Assessing the reliability of a novel cancer-specific multi-attribute utility instrument (FACT-8D) and comparing its validity to EQ-5D-5L in colorectal cancer patients.

OBJECTIVE: To examine the test-retest reliability of the Functional Assessment of Cancer Therapy - 8 Dimension (FACT-8D) for the first time, and to conduct a head-to-head comparison of the distribution properties and validity between the FACT-8D and EQ-5D-5L in Colorectal Cancer (CRC) Patients. METHODS: We conducted a longitudinal study on Chinese CRC patients, employing Functional Assessment of Cancer Therapy-General (FACT-G) and EQ-5D-5L at baseline, and FACT-G during follow-up (2-7 days from baseline). Utility scores for FACT-8D were derived from all available value sets (Australia, Canada and USA), while EQ-5D-5L scores were obtained from corresponding value sets for various countries. We assessed convergent validity using pairwise polychoric correlations between the FACT-8D and EQ-5D-5L; known-groups validity by discriminating participants' clinical characteristics, and effect size (ES) was tested; test-retest reliability for FACT-8D using kappa and weighted Kappa for choice consistency, and intraclass correlation coefficient (ICC) and Bland-Altman method for utility consistency. RESULTS: Among the 287 patients with CRC at baseline, 131 were included in the retest analysis. The utility scores of FACT-8D were highly positively correlated with EQ-5D-5L across various country value sets (r = 0.65-0.77), and most of the dimensions of FACT-8D and EQ-5D-5L were positively correlated. EQ-5D-5L failed to discriminate known-groups in cancer stage across all value sets, whereas both were significant in FACT-8D (ES = 0.35-0.48, ES = 0.38-0.52). FACT-8D showed good test-retest reliability (Cohen's weighted Kappa = 0.494-0.722, ICC = 0.748-0.786). CONCLUSION: The FACT-8D can be used as a valid and reliable instrument for clinical evaluation of patients with CRC, outperforming EQ-5D-5L in differentiating clinical subgroups and showing promise for cancer practice and research.

Recently, the Multi-Attribute Utility in Cancer Consortium developed the Functional Assessment of Cancer Therapy − 8 Dimension (FACT-8D), a new cancer-specific multi-attribute utility instrument based on the Functional Assessment of Cancer Therapy - General (FACT-G). This addresses the FACT-G's limitation in directly generating utility values, which has broad application prospects in cost-utility analysis within the field of oncology. To our knowledge, this is the first study to examine the test-retest reliability of FACT-8D and to conduct a head-to-head comparison of its distribution properties and validity against the EQ-5D-5L in colorectal cancer (CRC) patients. The results indicate that FACT-8D is a valid and reliable instrument for clinical evaluation of CRC patients, demonstrating superior performance in differentiating between known clinical groups compared to the generic MAUI EQ-5D-5L, and is a promising instrument for use in cancer practice and research.

Validity and Responsiveness of EQ-5D in Asthma: A Systematic Review and Meta-analysis.

OBJECTIVE: We aimed to synthesize the evidence on the construct validity and responsiveness of the EQ-5D and compare them with asthma-specific health-related quality-of-life scales, to guide further research and clinical applications in asthma. METHODS: We searched key databases from inception to 1 June, 2024 and used the COnsensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) method to appraise the evidence. The effect size estimates were aggregated using the inverse variance method to evaluate the relative efficiency of EQ-5D measures against the Asthma Quality of Life Questionnaire (AQLQ) and/or its corresponding preference-based index, Asthma Quality of Life-5 Dimensions (AQL-5D). RESULTS: There were 493 tests (construct validity: 428; responsiveness: 65) drawn from 37 selected articles (validation: 7; clinical: 30). Overall, 78.4% and 76.9% of the a priori hypotheses for assessing construct validity (convergent validity: 56.4%; known groups: 88.5%) and responsiveness, respectively, were satisfied. The methodological quality was "very good" or "adequate" in 78.2% of construct validity tests and 92.3% of responsiveness tests. The pooled correlation coefficient between EQ-5D index and AQLQ total scores was 0.52 (95% confidence interval 0.43-0.59), and between EQ visual analog scale and AQLQ total scores was 0.53 (95% confidence interval 0.34-0.69). The Cohen's d ratios for the index, level sum scores, and visual analog scale compared to AQLQ were 0.56 (n = 27), 1.16 (n = 16), and 0.75 (n = 37). The EQ-5D index's Cohen's d ratio compared to AQL-5D was 0.49 (n = 5). The standardized response mean ratios for the index and visual analog scale compared to AQLQ were 0.26 (n = 11) and 0.63 (n = 9). CONCLUSIONS: The EQ-5D demonstrated overall good validity and responsiveness in the adult asthma population. However, a comparison against disease-specific instruments suggested scope for improvement in its psychometric performance for this population.

