Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders?: Evidence from Observational and 2-Sample Mendelian Randomization Analyses.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and spinal degenerative disorders (SDD) are common diseases that frequently coexist. However, both traditional observational studies and recent Mendelian randomization (MR) studies have demonstrated conflicting evidence on the association between T2DM and SDD. This comparative study explored and compared the association between T2DM and SDD using observational and MR analyses. METHODS: For observational analyses, cross-sectional studies (44,972 participants with T2DM and 403,095 participants without T2DM), case-control studies (38,234 participants with SDD and 409,833 participants without SDD), and prospective studies (35,550 participants with T2DM and 392,046 participants without T2DM with follow-up information until 2022) were performed to test the relationship between T2DM and SDD using individual-level data from the U.K. Biobank from 2006 to 2022. For MR analyses, the associations between single-nucleotide polymorphisms with SDD susceptibility obtained using participant data from the U.K. Biobank, which had 407,938 participants from 2006 to 2022, and the FinnGen Consortium, which had 227,388 participants from 2017 to 2022, and genetic predisposition to T2DM obtained using summary statistics from a pooled genome-wide association study involving 1,407,282 individuals were examined. The onset and severity of T2DM are not available in the databases being used. RESULTS: Participants with T2DM were more likely to have SDD than their counterparts. Logistic regression analysis identified T2DM as an independent risk factor for SDD, which was confirmed by the Cox proportional hazard model results. However, using single-nucleotide polymorphisms as instruments, the MR analyses demonstrated no causal relationship between T2DM and SDD. The lack of such an association was robust in the sensitivity analysis, and no pleiotropy was seen. CONCLUSIONS: Our results suggest that the association between T2DM and SDD may be method-dependent. Researchers and clinicians should be cautious in interpreting the association, especially the causal association, between T2DM and SDD. Our findings provide fresh insights into the association between T2DM and SDD by various analysis methods and guide future research and clinical efforts in the effective prevention and management of T2DM and SDD. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Optimize individualized energy delivery for septic patients using predictive deep learning models.

BACKGROUND AND OBJECTIVES: We aim to establish deep learning models to optimize the individualized energy delivery for septic patients. METHODS AND STUDY DESIGN: We conducted a study of adult septic patients in ICU, collecting 47 indicators for 14 days. We filtered out nutrition-related features and divided the data into datasets according to the three metabolic phases proposed by ESPEN: acute early, acute late, and rehabilitation. We then established optimal energy target models for each phase using deep learning and conducted external validation. RESULTS: A total of 179 patients in training dataset and 98 patients in external validation dataset were included in this study, and total data size was 3115 elements. The age, weight and BMI of the patients were 63.05 (95%CI 60.42-65.68), 61.31(95%CI 59.62-63.00) and 22.70 (95%CI 22.21-23.19), respectively. And 26.0% (72) of the patients were female. The models indicated that the optimal energy targets in the three phases were 900kcal/d, 2300kcal/d, and 2000kcal/d, respectively. Excessive energy intake increased mortality rapidly in the early period of the acute phase. Insufficient energy in the late period of the acute phase significantly raised the mortality as well. For the rehabilitation phase, too much or too little energy delivery were both associated with elevated death risk. CONCLUSIONS: Our study established time-series prediction models for septic patients to optimize energy delivery in the ICU. We recommended permissive underfeeding only in the early acute phase. Later, increased energy intake may improve survival and settle energy debts caused by underfeeding.

Hidden blood loss and its risk factors after hip reconstruction in children.

