Global incidence trends of early-onset colorectal cancer and related exposures in early-life: an ecological analysis based on the GBD 2019.

Background: The incidence of early-onset colorectal cancer (EOCRC) is increasing globally. This study aims to describe the temporal trends of incidence and explore related risk exposures in early-life at the country level based on the GBD 2019. Methods: Data on the incidence and attributable risk factors of EOCRC were obtained from the GBD 2019. Temporal trends of age-standardized incidence were evaluated by average annual percentage change (AAPC). Early-life exposures were indicated as summary exposure values (SEV) of selected factors, SDI and GDP per capita in previous decades and at ages 0-4, 5-9, 10-14 and 15-19 years. Weighted linear or non-linear regressions were applied to evaluate the ecological aggregate associations of the exposures with incidences of EOCRC. Results: The global age-standardized incidence of EOCRC increased from 3.05 (3.03, 3.07) to 3.85 (3.83, 3.86) per 100,000 during 1990 and 2019. The incidence was higher in countries with high socioeconomic levels, and increased drastically in countries in East Asia and Caribbean, particularly Jamaica, Saudi Arabia and Vietnam. The GDP per capita, SDI, and SEVs of iron deficiency, alcohol use, high body-mass index, and child growth failure in earlier years were more closely related with the incidences of EOCRC in 2019. Exposures at ages 0-4, 5-9, 10-14 and 15-19 years were also associated with the incidences, particularly for the exposures at ages 15-19 years. Conclusion: The global incidence of EOCRC increased during past three decades. The large variations at regional and national level may be related with the distribution of risk exposures in early life.

Combining neuromodulation strategies in spinal cord injury gait rehabilitation: A proof of concept, randomized, crossover trial.

OBJECTIVE: To evaluate if acute intermittent hypoxia (AIH) coupled with transcutaneous spinal cord stimulation (tSCS) enhance task-specific training and lead to superior and more sustained gait improvements as compared to each of these strategies used in isolation in persons with chronic, incomplete spinal cord injury (SCI). DESIGN: Proof of concept, randomized crossover trial SETTING: Outpatient, rehabilitation hospital INTERVENTIONS: Ten participants completed 3 intervention arms: 1) AIH, tSCS, and gait training (AIH + tSCS), 2) tSCS plus gait training (SHAM AIH + tSCS), and 3) gait training alone (SHAM + SHAM). Each arm consisted of 5 consecutive days of intervention with a minimum of a 4-week washout between arms. The order of arms was randomized. The study took place from December 3, 2020 to January 4, 2023. MAIN OUTCOME MEASURES: 10-meter walk test (10MWT) at self-selected velocity (SSV) and fast velocity (FV), 6-minute walk test (6MWT), Timed Up and Go (TUG) SECONDARY OUTCOME MEASURES: Isometric ankle plantarflexion and dorsiflexion torque RESULTS: TUG improvements were 3.44 seconds (95% CI: 1.24-5.65) significantly greater in the AIH + tSCS arm than the SHAM AIH + tSCS arm at post-intervention (POST) and 3.31 seconds (95% CI: 1.03-5.58) greater than the SHAM + SHAM arm at 1-week follow up. SSV was 0.08 m/s (95% CI: 0.02-0.14) significantly greater following the AIH + tSCS arm than the SHAM AIH + tSCS at POST. Although not significant, the AIH + tSCS arm also demonstrated the greatest average improvements compared to the other two arms at POST and 1WK for the 6MWT, FV, and ankle plantarflexion torque. CONCLUSIONS: This pilot study is the first to demonstrate that combining these three neuromodulation strategies leads to superior improvements in the TUG and SSV for individuals with chronic incomplete SCI and warrants further investigation.

Open-ICL: Open-Set Modulation Classification via Incremental Contrastive Learning.

