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Objective : The objective of this study was to evaluate CELSR3 expression and explore its potential mechanism in oral squamous cell carcinoma. Study design : CELSR3 mRNA expression was analyzed using The Cancer Genome Atlas (TCGA) database. CELSR3 protein expression in 135 surgical oral squamous cell carcinoma specimens was observed by immunohistochemical staining. Staining results were used to investigate association between CELSR3 expression and clinicopathological characteristics and prognosis. Bioinformatics analyses were used to explore the potential mechanism of CELSR3 in head and neck squamous cell carcinoma. Results : CELSR3 mRNA expression was upregulated in patients with head and neck squamous cell carcinoma in the TCGA-HNSC dataset. Increased CELSR3 protein expression was associated with perineural invasion and poor clinical outcomes in oral squamous cell carcinoma patients. Bioinformatics analyses revealed that CELSR3 is involvement in axonogenesis, neuron migration and cell-cell adhesion, all of which are involved in the process of perineural invasion. Conclusion : CELSR3 may play a pro-oncogenic role in oral squamous cell carcinoma and can predict perineural invasion and poor survival. CELSR3 may be involved in oral squamous cell carcinoma progression by modulating perineural invasion.

Objective To investigate the association of the maternal serum albumin (MAlb) level with fetal growth and fetal growth restriction (FGR) risk in term-born singletons. Design Prospective cohort study. Setting Four hospital maternity units of the Tongji Maternal and Child Health Cohort study initiated from September 2013 to April 2016 at Wuhan City, in central China. Patient(s) A total of 3,065 mother–offspring pairs. Intervention(s) None. Main Outcome Measure(s) Fetal growth was evaluated by birth weight (BW) and birth length. Fetal growth restriction was defined as BW below the 10th percentile. Result(s) All MAlb levels were within the upper limit of normal. After adjustment for liver function parameters, inflammatory indicators, and others, a reverse U-shaped relationship between MAlb and fetal growth was observed. Specifically, BW increased significantly with an increasing MAlb level when the MAlb level was 36.1 g/L (per g/L: β = −15.1; 95% CI, −21.2, −8.9). There was a similar association between MAlb and birth length. Furthermore, the adjusted odd ratios of FGR across increasing tertiles of the MAlb levels were 1.0 (reference), 1.1 (0.7, 1.8), and 1.7 (1.0, 2.6). Conclusion(s) There was a reverse U-shaped association between MAlb and fetal growth. A higher MAlb level was associated with an increased risk of FGR. Clinical Trial Registration Number NCT03099837.

Background & aims Hepatocellular carcinoma (HCC) is one of the main types of primary liver cancer with high morbidity and mortality, and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC have not been elucidated. Approach & results Through clinical analysis, we found that the expression of TRIM11 was upregulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with PH domain leucine rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1, thus promoted activation of protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. Conclusions Our study confirmed that TRIM11 plays an oncogenic role in hepatocellular carcinoma through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of hepatocellular carcinoma.

PURPOSE High mobility group box 1 (HMGB1) and homocysteine (Hcy) play important roles in contrast-induced acute kidney injury (CI-AKI). We compared HMGB1 to Hcy as preprocedural predictors for CI-AKI in coronary artery disease (CAD) patients after percutaneous coronary artery intervention (PCI). METHODS We included 257 eligible patients who were categorized into CI-AKI ( +) and CI-AKI ( -) group. The differences in clinical characteristics and biochemical indexes between two groups were analyzed. RESULTS We observed that thirty-eight (14.8%) of 257 eligible CAD patients developed CI-AKI. HMGB1 (14.65 [11.13-24.89] vs 10.88 [7.94-13.23], p

Background Adenovirus pneumonia is prone to severe clinical and imaging manifestations in children. Bronchoscopic alveolar lavage (BAL) is an important adjunctive therapy for patients with severe imaging findings. The study aimed to evaluate the effect of the timing on the efficacy of bronchoalveolar lavage in children with adenovirus pneumonia. Methods This study included 134 patients with adenovirus pneumonia treated with BAL at Guangzhou Women and Children's Medical Center from January 2019 to January 2020.They were classified into the severe and mild groups. Based on the timing of BAL, each group was divided into the early BAL layer (received BAL within 1–9 days of the illness course) and the late BAL layer (received BAL within 10–14 days of the illness course). The clinical data of patients with different BAL timings were analyzed in two groups. Results Among the 134 patients, 70 were categorized into the mild group and 64 were categorized into the severe group. Of the 134 patients, 42 patients received BAL early (mild group: n = 21 and severe group: n = 21) and 92 patients received BAL later (mild group: n = 49 and severe group: n = 43). In the mild group, the fever and hospital duration were shorter in patients who received BAL early than in those who received BAL later (p p Conclusion For mild adenovirus pneumonia, early BAL may shorten the fever and hospital duration. However, early BAL in severe cases might not shorten the course of the disease or improve prognosis and may even increase the risks of mechanical ventilation and BAL complications.

Background: Tumor purity plays a vital role in the biological process of solid tumors, but its function in gynecologic cancers remains unclear. This study explored the correlation between tumor purity and immune function of gynecological cancers and its reliability as a prognostic indicator of immunotherapy. Methods: Gynecological cancer-related datasets were downloaded from The Cancer Genome Atlas (TCGA). Tumor purity was calculated by the ESTIMATE algorithm. A LASSO Cox regression analysis was performed to construct the risk score model. A Kaplan–Meier Plotter was used to explore the relationships between tumor purity and cancer prognosis. We performed the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) to explore the pathways in the subgroups. A nomogram was used to quantitatively assess the cancer prognosis. Results: Tumor purity was negatively correlated with B cell infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Approximately 420 genes were positively associated with B cell infiltration and CESC prognosis and were enriched in immune-related signaling pathways. There were 11 key genes used to construct a risk score model. The low-risk group had a higher immune score and better prognosis than the high-risk group. A nomogram based on risk score, T stage, and clinical-stage had good predictive value in quantitatively evaluating CESC prognosis. Conclusions: This study is the first to reveal the correlation between tumor purity and immunity in CESC and suggests that low-risk patients may be more sensitive to immunotherapy. This provides a theoretical basis for the clinical treatment of CESC.

Background To explore the clinical application of a population pharmacokinetics (PPK) model of vancomycin in patients with hematological diseases and neutropenia. Methods Patients with hematological diseases and neutropenia were included in the PPK model study. Nonlinear mixed effect modeling approach (NONMEM) was used for model establishment. Monte Carlo simulation was carried out. A total of 74 patients were divided into model group and non-model group for clinical application research. The model group was given the initial dose of 1g q8h, and the non-model group was given 1g q12h as an empiric initial dosage.the follow-up dose adjustments were made according to the concentration results. Results This two-compartment model showed good stability and accuracy. The first trough concentration(C0 ) and the compliance rate of the first C0 were much higher in the model group than that in the non-model group(14.30 ± 4.73 μg/ml and 59.38% vs. 8.02 ± 2.61 μg/ml, 35.71% ). Less patients needed dose adjustments and fewer adjustment times in the model group than those in the non-model group(12.50% and 0.13 ± 0.34times vs 50.00% and 0.61 ± 0.66times). This suggested that for those patients who had a CLCR≥90 ml/min/1.73m2 , the initial dose of 1g q8h may help to reach the target C0 (10∼20μg/ml) quickly. It also helped to reduce the times and number of patients who need dose adjustments. Conclusions Our PPK model of vancomycin in patients with hematologic diseases and neutropenia can be used to shorten the time to reach the target concentration anddn reduce the number of dose adjustments. This article is protected by copyright. All rights reserved.