OBJECTIVE: There were few reports in the literature regarding hidden blood loss following surgery for developmental dysplasia of the hip in children. This study aimed to evaluate the volume of hidden blood loss and its risk factors among children undergoing hip reconstruction for developmental dysplasia of the hip. METHODS: A retrospective analysis of clinical data from 42 patients (58 hips), who underwent Pemberton and femoral osteotomies between March 2020 and March 2023, was conducted. Serial complete blood count assays were conducted on the day of admission and four days post-surgery. Preoperative and postoperative hematocrit levels were documented to calculate hidden blood loss utilizing the Gross formula. Pearson and Spearman correlation analyses, along with multivariable linear regression, were employed to ascertain associations between patient characteristics and hidden blood loss. RESULTS: The mean hidden blood loss was recorded as 283.06 ± 271.05 mL, constituting 70.22% of the total blood loss. Multiple linear regression analysis identified weight and surgical duration as independent risk factors contributing to hidden blood loss. CONCLUSIONS: A relevant amount of postoperative hidden blood loss occurs after Pemberton osteotomy and femoral osteotomy for developmental dysplasia of the hip. Surgeons should be aware that patients who require blood transfusions and have longer surgical durations are at a higher risk of developing more hidden blood loss. Therefore, attention should be given to hidden blood loss to ensure patient safety during the perioperative period for those undergoing Pemberton and femoral osteotomies. LEVEL OF EVIDENCE: IV.

Subcellular location of L1 retrotransposon-encoded ORF1p, reverse transcription products, and DNA sensors in lupus granulocytes.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p. RESULTS: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis. CONCLUSIONS: These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease.

Oral nutritional supplements improve clinical outcomes and are cost-effective for hospitalized patients in China.

OBJECTIVE: This study assessed the therapeutic benefits and modeled the cost-effectiveness of oral nutritional supplements (ONS) in China. METHODS: Data were collected from 27 152 adult inpatients between January 1, 2018, and December 31, 2020. Propensity score matching was used for balancing the baseline characteristics between the ONS group and non-ONS group. A decision-tree model was developed to assess the cost-effectiveness of ONS for patients with nutritional risk, and the incremental cost-effectiveness ratio was the metric to determine the most cost-effective strategy. One-way sensitivity and probabilistic sensitivity analyses were conducted to assess the model's stability. In addition, subgroup analysis was conducted based on clinical characteristics. Differences in clinical outcomes between the groups were compared using Student's t test, Mann-Whitney U test, or chi-square test. RESULTS: The ONS group displayed significantly lower levels of prealbumin, albumin, hemoglobin, and BMI than the non-ONS group at admission. The incidence of malignant tumors, intestinal obstruction, and inflammatory bowel disease was significantly higher in the ONS group than the non-ONS group. The ONS group had a significantly higher effective rate than the non-ONS group (51.7% versus 50.3%, P < 0.05). Analysis of the decision-tree model revealed that the ONS group experienced an increase in cost of 19 850.96 yuan but achieved an additional 1.3406 effectiveness rate, resulting in an incremental cost-effectiveness ratio of 14 807.51, which fell below China's 2020 per capita gross domestic product of 71 965 yuan. Sensitivity analysis further confirmed the robustness of the model. CONCLUSIONS: ONS are demonstrated a high rate of efficacy, although patients currently using ONS are typically in a severe disease state. In addition, ONS is cost-effective. We suggest that the reimbursement coverage of ONS be expanded to include in-hospital patients who are at high nutritional risk.

Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions.

The complex process of aging leads to a gradual deterioration in the function of cells, tissues, and the entire organism, thereby increasing the risk of disease and death. Nicotinamide N-methyltransferase (NNMT) has attracted attention as a potential target for combating aging and its related pathologies. Studies have shown that NNMT activity increases over time, which is closely associated with the onset and progression of age-related diseases. NNMT uses S-adenosylmethionine (SAM) as a methyl donor to facilitate the methylation of nicotinamide (NAM), converting NAM into S-adenosyl-L-homocysteine (SAH) and methylnicotinamide (MNA). This enzymatic action depletes NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in the NAD+ levels and the increase in the Hcy levels are considered important factors in the aging process and age-related diseases. The efficacy of RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT demonstrates the potential of NNMT as a therapeutic target. Despite these advances, the exact mechanisms by which NNMT influences aging and age-related diseases remain unclear, and there is a lack of clinical trials involving NNMT inhibitors and RNAi drugs. Therefore, more in-depth research is needed to elucidate the precise functions of NNMT in aging and promote the development of targeted pharmaceutical interventions. This paper aims to explore the specific role of NNMT in aging, and to evaluate its potential as a therapeutic target.

Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome.

Metabolic syndrome (MetS) represents a constellation of metabolic abnormalities, typified by obesity, hypertension, hyperglycemia, and hyperlipidemia. It stems from intricate dysregulations in metabolic pathways governing energy and substrate metabolism. While comprehending the precise etiological mechanisms of MetS remains challenging, evidence underscores the pivotal roles of aberrations in lipid metabolism and insulin resistance (IR) in its pathogenesis. Notably, nicotinamide N-methyltransferase (NNMT) has recently surfaced as a promising therapeutic target for addressing MetS. Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism, obesity, type 2 diabetes (T2D), hyperlipidemia, and hypertension. Elevated NNMT gene expression is notably observed in the liver and white adipose tissue (WAT) of individuals with diabetic mice, obesity, and rats afflicted with MetS. Knockdown of NNMT elicits heightened energy expenditure in adipose and hepatic tissues, mitigates lipid accumulation, and enhances insulin sensitivity. NNMT catalyzes the methylation of nicotinamide (NAM) using S-adenosyl-methionine (SAM) as the donor methyl group, resulting in the formation of S-adenosyl-l-homocysteine (SAH) and methylnicotinamide (MNAM). This enzymatic process results in the depletion of NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and the generation of SAH, a precursor of homocysteine (Hcy). Consequently, this cascade leads to reduced NAD+ levels and elevated Hcy levels, implicating NNMT in the pathogenesis of MetS. Moreover, experimental studies employing RNA interference (RNAi) strategies and small molecule inhibitors targeting NNMT have underscored its potential as a therapeutic target for preventing or treating MetS-related diseases. Nonetheless, the precise mechanistic underpinnings remain elusive, and as of yet, clinical trials focusing on NNMT have not been documented. Therefore, further investigations are warranted to elucidate the intricate roles of NNMT in MetS and to develop targeted therapeutic interventions.

Integrated Analysis Reveals COL4A3 as a Novel Diagnostic and Therapeutic Target in UV-Related Skin Cutaneous Melanoma.

Background: High levels of UV exposure are a significant factor that can trigger the onset and progression of SKCM. Moreover, this exposure is closely linked to the malignancy of the tumor and the prognosis of patients. Our objective is to identify a tumor biomarker database associated with UV exposure, which can be utilized for prognostic analysis and diagnosis and treatment of SKCM. Methods: This study used the weighted gene co-expression network analyses (WGCNA) and gene mutation frequency analyses to screen for UV-related target genes using the GSE59455 and the cancer genome atlas databases (TCGA). The prognostic model was created using Cox regression and least absolute shrinkage and selection operator analyses (LASSCO). Furthermore, in vitro experiments further validated that the overexpression or knockdown of COL4A3 could regulate the proliferation and migration abilities of SKMEL28 and A357 melanoma cells. Results: A prognostic model was created that included six genes with a high UV-related mutation in SKCM: COL4A3, CHRM2, DSC3, GIMAP5, LAMC2, and PSG7. The model had a strong patient survival correlation (P˂0.001, hazard ratio (HR) = 1.57) and significant predictor (P˂0.001, HR = 3.050). Furthermore, the model negatively correlated with immune cells, including CD8+ T cells (Cor=-0.408, P˂0.001), and M1-type macrophages (Cor=-0.385, P˂0.001), and immune checkpoints, including programmed cell death ligand-1. Moreover, we identified COL4A3 as a molecule with significant predictive functionality. Overexpression of COL4A3 significantly inhibited the proliferation, migration, and invasion abilities of SKMEL28 and A357 melanoma cells, while knockdown of COL4A3 yielded the opposite results. And overexpression of COL4A3 enhanced the inhibitory effects of imatinib on the proliferation, migration, and invasion abilities of SKMEL28 and A357 cells. Conclusion: The efficacy of the prognostic model was validated by analyzing the prognosis, immune infiltration, and immune checkpoint profiles. COL4A3 stands out as a novel diagnostic and therapeutic target for SKCM, offering new strategies for small-molecule targeted drug therapies.

