Efgartigimod as a fast-acting add-on therapy in manifest and impending myasthenic crisis: A single-center case series.

Efgartigimod was the first-in-class neonatal Fc receptor antagonist approved for the treatment of acetylcholine receptor antibody positive (AChR+), Myasthenia Gravis Foundation of America (MGFA) Class II-IV generalized myasthenia gravis (gMG) patients. As a novel therapy, the clinical experiences are still lacking, especially for the use of efgartigimod in manifest and impending myasthenic crisis (IMC). We reported three AChR+, gMG patients, two with myasthenic crisis (MC) and one with IMC, treated with efgartigimod. MGFA class, MG-Activity of Daily Living score (MG-ADL), Quantitative MG score (QMG), and Muscle Research Council sum score (MRC), concentration of anti-AChR antibody, IgG, globulin, and albumin, subsets of T and B lymphocyte were evaluated or measured before, during and after efgartigimod treatment. All patients showed fast and robust response to efgartigimod with marked improvement in MGFA, MG-ADL, QMG, and MRC scores. Patient 1 did not respond effectively to IVIg but was successfully rescued by add-on efgartigimod. She extubated at 7 days after the first infusion and got rid of NIV after 14-days treatment. Patient 2 and patient 3 directly used efgartigimod when symptoms were not ameliorated by adjusting of oral drugs. Patient 2 wean from BiPAP at seven days after the first infusion. Patient 3 in IMC status, overcame the severe dysphagia at three days after the first infusion. Clinical symptoms continued to improve 1-2 weeks after discharge. Concentration of anti-AChR antibody, IgG and globulin were remarkably reduced by efgartigimod treatment. Our study supported that efgartigimod could act as a fast-acting rescue therapy for patients with MC or IMC. Larger studies from multicenter are required to provide further evidence.

Surface Molecularly Engineered Mitochondria Conduct Immunophenotype Repolarization of Tumor-Associated Macrophages to Potentiate Cancer Immunotherapy.

Reprogramming tumor-associated macrophages (TAMs) to an inflammatory phenotype effectively increases the potential of immune checkpoint blockade (ICB) therapy. Artificial mitochondrial transplantation, an emerging and safe strategy, has made brilliant achievements in regulating the function of recipient cells in preclinic and clinic, but its performance in reprogramming the immunophenotype of TAMs has not been reported. Here, the metabolism of M2 TAMs is proposed resetting from oxidative phosphorylation (OXPHOS) to glycolysis for polarizing M1 TAMs through targeted transplantation of mannosylated mitochondria (mPEI/M1mt). Mitochondria isolated from M1 macrophages are coated with mannosylated polyethyleneimine (mPEI) through electrostatic interaction to form mPEI/M1mt, which can be targeted uptake by M2 macrophages expressed a high level of mannose receptors. Mechanistically, mPEI/M1mt accelerates phosphorylation of NF-κB p65, MAPK p38 and JNK by glycolysis-mediated elevation of intracellular ROS, thus prompting M1 macrophage polarization. In vivo, the transplantation of mPEI/M1mt excellently potentiates therapeutic effects of anti-PD-L1 by resetting an antitumor proinflammatory tumor microenvironment and stimulating CD8 and CD4 T cells dependent immune response. Altogether, this work provides a novel platform for improving cancer immunotherapy, meanwhile, broadens the scope of mitochondrial transplantation technology in clinics in the future.

Substrate Characterization for Hydrolysis of Multiple Types of Aromatic Esters by Promiscuous Aminopeptidases.

Synthetic aromatic esters, widely employed in agriculture, food, and chemical industries, have become emerging environmental pollutants due to their strong hydrophobicity and poor bioavailability. This study attempted to address this issue by extracellularly expressing the promiscuous aminopeptidase (Aps) from Pseudomonas aeruginosa GF31 in B. subtilis, achieving an impressive enzyme activity of 13.7 U/mg. Notably, we have demonstrated, for the first time, the Aps-mediated degradation of diverse aromatic esters, including but not limited to pyrethroids, phthalates, and parabens. A biochemical characterization of Aps reveals its esterase properties and a broader spectrum of substrate profiles. The degradation rates of p-nitrobenzene esters (p-NB) with different side chain structures vary under the action of Aps, showing a preference for substrates with relatively longer alkyl side chains. The structure-dependent degradability aligns well with the binding energies between Aps and p-NB. Molecular docking and enzyme-substrate interaction elucidate that hydrogen bonding, hydrophobic interactions, and π-π stacking collectively stabilize the enzyme-substrate conformation, promoting substrate hydrolysis. These findings provide new insights into the enzymatic degradation of aromatic ester pollutants, laying a foundation for the further development and modification of promiscuous enzymes.