BACKGROUND Risk factors, virological parameters, and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined. METHODS The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 d in the PET group were tested for HHV-6 viremia using a real-time quantitative polymerase chain reaction. Assessments included virological characteristics and relationship with CMV, risk factors, and impact of HHV-6 viremia with outcomes through 12 mo posttransplant. RESULTS HHV-6 viremia at any level developed in 42% (40 of 96). Older patient age (P = 0.03), longer hospitalization (P = 0.015), and ICU stay at transplantation (P = 0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (P = 0.004), higher HHV-6 area under the curve (P = 0.043), and higher peak HHV-6 viral load (P = 0.006) versus HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 mo (P = 0.045) posttransplant. CONCLUSIONS Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical illness in ICU at time of transplant and was independently associated with allograft rejection.

Osteoporosis is a widely distributed disease that may cause complications such as accelerated tooth movement, bone resorption, and tooth loss during orthodontic treatment. Promoting bone formation and reducing bone resorption are strategies for controlling these complications. For several decades, the autophagy inducer lithium chloride (LiCl) has been explored for bipolar . In this study, we investigated the autophagy-promoting effect of LiCl on bone remodeling under osteoporotic conditions during tooth movement. Ovariectomy was used to induce osteoporosis status in vivo. The results showed that LiCl rejuvenated autophagy, decreased apoptosis, and promoted bone formation, thus protecting tooth movement in osteoporotic mice. Furthermore, in vitro experiments showed that LiCl reversed the effects of ovariectomy on bone marrow-derived mesenchymal stem cells (BMSCs) extracted from ovariectomized mice, promoting osteogenesis and suppressing apoptosis by positively regulating autophagy. These findings suggest that LiCl can significantly decrease adverse effects of osteoporosis on bone remodeling, and that it has great potential significance in the field of bone formation during tooth movement in osteoporosis patients., Graphical abstract Image 1, Highlights • Lithium chloride was shown for the first time to promotes bone formation in ovariectomized mice during orthodontic tooth movement. • The osteogenesis of lithium chloride in orthodontic tooth movement is through promoting autophagy and inhibiting apoptosis. • The effect of lithium chloride on autophagy and osteogenesis could be blocked by 3-MA. • Our study provides a clue and cue for effective OTM in patients with osteoporosis.

Background Some children hospitalized for severe pertussis need intensive care; moreover, some children die because of deterioration alone or in combination with other complications. The purpose of this study was to identify the mortality risk factors among hospitalized children with severe pertussis. Methods This study evaluated the medical records of 144 hospitalized children with severe pertussis at the Guangzhou Women and Children’s Medical Centre between January 2016 and December 2019. Results The median age of patients was 2 months (IQR 1–4 months), with 90.3% of the patients aged 70.0 × 109/L (odds ratio [OR], 230.66; 95% confidence interval [CI], 5.16–10,319.09 P = 0.005) and pulmonary hypertension (PH) (OR 323.29; 95% CI 16.01–6529.42; P Conclusion Severe pertussis mainly occurred in children aged 70.0 × 109/L and PH were the prognostic independent variables associated with death.

Background This study retrospectively analyzed the feasibility and surgical outcome of an algorithmic approach using negative pressure wound therapy for patients with synchronous hypopharyngeal and esophageal cancer undergoing pharyngolaryngoesophagectomy with gastric tube reconstruction. Methods Patients undergoing pharyngolaryngoesophagectomy and gastric tube reconstruction for hypopharyngeal cancer between 2011 and 2019 were candidates for this study. Data were collected on patient demographics, comorbidities, performance status, cancer stage, treatment, complication, and survival. Survival analysis was performed using the Kaplan-Meier method. The Cox proportional hazards model was used for prognostic factors. Results The study enrolled 43 patients. Anastomotic leakage was found in 21 of the patients with a conventional surgical drain (61.9%) and in 10 of the 22 patients with negative pressure wound therapy (45.5%) (p = 0.280). Nine patients in the conventional drain group (42.9%) and two patients in the negative pressure wound therapy group (9.1%) had leakage-associated complications (p = 0.011). The incidence of pulmonary complications was higher in the conventional surgical drain group (9 vs 2; p = 0.011). The number of complications requiring surgery was higher in the conventional drain group (7 vs 0; p = 0.004). The overall survival in the negative pressure wound therapy group was better (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.15-0.76; p = 0.009). Negative pressure wound therapy was independently associated with overall survival (HR, 0.31; 95% CI, 0.13-0.77; p = 0.011). Conclusions Negative pressure wound therapy with an algorithmic approach improved the overall survival for the patients undergoing gastric tube reconstruction after pharyngolaryngoesophagectomy for hypopharyngeal and esophageal cancer by preventing deadly complications secondary to anastomotic leakage.

BACKGROUND The ATP6AP1 gene coding for the accessory protein Ac45 of the vacuolar-type adenosine triphosphatases (V-ATPase) is located on chromosome Xq28. Defects in certain subunits or accessory subunits of the V-ATPase can lead to congenital disorders of glycosylation (CDG). CDG is a group of metabolic disorders in which defective protein and lipid glycosylation processes affect multiple tissues and organs. Therefore, the clinical presentation of patients with ATP6AP1-CDG varies widely. In this report, we present a case of ATP6AP1-CDG in a Chinese infant, with clinical features and genotype. CASE SUMMARY An 8-mo-old boy was admitted to our hospital because unexplained hepatosplenomegaly and elevated transaminases that had been noted while he was being treated for a cough at a local hospital. A post-admission examination at our hospital revealed abnormalities in the infant’s liver, brain, and immune system. Trio-based whole exome gene analysis identified a hemizygous pathogenic mutation c.1036G>A (p.E346K) in exon 9 of the ATP6AP1 gene. This variant of the ATP6AP1 gene has not been reported in East Asian countries until now. CONCLUSION Based on the infant’s clinical manifestations and the results of genetic detection, he was clearly diagnosed with ATP6AP1-CDG. The clinical manifestations of children with CDG vary widely. Genetic testing analysis helps in the clinical diagnosis of children with CDG.