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.

Rules for dissipationless topotronics.

Topological systems hosting gapless boundary states have attracted huge attention as promising components for next-generation information processing, attributed to their capacity for dissipationless electronics. Nevertheless, recent theoretical and experimental inquiries have revealed the emergence of energy dissipation in precisely quantized electrical transport. Here, we present a criterion for the realization of truly no-dissipation design, characterized as Nin = Ntunl + Nbs, where Nin, Ntunl, and Nbs represent the number of modes participating in injecting, tunneling, and backscattering processes, respectively. The key lies in matching the number of injecting, tunneling, and backscattering modes, ensuring the equilibrium among all engaged modes inside the device. Among all the topological materials, we advocate for the indispensability of Chern insulators exhibiting higher Chern numbers to achieve functional devices and uphold the no-dissipation rule simultaneously. Furthermore, we design the topological current divider and collector, evading dissipation upon fulfilling the established criterion. Our work paves the path for developing the prospective topotronics.

[Relationship between serum 25-hydroxyvitamin D and handgrip strength in middle-aged and elderly people in five cities of Western China].

OBJECTIVE: To explore the association between serum 25-hydroxyvitamin D [25(OH)D] and handgrip strength in middle-aged and elderly people in 5 cities of Western China. METHODS: Based on the data of a cross-sectional survey conducted in the 5 cities of Western China from February to July 2023, the relevant demographic characteristics of people were collected by questionnaire, handgrip strength was collected by physical examination, and serum 25(OH)D was detected by HPLC-MS/MS. The association between the serum 25(OH)D and handgrip strength was analyzed using Logistic regression and Chi-square test for between-group comparisons models. RESULTS: The prevalence of 25(OH)D deficiency and insufficiency among the middle-aged and elderly people in the 5 cities of Western China was 52.9% and 34.5%, respectively. The people who were older, female, and sampled in winter had lower serum 25(OH)D levels (P < 0.05). The prevalence of loss of handgrip strength among the middle-aged and elderly people was 25.3%. The prevalence of handgrip strength loss was higher in the aged 65-80 participants with 25(OH)D deficiency (45. 0%) than in those with 25(OH)D insufficiency (32.6%) and 25(OH)D sufficiency (20.6%). The highest prevalence of loss of handgrip strength was found in the aged 75-80 participants with 25(OH)D deficiency (62. 1%), followed by the 25(OH)D insufficient group (11.1%, P < 0.05). The study found that middle-aged and elderly people with 25(OH)D deficiency had a 1.4-fold increased risk of handgrip strength loss compared with those with 25(OH)D sufficiency (OR=2.403, 95%CI: 1.202-4.804, P=0.013). No significant association was found between 25(OH)D insufficiency and handgrip strength status in the middle-aged and elderly people. For every 5 µg/L increase in total serum 25(OH)D, the risk of handgrip strength loss reduced by 13.1% (OR=0.869, 95%CI: 0.768-0.982, P=0.025). For every 5 µg/L increase in serum 25(OH)D2, the risk of handgrip strength loss reduced by 24.1% (OR=0.759, 95%CI: 0.582-0.990, P=0.042). No significant association was found between serum 25(OH)D3 levels and the risk of handgrip strength loss. The risk of handgrip strength loss in middle-aged and elderly people was reduced by 25.2% for each incremental increase in the total serum 25(OH)D levels (deficient, insufficient and sufficient) (OR=0.748, 95%CI: 0.598-0.936, P=0.011). The risk of handgrip loss was reduced by 40.0% for each incremental increase in serum 25(OH)D levels in the aged 65-80 and aged 65-69 participants, and by 80.0% for each incremental increase in 25(OH)D levels in the aged 75-80 parti-cipants. CONCLUSION: Serum total 25(OH)D and 25(OH)D2 levels are associated with handgrip strength status in middle-aged and elderly people in the 5 cities of Western China.