Molecular Identification and Survey of Cyclospora spp. in Cattle in Shanxi Province, North China.

To date, more than 20 species in the genus Cyclospora have been reported. Among them, Cyclospora cayetanensis has been recognized as the causative agent of human cyclosporiasis, which is characterized by severe intestinal injury and prolonged diarrhea in patients with immune dysfunction. The presence of C. cayetanensis in cattle has been confirmed. To date, however, no surveillance data are available on the occurrence and prevalence of Cyclospora spp. in cattle in Shanxi Province, North China. In the present study, a total of 761 fecal samples collected from cattle in three representative counties (Qi, Jishan, and Shanyin) in this Province were examined for Cyclospora spp. by using a polymerase-chain-reaction-restriction-fragment-length polymorphism (PCR-RFLP) test based on the nuclear small subunit ribosomal RNA (SSU rRNA) gene. The prevalence of Cyclospora spp. in cattle was 2.1%, and region, age, sex, and breed were not identified to be risk factors. Molecular evolutionary analysis based on the SSU rRNA sequences revealed that all 12 of the isolates were relatively distant from the human pathogen C. cayetanensis; seven isolates were grouped with Cyclospora colobi, whereas the others were grouped with cattle Cyclospora spp. reported previously. Though C. cayetanensis was not detected in cattle in the present study, more investigations should be performed in human populations, other animal species, or cattle from other regions of Shanxi Province and other environmental sources from the One Health perspective.

Short-term OS as a surrogate endpoint for 5-year OS in nasopharyngeal carcinoma in non-endemic area.

PURPOSE: To address this evidence gap and validate short-term OS at less than 5 years as a reliable surrogate endpoint for 5-year OS. METHODS: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on non-metastatic NPC patients diagnosed between 2010 and 2015. Patients were categorized into radiotherapy and chemoradiotherapy groups. RESULTS: This retrospective study examined 2,047 non-metastatic NPC patients. Among them, 217 received radiotherapy, and 1,830 received chemoradiotherapy. Our analysis results indicated that the 4-year OS may serve as a reliable surrogate endpoint for patients with AJCC clinical stage I (80 vs. 78%, P = 0.250), regardless of the treatment received. Specifically, in the radiotherapy group, patients with stage I, T0-T1, and N0 NPC showed similar OS rates at 4 and 5 years (83 vs. 82%, P = 1.000; 78 vs. 76%, P = 0.250; 78 vs. 77%, P = 0.500, respectively). Similarly, patients with stage II-IV, T2-T4, and N1-3 NPC showed no significant difference in OS rates between 3 and 5 years (57 vs. 51%, P = 0.063; 52 vs. 46%, P = 0.250; 54 vs. 46%, P = 0.125, respectively) in the radiotherapy group. In the chemoradiotherapy group, only the 3-year OS rate did not significantly differ from that at 5 years in stage I patients (79vs. 72%, P = 0.063). CONCLUSIONS: Our study suggests that short-term surrogate endpoints may be valuable for evaluating 5-year OS outcomes in NPC patients in non-endemic areas.

Deltoid Tuberosity Index for Proximal Humerus Fracture: Reliability and A Predictor of Systemic Osteoporosis in an Asian Population.