Background In order to recommend the optimal type of exercise for type 2 diabetes prevention, different exercise interventions were compared with respect to their effects on glycemic control and insulin resistance. Methods Studies on the curative effect of aerobic exercise training (AET), resistance training (RT), or control training (CT) on prediabetes were retrieved from the PubMed, Embase, SPORTDiscus, and Cochrane Library databases. Body mass index (BMI); homeostasis model assessment of insulin resistance index (HOMA-IR); and fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and insulin levels were used as outcome indicators. The Q statistic was calculated to evaluate heterogeneity within studies. A fixed- or random-effects model was used for pooling data based on nonsignificant or significant heterogeneities. A consistency test was conducted using a node-splitting analysis. Results A total of 13 eligible studies were included. The results of the direct meta-analysis indicated that AET or RT could significantly reduce the HbA1c level in prediabetic individuals compared to CT [AET vs. CT: standardized mean difference (SMD) = − 0.6739, 95% confidence interval (CI) = − 0.9424 to − 0.4055 to RT vs. CT: SMD = − 1.0014, 95% CI = − 1.3582 to − 0.6446]. The findings from the network meta-analysis showed that there were no statistical differences among the four comparisons for all the indicators except for lower HbA1c level (SMD = − 0.75, 95% CI = − 1.31 to − 0.19) and HOMA-IR (SMD = − 1.03, 95% CI = − 1.96 to − 0.10) in the AET group than in the CT group. In addition, prediabetic individuals in the AET + RT group showed greater control of BMI and insulin and FBG levels than those in the other groups, whereas AET was the most effective in controlling HbA1c and HOMA-IR levels in prediabetic individuals. Conclusion AET, AET + RT, and RT exerted beneficial effects on insulin resistance and glycemic control in prediabetic patients. From the existing data, AET or AET + RT is preferentially recommended for these patients, although further studies may unveil RT as a promising therapy. Benefits from all types of exercise seem to occur in an intensity-dependent manner.

This study aimed to investigate the role and regulatory mechanisms of Ezrin in synovial vessels in rheumatoid arthritis (RA). Synovial tissues were obtained from people with osteoarthritis people and patients with RA patients. We also used an antigen‐induced arthritis (AIA) mice model by using Freund's adjuvant injections. Ezrin expression was analysed by immunofluorescence and immunohistochemical staining in synovial vessels of patients with RA and AIA mice. We investigated the role of Ezrin on vascular endothelial cells and its regulatory mechanism in vivo and in vitro by adenoviral transfection technology. Our results suggest a role for the Ezrin protein in proliferation, migration and angiogenesis of vascular endothelial cells in RA. We also demonstrate that Ezrin plays an important role in vascular endothelial cell migration and tube formation through regulation of the Hippo‐yes‐associated protein 1 (YAP) pathway. YAP, as a key protein, can further regulate the activity of PI3K/Akt signalling pathway in vascular endothelial cells. In AIA mice experiments, we observed that the inhibition of Ezrin or of its downstream YAP pathway can affect synovial angiogenesis and may lead to progression of RA. In conclusion, Ezrin plays an important role in angiogenesis in the RA synovium by regulating YAP nuclear translocation and interacting with the PI3K/Akt signalling pathway.

BACKGROUND Multiple primary cancer refers to more than one synchronous or sequential cancer in the same individual. Multiple primary cancer always presents as solid cancer or acute myeloid leukemia (AML) secondary to lymphoma. Here, we report a rare case of secondary peripheral T-cell lymphoma and AML after Burkitt lymphoma treatment. CASE SUMMARY A 54-year-old female patient was admitted to our hospital complaining of edema on her left lower limb. Physical examination revealed multiple superficial lymphadenectasis on her neck and pelvis. Color ultrasonography examination showed multiple uterine fibroids and a solid mass at the lower left side of the abdomen. Pathological biopsy revealed Burkitt lymphoma. After three hyper-CVAD (A + B) regimens, she achieved complete remission. Two years later, lymphadenectasis reoccurred. A relevant biopsy confirmed the diagnosis of peripheral T-cell lymphoma, which was accompanied by gastrointestinal invasion and hemocytopenia. Meanwhile, bone marrow examination revealed AML. On the second day of scheduled treatment, she developed gastrointestinal bleeding, peptic ulcers, and hemorrhagic shock and was critically ill. She was then discharged from the hospital due to financial concerns. CONCLUSION This is the first report of secondary peripheral T-cell lymphoma and AML after Burkitt lymphoma treatment with heterochronous and synchronal multiple primary cancers.

PURPOSE Adrenocortical carcinoma (ACC) is a rare aggressive pediatric malignancy with distinct biology. Its treatment follows the principles developed for adults; pediatric-specific studies are scarce. PATIENTS AND METHODS Prospective single-arm risk-stratified interventional study. Study objectives were (1) to describe the outcome of patients with stage I ACC treated with adrenalectomy alone; (2) to describe the outcome of stage II patients (completely resected > 200 cc or > 100 g) treated with adrenalectomy and retroperitoneal lymph node dissection; and (3) to describe the outcome of patients with stage III or IV treated with mitotane and chemotherapy. RESULTS Between September 2006 and May 2013, 78 patients (77 eligible, 51 females) were enrolled. The 5-year event-free survival estimates for stages I (24 patients), II (15 patients), III (24 patients), and IV (14 patients) were 86.2%, 53.3%, 81%, and 7.1%, respectively. The corresponding 5-year overall survival estimates were 95.2%, 78.8%, 94.7%, and 15.6%, respectively. On univariate analysis, age, stage, presence of virilization, Cushing syndrome, or hypertension, germline TP53 status, and presence of a somatic ATRX mutation were associated with outcome. On multivariable analysis, only stage and age were significantly associated with outcome. The probabilities of mitotane and chemotherapy feasibility events were 10.5% and 31.6%, respectively. CONCLUSION Outcome for children with stage I ACC is excellent with surgery. Outcome for patients with stage II disease is inferior despite retroperitoneal lymph node dissection. Patients with stage III ACC have an excellent outcome combining surgery and chemotherapy. Patients with stage IV ACC are older and have a poor outcome; new treatments should be explored for this high-risk group. The combination of mitotane and chemotherapy as prescribed in ARAR0332 resulted in significant toxicity; one third of patients with advanced disease could not complete the scheduled treatment.

Objectives: Systematically summarize the trend of research and the orientation of macular edema in recent decades by analyzing the characteristics of the 100 top-ranked articles.Methods: The 100 most cited papers on macular edema published from January 1, 1950, to August 27, 2020, were reviewed by Web of Science (including the Scientific Citation Index). The each article is analyzed by extracting information such as the publication date, journal, author, country of origin, institution, number of citations, research topics, and research design types. Results: Among the 100 articles, the highest cited number was 1907, and the lowest cited number was 166. These articles were published in 18 journals from 1983 to 2016, as well as in 10 countries. The most published newspapers were Ophthalmology (n = 51). The countries were the USA (n = 66). Out of 100 articles, 12 institutions and 10 authors contributed over 3 articles. The emphasis of these studies was placed on clinical studies. The most prevalent design type was the randomized controlled trial (n = 42). The etiology on macular edema can be divided into diabetic (n = 68), retinal vein occlusion (n = 21), and other (n = 11), of which the most common research topic is the non-surgical treatment of macular edema (n = 65).Conclusion: This study analyzed the research trends and progress of macular edema in the past 70 years, emphasizing the treatment of diabetic macular edema and the contribution of USA in the study of macular edema.