Cystathionine γ lyase Attenuates Vascular Smooth Muscle Cell Senescence via Foxm1-Gas1 Pathway to Mediate Arterial Stiffness.

Aims Arterial stiffness, a hallmark of vascular aging, significantly contributes to hypertension and impaired organ perfusion. Vascular smooth muscle cell (VSMC) dysfunction, particularly VSMC senescence and its interaction with stiffness, is crucial in the pathogenesis of arterial stiffness. Although hydrogen sulfide (H2S) and its key enzyme cystathionine γ-lyase (CSE) are known to play roles in cardiovascular diseases, their effects on arterial stiffness are not well understood. Methods & Results First, we observed a downregulation of CSE/H2S in the aortic media during biological aging and Angiotensin II (AngII)-induced aging. The VSMC-specific CSE knockout mice were created by loxp-cre (Tagln-cre) system, and which exacerbated AngII-induced aortic aging and stiffness in vivo and VSMC senescence and stiffness in vitro. Conversely, the CSE agonist norswertianolin mitigated these effects. Next, we identified growth arrest-specific 1 (Gas1) as a crucial target of CSE/H2S and found it to be a downstream target gene of forkhead box protein M1 (Foxm1). siRNA knockdown Foxm1 increased Gas1 transcription and reduced the protective effects of H2S on VSMC senescence and stiffness. Finally, we demonstrated that CSE/H2S sulfhydrates Foxm1 at the C210 site, regulating its nuclear translocation and activity, thus reducing VSMC senescence and stiffness. Innovation Our findings highlight the protective role of CSE/H2S in arterial stiffness, emphasizing the novel contributions of CSE, Gas1, and Foxm1 to VSMC senescence and stiffness. Conclusion Endogenous CSE/H2S in VSMCs reduces VSMC senescence and stiffness, thereby attenuating arterial stiffness and aging, partly through sulfhydration-mediated activation of Foxm1 and subsequent inhibition of Gas1 signaling pathways.

Characterization of pKPN945B, a novel transferable IncR plasmid from hypervirulent carbapenem-resistant Klebsiella pneumoniae, harboring blaIMP-4 and qnrS1.

Carbapenem-resistant Klebsiella pneumoniae producing metallo-ß-lactamase poses a major public health threat worldwide. Imipenemase often coexists with other resistance genes leading to the formation of multidrug-resistant bacteria. In this study, we describe the microbiological and genomic characteristics of the hypervirulent carbapenem-resistant K. pneumoniae ST20-K23 strain KPN945 harboring blaIMP-4 and qnrS1. The minimum inhibitory concentration of KPN945 against antimicrobials was determined by the broth microdilution method. The virulence of KPN945 was evaluated through string test, serum killing resistance, and Galleria mellonella larvae infection models. The transferability of pKPN945B was assessed using a conjugation test. The genome sequence characteristics of KPN945 were analyzed through whole genome sequencing, and a phylogenetic tree was constructed to evaluate the prevalence of imipenemase. Our findings showed that KPN945 was non-susceptible to ß-lactam antibiotics, highly resistant to serum killing, and highly lethal to G. mellonella larvae. The fusion plasmid pKPN945B carried by the isolate KPN945 belonged to the IncR incompatibility group and harbored multiple drug resistance genes such as blaIMP-4, blaCTX-M-14, qnrS1, and sul2. The most important point is that the IncR plasmid is a novel plasmid that arose by the accretion of parts from different plasmids, making it transferable and with a fitness cost. Globally, blaIMP-4 is the most prevalent imipenemase subtype, with the highest isolation rates in Asia, particularly China. The spread of blaIMP-4, especially the emergence of transferable plasmids, deserves our vigilance and prevention. Additionally, we should pay attention to the formation of hypervirulent K. pneumoniae mediated by non-virulent plasmids. IMPORTANCE: Up to now, IncR replicons carrying blaIMP-4 have not been reported, and the IncR plasmids described in previous studies have been found to be non-transferrable to other bacteria through conjugation. Moreover, there have been no extensive phylogenetic analyses of strains carrying blaIMP in the published papers. The lack of data in these studies is noteworthy because blaIMP appears in the novel transferable fusion plasmid IncR. Although the IncR plasmid has no tra operon, it can still be transferred to Escherichia coli EC600 or Klebsiella pneumoniae ATCC13883 (RIFR) without high fitness cost, but it only affects the MIC of imipenem. blaIMP integrates with other resistance mechanisms leading to the formation of multidrug-resistant strains. Notably, the high prevalence of blaIMP-4 in Asia and the presence of blaIMP-4 on novel transferable IncR plasmids suggest the urgent need to monitor the emergence of such plasmids and control their spread.

