Development and Validation of a Prediction Model for Thyroid Dysfunction in Patients During Immunotherapy.

OBJECTIVE: This study was designed to develop and validate a predictive model for assessing the risk of thyroid toxicity following treatment with immune checkpoint inhibitors (ICIs). METHODS: A retrospective analysis was conducted on a cohort of 586 patients diagnosed with malignant tumors who received programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. Logistic regression analyses were performed on the training set to identify risk factors of thyroid dysfunction, and a nomogram was developed based on these findings. Internal validation was performed using K-fold cross-validation on the validation set. The performance of the nomogram was assessed in terms of discrimination and calibration. Additionally, decision curve analysis (DCA) was utilized to demonstrate the decision efficiency of the model. RESULTS: Our clinical prediction model consisted of four independent predictors of thyroid immune-related adverse events (irAEs), namely baseline thyrotropin (TSH, OR=1.427, 95%CI:1.163-1.876), baseline thyroglobulin antibody (TgAb, OR=1.105, 95%CI:1.035-1.180), baseline thyroid peroxidase antibody (TPOAb, OR=1.172, 95%CI:1.110-1.237), and baseline platelet count (PLT, OR=1.004, 95%CI:1.000-1.007). The developed nomogram achieved excellent discrimination with an area under the curve (AUC) of 0.863 (95%CI: 0.817-0.909) and 0.885 (95%CI: 0.827-0.944) in the training and internal validation cohorts respectively. Calibration curves exhibited a good fit, and the decision curve indicated favorable clinical benefits. CONCLUSION: The proposed nomogram serves as an effective and intuitive tool for predicting the risk of thyroid irAEs, facilitating clinicians making individualized decisions based on patient-specific information.

Decoding cellular plasticity and niche regulation of limbal stem cells during corneal wound healing.

BACKGROUND: Dysfunction or deficiency of corneal epithelium results in vision impairment or blindness in severe cases. The rapid and effective regeneration of corneal epithelial cells relies on the limbal stem cells (LSCs). However, the molecular and functional responses of LSCs and their niche cells to injury remain elusive. METHODS: Single-cell RNA sequencing was performed on corneal tissues from normal mice and corneal epithelium defect models. Bioinformatics analysis was performed to confirm the distinct characteristics and cell fates of LSCs. Knockdown of Creb5 and OSM treatment experiment were performed to determine their roles of in corneal epithelial wound healing. RESULTS: Our data defined the molecular signatures of LSCs and reconstructed the pseudotime trajectory of corneal epithelial cells. Gene network analyses characterized transcriptional landmarks that potentially regulate LSC dynamics, and identified a transcription factor Creb5, that was expressed in LSCs and significantly upregulated after injury. Loss-of-function experiments revealed that silencing Creb5 delayed the corneal epithelial healing and LSC mobilization. Through cell-cell communication analysis, we identified 609 candidate regeneration-associated ligand-receptor interaction pairs between LSCs and distinct niche cells, and discovered a unique subset of Arg1+ macrophages infiltrated after injury, which were present as the source of Oncostatin M (OSM), an IL-6 family cytokine, that were demonstrated to effectively accelerate the corneal epithelial wound healing. CONCLUSIONS: This research provides a valuable single-cell resource and reference for the discovery of mechanisms and potential clinical interventions aimed at ocular surface reconstruction.

Overall, sex-and race/ethnicity-specific prevalence of thyroid dysfunction in US adolescents aged 12-18 years.

Background: Thyroid dysfunction significantly affects the health and development of adolescents. However, comprehensive studies on its prevalence and characteristics in US adolescents are lacking. Methods: We investigated the prevalence of thyroid dysfunction in US adolescents aged 12-18 years using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2002 and 2007-2012 cycles. Thyroid dysfunction was assessed using serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) measurements. We analyzed the prevalence across demographic subgroups and identified associated risk factors. Results: The study included 2,182 participants, representing an estimated 12.97 million adolescents. The group had a weighted mean age of 15.1 ± 0.06 years, with males constituting 51.4%. Subclinical hyperthyroidism emerged as the most prevalent thyroid dysfunction, affecting 4.4% of the population. From 2001-2002 to 2011-2012, subclinical hyperthyroidism remained consistent at 4.99% vs. 5.13% in the overall cohort. Subclinical and overt hypothyroidism was found in 0.41 and 1.03% of adolescents respectively, and overt hyperthyroidism was rare (0.04%). The prevalence of thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) positivity in the overall population were 5.8 and 9.8%, respectively. Positivity for TgAb was risk factors for hypothyroidism, while older age, female and Black Americans were risk factors for hyperthyroidism. Female adolescents and adolescents with an older age were more likely to be positive for TPOAb and TgAb, while Black and Mexican Americans had a lower risk of TPOAb and TgAb positivity. Conclusion: Subclinical hyperthyroidism was the most common form of thyroid dysfunction, and its prevalence remained stable from 2001-2002 to 2011-2012. Notable disparities in the prevalence of hyperthyroidism and antibody positivity were observed among different age, sex and racial/ethnic groups.

