = -1.09, 95% confidence interval [CI] = -0.81 to -1.37). The DLQI scores after treatment were higher than those before treatment (SMD = -1.451, 95% CI = -1.091 to -1.810). The pooled estimates for the overall DLQI and RosaQoL scores were 8.61 and 3.06, respectively. In conclusion, patients with rosacea have lower HRQoL compared with healthy individuals, and treatment for rosacea improves their HRQoL.

MicroRNA-146a Signature in Psoriasis: A Systematic Review and Meta-Analysis.

BACKGROUND: Psoriasis is a chronic, inflammatory, T-cell-mediated disease with a multifactorial pathogenesis. MicroRNA (miRNA) alteration in psoriasis has been identified within the last few years. In particular, miR-146a levels were altered. However, previous studies have equivocal or even contradictory findings. OBJECTIVE: The current study aimed to perform a systematic review and meta-analysis to evaluate the miRNA expression profile in different tissues in patients with psoriasis. Further, the correlation between miR-146a levels and psoriasis severity as well as the specific expression patterns of the miR-146a profile in patients with psoriasis after treatment were evaluated. METHODS: To retrieve studies investigating the correlation between miRNA and psoriasis, a comprehensive search of databases including PubMed, Cochrane Library, and Embase was performed from inception to 30 June 2023. Relevant journals and references of the included studies were also reviewed. A meta-analysis was conducted using the comprehensive meta-analysis version 3. RESULTS: The correlation between the miR-146a expression levels and psoriasis susceptibility in 14 studies was assessed. Results showed that the miR-146a expression level was upregulated in psoriasis samples [P = 0.001, standardized mean difference (SMD) = 1.489, 95% confidence interval (CI) = 0.618-2.360]. In a subgroup analysis based on sample type, the correlation between the peripheral blood mononuclear cell, blood, and tissue miR-146a expression level and psoriasis was significant (SMD = 1.293, 95% CI 0.310-2.276, P = 0.01; SMD = 2.526, 95% CI 1.710-3.342, P = 0.000; SMD = 3.153, 95% CI 1.432-4.874, P = 0.00, respectively). A positive correlation was observed between the miR-146a expression levels and Psoriasis Area and Severity Index (PASI) score. However, the result was not statistically significant (correlation coefficient = 0.29, 95% CI - 0.038 to 0.575, P = 0.081). Further, the miR-146a levels decreased after treatment (SMD = - 1.592, 95% CI - 2.067 to - 1.117, P = 0.000, I2 = 74.104). CONCLUSIONS: The miR-146a expression level is positively correlated with and can contribute to the pathobiology of psoriasis.

Anti-Inflammatory Effects of Anthocyanin-Enriched Black Soybean Seed Coat (BSSC) Crude Extract on LPS-Induced Acute Liver Injury in Mice.

Soybeans rank among the top five globally produced crops. Black soybeans contain anthocyanins in their seed coat, offering strong antioxidant and anti-inflammatory benefits. This study explores the protective effects of black soybean seed coat (BSSC) against acute liver injury (ALI) in mice. Mice pretreated with BSSC crude extract showed reduced liver damage, inflammation, and apoptosis. High doses (300 mg/kg) of the extract decreased levels of proinflammatory cytokines (IL-6, IFN-γ) and increased levels of anti-inflammatory ones (IL-4, IL-10), alongside mitigating liver pathological damage. Additionally, it influenced the Nrf2/HO-1 pathway and reduced levels of apoptosis-related proteins. In vitro, the compounds delphinidin-3-O-glucoside (D3G) and cyanidin-3-O-glucoside (C3G) in BSSC were found to modulate cytokine levels, suggesting their role in ALI protection. The study concludes that BSSC extract, particularly due to D3G and C3G, effectively protects against LPS-induced ALI in mice by inhibiting inflammation, oxidative stress, and apoptosis.

Oral Dexmedetomidine Achieves Superior Effects in Mitigating Emergence Agitation and Demonstrates Comparable Sedative Effects to Oral Midazolam for Pediatric Premedication: A Systematic Review and Meta-Analysis of Randomized Controlled Studies.