HYPOTHESIS: Our study investigates the reliability of deltoid tuberosity index (DTI) and DTI as a predictor of systemic osteoporosis. BACKGROUND: The proximal humerus is a common fragility fracture. Current literature suggests that poor local bone density is a significant predictor for surgical fixation failure. The DTI is a simple radiographical tool that is strongly correlates with local humeral BMD aiding surgical planning to consider adjuncts or arthroplasty. However, there is a lack of data in the reliability of assessment of DTI, as well as its correlation to systemic osteoporosis. METHODS: Respective cohort of patients with PHF treated at a trauma center in Singapore from August 2017 to July 2018 were recruited. Four raters at different levels of varying clinical seniority measured DTI using shoulder radiographs. The dual energy X-ray Absorptiometry (DEXA) bone mineral density (BMD) scan of the hip and lumbar spine was used to diagnose osteoporosis. Area under receiver operating characteristics (AUROC) analysis was conducted to study the diagnostic utility of DTI to predict the risk of osteoporosis. RESULTS: Our study had 87 patients consisting 18 males and 69 females, mainly of Chinese ethnicity (84%) and mean age of 69.7 years (SD 9.52, range 39-92yrs). For assessment of DTI, there was good intra-rater reliability amongst four raters (correlation coefficient range 0.805- 0.843) and excellent inter-rater reliability between al raters (intraclass correlation coefficient = 0.898; 95% CI 0.784-0.950, p-value <0.001). Based on BMD, 55.2% (n=48) were osteoporotic using T-score <-2.5. The highest correlation of DTI to BMD was with femoral neck density at 0.580. The DTI cut-off of 1.6 had the highest combined sensitivity and false positive rate, with area under curve (AUC) = 0.682 (95% CI, 0.564-0.799) for the overall population and AUC =0.706 (95% CI, 0.569-0.842) for patients <75 years. DISCUSSION: The DTI is a simple and reliable tool, strengthening its applicability in clinical practice to enhance preoperative planning in the surgical fixation of PHF. DTI with a cut off of 1.6 may be helpful tool prompting clinicians to workup and manage underlying osteoporosis.

[Mechanism of Dabugan Decoction in treatment of generalized anxiety disorder based on network pharmacology and experimental verification].

This study aims to explore the mechanism of Dabugan Decoction in the treatment of generalized anxiety disorder(GAD) based on network pharmacology, molecular docking, and animal experiments. Network pharmacology and molecular docking technology were used to obtain the possible targets and related signaling pathways of Dabugan Decoction in the treatment of GAD. The GAD rat model was established, and the corresponding drugs were given by gavage after randomization. After 28 days of continuous intervention, the anxiety state of rats was detected, and the pathological changes of the hippocampus were detected in each group. ELISA and Western blot were used to detect the protein expression levels of related molecules. A total of 65 drug compounds in Dabugan Decoction were obtained, involving 403 targets of action, 7 398 disease targets of GAD, and 279 common targets of "drug-disease". The key nodes in the protein-protein interaction(PPI) network were Akt1, TNF, IL-6, TP53, IL-1ß, etc. Function analysis of Gene Ontology(GO) and enrichment analysis of Kyoto Encyclopedia of Genes and Genomes(KEGG) showed that the PI3K-Akt signaling pathway was the most important pathway. The results of molecular docking showed that the core components of the drug had good binding activity with the corresponding key targets. Animal experiments showed that Dabugan Decoction could effectively improve the anxiety behavior of rats and increase the open arm end movement distance and total distance of rats in the elevated cross labyrinth, the number and stay time of entering the open box, and the time(%) and the number of entering the center of the open field. At the same time, HE staining and Nicil staining showed that the number of hippocampal nerve cells in rats increased, and they were closely arranged. The damage to the cell body was improved, and there was an increase in Nissl substances in the cells. The expression of TNF-α, IL-6, and IL-1ß in rat hippocampus decreased, and the expression of TP53, p-Akt1, and p-PI3K increased. The mechanism may be related to the activation of the PI3K-Akt signaling pathway and the inhibition of inflammatory response. Dabugan Decoction can play a good therapeutic and regulatory role in GAD, reflecting the overall effect of traditional Chinese medicine(TCM) compound and the characteristics of multiple targets and multiple pathways. At the same time, it is preliminarily discussed that the state of GAD may be improved by Dabugan Decoction via-activating PI3K-Akt signaling pathway and inhibiting inflammatory response and anti-apoptosis, thus providing experimental data support for the clinical application of Dabugan Decoction.

Development of Novel N-Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group.

The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.

Prospective study of urinary incontinence recovery following endoscopic enucleation of the prostate.