Cucurbitacin E elicits apoptosis in laryngeal squamous cell carcinoma by enhancing reactive oxygen species-regulated mitochondrial dysfunction and endoplasmic reticulum stress.

Laryngeal squamous cell carcinoma (LSCC) is a prevalent head and neck neoplasm with escalating global morbidity and mortality rates. Despite the increasing burden of LSCC, the drugs currently approved for its treatment are limited. Therefore, it is necessary to identify novel and promising drugs that target LSCC. Cucurbitacin E (CuE) is a naturally oxygenated tetracyclic triterpenoid that suppresses several cancers. However, its anti-LSCC activity and the molecular mechanisms of action remain unclear. This study explored its impact on LSCC, revealing cell viability attenuation and apoptosis enhancement in vitro. Further investigations indicated that CuE significantly decreased mitochondrial membrane potential, thereby promoting cytochrome c release, increasing cleaved-Caspase 3 and cleaved-PARP levels, and triggering mitochondria-dependent apoptosis. Concurrently, exposure of LSCC cells to CuE enhanced endoplasmic reticulum (ER) stress, mobilized the protein kinase RNA-like endoplasmic reticulum kinase/initiation factor 2a/ATF4/C-EBP homologous protein pathway, and induced LSCC cell apoptosis. Finally, CuE markedly elevated intracellular reactive oxygen species (ROS) levels. When ROS were eliminated with N-acetylcysteine, CuE-mediated mitochondrial dysfunction, ER stress, and cell apoptosis were nearly abolished. Similar outcomes were observed in murine LSCC models. Together, these results highlight that CuE suppresses proliferation while triggering apoptosis in LSCC cells via ROS-regulated mitochondrial dysfunction and the ER stress pathway. Hence, CuE may serve as a promising candidate for LCSS treatment.

Assessment of perioperative cardiac risk using preoperative quantitative flow ratio in patients with coronary artery disease undergoing noncardiac surgery: a retrospective cohort study.

Background: Quantitative flow ratio (QFR) is a novel diagnostic modality for the functional testing of coronary artery stenosis, but evidence concerning the postoperative prognostic implication of QFR in noncardiac surgery (NCS) of patients with coronary artery disease (CAD) is limited. The purpose of this study was to examine the role of QFR in perioperative risk prediction in patients with coronary heart disease. Methods: This retrospective cohort study was conducted in The First Affiliated Hospital of Wenzhou Medical University between 2013 and 2022, and consecutively included patients with CAD who had undergone NCS <1 year after coronary angiography. The primary endpoint was major adverse cardiovascular events (MACEs), which were defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, cardiopulmonary arrest, malignant ventricular arrhythmia (MVA), congestive heart failure, and revascularization. Univariate and multifactorial Cox regression was used to identify the independent risk factors for perioperative cardiovascular events and to construct new models. The area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to compare the newly constructed model with existing traditional models. Results: Among the 929 participants enrolled (median age 68 years; 72.0% male), the primary endpoint was met in 67 (7.2%) patients within 30 days of follow-up. There was no significant difference in the incidence of the primary endpoint between patients with QFR <0.75 and those with "gray zone" lesions (0.75≤ QFR ≤0.8) (log-rank P=0.325). Patients with QFR <0.75 and those with "gray zone" lesions (0.75≤ QFR ≤0.8) had a higher incidence of primary endpoint events compared to patients with QFR >0.8. [QFR <0.75 vs. QFR >0.8: adjusted hazard ratio (HR) =20.70, P<0.001; 0.75≤ QFR ≤0.8 vs. QFR >0.8: HR =15.99, P<0.001]. The independent predictors of MACEs events within 30 days after NCS were albumin level [HR =0.92, 95% confidence interval (CI): 0.87-0.98; P=0.008], emergency surgery (HR =4.12, 95% CI: 1.66-10.23; P=0.002), and QFR ≤0.8 (HR =15.92, 95% CI: 5.96-42.51; P<0.001). In addition, adjusting the original Revised Cardiac Risk Index (RCRI) with QFR ≤0.8 as a risk factor significantly improved the risk stratification of postoperative adverse events, with the adjusted AUC rising from 0.574 to 0.740 (P<0.001). Conclusions: QFR ≤0.8 could independently predict perioperative cardiovascular adverse events in patients with CAD undergoing NCS and improve the predictive value of original predictive index. Gray-zone lesions (0.75≤ QFR ≤0.8) should be actively treated.

