Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Complete genome sequence of Sphingomonas sp. strain R1, a bacterium isolated from tomato (Solanum lycopersicum).

Sphingomonas sp. strain R1 was isolated from the stem of a tomato plant and exhibited antagonism with Agrobacterium. The complete genome sequence of this bacterium consists of one 3,874,532 bp circular chromosome and two plasmids.

Ti3C2Tx Coated with TiO2 Nanosheets for the Simultaneous Detection of Ascorbic Acid, Dopamine and Uric Acid.

Two-dimensional MXenes have become an important material for electrochemical sensing of biomolecules due to their excellent electric properties, large surface area and hydrophilicity. However, the simultaneous detection of multiple biomolecules using MXene-based electrodes is still a challenge. Here, a simple solvothermal process was used to synthesis the Ti3C2Tx coated with TiO2 nanosheets (Ti3C2Tx@TiO2 NSs). The surface modification of TiO2 NSs on Ti3C2Tx can effectively reduce the self-accumulation of Ti3C2Tx and improve stability. Glassy carbon electrode was modified by Ti3C2Tx@TiO2 NSs (Ti3C2Tx@TiO2 NSs/GCE) and was able simultaneously to detect dopamine (DA), ascorbic acid (AA) and uric acid (UA). Under concentrations ranging from 200 to 1000 µM, 40 to 300 µM and 50 to 400 µM, the limit of detection (LOD) is 2.91 µM, 0.19 µM and 0.25 µM for AA, DA and UA, respectively. Furthermore, Ti3C2Tx@TiO2 NSs/GCE demonstrated remarkable stability and reliable reproducibility for the detection of AA/DA/UA.

Transcriptional, post-transcriptional, and post-translational regulation of polyunsaturated fatty acid synthase genes in Aurantiochytrium limacinum strain BL10: Responses to nitrogen starvation.

Under nitrogen deficient conditions, the Aurantiochytrium limacinum strain BL10 greatly increases the production of docosahexaenoic acid (DHA) and n-6 docosapentaenoic acid. Researchers have yet to elucidate the mechanism by which BL10 promotes the activity of polyunsaturated fatty acid synthase (Pfa), which plays a key role in the synthesis of polyunsaturated fatty acid (PUFA). Analysis in the current study revealed that in nitrogen-depleted environments, BL10 boosts the transcription and synthesis of proteins by facilitating the expression of pfa genes via transcriptional regulation. It was also determined that BL10 adjusts the lengths of the 5'- and 3'-untranslated regions (suggesting post-transcriptional regulation) and modifies the ratio of two Pfa1 isoforms to favor PUFA production via post-translational regulation (ubiquitination). These findings clarify the exceptional DHA production of BL10 and provide additional insights into the regulatory mechanisms of PUFA biosynthesis in Aurantiochytrium.

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Non-Squamous EGFR-Wildtype NSCLC in the Phase 2 LUMINOSITY Trial.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase 2 LUMINOSITY trial (NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage 1) and expand the selected group for efficacy evaluation (stage 2). Stage 2 enrolled patients with non-squamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 prior lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in non-squamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg every 2 weeks. Primary endpoint was overall response rate (ORR) by independent central review. RESULTS: In total, 172 patients with non-squamous EGFR-wildtype NSCLC received Teliso-V in stages 1 and 2. ORR was 28.6% (95% CI, 21.7-36.2; c-Met high, 34.6% [24.2-46.2]; c-Met intermediate, 22.9% [14.4-33.4]). Median duration of response was 8.3 months (95% CI, 5.6-11.3; c-Met high, 9.0 [4.2-13.0]; c-Met intermediate: 7.2 [5.3-11.5]). Median overall survival was 14.5 months (95% CI, 9.9-16.6; c-Met high, 14.6 [9.2-25.6]; c-Met intermediate, 14.2 [9.6-16.6]). Median progression-free survival was 5.7 months (95% CI, 4.6-6.9; c-Met high, 5.5 [4.1-8.3]; c-Met intermediate: 6.0 [4.5-8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 was peripheral sensory neuropathy (7%). CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing non-squamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Systematic Studies on the Anti-SARS-CoV-2 Mechanisms of Tea Polyphenol-Related Natural Products.