A novel selenium analog of HDACi-based twin drug induces apoptosis and cell cycle arrest via CDC25A to improve prostate cancer therapy.

Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo. Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.

Hip fracture is associated with a reduced risk of type 2 diabetes: A retrospective cohort study.

Objectives: Type 2 diabetes mellitus (T2DM) shares a complex relationship with bone metabolism and few studies investigated the effect of impaired bone health on the risk of T2DM. This study was conducted to investigate the association between hip fractures and the risk of incident T2DM. Methods: This is a retrospective cohort study using data from the real-world hip fracture cohort. Hong Kong Chinese patients aged ≥ 65 years without T2DM who were admitted to public hospitals due to a fall between 2008 and 2015 were included in the study. Patients who sustained falls with and without hip fractures were matched by propensity score (PS) at a 1:1 ratio. Competing risk regression was used to evaluate the association between hip fracture and incident T2DM, with death being the competing event. Results: A total of 23,314 hip fracture cases were matched to 23,314 controls. The median follow-up time was 5.09 years. The incidence rate of T2DM was 11.947 and 14.505 per 1000 person-years for the hip fracture and control group respectively. After accounting for the competing risk of death, the hip fracture group had a significantly lower risk of developing T2DM (HR: 0.771, 95% CI: 0.719-0.827). Similar results were observed in all subgroups after stratification by age and sex. Conclusions: Hip fracture was found to be associated with a reduced risk of T2DM. These findings provide insight into the topic of bone and glucose metabolism and prompt further research in evaluating the role of bone health in the management of T2DM.

Inducing Intermolecular Oxygen Coupling by Introducing S and FeOOH on Co(OH)2 Nanoneedle Arrays for Industrial Water Oxidation.

The design of electrocatalysts for oxygen evolution reaction (OER) remains a limitation of industrial hydrogen production by electrolysis of water. Excellent and stable OER catalysts can be developed by activating lattice oxygen and changing the reaction path. Herein, S and FeOOH on the Co(OH)2 nanoneedle arrays are introduced to construct a heterostructure (S-FeOOH/Co(OH)2/NF) as a proof of concept. Theoretical calculations and experimental suggest that the Co-O-Fe motif formed at the heterogeneous interface with the introduction of FeOOH, inducing electron transfer from Co to Fe, enhancing Co─O covalency and reducing intramolecular charge transfer energy, thereby stimulating direct intramolecular lattice oxygen coupling. Doping of S in FeOOH further accelerates electron transfer, improves lattice oxygen activity, and prevents dissolution of FeOOH. Consequently, the overpotential of S-FeOOH/Co(OH)2/NF is only 199 mV at 10 mA cm-2, and coupled with the Pt/C electrode can be up to 1 A cm-2 under 1.79 V and remain stable for over 120 h in an anion exchange membrane water electrolyzer (AEMWE). This work proposes a strategy for the design of efficient and stable electrocatalysts for industrial water electrolysis and promotes the commercialization of AEMWE.

Exploring e-sports fans' motivation for watching live streams based on self-determination theory.