An Exploratory Study of Alternative Time Frames and Descriptors for EQ-5D-5L in Obstructive Airway Diseases Using Mixed Methods.

OBJECTIVES: EQ-5D-5L with its recall time of "today" may limit its ability to capture episodic symptoms and exacerbations in chronic obstructive airway diseases (OAD). We examined whether longer time frames and changing the intensity response scales to frequency scales could improve the measurement properties of EQ-5D-5L. METHODS: We used a mixed-method design starting with in-depth interviews with 20 patients and clinicians to elicit preferred time frames using concept elicitation techniques and content analyses. We then administered the top 4 preferred variants using 1- and 4-weeks' time frames with the original intensity or an alternative frequency response scale alongside EQ-5D-5L and St George Respiratory Questionnaire to OAD patients during 2 different visits. We compared the ceiling effects and construct validity by testing a priori hypotheses in relation to St George Respiratory Questionnaire and clinical outcomes via correlation and receiver operating characteristic (ROC) analyses, respectively. Follow-up patients were categorized into "better," "stable," and "worse" groups to assess reliability using intraclass correlation coefficient (ICC) or Cohen's Kappa (k) and responsiveness using ROC analysis. RESULTS: A total of 184 patients (mean [SD] age: 54[18]; female: 37.0%) completed baseline assessments. A total of 120 patients also completed follow-up assessments (mean [SD] interval: 2.8 [1.7] months). The ceilings were lower in the variants compared with EQ-5D-5L (P < .001). Reliability of the variants were comparable to or higher than EQ-5D-5L. The c-statistic values derived from ROC analyses of the variants were consistently higher than EQ-5D-5L. CONCLUSIONS: Use of longer time frames with the original intensity or the frequency response scales may improve EQ-5D-5L's psychometric properties in OAD patients.

Concurrent Gitelman Syndrome and Hyperthyroidism: Diagnostic Challenges in a 51-Year-Old Patient.

BACKGROUND Gitelman syndrome (GS) is an uncommon autosomal recessive inherited disease caused by inactivating mutations in the SLC12A3 gene located on chromosome 16q13, resulting in distal tubular dysfunction. Most cases are detected during routine examinations in adulthood, due to hypokalemia and alkalosis. GS needs to be distinguished from diseases that cause hypokalemia, such as Classic Bartter syndrome and hyperthyroidism. In individual cases, GS and hyperthyroidism occur simultaneously, which is prone to misdiagnosis. CASE REPORT A 51-year-old woman with intermittent palpitations and lower limb fatigue for 4 years received a diagnosis of hypokalemia at a local hospital. Treatment with potassium supplementation did not improve the patient's palpitations and fatigue. After coming to our hospital for examination, it was found that the patient had hyperthyroidism. After receiving treatment of hyperthyroidism remission and sufficient potassium replacement, the patient's serum potassium level remained low. Meanwhile, the patient had hypomagnesemia and metabolic alkalosis. Subsequently, according to our suggestion, the patient continued to take oral supplements of potassium and magnesium, while also started on spironolactone. We convinced the patient to undergo genetic testing and discovered compound heterozygous mutations in the SLC12A3 gene, which presented a definitive diagnosis of GS. In the following 3 months, the patient's serum potassium level was within the normal range, and the dose of methimazole was reduced. CONCLUSIONS As a rare disease, GS may have only mild or occasional manifestations, making it prone to misdiagnosis. GS remains therapeutically challenging, and future progress in treatment will depend on further research of the disease.

Cold tolerance and metabolism of red-haired pine bark beetle Hylurgus ligniperda (Coleoptera: Curculionidae) during the overwintering period.

