[Pharmacokinetics and pharmacodynamics of antibiotics in septic children treated with extracorporeal membrane oxygenation].

Objective: To investigate the characteristics of pharmacokinetic (PK) and pharmacodynamic (PD) parameters of antibacterial agents in children with sepsis treated by extracorporeal membrane oxygenation (ECMO). Methods: In this prospective cohort study, 20 children with sepsis (confirmed or suspected) who were treated with ECMO and antimicrobial in the Department of Critical Medicine of Hunan Children's Hospital from March 2021 to December 2022 were enrolled as the ECMO group. Through therapeutic drug monitoring (TDM), the PK-PD parameters of antibacterial agents were analyzed. Twenty five children with sepsis in the same department who were treated with vancomycin but no ECMO at the same time were enrolled as the control group. The individual PK parameters of vancomycin were calculated by Bayesian feedback method. The PK parameters in the two groups were compared, and the correlation between trough concentration and area under the curve (AUC) was analyzed. Wilcoxon rank sum test was used for inter group comparison. Results: Twenty patients in the ECMO group, included 6 males and 14 females, with an onset age of 47 (9, 76) months. In the ECMO group, 12 children (60%) were treated with vancomycin, and the trough concentration was less than 10 mg/L in 7 cases, 10-20 mg/L in 3 cases, and >20 mg/L in 2 cases; AUC/minimum inhibitory concentration (MIC) (MIC=1 mg/L)<400 was in 1 case, 400-600 in 3 cases, and >600 in 8 cases. Among the 11 children (55%) who were treated with ß-lactam antibiotics, there were 10 cases with drug concentration at 50% dosing interval (CT50)>4 MIC and 9 cases with trough concentration>MIC, both CT50 and trough concentration of cefoperazone reached the target. Among the 25 cases of control group, 16 were males and 9 females, with an onset age of 12 (8, 32) months. There was a positive correlation between vancomycin trough concentration and AUC (r2=0.36, P<0.001). The half-life of vancomycin and the 24-hour AUC (AUC0-24 h) in the ECMO group were higher than those in the control group (5.3 (3.6, 6.8) vs. 1.9 (1.5, 2.9) h, and 685 (505, 1 227) vs. 261 (210, 355) mg·h/L, Z=2.99, 3.50, respectively; both P<0.05), and the elimination rate constant and clearance rate was lower than those in the control group (0.1 (0.1, 0.2) vs. 0.4 (0.2, 0.5), 0.7 (0.5, 1.3) vs. 2.0 (1.1, 2.8) L/h, Z=2.99, 2.11, respectively; both P<0.05). Conclusion: The PK-PD parameters in septic children treated by ECMO varied with a longer half-life, higher AUC0-24 h, lower elimination rate constant and clearance rate.

[Effect and influence factors of cardiopulmonary resuscitation in children with congenital heart disease in pediatric intensive care unit].