Open-set modulation classification (OMC) of signals is a challenging task for handling "unknown" modulation types that are not included in the training dataset. This article proposes an incremental contrastive learning method for OMC, called Open-ICL, to accurately identify unknown modulation types of signals. First, a dual-path 1-D network (DONet) with a classification path (CLP) and a contrast path (COP) is designed to learn discriminative signal features cooperatively. In the COP, the deep features of the input signal are compared with the semantic feature centers (SFCs) of known classes calculated from the network, to infer its signal novelty. An unknown signal bank (USB) is defined to store unknown signals, and a novel moving intersection algorithm (MIA) is proposed to dynamically select reliable unknown signals for the USB. The "unknown" instances, together with SFCs, are continuously optimized and updated, facilitating the process of incremental learning. Furthermore, a dynamic adaptive threshold (DAT) strategy is proposed to enable Open-ICL to adaptively learn changing signal distributions. Extensive experiments are performed on two benchmark datasets, and the results demonstrate the effectiveness of Open-ICL for OMC.

The short-term effects of Jin's three needles in conjunction with mirror therapy on brain function in patients with upper limb disability following an ischemic stroke were evaluated using ReHo analysis.

BACKGROUND: Jin's three needle (JTN) is a commonly utilized treatment for ischemic stroke in China. Mirror therapy (MT) is also gradually transitioning from treating limb discomfort to restoring motor function in the damaged limb. Investigations into the 2 treatments' mechanisms of action are still ongoing. We used functional magnetic resonance imaging (fMRI) technique in this study to examine the effects of JTN combined with mirror therapy MT on brain function in patients with upper limb dysfunction in ischemic stroke, as well as potential central mechanisms. The goal was to provide a solid evidence-based medical basis to support the continued use of JTN combination MT. METHODS: This study will be a single-blind, randomized, and controlled experiment. Randomization was used to assign 20 patients who met the study's eligibility requirements to the JTN + MT treatment group or the JTN control group. Each intervention will last for 4 weeks, with 6 days of treatment per week. The JTN acupuncture points are 3 temporal acupuncture points on the opposite side of the wounded limb, 3 hand acupuncture points on the injured upper limb, 3 shoulder acupuncture points, Renzhong and Baihui, The (JTN + MT) group simultaneously takes MT for 30 minutes. fMRI of the brain using BOLD and T1-weighted images was done both before and after therapy. Brain areas exhibiting changes in regional homogeneity during the pre and posttreatment periods were analyzed. RESULTS: By the end of the treatment course, Jin three-needle therapy plus MT activated more relevant brain functional regions and increased cerebral blood oxygen perfusion than Jin three-needle therapy alone (P <.05). CONCLUSION: In patients with upper limb impairment following an ischemic stroke, JTN with MT may improve brain function reconstruction in the relevant areas.

Development of an effective meropenem/KPC-2 inhibitor combination to combat infections caused by carbapenem-resistant K. pneumoniae.

The global public health threat of bacterial antibiotic resistance continues to escalate and necessitates the implementation of urgent measures to expand our arsenal of antimicrobial drugs. In this study, we identified a benzoxaborane compound, namely 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2178), which can effectively inhibit the catalytic activity of the Klebsiella pneumoniae carbapenemase (KPC-2) enzyme. The efficacy of AN2718 as an inhibitor for the KPC-2 enzyme was verified through various assays, including enzyme activity assays and isothermal titration calorimetry. Results of multiple biochemical assays, minimum inhibitory concentration assay, and time-killing assay also showed that binding of AN2718 to KPC-2 enabled the restoration of the bactericidal effect of meropenem. The survival rate of mice infected by carbapenem-resistant, high-virulence strains increased significantly upon treatment with this agent. Most importantly, the meropenem and AN2718 combination is effective on KPC-2 mutations such as KPC-33 that were clinically evolved and exhibited resistance to ceftazidime-avibactam upon the clinical uses of this drug for a couple of years. Comprehensive safety tests both in vitro and in vivo, such as cytotoxicity, haemolytic activity, and cytochrome P450 inhibition assays demonstrated that AN2718 was safe for clinical use. These promising data indicate that AN2718 has a high potential for being approved for the treatment of drug resistant bacterial infections, including those caused by the Ceftazidime-Avibactam resistant strains. To conclude, the compound AN2718 can be regarded as a valuable addition to the current antimicrobial armamentarium and a promising tool to combat antimicrobial resistance.

A comparative analysis of different reduced-port laparoscopic surgical procedures after non-curative endoscopic resection for early colorectal cancer.