Hylurgus ligniperda invaded Shandong, China, through imported forest timber, posing a threat to China's forest health. Exotic insects with broad environmental tolerance, including low temperatures, may have a better chance of surviving the winters and becoming invasive. Understanding the cold-tolerance strategies of H. ligniperda may help to design sustainable pest management approaches. In this study, we aim to investigate the cold-tolerance ability and relevant physiological indicators in overwintering H. ligniperda adults to determine any possible overwintering strategies. Supercooling points (SCPs) for adults H. ligniperda differed significantly across months and reached the lowest level in the mid- and post-overwintering period, the minimum SCPs -6.45 ±â€…0.18 °C. As the cold exposure temperature decreased, the survival rate of adults gradually decreased, and no adult survived more than 1 day at -15 °C, and the LLT50 for 1 day was -7.1 °C. Since H. ligniperda adults can survive internal ice formation, they are freeze-tolerant insects. Throughout the overwintering period, the SCPs and the water, protein, sorbitol, and glycerol content in adults decreased initially and then increased. We reported significant correlations between total protein, sorbitol, trehalose, and glycerol content in the beetles and SCPs. Glycogen, lipid, protein, trehalose, and sorbitol content in adult beetles may directly affect their cold-tolerance capacity and survival during winter. This study provides a physiological and biochemical basis for further study of metabolism and cold-tolerance strategies in H. ligniperda adults, which may help predict population dynamics and distribution potential of pests.

Effectiveness of Technology-Delivered Psychosocial Interventions for Family Caregivers of Patients With Dementia: A Systematic Review, Meta-Analysis and Meta-Regression.

Family caregivers living with patients with dementia (PwD) face psychological challenges due to care burden. Technology-delivered psychosocial interventions (TPIs) have played a promising role in improving health outcomes among family caregivers living with PwD. This review aims to synthesise evidence of the effectiveness of TPIs on primary (burden and depression) and secondary outcomes (self-efficacy, stress and anxiety) for family caregivers living with PwD. Random-effects meta-analyses were performed to determine effect size. Using Cochran's Q and I2 tests, statistical heterogeneity was evaluated. Sensitivity, subgroup analyses and meta-regression were employed to explain statistical heterogeneity. Twenty-eight trials comprising 4160 family caregivers from eight countries were included. Our meta-analysis revealed that TPIs resulted in slight reduction in depression, probably resulted in a slight reduction in burden and anxiety and slight increase in self-efficacy. Subgroup differences were detected in geographical regions (Western Pacific and Southeast Asia) for burden. While there were no significant subgroup differences in other factors, TPIs with preventive function and mobile applications had a more prominent larger effect size. Meta-regression analysis showed that attrition rate was a significant moderator on depression. Results are limited by the high risk of bias of included trials, which may reduce certainty of evidence. This review suggest TPIs are recommended as an adjunct treatment for alleviating burden and depressive outcomes in healthcare institutions. PROSPERO Registration Number: PROSPERO (CRD42023387962).

Unveiling winter survival strategies: physiological and metabolic responses to cold stress of Monochamus saltuarius larvae during overwintering.

BACKGROUND: Monochamus saltuarius is a destructive trunk-borer of pine forest and an effective dispersal vector for pinewood nematode (PWN), a causative agent of pine wilt disease (PWD), which leads to major ecological disasters. Cold winter temperatures determine insect survival and distribution. However, little is known about the cold tolerance and potential physiological mechanisms of M. saltuarius. RESULTS: We demonstrated that dead Pinus koraiensis trunks do not provide larvae with insulation. The M. saltuarius larvae are freeze-tolerant species. Unlike most other freeze-tolerant insects, they can actively freeze extracellular fluid at higher subzero temperatures by increasing their supercooling points. The main energy sources for larvae overwintering are glycogen and the mid-late switch to lipid. The water balance showed a decrease in free and an increase in bound water of small magnitude. Cold stress promoted lipid peroxidation, thus activating the antioxidant system to prevent cold-induced oxidative damage. We found eight main pathways linked to cold stress and 39 important metabolites, ten of which are cryoprotectants, including maltose, UDP-glucose, d-fructose 6P, galactinol, dulcitol, inositol, sorbitol, l-methionine, sarcosine, and d-proline. The M. saltuarius larvae engage in a dual respiration process involving both anaerobic and aerobic pathways when their bodily fluids freeze. Cysteine and methionine metabolism, as well as alanine, aspartate, and glutamate metabolism, are the most important pathways linked to antioxidation and energy production. CONCLUSIONS: The implications of our findings may help strengthen and supplement the management strategies for monitoring, quarantine, and control of this pest, thereby contributing to controlling the further spread of PWD. © 2024 Society of Chemical Industry.