Objective: To investigate the prognostic factors of children with congenital heart disease (CHD) who had undergone cardiopulmonary resuscitation (CPR) in pediatric intensive care unit (PICU) in China. Methods: From November 2017 to October 2018, this retrospective multi-center study was conducted in 11 hospitals in China. It contained data from 281 cases who had undergone CPR and all of the subjects were divided into CHD group and non-CHD group. The general condition, duration of CPR, epinephrine doses during resuscitation, recovery of spontaneous circulation (ROSC), discharge survival rate and pediatric cerebral performance category in viable children at discharge were compared. According to whether malignant arrhythmia is the direct cause of cardiopulmonary arrest or not, children in CHD and non-CHD groups were divided into 2 subgroups: arrhythmia and non-arrhythmia, and the ROSC and survival rate to discharge were compared. Data in both groups were analyzed by t-test, chi-square analysis or ANOVA, and logistic regression were used to analyze the prognostic factors for ROSC and survival to discharge after cardiac arrest (CA). Results: The incidence of CA in PICU was 3.2% (372/11 588), and the implementation rate of CPR was 75.5% (281/372). There were 144 males and 137 females with median age of 32.8 (5.6, 42.7) months in all 281 CPA cases who received CPR. CHD group had 56 cases while non-CHD had 225 cases, with the percentage of 19.9% (56/281) and 80.1% (225/281) respectively. The proportion of female in CHD group was 60.7% (34/56) which was higher than that in non-CHD group (45.8%, 103/225) (χ2=4.00, P=0.045). There were no differences in ROSC and rate of survival to discharge between the two groups (P>0.05). The ROSC rate of children with arthythmid in CHD group was 70.0% (28/40), higher than 6/16 for non-arrhythmic children (χ2=5.06, P=0.024). At discharge, the pediatric cerebral performance category scores (1-3 scores) of CHD and non-CHD child were 50.9% (26/51) and 44.9% (92/205) respectively. Logistic regression analysis indicated that the independent prognostic factors of ROSC and survival to discharge in children with CHD were CPR duration (odds ratio (OR)=0.95, 0.97; 95%CI: 0.92~0.97, 0.95~0.99; both P<0.05) and epinephrine dosage (OR=0.87 and 0.79, 95%CI: 0.76-1.00 and 0.69-0.89, respectively; both P<0.05). Conclusions: There is no difference between CHD and non-CHD children in ROSC and survival rate of survival to discharge was low. The epinephrine dosage and the duration of CPR are related to the ROSC and survival to discharge of children with CHD.

[Treatment outcome of 100 patients with hepatoblastoma based on a new risk stratification].

Objective: To provide the risk stratification method of hepatoblastoma (HB) suitable for implementation in China and explore the new treatment method for high-risk HB patients. Methods: A total of 100 cases of children and adolescents under 18 years old with newly diagnosed HB in Sun Yat-sen University Cancer Center and Sun Yat-sen University First Affiliated Hospital from September 2014 to September 2018 were included. According to the clinical stage, AFP level, pathological subtype and other factors, patients were stratified into four groups: extremely low-, low-, intermediate- and high-risk. The patients at very low risk were treated with surgery only and followed-up. The patients at very low risk were treated with C5V(Cisplatin+ 5-Fluroracil+ Vincristine) regimen for 4 courses. The patients at intermediate risk were treated with C5VD(Cisplatin+ 5-Fluroracil+ Vincristine+ Doxorubicin)regimen before and after surgery for 6-8 courses. The patients at high risk were treated with C5VD and IIV (ifoshamide+ irinotecan+ vincristine) alternately before and after surgery for 8 courses. Results: One hundred patients were stratified into extremely low-risk, low-risk, medium-risk and high-risk groups for 2, 10, 51 and 37 cases, respectively. Eighty three cases had evaluable lesions before chemotherapy. Among them, 65 patients achieved partial remission, stable disease and progressive disease were observed in 10, and 8 cases, respectively, with a response rate of 78.3%. During a median follow-up of 20 months, 30 patients experienced tumor relapse or progression, and 27 of them died. The 2-years progression-free survival (PFS) and overall survival (OS) rates were 69.2% and 72.0%, respectively. The 2-years PFS rates of patients with extremely low risk, low risk, medium risk and high risk were 100%, 88.9%, 75.3% and 43.2%, respectively. The 2-years OS rates were 100%, 100%, 81.0% and 44.8%, respectively. Conclusions: The novel HB risk classification is simple and feasible. With active comprehensive treatment, patients at extremely low-, low- and medium-risk have excellent outcomes. The survival rate of high-risk HB patients remains to be improved, and new treatment strategies need to be explored.

Analysis of factors for disease progression in 61 patients with COVID-19 in Xiaogan, Hubei, China.