Metabolomics reveals that ferroptosis participates in bisphenol A-induced testicular injury.

Objective: Bisphenol A (BPA) is a common environmental endocrine disruptor that negatively impairs male reproductive ability. This study aimed to explore the alterations in serum metabolomics that occur following BPA exposure and the mechanism via which BPA induces the death of testicular cells in a male mouse model. Methods: The mice were classified into two groups: BPA-exposed and control groups, and samples were collected for metabolomic determination, semen quality analysis, electron microscopy, enzyme-linked immunosorbent assay, quantitative real-time PCR, pathological staining, and Western blot analysis. Results: BPA exposure caused testicular damage and significantly decreased sperm quality in mice. Combined with non-target metabolomic analysis, this was closely related to ferroptosis induced by abnormal metabolites of arachidonic acid and phosphatidylcholine, and the expression of its related genes, acyl CoA synthetase 4, glutathione peroxidase 4, lysophosphatidylcholine acyltransferase 3, and phosphatidylethanolamine-binding protein 1 were altered. Conclusion: BPA induced ferroptosis, caused testicular damage, and reduced fertility by affecting lipid metabolism in male mice. Inhibiting ferroptosis may potentially function as a therapeutic strategy to mitigate the male reproductive toxicity induced by BPA.

Dynamic immune status analysis of peripheral blood mononuclear cells in patients with Klebsiella pneumoniae bloodstream infection sepsis using single-cell RNA sequencing.

Background: Klebsiella pneumoniae is a common Gram-negative bacterium. Blood infection caused by K. pneumoniae is one of the most common causes of human sepsis, which seriously threatens the life of patients. The immune status of peripheral blood mononuclear cells (PBMCs) based on single-cell RNA sequencing (scRNA-seq) in acute stage and recovery stage of sepsis caused by K. pneumoniae bloodstream infection has not been studied. Methods: A total of 13 subjects were included in this study, 3 healthy controls, 7 patients with K. pneumoniae bloodstream infection in the acute stage (4 patients died), and 3 patients in the recovery stage. Peripheral blood of all patients was collected and PBMCs were isolated for scRNA-seq analysis. We studied the changes of PBMCs components, signaling pathways, differential genes, and cytokines in acute and recovery stages. Results: During K. pneumoniae acute infection we observed a decrease in the proportion of T cells, most probably due to apoptosis and the function of T cell subtypes was disorder. The proportion of monocytes increased in acute stage. Although genes related to their phagocytosis function were upregulated, their antigen presentation capacity-associated genes were downregulated. The expression of IL-1ß, IL-18, IFNGR1 and IFNGR2 genes was also increased in monocytes. The proportion of DCs was depleted during the acute stage and did not recover during sepsis recovery. DCs antigen presentation was weakened during the acute stage but recovered fast during the recovery stage. pDCs response to MCP-1 chemokine was weakened, they recovered it quickly during the recovery stage. B cells showed apoptosis both in the acute stage and recovery stage. Their response to complement was weakened, but their antigen presentation function was enhanced. The proportion of NK cells stable during all disease's stages, and the expression of IFN-γ gene was upregulated. Conclusion: The proportion of PBMCs and their immune functions undergo variations throughout the course of the disease, spanning from the acute stage to recovery. These findings provide new insights into the mechanism of PBMCs immune function during K. pneumoniae bloodstream infection sepsis and recovery and sets the basis for further understanding and treatment.

Impact of infection on healthcare costs and clinical outcomes in elderly hospitalized patients with multimorbidity.