Promoting dementia-friendly communities is an important strategy for improving quality of life for people with dementia and dementia-family caregivers. The process of building dementia-friendly communities should include all people living in the community. The objective of this study was to compare perceived dementia friendliness in the community among people with dementia, family caregivers, service providers, and the general public. In Taiwan, we surveyed 60 people with dementia, 140 family caregivers, and 200 members of the general public face to face, with 200 service providers surveyed by mail. Participants completed the Perceived Community Dementia Friendliness measure, consisting of seven subscales: care services, community members, community environment, community interactions, transportation, hospitals, and stores and organisations. This measure has acceptable convergent validity, construct validity, and internal consistency reliability for use in Taiwan. Differences in perceived dementia friendliness were examined by chi-square tests/analysis of variance. Among the seven subscales, hospitals were rated with good dementia friendliness by 70% of people with dementia (n = 42); however, care services were rated poor by 23.3% of people with dementia (n = 14). Hospitals were also rated with good dementia friendliness by 39.2% of family caregivers (n = 54). Care services were rated as having good dementia friendliness by 43.5% of service providers (n = 87) and 47% of the general public (n = 86). Furthermore, community interactions were rated as good by small percentages of family caregivers (11.4%, n = 16), service providers (22.2%, n = 44), and the general public (30.9%, n = 58). Family caregivers, service providers, and the general public rated hospitals with the highest mean dementia-friendliness score and community interactions with the lowest. Perceived community-dementia friendliness among participants with dementia differed from that of participants without. People with dementia prioritised improving care services, while people without dementia rated facilitating community interactions as more vital. These differences provide vital insights into understanding the policies and administration of dementia-friendly communities.

Background Cytomegalovirus (CMV) viremia is common in human immunodeficiency virus (HIV) infection and is associated with worse long-term outcomes. To date, no studies have assessed CMV viremia in children diagnosed with HIV in hospital. Methods We studied CMV viremia and clinical outcomes in 163 Kenyan children aged 2 months to 12 years, diagnosed with HIV in hospital. CMV DNA levels in plasma were measured using quantitative polymerase chain reaction (PCR). Regression models were used to assess associations between CMV viremia ≥1000 IU/mL and the risk of continued hospitalization or death at 15 days, duration of hospitalization, and 6-month mortality. Results At enrollment, 62/114 (54%) children had CMV viremia, and 20 (32%) were ≥1000 IU/mL. Eleven CMV reactivations were observed after admission. The prevalence and level of CMV viremia were highest in children −2 (P = .02). Adjusting for age and log10 HIV RNA, the relative risk of death or continued hospitalization at 15 days was 1.74 (95% confidence interval [CI] = 1.04, 2.90), and the hazard ratio of 6-month mortality was 1.97 (95% CI = .57, 5.07) for children with CMV DNA ≥1000 IU/mL compared to lower-level or undetectable CMV DNA. Children with CMV DNA ≥1000 IU/mL were hospitalized a median ~5 days longer than children with lower-level or undetectable CMV DNA (P = .002). Conclusions In this nested observational study, CMV viremia was common in hospitalized children with HIV, and levels ≥1000 IU/mL were associated with increased risk of mortality and longer hospitalization.

Objectives The effects of ligating the pulmonary vein first or pulmonary artery first during lobectomy on the long-term survival of patients with non-small cell lung cancer (NSCLC) remain controversial. We conducted the first systematic review and meta-analysis to determine the association between different sequences of vessel ligation during lobectomy and the prognosis of patients with NSCLC. Methods Literature retrieval was performed by systematically searching Embase, PubMed and Web of Science to identify relevant articles published from the inception of each database to November 2020. The overall survival (OS) and disease-free survival (DFS) of patients treated with vein-first ligation versus those treated with artery-first ligation during lobectomy were analyzed. A standard fixed-effect model test (Mantel-Haenszel method) was used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Heterogeneity was assessed using the Q-test and I2-test. Sensitivity analysis was performed to further examine the stability of pooled HRs. Results Five studies with a total of 1109 patients receiving lobectomy, including one randomized controlled trial and four retrospective studies, were included in this meta-analysis. The results showed that patients with vein-first ligation had a significantly better OS (HR 1.25, 95% CI 1.03–1.50; P = 0.02) and DFS (HR 1.54, 95% CI 1.16–2.04; P = 0.003) than those with artery-first ligation during lobectomy. Significant heterogeneity and publication bias were not observed during analysis. Conclusion Our meta-analysis indicates that vein-first ligation may improve the prognosis of NSCLC patients receiving lobectomy. Therefore, vein-first ligation is recommended during lobectomy for patients with non-small cell lung cancer whenever possible.

The submental artery perforator flap (SMAPF) has an elongated pedicle, allowing good cosmetic outcomes to be achieved following oral reconstruction surgery. The improper dissection of perforators often leads to a vascular flap crisis. To avoid this, some surgeons choose to carry amounts of connective tissue around the pedicle. However the inclusion of connective tissue on the pedicle raises concerns about oncological safety. A surgical anatomical study of the submental vessel patterns and subdivisions of the cervical level I lymph nodes was conducted on 33 patients with primary oral cancer who underwent reconstruction with a SMAPF after tumour resection. The variations in vessels and cervical level I lymph nodes observed during SMAPF harvesting were recorded and analyzed. Two patterns of submental artery perforators and three patterns of submental veins were identified. The different characteristics of the lymph node distribution were elucidated for five subdivisions. All SMAPFs survived (n=33, 100%); however, two SMAPFs exhibited partial losses. The 3-year survival rate of patients was 84.5±6.4%, and there were no suspected flap-related recurrences. With detailed anatomical information on the vascular system and lymph node subdivision, SMAPFs are a reliable choice for postoperative reconstruction following oral cancer surgery, meeting the standards for oncological safety.

OBJECTIVE To study whether serum estradiol (E2) levels prior to progesterone administration in the artificial endometrial preparation (AEP) of frozen-thawed blastocyst transfer affect the live birth rate. DESIGN Retrospective cohort study. SETTING Tertiary-care academic medical centre. POPULATION A total of 3857 frozen-thawed blastocyst transfer cycles were divided into three groups

Peng Yu,1,2 Li Huang,1,2 Zhihan Wang,1,2 Xiaoyu Meng,1,2 Xuefeng Yu1,2 1Department of Internal Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Branch of National Clinical Research Center for Metabolic Diseases, Hubei, ChinaCorrespondence: Xuefeng Yu Tel/Fax +8602783663331Email xfyu188@163.comPurpose: Higher serum levels of uric acid (SUA) are associated with an increased risk of developing type 2 diabetes. Meanwhile, insulin resistance and beta-cell dysfunction are critical factors that mediate the progression from normal glucose tolerance to impaired fasting glucose (IFG) and type 2 diabetes. We aimed to investigate the association between SUA levels and insulin resistance and beta-cell dysfunction in individuals without diabetes, thus explicating the role of uric acid in the early stage of the natural history of type 2 diabetes.Patients and Methods: We used cross-sectional data from the China Health and Nutrition Survey to examine the association. Insulin resistance and beta-cell dysfunction were estimated using the homeostasis model assessment of insulin resistance (HOMA-IR) index and homeostasis model assessment of beta-cell function (HOMA-beta) index, respectively. The associations were analyzed by using partial correlation analysis and multivariate logistic regressionlanalysis.Results: SUA levels were positively associated with fasting glucose, fasting insulin, HOMA-IR in the total population. After adjustment for age, drinking, smoking, living area, daily dietary nutrient intake, body mass index (BMI), estimated glomerular filtration rate (eGFR), hypertension, and dyslipidemia, compared with participants in the lowest quartile of SUA, the adjusted odds ratios for the fourth quartiles were 1.56(1.09-2.24) for IFG, 1.51(1.27-1.78) for insulin resistance, and 1.06(0.88-1.27) for beta-cell dysfunction. In the subgroup analysis, no interactions were found between serum uric acid and age, drinking status, smoking status, BMI, hypertension, or dyslipidemia (all p for interaction> 0.05).Conclusion: In nondiabetic individuals, SUA levels are independently associated with IFG and insulin resistance, while no significant association exists between SUA and beta-cell dysfunction.Keywords: uric acid, beta-cell function, insulin resistance, nondiabetic

