Early intervention in Hirschsprung's disease: effects on enterocolitis and surgical outcomes.

BACKGROUND: The timing of surgical intervention for Hirschsprung's disease (HSCR) has been a topic of continued discussion. The objective of this study was to evaluate the significance of age at surgery in the management of HSCR by conducting a comparative analysis of the correlation between surgical age and midterm outcomes. METHODS: We conducted a retrospective analysis of children with HSCR who underwent one-stage laparoscopic assisted pull-through surgery with modified Swenson technology at our hospital between 2015 and 2019. The study population was stratified into two groups based on surgical age: patients who underwent surgery within a period of less than 3 months and those who underwent surgery between 3 and 12 months. The basic conditions, complications at 3-7 years after surgery, anal function (Rintala scale) and quality of life (PedsQLTM4.0) were compared between the groups. RESULTS: A total of 235 children (196 males and 39 females) were included in the study. No statistically significant differences in postoperative bowel function (P = 0.968) or quality of life (P = 0.32) were found between the two groups. However, there was a significant reduction in the incidence of Hirschsprung-associated enterocolitis (HAEC) among individuals under the age of three months prior to undergoing surgical intervention (69.1%) compared to the incidence observed postsurgery (30.9%). This difference was statistically significant (P < 0.001). CONCLUSION: In the current study, the age at which surgery was performed did not exhibit a discernible inclination towards influencing mid-term anal function or quality of life. Early surgical intervention can effectively diminish the occurrence of HAEC, minimize the extent of bowel resection, and expedite the duration of the surgical procedure.

The Association between Left Ventricular End-Diastolic Diameter and Long-Term Mortality in Patients with Coronary Artery Disease.

Background: Left ventricular end-diastolic diameter (LVEDD) is a common parameter in echocardiography. Increased LVEDD is associated with left ventricular (LV) dysfunction. However, the association between LVEDD and all-cause mortality in patients with coronary artery disease (CAD) is uncertain. Methods: This study enrolled 33,147 patients with CAD who had undergone transthoracic echocardiography between January 2007 and December 2018 from the Cardiorenal Improvement study (NCT04407936). The patients were stratified into four groups based on the quartile of LVEDD (Quartile 1: LVEDD ≤ 43 mm, Quartile 2: 43 mm < LVEDD ≤ 46 mm, Quartile 3: 46 mm < LVEDD ≤ 51 mm, Quartile 4: LVEDD > 51 mm) and were categorized into two groups (Quartile 1-3 versus Quartile 4). Survival curves were generated with the Kaplan-Meier analysis, and the differences between groups were assessed by log-rank test. Restricted cubic splines and cox proportional hazards models were used to investigate the association with LVEDD and all-cause mortality. Results: A total of 33,147 patients (average age: 63.0 ± 10.6 years; 24.0% female) were included in the final analysis. In the average follow-up period of 5.2 years, a total of 4288 patients died. The mortality of the larger LVEDD group (Quartile 4) was significantly higher than the lower LVEDD groups (Quartile 1-3) (18.05% vs 11.15%, p < 0.001). After adjusting for confounding factors, patients with the larger LVEDD (Quartile 4) had a 1.19-fold risk for all-cause mortality (95% CI: 1.09-1.30) compared with the lower quartile (Quartile 1-3). Conclusions: Enlarged LVEDD is an independent predictor of all-cause mortality in patients with CAD. LVEDD measurements may be helpful for risk stratification and providing therapeutic targets for the management of CAD patients.

Edaravone-loaded poly(amino acid) nanogel inhibits ferroptosis for neuroprotection in cerebral ischemia injury.