Background: Oral midazolam is the most commonly used sedative premedication agent in pediatric patients. While effective, oral midazolam cannot reduce the incidence of emergence agitation. Oral dexmedetomidine may be effective in providing satisfactory sedation and reduce the incidence of emergence agitation, although the results of different randomized controlled trials are conflicting. Methods: This study enrolled randomized controlled trials (RCTs) examining premedication with oral dexmedetomidine versus oral midazolam in pediatric patients undergoing general anesthesia. PubMed, the Cochrane Library, Embase, and the Web of Science database were searched from their inception until June 2023. The outcomes were the incidence of satisfactory preoperative sedation, satisfactory sedation during separation from parents, satisfactory sedation during anesthesia induction using an anesthesia mask, and the incidence of emergence agitation. Results: A total of 9 RCTs comprising 885 patients were analyzed. Our data revealed comparable effects of dexmedetomidine and midazolam with respect to satisfactory preoperative sedation and a satisfactory incidence of sedation during parental separation and mask acceptance before anesthesia induction. Notably, our data revealed that the rate of emergence agitation was significantly lower in pediatric patients receiving dexmedetomidine (n = 162) than in those receiving midazolam (n = 159) (odds ratio = 0.16; 95% confidence interval: 0.06 to 0.44; p < 0.001; I2 = 35%). Conclusions: Data from this meta-analysis revealed comparable effects for premedication with oral dexmedetomidine or oral midazolam with respect to satisfactory sedation; furthermore, premedication with oral dexmedetomidine more effectively mitigated emergence agitation in pediatric patients receiving general anesthesia compared with oral midazolam.

Synthesis and Characterization of DOPO-Containing Poly(2,6-dimethyl-1,4-phenylene oxide)s by Oxidative Coupling Polymerization.

A set of polyphenylene oxides incorporating DOPO (9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide) functionality, denoted as DOPO-R-PPO, was synthesized by copolymerization of 2,6-dimethylphenol (2,6-DMP) with various DOPO-substituted tetramethyl bisphenol monomers. In the initial step, a Friedel-Crafts acylation reaction was employed to react 2,6-DMP with different acyl chlorides, leading to the formation of ketone derivatives substituted with 2,6-dimethylphenyl groups. Subsequently, the ketones, along with DOPO and 2,6-DMP, underwent a condensation reaction to yield a series of DOPO-substituted bisphenol derivatives. Finally, polymerizations of 2,6-dimethylphenol with these DOPO-substituted bisphenols were carried out in organic solvents using copper(I) bromide/N-butyldimethylamine catalysts (CuBr/DMBA) under a continuous flow of oxygen, yielding telechelic PPO oligomers with DOPO moieties incorporated into the polymer backbone. The chemical structures of the synthesized compounds were characterized using various analytical techniques, including Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), phosphorus nuclear magnetic resonance (31P NMR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). When compared to conventional poly(2,6-dimethyl-1,4-phenylene oxide)s with a similar molecular weight range, all DOPO-PPOs exhibited higher glass transition temperatures, enhanced thermal degradability, and increased char yield formation at 800 °C without compromising solubility in organic solvents.

MiR-630 Promotes Radioresistance by Induction of Anti-Apoptotic Effect via Nrf2-GPX2 Molecular Axis in Head-Neck Cancer.

Head and neck cancer (HNC) ranks among the top ten prevalent cancers worldwide. Radiotherapy stands as a pivotal treatment component for HNC; however, radioresistance in cancerous cells often leads to local recurrence, becoming a substantial factor in treatment failure. MicroRNAs (miRNAs) are compact, non-coding RNAs that regulate gene expression by targeting mRNAs to inhibit protein translation. Although several studies have indicated that the dysregulation of miRNAs is intricately linked with malignant transformation, understanding this molecular family's role in radioresistance remains limited. This study determined the role of miR-630 in regulating radiosensitivity in HNC. We discovered that miR-630 functions as an oncomiR, marked by its overexpression in HNC patients, correlating with a poorer prognosis. We further delineated the malignant function of miR-630 in HNC cells. While it had a minimal impact on cell growth, the miR-630 contributed to radioresistance in HNC cells. This result was supported by decreased cellular apoptosis and caspase enzyme activities. Moreover, miR-630 overexpression mitigated irradiation-induced DNA damage, evidenced by the reduced levels of the γ-H2AX histone protein, a marker for double-strand DNA breaks. Mechanistically, the overexpression of miR-630 decreased the cellular ROS levels and initiated Nrf2 transcriptional activity, resulting in the upregulation of the antioxidant enzyme GPX2. Thus, this study elucidates that miR-630 augments radioresistance by inducing an anti-apoptotic effect via the Nrf2-GPX2 molecular axis in HNC. The modulation of miR-630 may serve as a novel radiosensitizing target for HNC.