OBJECTIVE: The aim of this study was to retrospectively analyze clinical characteristics and laboratory results of the novel coronavirus pneumonia (COVID-19) patients so as to identify factors related to disease progression. PATIENTS AND METHODS: Sixty-one patients with COVID-19 were divided into two groups: an improvement/stabilization group (n = 53) and a progression group (n = 8). Clinical data were collected to analyze and compare the differences between the two groups. RESULTS: Of the sixty-one patients, thirty-one were male (50.8%), and thirty were female (49.2%), with a median age of 53 years. On admission, significant differences were observed between the two groups with respect to the levels of Creatine Kinase (CK), lymphocytes, D-dimer and creatinine, and prothrombin time (PT). Univariate logistic regression analysis showed that Platelet-to-lymphocyte ratio (PLR), lymphocytes, Mean platelet volume to lymphocyte ratio (MPVLR), CK, White Blood count to mean platelet volume ratio (WMR), Lymphocyte-to-monocyte ratio (LMR), and serum creatinine were important factors for disease progression. Multivariate logistic regression analysis showed that PLR was an independent factor for disease progression in COVID-19 patients. The receiver operating characteristic (ROC) curve revealed that the best predictor of disease progression was CK. Dynamic changes in the laboratory indicators of patients were tracked, and significant differences were found in the variation trends of white blood cell count, neutrophil count, and WMR, which gradually increased in the progression group, but gradually decreased in the improvement/stabilization group. CONCLUSIONS: Risk factors for disease progression included PLR, lymphocytes, MPVLR, CK, WMR, LMR, and creatinine, among which, PLR is an independent risk factor for disease progression in COVID-19 patients.

[A single-center retrospective analysis of 85 children and adolescents with limited-stage Hodgkin lymphoma].

Objective: To summarize the efficiency and long-term outcomes of limited-stage Hodgkin lymphoma in children and adolescents with ABVD therapy and determined whether omitting radiotherapy for a low-risk patient enabled the achievement of complete response (CR) after chemotherapy. Methods: We retrospectively analyzed data from 13 y (2004-2016) from patients aged ≤18 y with limited-stage HL admitted to the Sun Yat-sen University Cancer Center. Patients received treatment with ABVD chemotherapy alone or ABVD chemotherapy followed by low-dose involved field radiotherapy. Results: Total 85 subjects were eligible for study inclusion; the median age was 12 (3-18) y; 66 (77.6%) were men, 80 (94.1%) had stage-II disease, 56 (65.9%) were at low-risk, and the median follow-up duration was 72 (8-196) months; 12 relapsed, 2 had secondary neoplasm, and 2 died. The 5-year event free survival (EFS) was (85.6±3.8) %, and the overall survival (OS) was 100%. The 5-year EFS and OS was (89.1±4.2) % and 100%, respectively, for the low-risk cohort and (79.3±7.5) % and 100%, respectively for the intermediate-risk cohort. Among the 39 low-risk patients who achieved CR after chemotherapy, 15 received treatment with chemotherapy followed by LD-IFRT. In the exploratory subset analysis, the low-risk cohort who achieved CR after chemotherapy, the 5-year EFS for comparing ABVD alone with chemotherapy followed by LD-IFRT was (87.0±7.0) % versus 100% (P=0.506) , and the OS was 100% for both the groups. Conclusions: Our retrospective analysis showed excellent survival of limited-stage HL patients with ABVD therapy. For patients who achieving CR after chemotherapy with low-risk HL, received chemotherapy followed by LD-IFRT does not improve 5-year OS and EFS. The use of risk- and response-based stratification may facilitate the development of effective and less toxic protocols.

Clinical features and outcomes of spitzoid proliferations in children and adolescents.

BACKGROUND: Spitzoid proliferations range from Spitz naevi to melanomas. There are few studies describing clinical features and outcomes in the paediatric population. OBJECTIVES: To determine the clinical features and outcomes of a large paediatric cohort with histopathologically confirmed Spitz tumours. METHODS: This was a retrospective cohort study of patients seen at Boston Children's Hospital who were aged < 20 years and had a histopathological diagnosis of spitzoid proliferation from 1 January 1994 to 23 October 2012. RESULTS: In total 595 patients with 622 spitzoid proliferations were identified (median age 7·4 years, interquartile range 4·6-11·7). Overall 512 proliferations (82·3%) were typical, 107 (17·2.%) were atypical and three (0·5%) were melanomas. The median ages at biopsy were 7·4, 7·2 and 17·2 years, respectively, and there was a significant difference in age at biopsy for patients with typical or atypical proliferations vs. melanoma (P < 0·01). Among samples with positive margins (n = 153), 55% (54 of 98) of typical proliferations, 77% (41 of 53) of atypical proliferations and 100% (two of two) of melanomas were re-excised. Six patients had sentinel lymph node biopsy performed, with three patients demonstrating nodes positive for melanocytic cells. Within a median follow-up of 4·1 years for the full cohort there were no related deaths. CONCLUSIONS: Spitz tumours have strikingly benign outcomes in the paediatric population, although this study is limited by the low number of melanomas and restriction to a single paediatric institution. Aggressive management recommendations should be reconsidered for children and adolescents with banal-appearing Spitz naevi, based on the clinically indolent behaviour in this cohort.