Background: Elderly patients with multimorbidity are at higher risk of greater healthcare costs and poor outcomes due to decreased physical function. The aim of this study was to investigate the impact of infection on healthcare costs and poor outcomes in elderly hospitalized patients with multimorbidity. Methods: We retrospectively enrolled 264 patients who met the inclusion criteria from the department of geriatrics of a large public hospital in Shanghai, China between January 2020 and December 2020. Patients were divided into two groups based on whether they had infection [infection present on admission (IPOA) or healthcare-associated infection(HAI)]. We recorded the basic information and follow-up information of all patients. The follow-up information included 30-day and 1-year all-cause readmission and mortality. Then we analyzed the association between infection and healthcare costs and clinical outcomes. Results: Among 264 subjects, 47.73 % of them achieved IPOA or HAI. The 30-day poor outcomes rate was 45.45 %, and the 1-year poor outcomes rate was 78.41 %. Compared with subjects without infection, the number of drugs and the disease burden were greater in subjects with infection(P < 0.001). Subjects with infection had longer length of hospital stay(P < 0.001) and had greater healthcare cost(P < 0.001). Moreover, subjects with infection had higher poor outcomes rates of 30-day and 1-year(P < 0.001). Infection could predict greater total cost [odds ratio (OR): 1.32, 95 % CI: 1.18,1.49,P < 0.001], nursing cost(OR: 11.45, 95 % CI: 3.49,37.63,P < 0.001), and medicine cost (OR: 2.37, 95 % CI: 1.70,3.31,P < 0.001). In addition, infection was also independently associated with the 30-day poor outcomes rate(OR:3.07, 95%CI: 1.80,5.24,P < 0.001), but we found no association between infection and 1-year poor outcomes rate(OR:1.43, 95 % CI:0.73,2.79,P = 0.300) after adjustment. Conclusions: Infection was a risk factor for higher healthcare cost and 30-day poor outcome rate in elderly hospitalized patients with multimorbidity.

T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.

A deep learning-powered diagnostic model for acute pancreatitis.

BACKGROUND: Acute pancreatitis is one of the most common diseases requiring emergency surgery. Rapid and accurate recognition of acute pancreatitis can help improve clinical outcomes. This study aimed to develop a deep learning-powered diagnostic model for acute pancreatitis. MATERIALS AND METHODS: In this investigation, we enrolled a cohort of 190 patients with acute pancreatitis who were admitted to Sichuan Provincial People's Hospital between January 2020 and December 2021. Abdominal computed tomography (CT) scans were obtained from both patients with acute pancreatitis and healthy individuals. Our model was constructed using two modules: (1) the acute pancreatitis classifier module; (2) the pancreatitis lesion segmentation module. Each model's performance was assessed based on precision, recall rate, F1-score, Area Under the Curve (AUC), loss rate, frequency-weighted accuracy (fwavacc), and Mean Intersection over Union (MIOU). RESULTS: Upon admission, significant variations were observed between patients with mild and severe acute pancreatitis in inflammatory indexes, liver, and kidney function indicators, as well as coagulation parameters. The acute pancreatitis classifier module exhibited commendable diagnostic efficacy, showing an impressive AUC of 0.993 (95%CI: 0.978-0.999) in the test set (comprising healthy examination patients vs. those with acute pancreatitis, P < 0.001) and an AUC of 0.850 (95%CI: 0.790-0.898) in the external validation set (healthy examination patients vs. patients with acute pancreatitis, P < 0.001). Furthermore, the acute pancreatitis lesion segmentation module demonstrated exceptional performance in the validation set. For pancreas segmentation, peripancreatic inflammatory exudation, peripancreatic effusion, and peripancreatic abscess necrosis, the MIOU values were 86.02 (84.52, 87.20), 61.81 (56.25, 64.83), 57.73 (49.90, 68.23), and 66.36 (55.08, 72.12), respectively. These findings underscore the robustness and reliability of the developed models in accurately characterizing and assessing acute pancreatitis. CONCLUSION: The diagnostic model for acute pancreatitis, driven by deep learning, exhibits excellent efficacy in accurately evaluating the severity of the condition. TRIAL REGISTRATION: This is a retrospective study.