OBJECTIVE: To investigate the clinical trajectories and identify risk factors linked to post-enucleation urinary incontinence (UI). PATIENTS AND METHODS: In this prospective study (April 2020 to March 2022) at a single institution, 316 consecutive patients receiving endoscopic enucleation due to benign prostatic enlargement were included. Patient information and perioperative details were collected. Follow-ups, from 1 to 6 months, assessed postoperative UI using International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form and a four-item pad questionnaire, classified per International Continence Society definitions. Logistic regression analysed predictors at 1 week, while generalised estimating equation assessed risk factors from 1 to 3 months postoperatively. RESULTS: Patients with a median prostate volume of 57 mL underwent enucleation, with 22.5% experiencing postoperative UI at 1 week, 5.6% at 3 months, decreasing to 1.9% at 6 months. Multivariable analysis identified age (>80 years), specimen weight (>70 g), en bloc with anteroposterior dissection, and anal tone (Digital Rectal Examination Scoring System score <3) as potential factors influencing UI. Subgroup analysis revealed that specimen weight was associated with both continuous and stress UI. Anal tone was related to both other types and stress UI, while overactive bladder symptoms were associated with urge UI. CONCLUSION: In summary, our study elucidates transient risk factors contributing to temporary post-enucleation UI after prostatectomy. Informed decisions and personalised interventions can effectively alleviate concerns regarding postoperative UI.

Successful treatment with efgartigimod as an add-on therapy in acute attack of anti-AQP4 antibody-positive NMOSD: a case report.

BACKGROUND: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an autoimmune demyelinating disease characterized by recurrent myelitis and optic neuritis. It is associated with high rates of relapse and disability. The main treatment strategies for acute attacks include intravenous methylprednisolone pulse (IVMP) treatment and rescue treatment with plasma exchange (PLEX). Recently, the blockade of neonatal Fc receptor (FcRn)-IgG interaction has gained momentum as a therapeutic strategy. Efgartigimod, the first approved FcRn inhibitor for treating generalized myasthenia gravis, has shown impressive safety, efficacy, and tolerability, and is being regarded as "PLEX in a bottle". CASE DESCRIPTION: We report a 65-year-old female patient who was diagnosed with anti-AQP4 antibody positive NMOSD. Add-on treatment with efgartigimod to IVMP and intravenous immunoglobulin (IVIG) at the second acute relapse showed favorable results. CONCLUSION: This case suggests that efgartigimod is a potentially effective add-on therapy in acute attacks of AQP4-IgG-positive NMOSD.

Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity.

The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.

GP-Recon: Online Monocular Neural 3D Reconstruction with Geometric Prior.

High-fidelity online 3D scene reconstruction from monocular videos continues to be challenging, especially for coherent and fine-grained geometry reconstruction. The previous learning-based online 3D reconstruction approaches with neural implicit representations have shown a promising ability for coherent scene reconstruction, but often fail to consistently reconstruct fine-grained geometric details during online reconstruction. This paper presents a new on-the-fly monocular 3D reconstruction approach, named GP-Recon, to perform high-fidelity online neural 3D reconstruction with fine-grained geometric details. We incorporate geometric prior (GP) into a scene's neural geometry learning to better capture its geometric details and, more importantly, propose an online volume rendering optimization to reconstruct and maintain geometric details during the online reconstruction task. The extensive comparisons with state-of-the-art approaches show that our GP-Recon consistently generates more accurate and complete reconstruction results with much better fine-grained details, both quantitatively and qualitatively.

Boron Neutron Capture Therapy Enhanced by Boronate Ester Polymer Micelles: Synthesis, Stability, and Tumor Inhibition Studies.

Boron neutron capture therapy (BNCT) targets invasive, radioresistant cancers but requires a selective and high B-10 loading boron drug. This manuscript investigates boron-rich poly(ethylene glycol)-block-(poly(4-vinylphenyl boronate ester)) polymer micelles synthesized via atom transfer radical polymerization for their potential application in BNCT. Transmission electron microscopy (TEM) revealed spherical micelles with a uniform size of 43 ± 10 nm, ideal for drug delivery. Additionally, probe sonication proved effective in maintaining the micelles' size and morphology postlyophilization and reconstitution. In vitro studies with B16-F10 melanoma cells demonstrated a 38-fold increase in boron accumulation compared to the borophenylalanine drug for BNCT. In vivo studies in a B16-F10 tumor-bearing mouse model confirmed enhanced tumor selectivity and accumulation, with a tumor-to-blood (T/B) ratio of 2.5, surpassing BPA's T/B ratio of 1.8. As a result, mice treated with these micelles experienced a significant delay in tumor growth, highlighting their potential for BNCT and warranting further research.