The causative pathogen of COVID-19, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), utilizes the receptor-binding domain (RBD) of the spike protein to bind to human receptor angiotensin-converting enzyme 2 (ACE2). Further cleavage of spike by human proteases furin, TMPRSS2, and/or cathepsin L facilitates viral entry into the host cells for replication, where the maturation of polyproteins by 3C-like protease (3CLpro) and papain-like protease (PLpro) yields functional nonstructural proteins (NSPs) such as RNA-dependent RNA polymerase (RdRp) to synthesize mRNA of structural proteins. By testing the tea polyphenol-related natural products through various assays, we found that the active antivirals prevented SARS-CoV-2 entry by blocking the RBD/ACE2 interaction and inhibiting the relevant human proteases, although some also inhibited the viral enzymes essential for replication. Due to their multitargeting properties, these compounds were often misinterpreted for their antiviral mechanisms. In this study, we provide a systematic protocol to check and clarify their anti-SARS-CoV-2 mechanisms, which should be applicable for all of the antivirals.

Molecular Characterization and Potential Host-switching of Swine Farm associated Clostridioides difficile ST11.

OBJECTIVE: To conduct molecular prevalence and genetic polymorphism analysis of 24 Swine Farm associated C. difficile ST11 strains, in addition to other representative sequenced ST strains. METHODS: The collected C. difficile strains underwent whole genome sequencing and bioinformatic analysis using the illumina NovaSeq platform, SPAdes, Prokka, MOB-suite, and FastTree. Virulence and antibiotic resistance genes were identified through NCBI Pathogen Database. Cytotoxicity tests were conducted on HT-29 cells and Vero cells to verify the function of toxin A and toxin B. RESULTS: The most prevalent resistance genes in ST11 were found to be against ß-lactamases, aminoglycosides, and tetracycline. A C. difficile isolate (strain 27) with tcdA deletion and high antibiotic resistance genes was far apart from other swine farm associated ST11 isolates in the phylogenetic branch. The remarkable genetic similarity between animal and human C. difficile strains suggests potential transmission of ST11 strains between animals and humans. The plasmid replicon sequences repUS43 were identified in all ST11 strains except one variant (strain 27), and 91.67% (22/24) of these were assessed by MOB-typer as having mobilizable plasmids. CONCLUSION: Swine farm associated C. difficile ST11 carried fewer virulence genes than ST11 strains collected from NCBI database. It is critical to monitor the evolution of C. difficile strains to understand their changing characteristics, host-switching, and develop effective control and prevention strategies.

A cyclic dipeptide for salinity stress alleviation and the trophic flexibility of endophyte provide insights into saltmarsh plant-microbe interactions.

In response to climate change, the nature of endophytes and their applications in sustainable agriculture have attracted the attention of academics and agro-industries. This work focused on the endophytic halophiles of the endangered Taiwanese salt marsh plant, Bolboschoenus planiculmis, and evaluated the functions of these isolates through in planta salinity stress alleviation assay using Arabidopsis. The endophytic strain Priestia megaterium BP01R2, which can promote plant growth and salinity tolerance, was further characterized through multi-omics approaches. The transcriptomics results suggested that BP01R2 could function by tuning hormone signal transduction, energy-producing metabolism, multiple stress responses, etc. In addition, the cyclodipeptide cyclo(L-Ala-Gly), which was identified by metabolomics analysis, was confirmed to contribute to the alleviation of salinity stress in stressed plants via exogenous supplementation. In this study, we used multi-omics approaches to investigate the genomics, metabolomics, and tropisms of endophytes, as well as the transcriptomics of plants in response to the endophyte. The results revealed the potential molecular mechanisms underlying the occurrence of biostimulant-based plant-endophyte symbioses with possible application in sustainable agriculture.