Introduction: Surgery serves as a salvage procedure for non-curative resection of early-stage colorectal cancer under endoscopy. A standard method for performing additional surgery after endoscopic submucosal dissection (ESD) for early colorectal cancer has yet to be established. Aim: To enhance the understanding of different surgical outcomes by discussing additional treatment strategies following non-complete curative endoscopic resection of early colorectal cancer. Material and methods: This retrospective study included 88 patients who were divided into three groups based on the surgical approach: conventional laparoscopic surgery (CLS), single-incision plus one-port laparoscopic surgery (SILS+1), and three-port laparoscopic surgery combined with natural orifice specimen extraction surgery (three-port NOSES). The study aimed to compare the surgical outcomes, safety, and postoperative recovery among these groups. Results: The SILS+1 and three-port NOSES groups demonstrated comparable safety and efficacy to the CLS group in terms of blood loss, complications, number of lymph node dissections, and length of bowel resection. However, the SILS+1 and three-port NOSES groups had advantages in terms of incision length (7.11 ±0.38, 4.24 ±0.33, 3.16 ±0.22, p < 0.001), postoperative pain (4.000 [3.0,5.0], 3.500 [3.0,4.0], 3.000 [3.0,4.0]; p = 0.003), cosmetic result (4.000 [3.8,5.0], 7.000 [7.0,8.0], 7.000 [7.0,8.0]; p < 0.001), and hospital stay (8.000 [7.0,9.0], 7.000 [6.3,8.0.], 7.000 [6.3,8.0]; p = 0.035). Conclusions: Different strategies of reduced-port laparoscopic surgery have been demonstrated to be effective and safe in additional surgery after non-curative ESD. These techniques have shown reduced pain and increased satisfaction among patients. Reduced-port laparoscopic surgery is expected to become the preferred treatment option for these patients.

Neuroimmune modulating and energy supporting nanozyme-mimic scaffold synergistically promotes axon regeneration after spinal cord injury.

Spinal cord injury (SCI) represents a profound central nervous system affliction, resulting in irreversibly compromised daily activities and disabilities. SCI involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages, and neuronal mitochondrial energy deficit, exacerbating secondary damage and impeding axon regeneration. This study delves into the mechanistic intricacies of SCI, offering insights from the perspectives of neuroimmune regulation and mitochondrial function, leading to a pro-fibrotic macrophage phenotype and energy-supplying deficit. To address these challenges, we developed a smart scaffold incorporating enzyme mimicry nanoparticle-ceriumoxide (COPs) into nanofibers (NS@COP), which aims to pioneer a targeted neuroimmune repair strategy, rescuing CGRP receptor on macrophage and concurrently remodeling mitochondrial function. Our findings indicate that the integrated COPs restore the responsiveness of pro-inflammatory macrophages to calcitonin gene-related peptide (CGRP) signal by up-regulating receptor activity modifying protein 1 (RAMP1), a vital component of the CGRP receptor. This promotes macrophage fate commitment to an anti-inflammatory pro-resolution M2 phenotype, then alleviating glial scar formation. In addition, NS@COP implantation also protected neuronal mitochondrial function. Collectively, our results suggest that the strategy of integrating nanozyme COP nanoparticles into a nanofiber scaffold provides a promising therapeutic candidate for spinal cord trauma via rational regulation of neuroimmune communication and mitochondrial function.

Investigation of deformation behavior and strain-induced precipitations in Al-Zn-Mg-Cu alloys across a wide temperature range.

This study explores the hot deformation behavior of Al-Zn-Mg-Cu alloy through uniaxial hot compression (200 °C-450°C) using the Gleeble-1500. True stress-strain curves were corrected, and three models were established: the Arrhenius model, strain compensated (SC) Arrhenius model, and strain compensated recrystallization temperature (RT) segmentation-based (TS-SC) Arrhenius model. Comparative analysis revealed the limited predictive accuracy of the SC Arrhenius model, with a 25.12% average absolute relative error (AARE), while the TS-SC Arrhenius model exhibited a significantly improved to 9.901% AARE. Material parameter calculations displayed variations across the temperature range. The SC Arrhenius model, utilizing an average slope method for parameter computation, failed to consider temperature-induced disparities, limiting its predictive capability. Hot processing map, utilizing the Murty improved Dynamic Materials Model (DMM), indicated optimal conditions for stable forming of the Al-Zn-Mg-Cu alloy. Microstructural analysis revealed MgZn2 precipitation induced by hot deformation, with crystallographic defects enhancing nucleation rates and precipitate refinement.