Decreased postpartum exercise capacity after a diagnosis of pre-eclampsia: Implications for CVD risk prediction.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are associated with increased long-term risk for cardiometabolic risk factors (chronic hypertension [HTN], obesity, diabetes) and heart failure. Exercise capacity is a known predictor of heart failure in patients with normal resting cardiac filling pressures. In this prospective observational cohort study, we sought to identify predictors of reduced postpartum exercise capacity in participants with normotensive vs preeclamptic pregnancies. METHODS: Preeclampsia (PreE) and normotensive subjects were enrolled to undergo bedside echocardiography within 48 hours of delivery, and rest/exercise echocardiography 12 weeks postpartum. RESULTS: Recruited subjects (n = 68) were grouped according to their blood pressure as: a) normotensive pregnancy n = 15; b) PreE with normotensive postpartum (PreE-Resolved, n = 36); c) PreE with persistent postpartum HTN (PreE-HTN, n = 17). At enrollment, a significantly higher percentage of subjects in the PreE-HTN group were Black. Compared to normotensive and PreE-Resolved subjects, those with PreE-HTN demonstrated higher resting systolic blood pressure (SBP, 112 [normotensive] vs 112 [PreE-Resolved] vs 134 [PreE-HTN], P < .001) and diastolic blood pressure (DBP, 70.0 vs 72.5 vs 85.0, P < .001), and significantly less postpartum weight loss (9.6% vs 13.6% vs 3.8%, P < .001). Following Bruce protocol stress testing, PreE-HTN subjects demonstrated achieved significantly lower exercise duration (10.4 vs 10.2 vs 7.9 minutes, P = .001). Subjects with PreE-HTN also demonstrated evidence of exercise-induced diastolic dysfunction as assessed by peak exercise lateral e' (18.0 vs 18.0 vs 13.5, P = .045) and peak exercise tricuspid regurgitation velocity (TR Vm, 2.4 vs 3.0 vs 3.1, P = 0.045). Exercise duration was negatively associated with gravidity (R = -0.27, P = .029) and postpartum LV mass index (R = -0.45, P < .001), resting average E/e' (R = -0.51, P < .001), BMI (R = -0.6, P < .001) and resting SBP (R = -0.51, P < .001). CONCLUSIONS: Postpartum exercise stress testing capacity is related to readily available clinical markers including pregnancy factors, echocardiographic parameters and unresolved cardiometabolic risk factors.

Intrathecal Fumagillin Alleviates Chronic Neuropathy-Induced Nociceptive Sensitization and Modulates Spinal Astrocyte-Neuronal Glycolytic and Angiogenic Proteins.

Nociceptive sensitization is accompanied by the upregulation of glycolysis in the central nervous system in neuropathic pain. Growing evidence has demonstrated glycolysis and angiogenesis to be related to the inflammatory processes. This study investigated whether fumagillin inhibits neuropathic pain by regulating glycolysis and angiogenesis. Fumagillin was administered through an intrathecal catheter implanted in rats with chronic constriction injury (CCI) of the sciatic nerve. Nociceptive, behavioral, and immunohistochemical analyses were performed to evaluate the effects of the inhibition of spinal glycolysis-related enzymes and angiogenic factors on CCI-induced neuropathic pain. Fumagillin reduced CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days (POD) 7 to 14. The expression of angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietin 2 (ANG2), increased in the ipsilateral lumbar spinal cord dorsal horn (SCDH) following CCI. The glycolysis-related enzymes, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) significantly increased in the ipsilateral lumbar SCDH following CCI on POD 7 and 14 compared to those in the control rats. Double immunofluorescence staining indicated that VEGF and PKM2 were predominantly expressed in the astrocytes, whereas ANG2 and LDHA were predominantly expressed in the neurons. Intrathecal infusion of fumagillin significantly reduced the expression of angiogenic factors and glycolytic enzymes upregulated by CCI. The expression of hypoxia-inducible factor-1α (HIF-1α), a crucial transcription factor that regulates angiogenesis and glycolysis, was also upregulated after CCI and inhibited by fumagillin. We concluded that intrathecal fumagillin may reduce the expression of ANG2 and LDHA in neurons and VEGF and PKM2 in the astrocytes of the SCDH, further attenuating spinal angiogenesis in neuropathy-induced nociceptive sensitization. Hence, fumagillin may play a role in the inhibition of peripheral neuropathy-induced neuropathic pain by modulating glycolysis and angiogenesis.