Systematic review reveals that EQ-5D minimally important differences vary with treatment type and may decrease with increasing baseline score.

OBJECTIVES: To provide an updated summary of published anchor-based Minimally Important Difference (MID) estimates for the EQ-5D index and EQ visual analog scale (EQ VAS) scores and identify factors influencing those estimates. STUDY DESIGN AND SETTING: We systematically searched eight electronic databases from January 1990 to March 2023. We examined the association of baseline score, type of score change (improvement/worsening), data source, value set, disease/condition, treatment type (surgical/non-surgical), and type of anchor (clinical vs. self-rated) with MID estimates for the EQ-5D-3L and EQ-5D-5L indices, and EQ VAS. Significant variables were used to develop prediction formulas for MID by testing both linear and nonlinear regression models. RESULTS: Of 6786 records reviewed, 47 articles were included for analysis. MID ranges for improved scores were -0.13 to 0.68 (EQ-5D-3L), 0.01-0.41 (EQ-5D-5L), and 0.42-23.0 (EQ VAS). Surgical intervention and lower baseline scores were associated with higher MIDs for both the EQ indices but not for EQ VAS. The nonlinear polynomial model outperformed the linear model in predicting the MIDs. MIDs based on deteriorated scores were insufficient for quantitative synthesis (mean: -0.02 for EQ-5D-3L; -0.04 for EQ-5D-5L; and -6.5 for EQ VAS). CONCLUSION: This review revealed that the MID of EQ-5D index scores varies with baseline score and treatment type, indicating that use of a uniform MID may not be appropriate. We recommend using baseline score-adjusted and treatment type-specific EQ-5D MIDs, and call for more MID research, particularly in the context of assessing deterioration in health using this widely used generic health-status instrument.

Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials.

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants: Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions: For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures: The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results: Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance: Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration: ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135.

Purine metabolite inosine induced by transforming growth factor­ß promotes epithelial­mesenchymal transition in colorectal cancer.

Transforming growth factor-ß (TGF-ß) signaling pathway serves a pivotal role in the pathogenesis of colorectal cancer (CRC). However, the specific molecular mechanisms by which the TGF-ß signaling pathway regulates CRC are still not fully understood. In the present study, metabolomics and transcriptomics were used to screen for key metabolites and regulatory genes most related to the regulation of the TGF-ß signaling pathway in CRC. Additionally, reverse transcription-quantitative PCR, western blotting and Transwell assays were performed to assess the process of epithelial-mesenchymal transition (EMT). Metabolomics analysis indicated that TGF-ß1 has an impact on purine metabolism, leading to an increase in the purine metabolite inosine. The increase of inosine is essential for facilitating EMT and cell migration in CRC cells. Furthermore, the integrated analysis of metabolomics and transcriptomics data revealed that TGF-ß1 induces the expression of laccase domain-containing 1 (LACC1), an enzyme involved in the regulation of inosine. Knockdown of LACC1 resulted in a reduction of TGF-ß1-induced alterations in inosine levels, EMT and cell migration in CRC cells. The results of the present study suggest that the TGF-ß signaling pathway is involved in the regulation of purine metabolism in CRC through the modulation of LACC1 expression. Furthermore, LACC1 appears to influence EMT and cell migration by elevating the levels of the purine metabolite inosine.

Effect of recombinant human brain natriuretic peptide on efficacy, hemodynamics and NT-proBNP in elderly patients with heart failure.

AIM: To investigate the effects of recombinant human brain natriuretic peptide (rhBNP) on efficacy, hemodynamics, and N-terminal pro-brain natriuretic peptide (NT-proBNP) in elderly patients with heart failure (HF). METHODS: In this retrospective analysis, the clinical data of 112 HF patients who visited the First Affiliated Hospital of Anhui University of Chinese Medicine between March 2019 and October 2022 were analyzed. On the basis of standard HF treatment, 52 patients additionally treated with milrinone intravenous were set as the control group (Con) and 60 patients with rhBNP were set as the observation group (Obs). The therapeutic efficacy and pre- and post-treatment echocardiographic indexes, NT-proBNP and hemodynamics were recorded and compared, and the adverse drug reactions and quality of life scores after treatment were counted. RESULTS: The Obs group showed a markedly higher post-treatment overall response rate than the Con (P=0.002). Besides, more obvious improvement of NT-proBNP and hemodynamic indexes were determined in the Obs group compared to the Con (P=0.000). Evidently ameliorated left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic diameter (LVESD) were observed in both groups after treatment, with more pronounced improvement in the Obs group (all P=0.000). The Obs group also exhibited an evidently lower incidence of adverse reactions and a better quality of life than the Con after treatment (P=0.000). CONCLUSIONS: rhBNP can effectively improve the cardiac function and hemodynamics in elderly HF patients, with high safety and few adverse reactions.