Study Objective Pediatric ovarian neoplasms with imaging appearance suggestive of teratoma are often presumed to have low risk of malignancy. We assessed the pre-operative imaging appearance of pediatric malignant ovarian germ cell tumors (MOGCT) and the presence of associated teratoma in a series of MOGCT. Design Retrospective review of clinical and pathology data. Setting Multicenter trial for extracranial malignant germ cell tumors in young female individuals by the Children's Oncology Group (COG study AGCT0132) that included yolk sac tumor, embryonal carcinoma and choriocarcinoma. Participants Female individuals 0-20 years of age at enrollment with ovarian primary nonseminomatous malignant germ cell tumors. Interventions Review of data forms, including prospectively collected surgical checklist documenting imaging characteristics of the tumor, and review of pathology reports. Main Outcome Measures Description of imaging appearance and frequency of mixed histology with benign teratoma elements. Results A total of 138 female individuals (11 months to 20 years of age) had primary ovarian tumors. Imaging appearance and pathology information were available for 133 patients. Among the 133 patients, tumor appearance was solid (10.5%), solid with calcification (3.0%), mixed cystic and solid (58.7%), mixed cystic and solid with calcification (24.8%), and unknown (3.0%). In all, 54% had elements of teratoma in addition to malignant histology. Conclusion Mixed cystic and solid appearance with or without calcification was seen in 83.5% of pediatric ovarian malignant germ cell tumors. Associated benign teratoma was common. The presence of a mixed cystic and solid appearance on preoperative imaging should not dissuade the surgeon from obtaining preoperative serum markers and undertaking complete surgical staging.

Purpose To evaluate the impact of music therapy (MT) on preoperative anxiety and degree of cooperation with anesthesia induction in children with simple congenital heart disease (CHD). Design A randomized controlled clinical study. Methods Ninety children were randomly assigned to the MT and control groups. The MT groups underwent a preoperative 30-minute session of MT, whereas the control group did not listen to any music and had the same amount of quiet time. The modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF) was used to evaluate the patients' preoperative anxiety on entering the anesthesia waiting area (T1), 10 minutes after entering the waiting area (T2), and during the initiation of anesthesia induction (T3); the degree of cooperation with anesthesia induction was assessed using the Induction Compliance Checklist. The mean arterial blood pressure (MAP) and heart rate (HR) at T1, T2, T3, and T4 (the time of successful anesthesia) were also recorded. Findings One child was excluded from the MT group, and one was excluded from the control group. No difference was found in the mYPAS-SF score, MAP, or HR between the two groups at T1. The mYPAS-SF scores of the MT group were significantly lower than those of the control group at T2 and T3. At T2, T3, and T4, the MAP and HR of the MT group were lower than those of the control group. A statistically significant difference was found in the Induction Compliance Checklist score between the two groups. Conclusions MT can reduce preoperative anxiety and improve the degree of cooperation with anesthesia induction.

Rationale: Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. Objectives: To evaluate the safety and efficacy of parenteral iron replacement in PAH. Methods: In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight

Purpose: To investigate the protective effect of floroindole against cecal ligation and puncture (CLP)- induced sepsis, as well as the underlying mechanism of action. Methods: Thirty-five 10–week-old male Wistar rats weighing 190 - 210 g (mean: 200.00 ± 10.10 g) were used for this study. The rats were randomly assigned to seven groups of five rats each, viz, normal control group, and six CLP groups. The CLP groups were those subjected to cecal ligation and puncture (CLP). The first 5 CLP groups received 2, 4, 6, 8 or 10 mg/kg floroindole, respectively, 1 h after CLP, via intraperitoneal route (i.p.) while the 6th CLP group served as untreated control. Western blotting, enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qRT-PCR) were used for the assessment of the expression levels of tumor necrosis factor-α (TNF- α), interleukn-6 (IL-6), nucleotide-binding oligomerization domain 2 (NOD2) and p-NF-κB p65. Results: Cecal ligation and puncture (CLP) significantly and time-dependently upregulated the expressions of TNF-α, IL-6 and NOD2 in intestinal tissues of rats (p < 0.05). However, treatment with floroindole significantly, and dose-dependently down-regulated CLP-induced expressions of these proteins (p < 0.05). Treatment of rats with floroindole also significantly and dose-dependently inhibited CLP-induced phosphorylation of NF-κB p65 in rat ileum (p < 0.05). Conclusion: The results obtained in this study demonstrate that floroindole confers some degree of protection against CLP-induced sepsis via inhibition of NF-κB p65 phosphorylation.

Glyburide (Gly) could inhibit NLRP3 inflammasome, as well as could be treated with Type 2 diabetes as a common medication. Despite more and more studies show that Gly could influence cancer risk and tumor growth, it remains unclear about the effect of Gly in lung tumorigenesis. To evaluate whether Gly inhibited lung tumorigenesis and explore the possible mechanisms, a benzo(a)pyrene [B(a)p] plus lipopolysaccharide (LPS)-induced non-diabetes mice model was established with B(a)p for 4 weeks and once a week (1 mg/mouse), then instilled with LPS for 15 weeks and once every 3 weeks (2.5 μg/mouse) intratracheally. Subsequently, Gly was administered by gavage (10 μl/g body weight) 1 week before B(a)p were given to the mice until the animal model finished (when Gly was first given named Week 0). At the end of the experiment called Week 34, we analyzed the incidence, number and histopathology of lung tumors, and detected the expression of NLRP3, IL-1β, and Cleaved-IL-1β protein. We found that vehicles and tricaprylin+Gly could not cause lung carcinogenesis in the whole process. While the incidence and mean tumor count of mice in B(a)P/LPS+Gly group were decreased compared with B(a)p/LPS group. Moreover, Gly could alleviate inflammatory changes and reduce pathological tumor nest numbers compared with mice administrated with B(a)p/LPS in histopathological examination. The B(a)p/LPS increased the expression of NLRP3, IL-1β, and Cleaved-IL-1β protein significantly than Vehicle, whereas decreased in B(a)P/LPS+Gly (0.96 mg/kg) group compared with B(a)p/LPS group. Results suggested glyburide might inhibit NLRP3 inflammasome to attenuate inflammation-related lung tumorigenesis caused by intratracheal instillation of B(a)p/LPS in non-diabetes mice.