trans-10,cis-12 conjugated linoleic acid alters lipid metabolism of goat mammary epithelial cells by regulation of de novo synthesis and the AMPK signaling pathway.

The trans-10,cis-12 isomer of conjugated linoleic acid (t10c12-CLA) is a biohydrogenation intermediate in the rumen and has been shown to cause milk fat depression in dairy goats. However, few studies have focused on the in vitro molecular mechanisms involved in the response of the goat mammary gland to t10c12-CLA. In the present study, RNA sequencing technology was used to investigate the effects of t10c12-CLA on goat mammary epithelial cells. From the data, 25,153 annotated transcripts were obtained, and differentially expressed genes were selected based on a false discovery rate <0.05. Candidate genes and potent cellular signaling pathways were identified through Gene Ontology (GO) and pathway analysis. Next, real-time quantitative PCR and Western blot analyses were used to verify the results of the RNA sequencing data. The results indicated that t10c12-CLA inhibits fatty acid synthesis through downregulation of genes involved in de novo fatty acid synthesis, and this process is likely correlated with the activation of the AMP-activated protein kinase signaling pathways.

[Impact of intensified maintenance therapy on the prognosis of children and adolescents with advanced lymphoblastic lymphoma].

Objective: To investigate the impact of intensified maintenance therapy on the prognosis of children and adolescents with advanced lymphoblastic lymphoma (LBL) . Methods: Retrospective analysis on the treatment results of children and adolescents with stage Ⅲ and stage Ⅳ LBL who underwent BFM-NHL-90/-95 regimen without prophylactic radiotherapy. The intensified therapy group included the patients admitted from 1998 to 2005, while others were classified as the non-intensified therapy group. Patients in the intensified therapy group were intravenously treated with "etoposide phosphate plus cytrarabine" and high-dose methotrexate alternately per 2.5-3 months in addition to the oral chemotherapy with 6-mercaptopurine and methotrexate during the maintenance phase. Results: A total of 187 LBL patients were enrolled. The rates of 5-year event free survival were (76.9 ± 5.8) % and (77.9 ± 4.3) % (χ(2)=0.249, P=0.617) respectively, in the intensified therapy (n=52) and the non-intensified therapy groups (n=135) , while the rates of 5-year overall survival of them were (78.8 ± 5.7) % and (79.8±4.1) % (χ(2)=0.353, P=0.552) , respectively. Stratified by stage, immunological type as well as risk stratification, the rates of long-term survival were similar between the two groups. During the maintenance phase, the rates of grade Ⅲ and Ⅳ myelosuppression in the intensified therapy and the non-intensified maintenance groups were 55.8% and 18.5%, respectively (χ(2)=25.363, P<0.05) . Conclusion: Intensified maintenance therapy failed to improve the prognosis of patients with advanced LBL.

Risk of melanocytic nevi and nonmelanoma skin cancer in children after allogeneic hematopoietic stem cell transplantation.