This study seeks to examine the multifaceted influences of diverse motivational factors on the live streaming engagement of e-sports fans based on self-determination theory. While previous research has focused on the offline participation in e-sports events, the shift towards live streaming engagement has created a new and underexplored area: the motivations for live streaming viewing among e-sports fans. Consequently, this research develops an e-sports Live Streaming Viewing Motivation Scale for evaluating both intrinsic and extrinsic motivations underlying e-sports fans' live streaming engagement, and then utilises SPSS 26.0 and AMOS 26.0 to assess the reliability and validity of the scale. Subsequently, multiple linear regression analysis of 1052 questionnaires is employed to construct models and evaluate hypotheses. Findings indicate that : (1) Intrinsic motivation exhibits significant impact on the live viewing behaviour of e-sports fans. (2) However, the impact of extrinsic motivation is insignificant. (3) When both intrinsic and extrinsic motivations coexist, intrinsic motivation maintains a positive impact, whereas extrinsic motivation demonstrates a negative influence. (4) The motivational influence is multifaceted; notably, dimensions such as idol worship, leisure entertainment, and competitive stimulation positively affect live viewing motivation, while belonging identification, social engagement, and peripheral activities exert a negative impact. In conclusion, intrinsic motivation emerges as the primary driving force behind e-sports fans' live streaming viewing behaviour. Extrinsic motivation fails to independently influence live streaming engagement and even dampens enthusiasm when combined with intrinsic motivation. Theoretically, this study contributes to the existing literature on Self-determination theory and motivations behind e-sports live streaming viewing behaviour. It not only refines the motivation scale, but also elucidates the impact of various motivations on viewing behaviour. Practically, it provides insights for optimising e-sports products and services.

Why can Mikania micrantha cover trees quickly during invasion?

The invasion of Mikania micrantha by climbing and covering trees has rapidly caused the death of many shrubs and trees, seriously endangering forest biodiversity. In this study, M. micrantha seedlings were planted together with local tree species (Cryptocarya concinna) to simulate the process of M. micrantha climbing under the forest. We found that the upper part of the M. micrantha stem lost its support after climbing to the top of the tree, grew in a turning and creeping manner, and then grew branches rapidly to cover the tree canopy. Then, we simulated the branching process through turning treatment. We found that a large number of branches had been formed near the turning part of the M. micrantha stem (TP). Compared with the upper part of the main stem (UP), the contents of plant hormones (auxin, cytokinin, gibberellin), soluble sugars (sucrose, glucose, fructose) and trehalose-6-phosphate (T6P) were significantly accumulated at TP. Further combining the transcriptome data of different parts of the main stem under erect or turning treatment, a hypothetical regulation model to illustrate how M. micrantha can quickly cover trees was proposed based on the regulation of sugars and hormones on plant branching; that is, the lack of support after ascending the top of the tree led to turning growth of the main stem, and the enhancement of sugars and T6P levels in the TP may first drive the release of nearby dormant buds. Plant hormone accumulation may regulate the entrance of buds into sustained growth and maintain the elongation of branches together with sugars to successfully covering trees.

Association of MAFLD and MASLD with all-cause and cause-specific dementia: a prospective cohort study.

BACKGROUND: Liver disease and dementia are both highly prevalent and share common pathological mechanisms. We aimed to investigate the associations between metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of all-cause and cause-specific dementia. METHODS: We conducted a prospective study with 403,506 participants from the UK Biobank. Outcomes included all-cause dementia, Alzheimer's disease, and vascular dementia. Multivariable Cox proportional hazards models were used for analyses. RESULTS: 155,068 (38.4%) participants had MAFLD, and 111,938 (27.7%) had MASLD at baseline. During a median follow-up of 13.7 years, 5,732 participants developed dementia (2,355 Alzheimer's disease and 1,274 vascular dementia). MAFLD was associated with an increased risk of vascular dementia (HR 1.32 [95% CI 1.18-1.48]) but a reduced risk of Alzheimer's disease (0.92 [0.84-1.0]). Differing risks emerged among MAFLD subtypes, with the diabetes subtype increasing risk of all-cause dementia (1.8 [1.65-1.96]), vascular dementia (2.95 [2.53-3.45]) and Alzheimer's disease (1.46 [1.26-1.69]), the lean metabolic disorder subtype only increasing vascular dementia risk (2.01 [1.25-3.22]), whereas the overweight/obesity subtype decreasing risk of Alzheimer's disease (0.83 [0.75-0.91]) and all-cause dementia (0.9 [0.84-0.95]). MASLD was associated with an increased risk of vascular dementia (1.24 [1.1-1.39]) but not Alzheimer's disease (1.0 [0.91-1.09]). The effect of MAFLD on vascular dementia was consistent regardless of MASLD presence, whereas associations with Alzheimer's disease were only present in those without MASLD (0.78 [0.67-0.91]). CONCLUSIONS: MAFLD and MASLD are associated with an increased risk of vascular dementia, with subtype-specific variations observed in dementia risks. Further research is needed to refine MAFLD and SLD subtyping and explore the underlying mechanisms contributing to dementia risk.