An injectable, chitosan-based hydrogel prepared by Schiff base reaction for anti-bacterial and sustained release applications.

Injectable hydrogels, providing sustained release as implanted materials, have received tremendous attention. In this study, chitosan-based hydrogels were prepared via Schiff base reaction of the aldehyde groups on Poly(NIPAM-co-FBEMA) and the amine groups on chitosan. Owing to the dynamic covalent linkage, the SC/PNF hydrogels exhibit pH-responsive, reversible sol-gel transition, injectable, and self-healing capacity. The mechanical strength of SC/PNF hydrogels can be operated simply by switching the composition or solid content of Poly(NIPAM-co-FBEMA) copolymers. Rheological analyses, including frequency sweeps, strain sweep scanning, and dynamic time sweeps, were employed to demonstrate the relationship between storage modulus (G'), loss modulus (G″), and composition of the SC/PNF hydrogels. In vitro release behaviors reveal that vancomycin-loaded SC/PNF hydrogel could contribute to both the initial burst release (over 1000 ppm within 4 h) and the sustained release (3000 ppm for at least 30 days). Pristine SC/PNF hydrogel holds good biocompatibility toward L929 cells and S. aureus that it degrades as incubated with S. aureus. However, vancomycin-wrapped SC/PNF hydrogel possesses a rapid bacterial-killing effect with a clear inhibition zone. In short, the SC/PNF hydrogels deliver not only sustainable release ability but also tunable physical properties, which are expected to be an outstanding candidate for non-invasive, anti-infection applications.

Hofmeister-Effect-Driven Hybrid Glycerogels for Perfect Wide-Temperature Shape Fixity and Shape Recovery in Soft Robotics Applications.

Shape memory gels have emerged as crucial elements in soft robotics, actuators, and biomedical devices; however, several problems persist, like the trade-off between shape fixity and shape recovery, and the limited temperature range for their application. This article introduces a new class of shape memory hybrid glycerogels (GGs) designed to address these limitations. The well-modulated internal structure of the GGs, facilitated by the Hofmeister salting-out effect, strategically incorporates a higher crystallite content, abundant crosslinking points, and a high elastic modulus. Unlike reported shape memory gels, the GG exhibits a perfect triple-step shape memory behavior in air with 100% shape fixity in a wide programming temperature range (75-135 °C) and simultaneously achieves 100% shape recoverability. The gel recovers its shape at -40 °C under near-infrared light across a wide programming temperature range (25-135 °C), showing unexpected initiation even at subzero temperatures. Inspired by the mechanics of composite structures, a method is proposed to integrate the GG seamlessly with a shape memory alloy, which further expands the temperature range that yields perfect shape memory properties. Finally, two light-controlled fluttering and crawling soft robot prototypes are engineered to illustrate the versatility and potential applications of the composite gel in soft robotics.

Biomechanical comparisons of F.E.R.I. techniques with different type of intramedullary screws fixation for Jones fractures.