There is a known increased risk of skin cancer in the adult population after hematopoietic stem cell transplantation (HSCT). However, late dermatologic effects that children may experience after HSCT have not been well described. The primary objective of this study was to characterize nevi and skin cancers affecting children after allogeneic HSCT. A cross-sectional cohort study of 85 pediatric HSCT recipients and 85 controls matched for age, sex and skin phototype was performed at a single institution. All participants underwent a full skin examination. Median age at study visit was 13.8 years in HSCT patients with median time post-HSCT of 3.6 years. HSCT patients had significantly more nevi than control patients (median (range): 44 (0-150) vs 11 (0-94), P<0.0001). HSCT patients also had significantly more nevi >5 mm in diameter and atypical nevi than controls. Factors associated with increased nevus count included malignant indication for HSCT, pretransplant chemotherapy, TBI exposure and myeloablative conditioning. A total of 16.5% of HSCT patients developed cancerous, precancerous lesions and/or lentigines. Our study suggests that pediatric HSCT recipients have an increased risk of benign and atypical melanocytic proliferations and nonmelanoma skin cancer that can manifest even during childhood.

Merkel cell carcinoma in a patient with GATA2 deficiency: a novel association with primary immunodeficiency.

A 55-year-old woman with GATA2 deficiency and neurofibromatosis 1 was diagnosed with Merkel cell carcinoma (MCC). This polyomavirus-associated cutaneous malignancy has previously been associated with immunosuppression and acquired immunodeficiencies such as HIV/AIDS. However, MCC has not been previously reported in the setting of underlying primary or inherited immunodeficiency.

Effects of supplemental nanoparticle trivalent chromium on the nutrient utilization, growth performance and serum traits of broilers.

The aim of this study was to investigate the effect of dietary supplementation of nanoparticle trivalent chromium on nutrient utilization, growth performance and serum traits of broilers. This study included two trials. In trial 1, 32 three-week-old broilers were divided into four groups: the control, chromium chloride (CrCl3), chromium picolinate (CrPic) and nanoparticle chromium picolinate (NanoCrPic). Chromium was added at a 1200 µg/kg level to evaluate the nutrient and chromium utilization. In trial 2, 160 one-day-old broilers were randomly divided into four groups as in trial 1, with four replicates. The results of trial 1 indicated that the chromium utilization is as follows: NanoCrPic > CrPic > CrCl3 and control groups, with significant differences between groups (p < 0.05). Crude fat utilization in CrCl3 group was lower than in that the control group (p < 0.05). The results of trial 2 indicated that feed intake of 4-5 weeks showed better result in the CrCl3 group than that in the CrPic group (p < 0.05). The results of serum traits indicated that the LDL-cholesterol in the NanoCrPic groups was lower than that in the CrPic group (p < 0.05). The NanoCrpic and CrPic groups showed significantly increased serum chromium concentration when compared with the control and CrCl3 groups; the triglyceride level in the CrCl3 group was lower than that in the CrPic group (p < 0.05). This study concluded that compared with CrPic, NanoCrpic supplementation could increase chromium utilization and lower the serum LDL-cholesterol of broilers.

Nail dystrophy, edema, and eosinophilia: harbingers of severe chronic GVHD of the skin in children.

The prognostic value of adnexal findings in chronic GVHD (cGVHD) has not been investigated in children. Dermatologic examinations were performed in a severe cohort of 11 children with skin cGVHD seen over a 2-year period. Findings were compared with 25 additional patients with skin cGVHD and 97 control patients. In 36 patients with skin cGVHD, nail dystrophy was present in 45% of patients, and was significantly associated with sclerotic disease and lung cGVHD. Pterygium inversum unguis (PIU) was associated with severe lung disease, with significantly lower % predicted FVC and FEV1 in those with PIU than those without. Forty-four percent of GVHD patients had preceding peripheral edema and 56% had preceding peripheral eosinophilia. Peripheral edema and eosinophilia were significantly associated with sclerotic cGVHD and persisted until the diagnosis of cGVHD in all patients. Comparison of data with control patients showed that incidence of nail dystrophy, incidence of peripheral edema and mean peak peripheral eosinophil count of patients with skin cGVHD was significantly higher than those without cGVHD. This study suggests that nail dystrophy, persistent peripheral edema and persistent peripheral eosinophilia are harbingers of severe cGVHD of the skin in children. The presence of PIU may be a harbinger of severe lung involvement.