CircHIPK3/miR-124 affects angiogenesis in early-onset preeclampsia via CPT1A-mediated fatty acid oxidation.

Multiple theories have been proposed to explain the pathogenesis of early-onset preeclampsia (EOPE), and angiogenic dysfunction is an important part of this pathogenesis. Carnitine palmitoyltransferase (CPT1A) is a key rate-limiting enzyme in the metabolic process of fatty acid oxidation (FAO). FAO regulates endothelial cell (EC) proliferation during vascular germination and is also essential for ab initio deoxyribonucleotide synthesis, but its role in EOPE needs to be further elucidated. In the present study, we investigated its functional role in EOPE by targeting the circHIPK3/miR-124-3p/CPT1A axis. In our study, reduced expression of circHIPK3 and CPT1A and increased expression of miR-124-3p in placental tissues from patients with EOPE were associated with EC dysfunction. Here, we confirmed that CPT1A regulates fatty acid oxidative activity, cell proliferation, and tube formation in ECs by regulating FAO. Functionally, knockdown of circHIPK3 suppressed EC angiogenesis by inhibiting CPT1A-mediated fatty acid oxidative activity, which was ameliorated by CPT1A overexpression. In addition, circHIPK3 regulates CPT1A expression by sponging miR-124-3p. Hence, circHIPK3 knockdown reduced fatty acid oxidation in ECs by sponging miR-124-3p in a CPT1A-dependent manner and inhibited EC proliferation and tube formation, which may have led to aberrant angiogenesis in EOPE. Thus, strategies targeting CPT1A-driven FAO may be promising approaches for the treatment of EOPE. KEY MESSAGES: Decreased Carnitine palmitoyltransferase (CPT1A) expression in preeclampsia(PE). CPT1A overexpression promotes FAO activity and tube formation in ECs. CircHIPK3 can affect CPT1A expression and impaire angiogenesis of EOPE. CircHIPK3 regulates CPT1A expression by acting as a ceRNA of miR-124-3p in HUVECs. Confirming the effect of circHIPK3/miR-124-3p/CPT1A axis on EOPE.

Correlation between thyroid hormone sensitivity and the risk of polycystic ovary syndrome.

OBJECTIVE: There has been some confusion in earlier research on the connection between thyroid function and polycystic ovary syndrome (PCOS). This research is aimed to probe into the correlation between thyroid condition and the risk of PCOS from a new standpoint of thyroid hormone sensitivity. METHODS: This research comprised 415 females with PCOS from Drum Tower Hospital Affiliated with the Medical School of Nanjing University, and 137 non-PCOS individuals were selected as the normal control. Based on free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH), we calculated the thyroid hormone sensitivity indices, which consist of Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), Thyrotroph Thyroxine Resistance Index (TT4RI) and Free Triiodothyronine /Free thyroxine (FT3/FT4). The binary logistic regression model was adopted to investigate the correlation between thyroid hormone sensitivity indices with the risk of PCOS. Pearson or Spearman correlation analysis was employed to explore the association among thyroid-related measures with metabolic parameters in PCOS. RESULTS: Results of this research showed that females with PCOS had rising TFQI, TSHI, TT4RI, and FT3/FT4 levels compared with the control group. After adjustment for the impact of various covariates, there was no significant correlation between FT3/FT4 and the risk of PCOS; However, the odds ratio of the third and fourth vs. the first quartile of TFQI were 3.57(95% confidence interval [CI]:1.08,11.87) and 4.90(95% CI:1.38,17.38) respectively; The odds ratio of the fourth vs. the first quartile of TSHI was 5.35(95% CI:1.48,19.37); The odds ratio of the second vs. the first quartile of TT4RI was 0.27(95%CI 0.09,0.82). In addition, no significant correlation was observed between thyroid-related measures and metabolic measures in females with PCOS. CONCLUSIONS: A reduction in the sensitivity of central thyroid hormone is closely correlated with a higher risk of PCOS. Further research is necessary to corroborate our findings and the supporting mechanisms.

Quaternized chitosan/polyvinyl alcohol anion exchange membrane enhanced by functionalized attapulgite clay with an ionic "chain-ball" surface structure.