A comparison of three-port and four-port Da Vinci robot-assisted thoracoscopic surgery for lung cancer: a retrospective study.

BACKGROUND: At present, research comparing the short-term postoperative outcomes of anatomical resection in lung cancer under different ports of da Vinci robot-assisted surgery is insufficient. This report aimed to compare the outcomes of three-port and four-port da Vinci robot-assisted thoracoscopic surgery for radical dissection of lung cancer. METHODS: 171 consecutive patients who presented to our hospital from January 2020 to October 2021 with non-small cell lung cancer and treated with da Vinci robot-assisted thoracoscopic surgery for radical resection of lung cancer were retrospectively collected and divided into the three-port group (n = 97) and the four-port group (n = 74). The general clinical data, perioperative data and life quality were individually compared between the two groups. RESULTS: All the 171 patients successfully underwent surgeries. Compared to the four-port group, the three-port group had comparable baseline characteristics in terms of age, sex, tumor location, tumor size, history of chronic disease, pathological type, and pathological staging. The three-port group also had shorter operation time, less intraoperative blood loss, lower chest tube drainage volume, shorter postoperative hospitalization stay durations, but showed no statistically significant difference (P > 0.05). Postoperative 24, 48 and 72 h visual analogue scale pain scores were lower in the three-port group (p < 0.001). No significant difference was observed between the two groups in the hospitalization costs (P = 0.664), number or stations of total lymph node dissected (p > 0.05) and postoperative respiratory complications (P > 0.05). CONCLUSIONS: The three-port robot-assisted thoracoscopic surgery is safe and effective and took better outcomes than the four-port robot-assisted thoracoscopic surgery in non-small cell lung cancer.

DNA Methylation Demonstrates Bronchoalveolar Cell Senescence in People Living with HIV: An Observational Cohort Study.

BACKGROUND: DNA methylation may be a link between HIV, aging, and the increased risk of lung comorbidities. We investigated whether bronchoalveolar lavage (BAL) cells of people living with HIV (PLWH) demonstrate epigenetic disruptions and advanced epigenetic aging. METHODS: BAL cell DNA methylation from 25 PLWH and 16 HIV-uninfected individuals were tested for differential methylation of Alu and LINE-1 sites, markers of aging. We used a weighted gene correlation network analysis to identify HIV- and age-associated co-methylation networks. We tested the effect of HIV on DNA methylation using a robust linear model (false discovery rate < 0.10). RESULTS: The BAL cells of PLWH were marked by global hypomethylation in both Alu and LINE-1 elements. Six co-methylated CpG networks were identified that were significantly associated with age; of these, the red module was significantly differentially methylated in PLWH and enriched pathways (e.g., Ras signaling and T-cell receptors). We identified 6428 CpG sites associated with HIV. CONCLUSIONS: We have shown here for the first time that alterations in the DNA methylation of BAL cells in the lung with HIV show a pattern of advanced aging. This study strongly supports that HIV may contribute to an increased the risk of lung comorbidities through the epigenetics of aging.

Characterization of Acinetobacter baumannii at a tertiary hospital in Guangzhou: a genomic and clinical study.