Feasibility of an exercise-nutrition-psychology integrated rehabilitation model based on mobile health and virtual reality for cancer patients: a single-center, single-arm, prospective phase II study.

OBJECTIVE: Explore the feasibility of a mobile health(mHealth) and virtual reality (VR) based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. METHODS: We recruited cancer patients in the Oncology department of the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from October 2022 to April 2023. The rehabilitation program was provided by a team of medical oncologists, dietitians, psychotherapists, and oncology specialist nurses. Participants received standard anti-cancer therapy and integrated intervention including hospitalized group-based exercise classes, at-home physical activity prescription, behavior change education, oral nutrition supplements, and psychological counseling. An effective intervention course includes two consecutive hospitalization and two periods of home-based rehabilitation (8 weeks). Access the feasibility as well as changes in aspects of physical, nutritional, and psychological status. RESULTS: At the cutoff date of April 2023, the recruitment rate was 75% (123/165). 11.4%patients were lost to follow-up, and 3.25% withdrew halfway. Respectively, the completion rate of nutrition, exercise, and psychology were 85%,55%, and 63%. Nutrition interventions show the highest compliance. The parameters in nutrition, psychology, muscle mass, and quality of life after the rehabilitation showed significant improvements (P < .05). There was no significant statistical difference (P > .05) in handgrip strength and 6-minute walking speed. CONCLUSION: It is feasible to conduct mHealth and VR-based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. A larger multi-center trial is warranted in the future. TRIAL REGISTRATION: ChiCTR2200065748 Registered 14 November 2022.

Lipoprotein (a)-Related Inflammatory Imbalance: A Novel Horizon for the Development of Atherosclerosis.

PURPOSE OF REVIEW: The primary objective of this review is to explore the pathophysiological roles and clinical implications of lipoprotein(a) [Lp(a)] in the context of atherosclerotic cardiovascular disease (ASCVD). We seek to understand how Lp(a) contributes to inflammation and arteriosclerosis, aiming to provide new insights into the mechanisms of ASCVD progression. RECENT FINDINGS: Recent research highlights Lp(a) as an independent risk factor for ASCVD. Studies show that Lp(a) not only promotes the inflammatory processes but also interacts with various cellular components, leading to endothelial dysfunction and smooth muscle cell proliferation. The dual role of Lp(a) in both instigating and, under certain conditions, mitigating inflammation is particularly noteworthy. This review finds that Lp(a) plays a complex role in the development of ASCVD through its involvement in inflammatory pathways. The interplay between Lp(a) levels and inflammatory responses highlights its potential as a target for therapeutic intervention. These insights could pave the way for novel approaches in managing and preventing ASCVD, urging further investigation into Lp(a) as a therapeutic target.

Research of the dynamic regulatory mechanism of Compound Danshen Dripping Pills on myocardial infarction based on metabolic trajectory analysis.