Risk factors for poor progression of addictive internet use across different COVID-19 periods in China.

BACKGROUND AND OBJECTIVES: Addictive behaviors are serious factors for mental health and usually increase during public crises. We identified the vulnerable characteristics for bad prognosis of addictive internet use across different periods of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Self-reported questionnaires were delivered in three waves through jdh.com during the outbreak (n = 17,960), remission (n = 15,666), and dynamic zero (n = 12,158) periods of COVID-19 pandemic in China. Internet addiction degree was assessed using the Internet Addiction Test. The different progression groups were divided using a latent class growth model among 1679 longitudinal participants. Risk factors for bad progression were identified by two-step logistic regression. RESULTS: A total of 40.16% of participants reported an increase in the addictive degree of internet use compared with prepandemic. Across different COVID-19 periods, the overall trend of addictive internet use was downward among general Chinese study participants (Mslope = -1.56). Childhood traumatic experiences, deterioration of physical health, depression, and anxiety during remission and dynamic periods were the main risk factors for the bad progression of pandemic-induced addictive internet use. DISCUSSION AND CONCLUSIONS: Addictive internet use was remitted following relaxed control policies during the COVID-19 pandemic. Negative childhood experiences and bad mental status during the recovery period were harmful to coping with pandemic-related addictive internet use. SCIENTIFIC SIGNIFICANCE: Our findings profiled the general trend of addictive internet use and the vulnerable characteristics of its bad progression across different periods of the first wave of COVID-19 pandemic in China. Our findings provide valuable insights for preventing the long-term adverse effects of negative public events on Internet addiction.

Risk Stratification for Herpes Simplex Virus Pneumonia Using Elastic Net Penalized Cox Proportional Hazard Algorithm with Enhanced Explainability.

Herpes simplex virus (HSV) pneumonia is a serious and often fatal respiratory tract infection that occurs in immunocompromised individuals. The early detection of accurate risk stratification is essential in identifying patients who are at high risk of mortality and may benefit from more aggressive treatment. In this study, we developed and validated a risk stratification model for HSV bronchopneumonia using an elastic net penalized Cox proportional hazard algorithm. We analyzed data from a cohort of 104 critically ill patients with HSV bronchopneumonia identified in Chang Gung Memorial Hospital, Linkou, Taiwan: one of the largest tertiary medical centers in the world. A total of 109 predictors, both clinical and laboratory, were identified in this process to develop a risk stratification model that could accurately predict mortality in patients with HSV bronchopneumonia. This model was able to differentiate the risk of death and predict mortality in patients with HSV bronchopneumonia compared to the APACHE II score in the early stage of ICU admissions. Both hazard ratio coefficient and selection frequency were used as the metrics to enhance the explainability of the informative predictors. Our findings suggest that the elastic net penalized Cox proportional hazard algorithm is a promising tool for risk stratification in patients with HSV bronchopneumonia and could be useful in identifying those at high risk of mortality.

Achieving a Highly Stable Perovskite Photodetector with a Long Lifetime Fabricated via an All-Vacuum Deposition Process.