Biomass chitosan has garnered considerable interest for alkaline anion exchange membranes (AEMs) due to its eco-friendly and sustainable characteristics, low reactant permeability and easily modifiable nature, but it still faces the trade-off between high hydroxide conductivity and sufficient mechanical properties. Herein, a novel functionalized attapulgite clay (f-ATP) with a unique ionic "chain-ball" surface structure was prepared and incorporated with quaternized chitosan (QCS)/polyvinyl alcohol (PVA) matrix to fabricate high-performance composite AEMs. Due to the strengthened interfacial bonding between f-ATP nanofillers and the QCS/PVA matrix, composite membranes are synergistically reinforced and toughened, achieving peak tensile strength and elongation at break of 24.62 MPa and 33.8 %. Meanwhile, abundant ion pairs on f-ATP surface facilitate ion transport in the composite AEMs, with the maximum OH- conductivity of 46 mS cm-1 at 80 °C and the highest residual IEC of 83 % after alkaline treatment for 120 h. Moreover, the assembled alkaline direct methanol fuel cell exhibits a remarkable power density of 49.3 mW cm-2 at 80 °C. This work provides a new strategy for fabricating high-performance anion exchange membranes.

Remote epitaxy of single-crystal rhombohedral WS2 bilayers.

Compared to transition metal dichalcogenide (TMD) monolayers, rhombohedral-stacked (R-stacked) TMD bilayers exhibit remarkable electrical performance, enhanced nonlinear optical response, giant piezo-photovoltaic effect and intrinsic interfacial ferroelectricity. However, from a thermodynamics perspective, the formation energies of R-stacked and hexagonal-stacked (H-stacked) TMD bilayers are nearly identical, leading to mixed stacking of both H- and R-stacked bilayers in epitaxial films. Here, we report the remote epitaxy of centimetre-scale single-crystal R-stacked WS2 bilayer films on sapphire substrates. The bilayer growth is realized by a high flux feeding of the tungsten source at high temperature on substrates. The R-stacked configuration is achieved by the symmetry breaking in a-plane sapphire, where the influence of atomic steps passes through the lower TMD layer and controls the R-stacking of the upper layer. The as-grown R-stacked bilayers show up-to-30-fold enhancements in carrier mobility (34 cm2V-1s-1), nearly doubled circular helicity (61%) and interfacial ferroelectricity, in contrast to monolayer films. Our work reveals a growth mechanism to obtain stacking-controlled bilayer TMD single crystals, and promotes large-scale applications of R-stacked TMD.

Bridging the Gender Gap in Academic Engagement among Young Adults: The Role of Anticipated Future Sex Discrimination and Gender-role Orientation.

Academic engagement is vital for college students, yet existing studies reveal inconsistencies in how gender influences academic engagement. Building upon the statistical discrimination theory and identity-based motivation theory, this study develops an integrated model to examine gender differences in college students' academic engagement. Further, the role that gender-role orientation in influencing academic engagement was investigated. Using a sample of 524 college students (Mage = 21.11, SD = 1.98; 47.7% women) from a large university collected in two time periods, the findings indicate that in the Chinese context, women anticipate higher future sex discrimination than men. However, gender-role orientation restores parity between men and women through a moderated mediation: egalitarian gender-role orientation has a stronger effect on women's anticipated future sex discrimination than on men's, resulting in increased academic engagement of women. The findings highlight the need to consider female students' egalitarian beliefs in gender-related academic research.

Automatically detecting OSAHS patients based on transfer learning and model fusion.

Objective. Snoring is the most typical symptom of obstructive sleep apnea hypopnea syndrome (OSAHS) that can be used to develop a non-invasive approach for automatically detecting OSAHS patients.Approach. In this work, a model based on transfer learning and model fusion was applied to classify simple snorers and OSAHS patients. Three kinds of basic models were constructed based on pretrained Visual Geometry Group-16 (VGG16), pretrained audio neural networks (PANN), and Mel-frequency cepstral coefficient (MFCC). The XGBoost was used to select features based on feature importance, the majority voting strategy was applied to fuse these basic models and leave-one-subject-out cross validation was used to evaluate the proposed model.Main results. The results show that the fused model embedded with top-5 VGG16 features, top-5 PANN features, and MFCC feature can correctly identify OSAHS patients (AHI > 5) with 100% accuracy.Significance. The proposed fused model provides a good classification performance with lower computational cost and higher robustness that makes detecting OSAHS patients at home possible.