The study objective was to investigate four common occlusal modes by using the finite element (FE) method and to conduct a biomechanical analysis of the periodontal ligament (PDL) and surrounding bone when orthodontic force is applied. A complete mandibular FE model including teeth and the PDL was established on the basis of cone-beam computed tomography images of an artificial mandible. In the FE model, the left and right mandibular first premolars were not modeled because both canines required distal movement. In addition, four occlusal modes were simulated: incisal clench (INC), intercuspal position (ICP), right unilateral molar clench (RMOL), and right group function (RGF). The effects of these four occlusal modes on the von Mises stress and strain of the canine PDLs and bone were analyzed. Occlusal mode strongly influenced the distribution and value of von Mises strain in the canine PDLs. The maximum von Mises strain values on the canine PDLs were 0.396, 1.811, 0.398, and 1.121 for INC, ICP, RMOL, and RGF, respectively. The four occlusal modes had smaller effects on strain distribution in the cortical bone, cancellous bone, and miniscrews. Occlusal mode strongly influenced von Mises strain on the canine PDLs when orthodontic force was applied. When an FE model is used to analyze the biomechanical behavior of orthodontic treatments, the effect of muscle forces caused by occlusion must be considered.

Background Spinal cord injury (SCI) is the most serious complication of spinal injury, often leading to severe dysfunction of the limbs below the injured segment. Conventional therapy approaches are becoming less and less effective, and gene therapy is a new research direction by now. Methods The Sprague-Dawley rats were haphazardly assigned to two groups, namely sham group and SCI model group, and lncRNA H19 and miR-370-3p levels were investigated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Correlation between lncRNA H19 and miR-370-3p was ascertained by luciferase report assay and RT-qPCR. After transfection with si-H19, miR-370-3p inhibitor, negative controls (NC), or both, primary spinal neurons were subjected to the simulation of lipopolysaccharide (LPS) for inducing in vitro model of SCI. Cell viability, apoptotic rate, caspase-3 activity, Bax and Bcl-2 protein, ROS generation, TNF-α, IL-1β, and IL-6 protein, as well as IκBα and p65 phosphorylation ratio were evaluated adopting 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), apoptosis, caspase-3 activity, ROS generation, and western blot assays, thereby searching for the specific action mechanism on LPS-induced spinal never injury. Results SCI resulted in lncRNA H19 higher expression and miR-370-3p lower expression. LPS simulation raised a series of cellular biological changes, such as decreased viability, promoted apoptosis, generated ROS, and released inflammatory factors. lncRNA H19 inhibition reversed above LPS-induced changes. Besides, as the downstream target of lncRNA H19, miR-370-3p was oppositely regulated by lncRNA H19. The above biological changes induced by lncRNA H19 inhibition were reversed by miR-370-3p upregulation. Moreover, lncRNA H19 inhibition could block NF-κB pathway through miR-370-3p upregulation. Conclusion Inhibition of lncRNA H19/miR-370-3p mitigated spinal neuron apoptosis in an in vitro model of SCI. This provided the possibility for clinical use of gene therapy.

What is already known? ### What this study adds? Traumatic brain injury (TBI) in children is the leading cause of disability and is associated with a significant burden of disease globally.1 Population-based studies reporting the incidence of TBI in Australia have focused on hospitalised patients.2 Most paediatric head trauma results in mild TBIs that do not require hospitalisation.1 In Australia, a 13% increase in emergency department (ED) presentations for paediatric head injuries were reported between 2014 and 2018.3 The most common mechanisms of head injuries are falls for children less than 11 years and transportation-related injuries for children 11 to 16 years.2 While falls are the most common mechanism of head injury in children and can be associated with the most long-term costs, transportation-related TBIs incur high acute care costs, with pedestrian injuries having the highest mean per-patient cost.2 3 This research estimates the effect of mechanisms of injury and severity on the acute care costs of TBI in children. A planned subanalysis of children

BackgroundInflammation might play a role in bipolar disorder (BD), but it remains unclear the relationship between inflammation and brain structural and functional abnormalities in patients with BD. In this study, we focused on the alterations of functional connectivity (FC), peripheral pro-inflammatory cytokines and their correlations to investigate the role of inflammation in FC in BD depression.MethodsIn this study, 42 unmedicated patients with BD II depression and 62 healthy controls (HCs) were enrolled. Resting-state-functional magnetic resonance imaging was performed in all participants and independent component analysis was used. Serum levels of Interleukin-6 (IL-6) and Interleukin-8 (IL-8) were measured in all participants. Correlation between FC values and IL-6 and IL-8 levels in BD was calculated.ResultsCompared with the HCs, BD II patients showed decreased FC in the left orbitofrontal cortex (OFC) implicating the limbic network and the right precentral gyrus implicating the somatomotor network. BD II showed increased IL-6 (p = 0.039), IL-8 (p = 0.002) levels. Moreover, abnormal FC in the right precentral gyrus were inversely correlated with the IL-8 (r = −0.458, p = 0.004) levels in BD II. No significant correlation was found between FC in the left OFC and cytokines levels.ConclusionsOur findings that serum IL-8 levels are associated with impaired FC in the right precentral gyrus in BD II patients suggest that inflammation might play a crucial role in brain functional abnormalities in BD.

Background Bronchiolitis is a clinical syndrome commonly encountered in practice, particularly among infants and young children. To investigate the prevalence of pathogens in hospitalized children with bronchiolitis and study the clinical characteristics of bronchiolitis with or without coinfections. Methods We investigated the respiratory specimens and clinical data of 1012 children with bronchiolitis who were treated at the Children’s Hospital of Soochow University between November 2011 and December 2018. The nasopharyngeal aspirates were examined to detect viruses by direct immunofluorescence assay or polymerase chain reaction (PCR). Mycoplasma pneumoniae (MP) was tested by PCR and enzyme-linked immunosorbent assay. Results Of the 1134 children less than 2 years with bronchiolitis, 122 were excluded by exclusion criteria. Causative pathogen was detected in 83.2% (842 of 1012). The majority of these (614 [72.9%] of 842) were single virus infection. The most common pathogens detected were respiratory syncytial virus (RSV) (44.4%), MP (15.6%), and human rhinovirus (HRV) (14.4%). Coinfection was identified in 13.5% (137 of 1012) of the patients. Coinfection included mixed virus infection and virus infection with MP infection. Children with single virus infection had a higher rate of oxygen therapy compared with single MP infection. Conclusions The most common pathogen detected in children with bronchiolitis is RSV, followed by MP and HRV. Coinfection leads to a longer period of illness, increased severity of the symptoms and increased risk of hypoxemia.