Moderate elimination of mycotoxins in vegetable oil triggered by superoxide anion and singlet oxygen.

Establishing a moderate elimination strategy for mycotoxins with the maintained food nutrition is significant to food safety. Herein, the Au-NPs decorated defective Bi2WO6 (Au-BWO-OV) with modulated ROS generation was successfully synthesized, integrating the merits of defect-engineering and Au-NPs induced LSPR-effect. The Au-BWO-OV exhibited modified photoelectrochemical property and O2-adsorption capacity, supporting the selective generation of •O2- and 1O2 with moderate oxidizing ability. As a result, >90% of AFB1 and ZEN were eliminated within 100 and 50 min, along with the maintained nutrition in vegetable oil. Moreover, the reasonable degradation mechanism triggered by •O2- and 1O2 was proposed based on the trapping experiments, DFT calculations and LC-MS analysis for intermediate products, including the steps of hydrolysis, oxidative dissociation, cis-trans isomerization, and dehydroxylation. This work not only paved the way for balancing the contradiction between detoxification and nutrient retention, but also casted new insights into the ROS-mediated degradation mechanism.

Efficacy and Safety of Upadacitinib or Elsubrutinib Alone or in Combination for Patients With Systemic Lupus Erythematosus: A Phase 2 Randomized Controlled Trial.

OBJECTIVE: The 48-week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (JAK inhibitor) and elsubrutinib (BTK inhibitor) alone or in combination (ABBV-599) in adults with moderately to severely active systemic lupus erythematosus (SLE). METHODS: Patients were randomized 1:1:1:1:1 to elsubrutinib 60 mg and upadacitinib 30 mg once daily (ABBV-599 high dose), elsubrutinib 60 mg and upadacitinib 15 mg once daily (ABBV-599 low dose), elsubrutinib 60 mg once daily (QD), upadacitinib 30 mg QD, or placebo QD. The primary endpoint was the proportion of patients achieving both Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and glucocorticoid dose ≤10 mg QD at week 24. Additional assessments through week 48 included British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS) responses, number of flares, time to first flare, and adverse events. RESULTS: The study enrolled 341 patients. The ABBV-599 low dose and elsubrutinib arms were discontinued after a planned interim analysis showed lack of efficacy (no safety concerns). More patients achieved the primary endpoint with upadacitinib (54.8%; P = 0.028) and ABBV-599 high dose (48.5%; P = 0.081) versus placebo (37.3%). SRI-4, BICLA, and LLDAS response rates were higher for both upadacitinib and ABBV-599 high dose versus placebo at weeks 24 and 48. Flares were reduced, and time to first flare through week 48 was substantially delayed with both upadacitinib and ABBV-599 high dose versus placebo. No new safety signals were observed beyond those previously reported for upadacitinib or elsubrutinib. CONCLUSION: Upadacitinib 30 mg alone or in combination with elsubrutinib (ABBV-599 high dose) demonstrated significant improvements in SLE disease activity and reduced flares and were well tolerated through 48 weeks.

Association of a healthy ageing index with health-related outcomes in a multi-ethnic cohort from Singapore.