Introduction: Jones fractures frequently fail to unite, and adequate fixation stability is crucial. This study aimed to elucidate the biomechanical stability of various intramedullary screw fixation constructs. Methods: Jones fracture model over the proximal 5th metatarsal of artificial bone was created in all specimens. Six groups were divided based on varied screw constructs with different screw lengths, either 30 or 40 mm, including cannulated screws-C30 and C40 groups, one high-resistance suture combined with intramedullary cannulated screws (F.E.R.I. technique)-CF30 and CF40 groups, and second-generation headless compression screws (SG-HCS) -HL30 and HL40 groups. Mechanical testing was conducted sequentially, and the maximal force (N) and stiffness (N/mm) of all constructs were recorded. Results: The maximal force (N) at 1.0 mm downward displacement in C30, C40, CF30, CF40, HL30, and HL40 groups were 0.56 ± 0.02, 0.49 ± 0.02, 0.65 ± 0.02, 0.49 ± 0.01, 0.68 ± 0.02, and 0.73 ± 0.02, respectively, and the stiffness (N/mm) in subgroups were 0.49 ± 0.01, 0.43 ± 0.01, 0.67 ± 0.01, 0.42 ± 0.01, 0.61 ± 0.01, and 0.58 ± 0.02, respectively. SG-HCS subgroups exhibited greater maximal force and stiffness than conventional cannulated screws. Screws of 30 mm in length demonstrated better stability than all 40 mm-length screws in each subgroup. In C30 fixation, the stiffness and maximum force endured increased by 1.16 and 1.12 times, respectively, compared with the C40 fixation method. There were no significant differences between CF30 and SG-HCS groups. Only the F.E.R.I technique combined with the 4.5 mm cannulated screw of 30 mm in length increased the biomechanical stability for Jones fractures. Discussion: These biomechanical findings help clinicians decide on better screw fixation options for greater stability in Jones fractures, especially when large-diameter screws are limited in use. However, this biomechanical testing of intramedullary screw fixation on Jones fracture model lacks clinical validation and no comparisons to extramedullary plate fixations. Moving forward, additional clinical and biomechanical research is necessary to validate our findings.

The nematode-trapping fungus Arthrobotrys oligospora detects prey pheromones via G protein-coupled receptors.

The ability to sense prey-derived cues is essential for predatory lifestyles. Under low-nutrient conditions, Arthrobotrys oligospora and other nematode-trapping fungi develop dedicated structures for nematode capture when exposed to nematode-derived cues, including a conserved family of pheromones, the ascarosides. A. oligospora senses ascarosides via conserved MAPK and cAMP-PKA pathways; however, the upstream receptors remain unknown. Here, using genomic, transcriptomic and functional analyses, we identified two families of G protein-coupled receptors (GPCRs) involved in sensing distinct nematode-derived cues. GPCRs homologous to yeast glucose receptors are required for ascaroside sensing, whereas Pth11-like GPCRs contribute to ascaroside-independent nematode sensing. Both GPCR classes activate conserved cAMP-PKA signalling to trigger trap development. This work demonstrates that predatory fungi use multiple GPCRs to sense several distinct nematode-derived cues for prey recognition and to enable a switch to a predatory lifestyle. Identification of these receptors reveals the molecular mechanisms of cross-kingdom communication via conserved pheromones also sensed by plants and animals.

Intergenerational Transmission of Human Parenting Styles to Human-Dog Relationships.

Parenting style and intergenerational transmission have been extensively studied in parent-child relationships. As dogs are increasingly recognized as integral members of the family system, there is a growing interest in understanding how parenting behaviors directed towards dogs can also influence a dog's behaviors. However, the reasons why people adopt certain parenting behaviors towards dogs remain relatively unknown. This study delved into the intergenerational transmission of parenting styles from one's upbringing to caregiving for dogs. Using a mixed methods approach with 391 dog caregivers and 10 interviews, this study employed multivariate linear regression and thematic analysis. Permissive parenting exhibited an intergenerational effect, with those experiencing it being more likely to replicate the style with their dogs. Orientation towards dogs emerged as a crucial mediator, with protectionistic attitudes reducing the likelihood of replicating authoritarian parenting. Humanistic and protectionistic orientation increased the likelihood of compensatory permissive behaviors. Insights from interviews underscored the impact of perceived childhood experiences on adopting specific parenting behaviors. Ultimately, this study provides valuable insights that can contribute to the promotion of appropriate caregiving behaviors toward dogs. By drawing on our understanding of child-parent relationships, addressing the underlying elements of human-dog dynamics may lead to positive outcomes both for dogs and their caregivers.

Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy.