Background and Aims Emerging evidence points to a link between creeping fat and the pathogenesis of Crohn’s disease [CD]. Non-invasive assessment of the severity of creeping fat on cross-sectional imaging modality has seldom been investigated. This study aimed to develop and characterize a novel mesenteric creeping fat index [MCFI] based on computed tomography [CT] in CD patients. Methods MCFI was developed based on vascular findings on CT in a retrospective cohort [n = 91] and validated in a prospective cohort [n = 30]. The severity of creeping fat was graded based on the extent to which mesenteric fat extended around the intestinal circumference using the vessels in the fat as a marker. The accuracy of MCFI was assessed by comparing it with the degree of creeping fat observed in surgical specimens. The relationship between MCFI and fibrostenosis was characterized by determining if these correlated. The accuracy of MCFI was compared with other radiographic indices [i.e. visceral to subcutaneous fat area ratio and fibrofatty proliferation score]. Results In the retrospective cohort, MCFI had moderate accuracy in differentiating moderate–severe from mild fibrostenosis (area under the receiver operating characteristic [ROC] curve [AUC] = 0.799; p = 0.000). ROC analysis in the retrospective cohort identified a threshold MCFI of > 3 which accurately differentiated fibrostenosis severity in the prospective cohort [AUC = 0.756; p = 0.018]. An excellent correlation was shown between MCFI and the extent of fat wrapping in specimens in the prospective cohort [r = 0.840, p = 0.000]. Neither visceral to subcutaneous fat area ratio nor fibrofatty proliferation score correlated well with the degree of intestinal fibrosis. Conclusions MCFI can accurately characterize the extent of mesenteric fat wrapping in surgical specimens. It may become another non-invasive measure of CD fibrostenosis.

Background Children and older adults with coronavirus disease 2019 (COVID-19) display a distinct spectrum of disease severity yet the risk factors aren’t well understood. We sought to examine the expression pattern of angiotensin-converting enzyme 2 (ACE2), the cell-entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the role of lung progenitor cells in children and older patients. Methods We retrospectively analyzed clinical features in a cohort of 299 patients with COVID-19. The expression and distribution of ACE2 and lung progenitor cells were systematically examined using a combination of public single-cell RNA-seq data sets, lung biopsies, and ex vivo infection of lung tissues with SARS-CoV-2 pseudovirus in children and older adults. We also followed up patients who had recovered from COVID-19. Results Compared with children, older patients (>50 years.) were more likely to develop into serious pneumonia with reduced lymphocytes and aberrant inflammatory response (P = .001). The expression level of ACE2 and lung progenitor cell markers were generally decreased in older patients. Notably, ACE2 positive cells were mainly distributed in the alveolar region, including SFTPC positive cells, but rarely in airway regions in the older adults (P < .01). The follow-up of discharged patients revealed a prolonged recovery from pneumonia in the older (P < .025). Conclusions Compared to children, ACE2 positive cells are generally decreased in older adults and mainly presented in the lower pulmonary tract. The lung progenitor cells are also decreased. These risk factors may impact disease severity and recovery from pneumonia caused by SARS-Cov-2 infection in older patients.

Rituximab is a mouse and human chimeric CD20 (anti-B cell) specific monoclonal antibody that has been approved by the U.S. Food and Drug Administration for the treatment of lymphoma. The expression of CD20 antigen is expressed in the whole ontogeny of B cells, starting from the premature B cells in bone marrow to the differentiation of plasma cells in secondary lymphoid tissues. The wide distribution of CD20 molecules allows rituximab to eliminate a large number of B cells. Rituximab is the core drug for the treatment of hematological diseases, often combined with drugs as a first-line treatment. Long-term hormone therapy often results in serious adverse reactions, and new therapies, which can avoid widespread immunotoxicity, have great potential for treating diseases of the blood system.

Background: Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies in the world. High cholesterol intake may have a certain association with an elevated risk of PC, though dyslipidemia in PC patients has rarely been reported. In this study, we compared serum lipids levels between PC and non-PC tumor patients and assessed their prognostic value in PC. Methods: 271 patients treated at Wuhan Union Hospital from January 2012 to December 2016 and 204 individuals at Shanghai General Hospital from January 2018 to December 2019 were recruited. Their demographic parameters, laboratory data, pathological information, and clinical outcomes were extracted and analyzed. The mRNA expressions of related lipoprotein, low density lipoprotein receptor (LDLR) and high density lipoprotein binding protein (HDLBP), in PC tissues and paired noncancerous tissues and follow-up information were assessed based on the GEO database (GSE15471 and GSE62165) and TCGA database. Results: A total of 172 non-PC tumor patients and 260 PC patients were finally eligible for our analysis. PC patients exhibited higher levels of serum triglyceride, cholesterol, and low-density lipoprotein (LDL) and a lower serum high-density lipoprotein (HDL) level on admission versus the non-PC tumor group. In PC patients, LDLR mRNA expression was upregulated, and HDLBP mRNA expression was downregulated in cancerous tissues compared to these levels in paired noncancerous tissues. The survival analysis revealed that dyslipidemia had a non-significant association with a poor prognosis, but PC patients with a high LDLR level were at risk of poor survival. Conclusion: Dyslipidemia is detected in PC patients but has a non-significant relation to PC prognosis. However, LDLR may be a potential predictive marker for PC prognosis.

Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo, and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.

Objective Drug-induced acute interstitial nephritis (DAIN) is often associated with improved outcomes, whereas some patients may still progress to chronic kidney disease (CKD). The aim of this study was to evaluate the prognosis of patients with severe DAIN requiring renal replacement therapy (RRT) at baseline, and to explore the risk factors of progression to CKD. Methods We performed a retrospective study of patients with severe DAIN confirmed by renal biopsies in our center over a 10 years period, all the patients received RRT at presentation. The clinical and pathological characteristics at baseline were recorded, and the outcomes (renal function recovered or progressed to CKD) during follow-ups were also evaluated. Univariate and multivariate logistic regression analysis were performed to identify the independent risk factors of progression to CKD. Results Seventy-two patients who met the inclusion criteria were enrolled, 13 patients (18.0%) progressed to CKD (GFR < 60 ml/min/1.73 m2) after at least 6 months of follow-up, the remaining 59 patients achieved a favorable renal function recovery. Compared with patients who achieved renal function recovery (recovery group), the patients progressed to CKD (progression group) were older and had longer interval from symptom onset to treatment with steroids. The peak serum cystatin C concentration was higher in progression group than recovery group. Higher score of interstitial fibrosis/tubular atrophy (IFTA) and more interstitial inflammatory cells infiltration were detected in renal tissue in progression group. According to multivariable analysis, higher peak cystatin C concentration (OR = 2.443, 95% CI 1.257, 4.746, p = 0.008), longer interval to treatment with corticosteroids (OR = 1.183, 95% CI 1.035, 1.352, p = 0.014) were independent risk factors of progression to CKD. The cutoff value of cystatin C concentration was 4.34 mg/L, at which the sensitivity and specificity were 76.9% and 89.3%, respectively; the cutoff value of interval to treatment with corticosteroids was 22.5 days, at which the sensitivity and specificity were 81.8% and 79.5%, respectively. Conclusion Renal function was reversible in majority of patients with severe DAIN requiring RRT when early identification and treatment. Higher peak cystatin C concentration and longer interval to treatment with corticosteroids associated with worse renal prognosis.