Neurological injury caused by ischemic stroke is a major cause of permanent disability and death. The currently available neuroprotective drugs fail to achieve desired therapeutic efficacy mainly due to short circulation half-life and poor blood-brain barrier (BBB) permeability. For that, an edaravone-loaded pH/glutathione (pH/GSH) dual-responsive poly(amino acid) nanogel (NG/EDA) was developed to improve the neuroprotection of EDA. The nanogel was triggered by acidic and EDA-induced high-level GSH microenvironments, which enabled the selective and sustained release of EDA at the site of ischemic injury. NG/EDA exhibited a uniform sub-spherical morphology with a mean hydrodynamic diameter of 112.3 ± 8.2 nm. NG/EDA efficiently accumulated at the cerebral ischemic injury site of permanent middle cerebral artery occlusion (pMCAO) mice, showing an efficient BBB crossing feature. Notably, NG/EDA with 50 µM EDA significantly increased neuron survival (29.3%) following oxygen and glucose deprivation by inhibiting ferroptosis. In addition, administering NG/EDA for 7 d significantly reduced infarct volume to 22.2% ± 7.2% and decreased neurobehavioral scores from 9.0 ± 0.6 to 2.0 ± 0.8. Such a pH/GSH dual-responsive nanoplatform might provide a unique and promising modality for neuroprotection in ischemic stroke and other central nervous system diseases.

The Potential Value of Mean Platelet Volume and Platelet Distribution Width as Inflammatory Indicators in Surgical Necrotizing Enterocolitis.

Background: This study aims to investigate the potential significance of mean platelet volume (MPV) and platelet distribution width (PDW) in predicting surgical neonatal necrotizing enterocolitis (NEC) and establish the correlation between MPV/PDW levels and the severity/prognosis of NEC. Methods: A retrospective study was conducted on a cohort of 372 patients diagnosed with NEC. The patients were categorized into two groups based on whether they underwent surgical therapy. Univariate /multivariate analysis were employed to compare the MPV and PDW between the two groups. Moreover, patients in surgical group were categorized into multiple subgroups based on intraoperative findings and postoperative prognosis, and the levels of MPV and PDW were compared among these subgroups. Results: Of the 372 patients, the operative group exhibited significantly higher levels of MPV and PDW than the nonoperative group (P < 0.05). Logistic regression analysis revealed that MPV (OR = 4.895, P < 0.001) and PDW (OR = 1.476, P < 0.001) independently associated with surgical NEC. The analysis of the receiver operating characteristic (ROC) curve revealed that the area under the curve (AUC) was 0.706 for MPV alone, with a cut-off value of 11.8 fL. Similarly, the AUC was 0.728 for PDW alone, with a cut-off value of 16%. However, when MPV and PDW were combined, the AUC increased to 0.906 for predicting surgical NEC. In accordance with the intraoperative findings, the levels of MPV and PDW were found to be higher in the large area necrosis group than in the partial or mild necrosis group (P < 0.01). Furthermore, the MPV and PDW values in the death group were significantly greater than those in the survival group (P =0.040, P =0.008). Conclusion: MPV and PDW may serve as potentially valuable indicators for determining the need for surgical intervention and predicting the prognosis of patients with NEC.

18F-labeled somatostatin analogs for somatostatin receptors (SSTRs) targeted PET imaging of neuroendocrine tumors (NETs).

PURPOSE: A novel 18F-radiolabeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [Al18F]NODA-MPAA-HTA was designed and synthesized by conjugating 18F nuclide with a modified KE108 peptide, a somatostatin analog with high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), through coupling a bifunctional chelator (NODA) to target somatostatin receptor (SSTR) positive tumors. METHODS: The amino group of KE108 peptide, a SSTRs-targeting pharmacophore, was conjugated with the carboxyl group of NODA by a condensation reaction to obtain the labeling precursor of [Al18F]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for Al18F labeling of chelating agent-biomolecule conjugates was used to synthesize [Al18F]NODA-MPAA-HTA. In vitro stabilities of [Al18F]NODA-MPAA-HTA were evaluated by incubating it in saline or bovine serum for 2 h. Ex vivo biodistribution and in vivo imaging of [Al18F]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging. RESULTS: [Al18F]NODA-MPAA-HTA was synthesized using a one-step 18F-AlF labeling procedure resulting in moderate radiochemical yield (60-80 %, non-decay corrected) and high radiochemical purity (>95 %). It exhibited good hydrophilicity and excellent stability in vitro, with a molar activity of 122 GBq/µmol. At 30 min and 60 min, the uptake of [Al18F] NODA-MPAA-HTA by HEK293-SSTR2 cells was 5.47 ± 0.97 %/105 cells and 12.11 ± 0.32 %/105 cells, respectively. The affinity of [Al18F]NODA-MPAA-HTA for SSTR2 was determined to be 8.77 ± 1.14 nM. In micro-PET imaging of HEK293-SSTR2 tumor-bearing mice, [Al18F]NODA-MPAA-HTA showed high tumor uptake of radioactivity and a high tumor-to-muscle ratio. Biodistribution results confirmed that radioactivity uptake in the tumor was significantly higher than that in the muscle by more than five-fold (P<0.001). Furthermore, the relatively low bone uptake of [Al18F]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of Al18F-labeled somatostatin analogues as tumor probes for PET imaging of NETs. CONCLUSION: Fluorine-18 is widely used as a radionuclide for the production of radiopharmaceuticals for positron emission tomography (PET). Due to its short half-life (T1/2,109.8 min), its ease of production will facilitate the widespread dissemination of this radiopharmaceutical. A high-quality [Al18F]NODA-MPAA-HTA was synthesized with satisfactory yield. This radiopharmaceutical demonstrated higher tumor uptake and better tumor-to-muscle contrast, resulting to excellent image quality. These findings suggest that the novel 18F-labeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs.