Evolution of the SPX gene family and its role in the response mechanism to low phosphorus stress in self-rooted apple stock.

BACKGROUND: Phosphorus plays a key role in plant adaptation to adversity and plays a positive role in the yield and quality formation of apples. Genes of the SPX domain-containing family are widely involved in the regulation of phosphorus signalling networks. However, the mechanisms controlling phosphorus deficiency are not completely understood in self-rooted apple stock. RESULTS: In this study, 26 members of the apple SPX gene family were identified by genome-wide analysis, and further divided into four subfamilies (SPX, SPX-MFS, SPX-EXS, and SPX-RING) based on their structural features. The chromosome distribution and gene duplications of MdSPXs were also examined. The promoter regions of MdSPXs were enriched for multiple biotic/abiotic stresses, hormone responses and typical P1BS-related elements. Analysis of the expression levels of 26 MdSPXs showed that some members were remarkably induced when subjected to low phosphate (Pi) stress, and in particular MdSPX2, MdSPX3, and MdPHO1.5 exhibited an intense response to low Pi stress. MdSPX2 and MdSPX3 showed significantly divergent expression levels in low Pi sensitive and insensitive apple species. Protein interaction networks were predicted for 26 MdSPX proteins. The interaction of MdPHR1 with MdSPX2, MdSPX3, MdSPX4, and MdSPX6 was demonstrated by yeast two-hybrid assay, suggesting that these proteins might be involved in the Pi-signaling pathway by interacting with MdPHR1. CONCLUSION: This research improved the understanding of the apple SPX gene family and contribute to future biological studies of MdSPX genes in self-rooted apple stock.

Application of Patient-Reported Outcome Measurements in Adult Tumor Clinical Trials in China: Cross-Sectional Study.

BACKGROUND: International health policies and researchers have emphasized the value of evaluating patient-reported outcomes (PROs) in clinical studies. However, the characteristics of PROs in adult tumor clinical trials in China remain insufficiently elucidated. OBJECTIVE: This study aims to assess the application and characteristics of PRO instruments as primary or secondary outcomes in adult randomized clinical trials related to tumors in China. METHODS: This cross-sectional study identified tumor-focused randomized clinical trials conducted in China between January 1, 2010, and June 30, 2022. The ClinicalTrials.gov database and the Chinese Clinical Trial Registry were selected as the databases. Trials were classified into four groups based on the use of PRO instruments: (1) trials listing PRO instruments as primary outcomes, (2) trials listing PRO instruments as secondary outcomes, (3) trials listing PRO instruments as coprimary outcomes, and (4) trials without any mention of PRO instruments. Pertinent data, including study phase, settings, geographic regions, centers, participant demographics (age and sex), funding sources, intervention types, target diseases, and the names of PRO instruments, were extracted from these trials. The target diseases involved in the trials were grouped according to the American Joint Committee on Cancer Staging Manual, 8th Edition. RESULTS: Among the 6445 trials examined, 2390 (37.08%) incorporated PRO instruments as part of their outcomes. Within this subset, 26.82% (641/2390) listed PRO instruments as primary outcomes, 52.72% (1260/2390) as secondary outcomes, and 20.46% (489/2390) as coprimary outcomes. Among the 2,155,306 participants included in these trials, PRO instruments were used to collect data from 613,648 (28.47%) patients as primary or secondary outcomes and from 74,287 (3.45%) patients as coprimary outcomes. The most common conditions explicitly using specified PRO instruments included thorax tumors (217/1280, 16.95%), breast tumors (176/1280, 13.75%), and lower gastrointestinal tract tumors (173/1280, 13.52%). Frequently used PRO instruments included the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire-30, the visual analog scale, the numeric rating scale, the Traditional Chinese Medicine Symptom Scale, and the Pittsburgh Sleep Quality Index. CONCLUSIONS: Over recent years, the incorporation of PROs has demonstrated an upward trajectory in adult randomized clinical trials on tumors in China. Nonetheless, the infrequent measurement of the patient's voice remains noteworthy. Disease-specific PRO instruments should be more effectively incorporated into various tumor disease categories in clinical trials, and there is room for improvement in the inclusion of PRO instruments as clinical trial end points.

Unveiling unique clinical phenotypes of hip fracture patients and the temporal association with cardiovascular events.