BACKGROUND: Myocardial infarction (MI) is a serious cardiovascular disease, which presents different pathophysiological changes with the prolongation of the disease. Compound danshen dripping pills (CDDP) has obvious advantages in MI treatment and widely used in the clinic. However, the current studies were mostly focused on the endpoint of CDDP intervention, lacking the dynamic attention to the disease process. It is of great value to establish a dynamic research strategy focused on the changes in pharmacodynamic substances for guiding clinical medication more precisely. PURPOSE: It is aimed to explore the dynamic regulating pattern of CDDP on MI based on metabolic trajectory analysis, and then clarify the variation characteristic biomarkers and pharmacodynamic substances in the intervention process. METHODS: The MI model was successfully prepared by coronary artery left anterior descending branch ligation, and then CDDP intervention was given for 28 days. Endogenous metabolites and the components of CDDP in serum were measured by LC/MS technique simultaneously to identify dynamic the metabolic trajectory and screen the characteristic pharmacodynamic substances at different points. Finally, network pharmacology and molecular docking techniques were used to simulate the core pharmacodynamic substances and core target binding, then validated at the genetic and protein level by Q-PCR and western blotting technology. RESULTS: CDDP performed typical dynamic regulation features on metabolite distribution, biological processes, and pharmacodynamic substances. During 1-7 days, it mainly regulated lipid metabolism and inflammation, the Phosphatidylcholine (PC(18:1(9Z/18:1(9Z)) and Sphingomyelin (SM(d18:1/23:1(9Z)), SM(d18:1/24:1(15Z)), SM(d18:0/16:1(9Z))) were the main characteristic biomarkers. Lipid metabolism was the mainly regulation pathway during 14-21 days, and the characteristic biomarkers were the Lysophosphatidylethanolamine (LysoPE(0:0/20:0), PE-NMe2(22:1(13Z)/15:0)) and Sphingomyelin (SM(d18:1/23:1(9Z))). At 28 days, in addition to inflammatory response and lipid metabolism, fatty acid metabolism also played the most important role. Correspondingly, Lysophosphatidylcholine (LysoPC(20:0/0:0)), Lysophosphatidylserine (LPS(18:0/0:0)) and Fatty acids (Linoelaidic acid) were the characteristic biomarkers. Based on the results of metabolite distribution and biological process, the characteristic pharmacodynamic substances during the intervention were further identified. The results showed that various kinds of Saponins and Tanshinones as the important active ingredients performed a long-range regulating effect on MI. And the other components, such as Tanshinol and Salvianolic acid B affected Phosphatidylcholine and Sphingomyelin through Relaxin Signaling pathway during the early intervention. Protocatechualdehyde and Rosmarinic acid affected Lysophosphatidylethanolamine and Sphingomyelin through EGFR Tyrosine kinase inhibitor resistance during the late intervention. Tanshinone IIB and Isocryptotanshinone via PPAR signaling pathway affected Lysophosphatidylcholine, Lysophosphatidylserine, and Fatty acids. CONCLUSION: The dynamic regulating pattern was taken as the entry point and constructs the dynamic network based on metabolic trajectory analysis, establishes the dynamic correlation between the drug-derived components and the endogenous metabolites, and elucidates the characteristic biomarkers affecting the changes of the pharmacodynamic indexes, systematically and deeply elucidate the pharmacodynamic substance and mechanism of CDDP on MI. It also enriched the understanding of CDDP and provided a methodological reference for the dynamic analysis of complex systems of TCM.

Surface and grain boundary coating for stabilizing LiNi0.8Mn0.1Co0.1O2 based electrodes.

The widespread use of high-capacity Ni-rich layered oxides such as LiNi0.8Mn0.1Co0.1O2 (NMC811), in lithium-ion batteries is hindered due to practical capacity loss and reduced working voltage during operation. Aging leads to defective NMC811 particles, affecting electrochemical performance. Surface modification offers a promising approach to improve cycle life. Here, we introduce an amorphous lithium titanate (LTO) coating via atomic layer deposition (ALD), not only covering NMC811 surfaces but also penetrating cavities and grain boundaries. As NMC811 electrodes suffer from low structural stability during charge and discharge, We combined electrochemistry, operando X-ray diffraction (XRD), and dilatometry to understand structural changes and the coating protective effects. XRD reveals significant structural evolution during delithiation for uncoated NMC811. The highly reversible phase change in coated NMC811 highlights enhanced bulk structure stability. The LTO coating retards NMC811 degradation, boosting capacity retention from 86% to 93% after 140 cycles. This study underscores the importance of grain boundary engineering for Ni-rich layered oxide electrode stability and the interplay of chemical and mechanical factors in battery aging.