Hybrid organic-inorganic metal halide perovskites (HOIP) have become a promising visible light sensing material due to their excellent optoelectronic characteristics. Despite the superiority, overcoming the stability issue for commercialization remains a challenge. Herein, an extremely stable photodetector was demonstrated and fabricated with Cs0.06FA0.94Pb(I0.68Br0.32)3 perovskite by an all-vacuum process. The photodetector achieves a current density up to 1.793 × 10-2 A cm-2 under standard one sun solar illumination while maintaining a current density as low as 8.627 × 10-10 A cm-2 at zero bias voltage. The linear dynamic range (LDR) and transient voltage response were found to be comparable to the silicon-based photodetector (Newport 818-SL). Most importantly, the device maintains 95% of the initial performance after 960 h of incessant exposure under one sun solar illumination. The achievements of these outstanding results contributed to the all-vacuum deposition process delivering a film with high stability and good uniformity, which in turn delays the degradation process. The degradation mechanism is further investigated by impedance spectroscopy to reveal the charge dynamics in the photodetector under different exposure times.

Risk Factors for Influenza-Induced Exacerbations and Mortality in Non-Cystic Fibrosis Bronchiectasis.

Influenza infection is a cause of exacerbations in patients with chronic pulmonary diseases. The aim of this study was to investigate the clinical outcomes and identify risk factors associated with hospitalization and mortality following influenza infection in adult patients with bronchiectasis. Using the Chang Gung Research Database, we identified patients with bronchiectasis and influenza-related infection (ICD-9-CM 487 and anti-viral medicine) between 2008 and 2017. The main outcomes were influenza-related hospitalization and in-hospital mortality rate. Eight hundred sixty-five patients with bronchiectasis and influenza infection were identified. Five hundred thirty-six (62%) patients with bronchiectasis were hospitalized for influenza-related infection and 118 (22%) patients had respiratory failure. Compared to the group only seen in clinic, the hospitalization group was older, with more male patients, a lower FEV1, higher bronchiectasis aetiology comorbidity index (BACI), and more acute exacerbations in the previous year. Co-infections were evident in 55.6% of hospitalized patients, mainly caused by Pseudomonas aeruginosa (15%), fungus (7%), and Klebsiella pneumoniae (6%). The respiratory failure group developed acute kidney injury (36% vs. 16%; p < 0.001), and shock (47% vs. 6%; p < 0.001) more often than influenza patients without respiratory failure. The overall mortality rate was 10.8% and the respiratory failure group exhibited significantly higher in-hospital mortality rates (27.1% vs. 6.2%; p < 0.001). Age, BACI, and previous exacerbations were independently associated with influenza-related hospitalization. Age, presence of shock, and low platelet counts were associated with increased hospital mortality. Influenza virus caused severe exacerbation in bronchiectasis, especially in those who were older and who had high BACI scores and previous exacerbations. A high risk of respiratory failure and mortality were observed in influenza-related hospitalization in bronchiectasis. We highlight the importance of preventing or treating influenza infection in bronchiectasis.

Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (S)-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFRL858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52. Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (F = 27%), respectively. With an extraordinary kinome selectivity (S(10) score of 0.017), 52 undergoes detailed preclinical development.

Treating fibromyalgia with electrical neuromodulation: A systematic review and meta-analysis.

OBJECTIVE: Several types of electrical neuromodulation (such as transcranial direct current stimulation, tDCS; transcutaneous electrical nerve stimulation) have been applied in the treatment of fibromyalgia. These trials had different outcome measurements, such as subjective pain, pain threshold, depression, anxiety, and functioning. We intended to integrate data from different trials into a meta-analysis to clearly present the clinical value of electrical neuromodulation in fibromyalgia. METHODS: A systematic review and meta-analysis of randomized controlled trials comparing the effect of all types of electrical neuromodulation in patients with fibromyalgia was conducted. The main outcome was subjective pain; the secondary outcomes included depression, anxiety, and functioning. RESULTS: Twenty-five studies and 1061 fibromyalgia patients were included in the quantitative analysis. Active electrical neuromodulation and active tDCS both showed significant effects on subjective pain, depression, and functioning. For different anode tDCS electrode positions, only F3-F4 revealed a significant effect on depression. Meta-regression tDCS effects on depression were significantly associated with age. CONCLUSIONS: Electrical neuromodulation is significantly effective in treating pain, depression, and functioning in patients with fibromyalgia. SIGNIFICANCE: The results may help clinicians to arrange effective treatment plans for patients with fibromyalgia, especially in those patients who reveal limited response to pharmacotherapy and psychotherapy.