BACKGROUND: The global population is ageing rapidly and it is important to promote healthy ageing. The Healthy Ageing Index (HAI) is a comprehensive measure of health, but there is limited research on its association with other age-related outcomes. The management of an aging population necessitates considerations even among generally healthy adults, as age-related diseases often remain unaccounted for until later stages of life. This study explores the association of risk factors with HAI and its association with peripheral artery disease (PAD), muscle strength, health-related quality of life (HRQoL), and psychological distress in the Singapore Multi-Ethnic Cohort study. METHODS: This cross-sectional study involved 1909 participants (median (Q1, Q3) age: 53 (48, 60) years and 59.3% females) from Singapore Multi-Ethnic Cohort study. The risk factors of HAI included age, gender, ethnicity, education level, smoking, alcohol consumption, employment, BMI and past medical histories. PAD was assessed using ankle-brachial index (ABI), handgrip strength (HGS), HRQoL with the EQ-5D-5 L questionnaire and psychological distress via the Kessler Psychological Distress Scale (K10). HAI components were assessed using relevant marker tests. RESULTS: Older age, Malay and Indian ethnicities, unemployment, high BMI and histories of CHD, hypercholesterolaemia, tumours and TIA/stroke were associated with lower HAI scores indicative of poorer health. Higher HAI scores were associated with females and higher education levels. Lower HAI scores were significantly associated with low ABI, high K10 scores, mobility and anxiety/depression dimensions of EQ-5D-5 L. CONCLUSION: The most important factors associated with HAI were age, sex, ethnicity, education, unemployment, BMI and a history of health conditions. Lower HAI scores were significantly associated with PAD, lower HRQoL and psychological distress. Thus, the HAI demonstrates promise as an evaluation method for assessing PAD, overall muscle strength and HRQoL in a population-based setting.

Transcriptomic analysis reveals the regulatory mechanisms of messenger RNA (mRNA) and long non-coding RNA (lncRNA) in response to waterlogging stress in rye (Secale cereale L.).

BACKGROUND: Waterlogging stress (WS) negatively impacts crop growth and productivity, making it important to understand crop resistance processes and discover useful WS resistance genes. In this study, rye cultivars and wild rye species were subjected to 12-day WS treatment, and the cultivar Secale cereale L. Imperil showed higher tolerance. Whole transcriptome sequencing was performed on this cultivar to identify differentially expressed (DE) messenger RNAs (DE-mRNAs) and long non-coding RNAs (DE-lncRNAs) involved in WS response. RESULTS: Among the 6 species, Secale cereale L. Imperil showed higher tolerance than wild rye species against WS. The cultivar effectively mitigated oxidative stress, and regulated hydrogen peroxide and superoxide anion. A total of 728 DE-mRNAs and 60 DE-lncRNAs were discovered. Among these, 318 DE-mRNAs and 32 DE-lncRNAs were upregulated, and 410 DE-mRNAs and 28 DE-lncRNAs were downregulated. GO enrichment analysis discovered metabolic processes, cellular processes, and single-organism processes as enriched biological processes (BP). For cellular components (CC), the enriched terms were membrane, membrane part, cell, and cell part. Enriched molecular functions (MF) terms were catalytic activity, binding, and transporter activity. LncRNA and mRNA regulatory processes were mainly related to MAPK signaling pathway-plant, plant hormone signal transduction, phenylpropanoid biosynthesis, anthocyanin biosynthesis, glutathione metabolism, ubiquitin-mediated proteolysis, ABC transporter, Cytochrome b6/f complex, secondary metabolite biosynthesis, and carotenoid biosynthesis pathways. The signalling of ethylene-related pathways was not mainly dependent on AP2/ERF and WRKY transcription factors (TF), but on other factors. Photosynthetic activity was active, and carotenoid levels increased in rye under WS. Sphingolipids, the cytochrome b6/f complex, and glutamate are involved in rye WS response. Sucrose transportation was not significantly inhibited, and sucrose breakdown occurs in rye under WS. CONCLUSIONS: This study investigated the expression levels and regulatory functions of mRNAs and lncRNAs in 12-day waterlogged rye seedlings. The findings shed light on the genes that play a significant role in rye ability to withstand WS. The findings from this study will serve as a foundation for further investigations into the mRNA and lncRNA WS responses in rye.

Functional Characterization of the First Bona Fide Phytoene Synthase in Red Algae from Pyropia yezoensis.

The formation of phytoene by condensing two geranylgeranyl diphosphate molecules catalyzed by phytoene synthase (PSY) is the first committed and rate-limiting step in carotenoid biosynthesis, which has been extensively investigated in bacteria, land plants and microalgae. However, this step in macroalgae remains unknown. In the present study, a gene encoding putative phytoene synthase was cloned from the economic red alga Pyropia yezoensis-a species that has long been used in food and pharmaceuticals. The conservative motifs/domains and the tertiary structure predicted using bioinformatic tools suggested that the cloned PyPSY should encode a phytoene synthase; this was empirically confirmed by pigment complementation in E. coli. This phytoene synthase was encoded by a single copy gene, whose expression was presumably regulated by many factors. The phylogenetic relationship of PSYs from different organisms suggested that red algae are probably the progeny of primary endosymbiosis and plastid donors of secondary endosymbiosis.