Relationship between low molecular weight heparin calcium therapy and prognosis in severe acute kidney injury in sepsis: Mendelian randomized analysis and retrospective study.

Background: Sepsis-associated acute kidney injury (SA-AKI) poses an independent risk for mortality due to the absence of highly sensitive biomarkers and a specific treatment plan. Objective: Investigate the association between low molecular weight heparin (LMWH) calcium therapy and prognosis in critically ill SA-AKI patients, and assess the causal relationship through Mendelian randomization (MR) analysis. Methods: A single-center, retrospective, cross-sectional study included 90 SA-AKI patients and 30 septic patients without acute kidney injury (AKI) from the intensive care unit (ICU) of the First Hospital of Lanzhou University. SA-AKI patients were categorized into control or LMWH groups based on LMWH calcium usage. Primary outcome was renal function recovery, with secondary outcomes including 28-day mortality, ICU stay length, number of renal replacement therapy (RRT) recipients, and 90-day survival. MR and related sensitivity analyses explored causal effects. Results: The combination of heparin-binding protein (HBP), heparanase (HPA), and neutrophil gelatinase-associated lipocalin (NGAL) demonstrated high diagnostic value for SA-AKI. MR analysis suggested a potential causal link between gene-predicted HBP and AKI (OR: 1.369, 95%CI: 1.040-1.801, p = 0.024). In the retrospective study, LMWH-treated patients exhibited improved renal function, reduced levels of HPA, HBP, Syndecan-1, and inflammation, along with enhanced immune function compared to controls. However, LMWH did not impact 28-day mortality, 90-day survival, or ICU stay length. Conclusion: LMWH could enhance renal function in SA-AKI patients. MR analysis supports this causal link, underscoring the need for further validation in randomized controlled trials.

Asymmetric (3 + 3) and (4 + 2) Annulation Reactions of 2,3-Dioxopyrrolidines with 3-Alkylidene Oxindoles to Construct Diverse Chiral Heterocyclic Frameworks.

Two substrate-controlled regiodivergent annulation protocols for 2,3-dioxopyrrolidines with 3-alkylidene oxindoles have been developed, which furnished a series of fused dihydropyrrolidone derivatives in high yields with excellent stereoselectivities. Plausible mechanistic pathways for both annulation reactions are proposed that [3 + 3] annulation reaction involves vinylogous Michael addition followed by intramolecular aldol cyclization, while [4 + 2] annulation reaction occurs through a vinylogous Michael addition and a subsequent intramolecular oxa-Michael cyclization.

Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.

Association analyses of apolipoprotein E genotypes and cognitive performance in patients with Parkinson's disease.

BACKGROUND: Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD). The apolipoprotein E (APOE) ε4 genotype increases the risk of Alzheimer's disease (AD). However, the effect of APOEε4 on cognitive function of PD patients remains unclear. In this study, we aimed to understand whether and how carrying APOEε4 affects cognitive performance in patients with early-stage and advanced PD. METHODS: A total of 119 Chinese early-stage PD patients were recruited. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hamilton anxiety scale, Hamilton depression scale, non-motor symptoms scale, Mini-mental State Examination, Montreal Cognitive Assessment, and Fazekas scale were evaluated. APOE genotypes were determined by polymerase chain reactions and direct sequencing. Demographic and clinical information of 521 early-stage and 262 advanced PD patients were obtained from Parkinson's Progression Marker Initiative (PPMI). RESULTS: No significant difference in cognitive performance was found between ApoEε4 carriers and non-carriers in early-stage PD patients from our cohort and PPMI. The cerebrospinal fluid (CSF) Amyloid Beta 42 (Aß42) level was significantly lower in ApoEε4 carrier than non-carriers in early-stage PD patients from PPMI. In advanced PD patients from PPMI, the BJLOT, HVLT retention and SDMT scores seem to be lower in ApoEε4 carriers without reach the statistical significance. CONCLUSIONS: APOEε4 carriage does not affect the cognitive performance of early-stage PD patients. However, it may promote the decline of CSF Aß42 level and the associated amyloidopathy, which is likely to further contribute to the cognitive dysfunction of PD patients in the advanced stage.