Backgrounds and Aim: Chronic hepatitis C (CHC) patients who fail antiviral therapy have a high risk of developing hepatocellular carcinoma (HCC). We investigated the effects of metformin and statins, commonly used to treat diabetes mellitus (DM) and hyperlipidemia (HLP), on HCC risk in CHC patients who failed antiviral therapy. Methods: CHC patients with failed interferon-based therapy were enrolled in a large-scale multicenter cohort study in Taiwan (T-COACH). HCC occurrence 1.5 years after the end of antiviral therapy was identified by linking to the cancer registry databases from 2003 to 2019. After considering death and liver transplantation as competing risks, Gray's cumulative incidence and Cox sub-distribution hazards for HCC development were used. Results: Among the 2,779 CHC patients, 480 (17.3%) developed new-onset HCC and 238 (8.6%) died after antiviral therapy. Metformin non-users with DM had a 51% higher risk of liver cancer than patients without DM, while statin users with HLP had a 50% lower risk of liver cancer than patients without HLP. The 5-year cumulative incidence of HCC was 16.5% in metformin non-users, significantly higher in metformin non-users than in patients without DM (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Conversely, HLP statin users had a significantly lower HCC risk than patients without HLP (3.8% vs. 12.5%; aSHR=0.50; P<0.001). Notably, the unfavorable effect of non-metformin use on increased HCC risk was mainly observed among patients without cirrhosis but not in patients with cirrhosis. In contrast, a favorable effect of statins reduced the risk of HCC in both cirrhotic and non-cirrhotic patients. Conclusion: Metformin for DM and statins for HLP have chemopreventive effects on HCC risk in CHC patients who failed antiviral therapy. These findings emphasize the importance of personalized preventive strategies for managing patients with these clinical profiles.

Real-World Efficacy and Safety of Universal 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve Patients from a Nationwide HCV Registry in Taiwan.

INTRODUCTION: Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitis C (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitis C virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). METHODS: The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week 12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. RESULTS: A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype 3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. CONCLUSION: Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Distinct growth patterns in seedling and tillering wheat plants suggests a developmentally restricted role of HYD2 in salt-stress response.

KEY MESSAGE: Mutants lacking functional HYD2 homoeologs showed improved seedling growth, but comparable or increased susceptibility to salt stress in tillering plants, suggesting a developmentally restricted role of HYD2 in salt response. Salinity stress threatens global food security by reducing the yield of staple crops such as wheat (Triticum ssp.). Understanding how wheat responds to salinity stress is crucial for developing climate resilient varieties. In this study, we examined the interplay between carotenoid metabolism and the response to salt (NaCl) stress, a specific form of salinity stress, in tetraploid wheat plants with mutations in carotenoid ß-hydroxylase 1 (HYD1) and HYD2. Our investigation encompassed both the vulnerable seedling stage and the more developed tillering stage of wheat plant growth. Mutant combinations lacking functional HYD2 homoeologs, including hyd-A2 hyd-B2, hyd-A1 hyd-A2 hyd-B2, hyd-B1 hyd-A2 hyd-B2, and hyd-A1 hyd-B1 hyd-A2 hyd-B2, had longer first true leaves and slightly enhanced root growth during germination under salt stress compared to the segregate wild-type (control) plants. Interestingly, these mutant seedlings also showed decreased levels of neoxanthin and violaxanthin (xanthophylls derived from ß-carotene) and an increase in ß-carotene in roots. However, tillering hyd mutant and segregate wild-type plants generally did not differ in their height, tiller count, and biomass production under acute or prolonged salt stress, except for decreases in these parameters observed in the hyd-A1 hyd-B1 hyd-A2 hyd-B2 mutant that indicate its heightened susceptibility to salt stress. Taken together, these findings suggest a significant, yet developmentally restricted role of HYD2 homoeologs in salt-stress response in tetraploid wheat. They also show that hyd-A2 hyd-B2 mutant plants, previously demonstrated for possessing enriched nutritional (ß-carotene) content, maintain an unimpaired ability to withstand salt stress.