FLT4 gene polymorphisms influence isolated ventricular septal defect predisposition in a Southwest China population.

BACKGROUND: Ventricular septal defect (VSD) is the most common congenital heart disease. Although a small number of genes associated with VSD have been found, the genetic factors of VSD remain unclear. In this study, we evaluated the association of 10 candidate single nucleotide polymorphisms (SNPs) with isolated VSD in a population from Southwest China. METHODS: Based on the results of 34 congenital heart disease whole-exome sequencing and 1000 Genomes databases, 10 candidate SNPs were selected. A total of 618 samples were collected from the population of Southwest China, including 285 VSD samples and 333 normal samples. Ten SNPs in the case group and the control group were identified by SNaPshot genotyping. The chi-square (χ2) test was used to evaluate the relationship between VSD and each candidate SNP. The SNPs that had significant P value in the initial stage were further analysed using linkage disequilibrium, and haplotypes were assessed in 34 congenital heart disease whole-exome sequencing samples using Haploview software. The bins of SNPs that were in very strong linkage disequilibrium were further used to predict haplotypes by Arlequin software. ViennaRNA v2.5.1 predicted the haplotype mRNA secondary structure. We evaluated the correlation between mRNA secondary structure changes and ventricular septal defects. RESULTS: The χ2 results showed that the allele frequency of FLT4 rs383985 (P = 0.040) was different between the control group and the case group (P < 0.05). FLT4 rs3736061 (r2 = 1), rs3736062 (r2 = 0.84), rs3736063 (r2 = 0.84) and FLT4 rs383985 were in high linkage disequilibrium (r2 > 0.8). Among them, rs3736061 and rs3736062 SNPs in the FLT4 gene led to synonymous variations of amino acids, but predicting the secondary structure of mRNA might change the secondary structure of mRNA and reduce the free energy. CONCLUSIONS: These findings suggest a possible molecular pathogenesis associated with isolated VSD, which warrants investigation in future studies.

Association study of FLT4 and HYDIN single nucleotide polymorphisms with atrial septal defect susceptibility in the Han Chinese population of Southwest China.

BACKGROUND: Atrial septal defect (ASD) is a common form of congenital heart disease. Although several genes related to ASD have been found, the genetic factors of ASD remain unclear. This study aimed to evaluate the correlation between 10 candidate single nucleotide polymorphisms (SNPs) and sporadic atrial septal defects. METHODS: Based on the results of 34 individual whole exome sequences, 10 candidate SNPs were selected. In total, 489 ASD samples and 420 normal samples were collected. The 10 SNPs in the case group and the control group were identified through Snapshot genotyping technology. The χ2-test and unconditional regression model were used to evaluate the relationship between ASD and each candidate SNP. Haploview software was used to perform linkage disequilibrium and haplotype analysis. RESULTS: The χ2 results showed that the FLT4 rs383985 (P = 0.003, OR = 1.115-1.773), HYDIN rs7198975 (P = 0.04621, OR = 1.003-1.461), and HYDIN rs1774266 (P = 0.04621, OR = 1.003-1.461) alleles were significantly different between the control group and the case group (P < 0.05). Only the association with the FLT4 polymorphism was statistically significant after adjustment for multiple comparisons. CONCLUSION: These findings suggest that a possible molecular pathogenesis associated with sporadic ASD is worth exploring in future studies.