Acinetobacter baumannii (AB) infections have become a global public health concern due to the continued increase in the incidence of infection and the rate of resistance to carbapenems. This study aimed to investigate the genomic features of AB strains recovered from a tertiary hospital and assess the clinical implications of the findings. A total of 217 AB strains were collected between 2016 and 2018 at a tertiary hospital in Guangzhou, with 183 (84.33%) being carbapenem-resistant AB (CRAB), with the main mechanism being the carriage of the blaOXA-23 gene. The overall mortality rate of patients caused by such strains was 15.21% (n = 33). Artificial lung ventilation and the use of meropenem were mortality risk factors in AB-infected patients, while KL2 AB infection was negatively associated. Core genome multilocus sequence typing and clustering analysis were performed on the integrated AB genome collection from the NCBI database and this study to illustrate the population structure among China. The results revealed diverse core genome profiles (n = 17) among AB strains from China, and strains from this single hospital exhibited most of the core genome profiles (n = 13), suggesting genetic variability within the hospital and transmission across the country. These findings show that the high transmission potential of the CRAB strains and meropenem usage that confers a selective advantage of CRAB clinically are two major factors that pose significant challenges to the effective clinical management of AB infections. Understanding the genetic features and transmission patterns of clinical AB strains is crucial for the effective control of infections caused by this pathogen.

The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity.

Proper transcription regulation by key transcription factors, such as IRF3, is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we have performed H3K27ac ChIP-Seq and identified three transcription factors, NR2F6, MEF2D and MAFF, in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, but not dependent on cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activates AP-1/c-Jun pathway, which is critical for DNA virus replication. On the other hand, NR2F6 is transcriptionally repressed by c-Jun and forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors and revealed the underlying mechanisms involved in the network between DNA viruses and host cells.

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

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

Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre- and early-symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early-onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with post-symptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over nine years. The most common adverse events (AEs) within two months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with post-symptomatic juvenile MLD.

High-Precision Photoacoustic Neural Modulation Uses a Non-Thermal Mechanism.

Neuromodulation is a powerful tool for fundamental studies in neuroscience and potential treatments of neurological disorders. Both photoacoustic (PA) and photothermal (PT) effects are harnessed for non-genetic high-precision neural stimulation. Using a fiber-based device excitable by a nanosecond pulsed laser and a continuous wave laser for PA and PT stimulation, respectively, PA and PT neuromodulation is systematically investigated at the single neuron level. These results show that to achieve the same level of neuron activation recorded by Ca2+ imaging, the laser energy needed for PA stimulation is 1/40 of that needed for PT stimulation. The threshold energy for PA stimulation is found to be further reduced in neurons overexpressing mechano-sensitive channels, indicating direct involvement of mechano-sensitive channels in PA stimulation. Electrophysiology study of single neurons upon PA and PT stimulation is performed by patch clamp recordings. Electrophysiological features induced by PA are distinct from those by PT, confirming that PA and PT stimulation operate through different mechanisms. These insights offer a foundation for the rational design of more efficient and safer non-genetic neural modulation approaches.

Novel organic-inorganic composite pea protein silica food-grade aerogel materials: Fabrication, mechanisms, high oil-holding property and curcumin delivery capacity.

The fragility of the skeleton and poor bioaccessibility limit Silica aerogel's application in the food industry. In this study, composite gels were obtained by cross-linking pea proteins isolate (PPI) with Tetraethoxysilane (TEOS)to improve the bioavailability of silica-derived aerogels. It indicated that TEOS first condensed with H+ to form secondary particles and then complexed with PPI via hydroxyl groups to form a composite aerogel. Meanwhile, the PPI-Si composite aerogel formed a dense mesoporous structure with a specific surface area of 312.5 g/cm3. This resulted in a higher oil holding percentage of 89.67 % for the PPI (10 %)-Si aerogel, which was 34.1 % higher than other studies, leading to a more stable oleogel. Finally, as a delivery system, the composite oleogel not only could significantly increase the bioaccessibility rate by 27.4 % compared with silica aerogel, but also could efficiently inhibit the premature release of curcumin in the simulated gastric fluids, while allowed sustainably release in the simulated intestinal fluids. These results provided a theoretical basis for the application of silica-derived aerogels in food and non-food applications.

Pan-cancer analysis of CDKN2A alterations identifies a subset of gastric cancer with a cold tumor immune microenvironment.

BACKGROUND: Although CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer. METHODS: This study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT). RESULTS: Our research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response. CONCLUSIONS: This study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.

A Multi-Level Model of Institutional Innovation and Knowledge Creation Capabilities: Insights From the Development of Taiwan's Nation Health Insurance.