Cardiovascular events are the leading cause of death among hip fracture patients. This study aims to identify subphenotypes of hip fracture patients and investigate their association with incident cardiovascular events, all-cause mortality, and health service utilisation in Hong Kong and the United Kingdom populations. By the latent class analysis, we show three distinct clusters in the Hong Kong cohort (n = 78,417): Cluster 1 has cerebrovascular and hypertensive diseases, hyperlipidemia, and diabetes; Cluster 2 has congestive heart failure; Cluster 3 consists of relatively healthy patients. Compared to Cluster 3, higher risks of major adverse cardiovascular events are observed in Cluster 1 (hazard ratio 1.97, 95% CI 1.83 to 2.12) and Cluster 2 (hazard ratio 4.06, 95% CI 3.78 to 4.35). Clusters 1 and 2 are also associated with a higher risk of mortality, more unplanned accident and emergency visits and longer hospital stays. Self-controlled case series analysis shows a significantly elevated risk of major adverse cardiovascular events within 60 days post-hip fracture. Similar associations are observed in the United Kingdom cohort (n = 27,948). Pre-existing heart failure is identified as a unique subphenotype associated with poor prognosis after hip fractures.

Sodium Houttuyfonate Alleviates MCT-induced Pulmonary Hypertension by Regulating Orai1 and Orai2.

Elevated intracellular Ca2+ concentration ([Ca2+]i) is a key trigger for pulmonary arterial smooth muscle cell (PASMC) proliferation and contributes greatly to pulmonary hypertension (PH). Extracellular Ca2+ influx via a store-operated Ca2+ channel (SOCC), termed store-operated Ca2+ entry (SOCE), is a crucial mechanism for [Ca2+]i elevation in PASMCs. Calcium release-activated calcium modulator (Orai) proteins, consisting of three members (Orai1-3), are the main components of SOCC. Sodium houttuyfonate (SH) is a product of the addition reaction of sodium bisulfite and houttuynin and has antibacterial, anti-inflammatory, and other properties. In this study, we assessed the contributions of Orai proteins to MCT-enhanced SOCE, [Ca2+]i, and cell proliferation in PASMCs and determined the effect of SH on MCT-PH and the underlying mechanism, focusing on Orai proteins, SOCE, and [Ca2+]i in PASMCs. Our results showed that 1) Orai1 and Orai2 were selectively upregulated in the distal pulmonary arteries (PAs) and the PASMCs of MCT-PH rats. 2) Knockdown of Orai1 or Orai2 reduced SOCE, [Ca2+]i, and cell proliferation without affecting their expression in PASMCs in MCT-PH rats. 3) SH significantly normalized the characteristic parameters in a dose-dependent manner in the MCT-PH rat model. 4) SH decreased MCT-enhanced SOCE, [Ca2+]i and PASMC proliferation via Orai1 or Orai2. These results indicate that SH likely exerts its protective role in MCT-PH by inhibiting the Orai1,2-SOCE-[Ca2+]i signaling pathway.

Investigating Novel Therapeutic Approaches for Idiopathic Short Stature: Targeting siRNA and Growth Hormone Delivery to the Growth Plate Using Exosome Nanoparticles.

Idiopathic short stature (ISS) is a common childhood condition with largely unknown underlying causes. Recent research highlights the role of circulating exosomes in the pathogenesis of various disorders, but their connection to ISS remains unexplored. In the experiments, human chondrocytes are cocultured with plasma exosomes from ISS patients, leading to impaired chondrocyte growth and bone formation. Elevated levels of a specific long non-coding RNA (lncRNA), ISSRL, are identified as a distinguishing factor in ISS, boasting high specificity and sensitivity. Silencing ISSRL in ISS plasma exosomes reverses the inhibition of chondrocyte proliferation and bone formation. Conversely, overexpression of ISSRL in chondrocytes impedes their growth and bone formation, revealing its mechanism of action through the miR-877-3p/GZMB axis. Subsequently, exosomes (CT-Exo-siISSRL-oeGH) with precise cartilage-targeting abilities are engineered, loaded with customized siRNA for ISSRL and growth hormone. This innovative approach offers a therapeutic strategy to address ISS by rectifying abnormal non-coding RNA expression in growth plate cartilage and delivering growth hormone with precision to promote bone growth. This research provides valuable insights into ISS diagnosis and treatment, highlighting the potential of engineered exosomes.