Design of sonochemical assisted synthesis of Zr-MOF/g-C3N4-modified electrode for ultrasensitive detection of antipsychotic drug chlorpromazine from biological samples.

The rapid fabrication is described of binary electrocatalyst based on a highly porous metal-organic framework with zirconium metal core (Zr-MOF) decorated over the graphitic carbon nitride (g-C3N4) nanosheets via facile ultrasonication method. It is used for the robust determination of antipsychotic drug chlorpromazine (CLP) from environmental samples. The electrochemical behaviour of 2D Zr-MOF@g-C3N4 was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) studies. The crystalline and porous nature of the composite was characterized by XRD and SEM analysis. The functional groups and surface characteristics were investigated by FT-IR, Raman and XPS. The major electrochemical properties of the Zr-MOF@g-C3N4 composite towards CLP detection were analyzed by CV, chronocoulometric (CC), chronoamperometric (CA) and differential pulse voltammetry (DPV) techniques. The composite exhibits a low detection limit (LOD) of 2.45 nM with a linear range of 0.02 to 2.99 µM and attractive sensitivity for CLP. The sensor system shows higher selectivity towards the possible interferences of CLP drug and exhibits better repeatability and stability. Finally, the fabricated sensor system shows a high recovery range varying from 96.2 to 98.9% towards the real samples. The proposed electrochemical probe might be a promising alternative to the prevailing diagnostic tools for the detection of CLP.

Young adults' views on the mechanisms underpinning the impact of pets on symptoms of anxiety and depression.

Introduction: Emerging adulthood is considered a peak age for the onset of mental health difficulties with approximately 75% of mental health disorders being diagnosed during this developmental period. Companion animals confer both risk and benefits to mental health yet the potential underpinning mechanisms which explain such impacts are not fully understood. This study aimed to gather an in-depth understanding of young adults' lived experience of how their companion dogs and cats may impact their mental health symptoms and the perceived mechanisms which explain their effects. Methods: Semi-structured interviews were carried out with 16 young adults aged 18-26 years, from the United Kingdom, who either had a companion dog, cat, or both. All participants had difficulties with anxiety and or depression, and 12 had received a formal diagnosis of an affective disorder. Results: Five overarching themes and one subtheme were identified through reflexive thematic analysis using an inductive approach: Theme 1: Pet impact on generalized anxiety and panic, Subtheme 1A: Pet impact on social anxiety and loneliness; Theme 2: Pet impact on low mood, depression, and stress; Theme 3: Pet impact on severe mental health and suicide prevention; Theme 4: Staying well; Theme 5: Positive outlook and successful futures. Several perceived mechanisms underpinning the impacts of pets for mental health were also identified. Discussion: These findings have relevance for the development and evaluation of mental health interventions and treatment protocols aimed at young adults with mental health difficulties, where companion animals may prove to be effective for symptom management and improvements in positive wellbeing.

Cesium Carbonate Promoted Direct Amidation of Unactivated Esters with Amino Alcohol Derivatives.

Cesium carbonate promoted direct amidation of unactivated esters with amino alcohols was developed without the use of transition-metal catalysts and coupling reagents. This method enabled the synthesis of several serine-containing oligopeptides and benzamide derivatives with yields up to 90%. The methodology proceeds under mild reaction conditions and exhibits no racemization for most naturally occurring amino acid substrates. The reaction demonstrates good compatibility with primary alkyl and benzyl esters and broad tolerance for a range of amino acid substrates with nonpolar and protected side chains. The hydroxy group on the amine nucleophile was found to be critical for the reaction to be successful. A likely mechanism involving cesium coordination to the substrates enabling the subsequent proximity-driven acyl transfer was proposed. The practicality of this approach was demonstrated in the preparation of a biologically active nicotinamide derivative in a reasonable yield.

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial.

Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.