This study proposes a multi-level model of institutional innovation in the healthcare sector-in other words, field-level institutional change pressures that start as network-level institutional innovation by hospitals and government for their organizational performance, with an emphasis on the effect of organizational-level construct-knowledge creation capabilities. A case study using in-depth interviews and a historical inquiry approach has been used to qualitatively analyze our cases during the development of Taiwan's National Health Insurance (NHI). Our results propose a multi-level explanation of institutional innovation by showing how field-level institutional change pressures can stimulate the government's institutional innovation at the network level. Moreover, knowledge creation capabilities may positively influence the government hospitals' ongoing institutional change pressures induced institutional innovation activity for their performance at the organizational level in an institutional setting. This study contributes to health organization management researchers and administrators by developing explanations of institutional innovation and creating a much-needed multi-level insight into hospital behavior in the highly institutionalized healthcare sector.

Correlation between dietary factors and Parkinson's disease revealed by the analysis of Mendelian randomization.

Background: The intricate interplay between dietary habits and the development of Parkinson's Disease (PD) has long been a subject of scientific inquiry. Mendelian Randomization (MR) emerges as a potent tool, harnessing genetic variants to infer causality in observational data. While evidence links diet to Parkinson's Disease (PD) etiology, a thorough MR exploration of dietary impacts on PD, particularly involving gut microbiota, is still emerging. Methods: This research leverages the IEU Open GWAS project's vast GWAS database to address the knowledge gap in understanding diet's influence on PD, employing a diverse range of dietary variables. Our holistic dataset includes various foods like processed fava beans, bap, red wine, to cheese, reflecting a commitment to untangling dietary complexities in PD etiology. Advancing from initial dietary-PD associations, we innovatively explore the gut microbiota, focusing on Parabacteroides goldsteinii, in relation to bap intake and PD, employing MR. Utilizing weighted median, MR-Egger, and inverse variance weighting methods, we ensure rigorous causality assessments, meticulously mitigating pleiotropy and heterogeneity biases to uphold finding validity. Results: Our findings indicate red wine (OR: 1.031; 95% CI 1.001-1.062; p = 0.044) and dried fruit consumption (OR: 2.019; 95% CI 1.052-3.875; p = 0.035) correlate with increased PD risk, whereas broad beans (OR: 0.967; 95% CI 0.939-0.996; p = 0.024) and bap intake (OR: 0.922; 95% CI 0.860-0.989; p = 0.023) show protective effects against PD. Employing MR, specifically the IVW method, revealed a significant inverse association between bap intake and gut microbiota, marked by an 8.010-fold decrease in Parabacteroides goldsteinii per standard deviation increase in bap intake (95% CI 1.005-63.818, p = 0.049). Furthermore, a connection between PD and Parabacteroides goldsteinii was observed (OR: 0.810; 95% CI 0.768-0.999; p = 0.049), suggesting a potential microbiota-mediated pathway in PD etiology. Conclusion: Our study links dietary habits to PD risk, showing higher PD risk with red wine and dried fruit consumption, and a protective effect from broad beans and bap. Using MR, we found bap intake inversely correlates with Parabacteroides goldsteinii in the gut, suggesting bap influences microbiota. Further, higher Parabacteroides goldsteinii levels correlate with lower PD risk, highlighting a complex interplay of diet, gut microbiome, and neurological health. These insights shed light on potential dietary interventions for PD.

Systematic assessment of long-read RNA-seq methods for transcript identification and quantification.

The Long-read RNA-Seq Genome Annotation Assessment Project Consortium was formed to evaluate the effectiveness of long-read approaches for transcriptome analysis. Using different protocols and sequencing platforms, the consortium generated over 427 million long-read sequences from complementary DNA and direct RNA datasets, encompassing human, mouse and manatee species. Developers utilized these data to address challenges in transcript isoform detection, quantification and de novo transcript detection. The study revealed that libraries with longer, more accurate sequences produce more accurate transcripts than those with increased read depth, whereas greater read depth improved quantification accuracy. In well-annotated genomes, tools based on reference sequences demonstrated the best performance. Incorporating additional orthogonal data and replicate samples is advised when aiming to detect rare and novel transcripts or using reference-free approaches. This collaborative study offers a benchmark for current practices and provides direction for future method development in transcriptome analysis.