Extensive studies have explored the involvements of long noncoding RNAs (lncRNAs) in liver cancer. Limitedly, the concrete function of lncRNA small nucleolar RNA host gene 15 (SNHG15) is still elusive. Therefore, the work was initiated to unearth SNHG15-oriented mechanism in liver cancer. Liver cancer tissues were resected. The connection between SNHG15 expression with prognosis and clinicopathological traits of liver cancer patients was evaluated. Liver cancer cells SMMC-7721 were transfected with restored microRNA (miR)-18b-5p or depleted SNHG15 to discover their effects on the proliferation, migration, invasion, cycle arrest, and apoptosis of SMMC-7721 cells. The transfected SMMC-7721 cells were injected into nude mice for further investigation. SNHG15, miR-18b-5p, and LIM-only 4 (LMO4) expressions in tissues and cells were tested. The regulatory connections among SNHG15, miR-18b-5p, and LMO4 were detected. SNHG15 and LMO4 were overexpressed while miR-18b-5p was downregulated in liver cancer tissues and cells. Up-regulated SNHG15 was connected with inferior prognosis and aggressive behaviors of liver cancer patients. SNHG15 knockdown or miR-18b-5p restoration depressed SMMC-7721 cell growth in vivo and in vitro. SNHG15 bound to miR-18b-5p and miR-18b-5p targeted LMO4. The work has illuminated that silencing SNHG15 represses liver cancer progression by modulating miR-18b-5p and LMO4, indicating the therapeutic potency of SNHG15/miR-18b-5p/LMO4 axis in liver cancer.

Summary Genital cytomegalovirus (CMV) reactivation is common during the third trimester of pregnancy. We hypothesized that cervical CMV shedding may increase risk of spontaneous preterm birth (sPTB) through the release of inflammatory cytokines in the cervix. We conducted a nested case–control analysis to determine the relationship between CMV shedding and sPTB using data and samples from a prospective cohort study in western Kenya. Women who delivered between 28 + 0 and 33 + 6 weeks gestation were matched by gestational age at sample collection to controls who delivered ≥ 37 + 0 weeks. Levels of CMV DNA and interleukin (IL)-1 beta (β), IL-6, IL-8 and tumor necrosis factor (TNF)-α were measured in cervical swabs. We used conditional logistic regression to assess relationships between CMV shedding, cervical cytokine levels and sPTB. Among 86 cases and 86 matched controls, cervical CMV levels were not significantly associated with sPTB [odds ratio (OR) = 1·23, 95% confidence interval (CI) = 0·59–2·56], but were significantly associated with higher levels of cervical IL-6 (β = 0·15, 95% CI = 0·02–0·29) and TNF-α (β = 0·14, 95% CI = 0·01–0·27). In univariate analysis, higher odds of sPTB was associated with higher cervical IL-6 levels (OR = 1·54, 95% CI = 1·00–2·38), but not with other cervical cytokines. In this cohort of Kenyan women, we did not find a significant association between cervical CMV shedding and sPTB before 34 weeks.

Abnormal expression of HMGB1 is closely related to non-small cell lung cancer (NSCLC). miR-1305 regulates HMGB1 level by MiRDB analysis. Therefore, we investigated whether miR-1305 affects NSCLC cell proliferation and apoptosis by regulating HMGB1. The control group (NC group), miR-1305 Mimics group and miR-1305 Mimics+pcDNA-HMGB1 group were set followed by analysis of miR-1305 and HMGB1 mRNA level real time-PCR, relationship between miR-1305 and HMGB1 by dual fluorescein reporter assay, HMGB1 and Tubulin level by Western blot, cell proliferation by clone formation assay, cell apoptosis by Annexin V-FITC/PI staining. Compared with normal tissues, miR-1305 was significantly downregulated in NSCLC tissues (P P P P

Background: Some children hospitalized due to severe community-acquired pneumonia (CAP) require to the pediatric intensive care unit (PICU) because of severe complications. The purpose of this study was to identify the risk factors for mortality in this patient population. Methods: This study evaluated the medical records of 113 hospitalized children with severe CAP, who were transferred to the PICU within 48 h of admission at the Guangzhou Women and Children's Medical Center between 2013 and 2017. Results: The study group consisted of 87 boys (77%) and 26 girls (33%), aged between 1 month and 9 years; 72.6% (82/113) of patients were aged 3 on admission, not receiving corticosteroid therapy prior to admission, the need for mechanical ventilation, septic shock, multi-organ dysfunction (MODS), and acute renal failure (ARF) occurring prior to transfer to the PICU, increased alanine aminotransferase (ALT) and aspartate transaminase (AST) levels, and decreased hemoglobin and albumin (ALB) levels were associated with mortality (P

Background Sepsis in children is one of the main causes of death in pediatric intensive care units (PICUs); however, the pathogenesis of sepsis is not fully clear. Previous studies revealed that many genetic variations were related to sepsis susceptibility. A long non-coding RNA SOX2 overlapping transcript (SOX2OT) may play a role in mitochondrial homeostasis and antioxidative activity, but the relationship between the lncRNA SOX2OT polymorphism and sepsis susceptibility has not been reported. Methods In this study, 474 pediatric sepsis patients and 678 healthy controls were recruited from southern China. After genotyping, the strength of the associations was evaluated through odds ratios (ORs) and 95% confidence intervals (CIs). Results The SOX2OT rs9839776 T allele was associated with decreased susceptibility to sepsis in southern Chinese children (TT/CT vs CC adjusted OR = 0.778, 95% CI = 0.610-0.992; P = 0.0431). Moreover, the difference in susceptibility was greater in children of age >60 months (adjusted OR = 0.458, 95% CI = 0.234-0.896; P = 0.0225), survivors (adjusted OR = 0.758, 95% CI = 0.585-0.972; P = 0.0358), males (adjusted OR = 0.655, 95% CI = 0.479-0.894; P = 0.0077) and the sepsis subgroup (adjusted OR = 0.548, 95% CI = 0.343-0.876; P = 0.0120). Conclusion The rs9839776 T allele may contribute to decreased sepsis risk in Chinese children. Future studies with a larger sample size are needed to verify these results.

Our study was designed to investigate premaxillary–maxillary suture growth in fetuses from the first trimester of pregnancy using the B‑ultrasound technique in order to determine the suture fusion time. We selected 169 healthy Han singleton pregnancies as subjects. All subjects received routine pregnancy tests and were divided into three groups based on the gestational age of the fetus: group 1, the 11th gestational week; group 2, the 12th gestational week; and group 3, the 13th gestational week. Fetal biometric measurements were recorded during consecutive prenatal ultrasonographic examinations. These measurements included nuchal translucency thickness, crown–rump length, and premaxillary–maxillary length. Intergroup comparisons were performed using analysis of variance (ANOVA). The premaxillary–maxillary suture grows gradually and its measured length at the 11th, 12th and 13th week was 0.54 cm, 0.65 cm, and 0.74 cm, respectively. We observed a significant linear correlation between the premaxillary–maxillary length and the week of gestation in the first trimester. The growth rate of the maxilla at the 11th, the 12th and the 13th week are significantly different with a descending order of growth rates being week 12, week 11 and week 13, with the 12th week rate being the most rapid. The premaxillary and maxillary growth at 11 and 12 gestational weeks in the first trimester steadily accelerated, peaking at the 12th week. The rate of growth slows down after week 12 which may be associated with the fusion of the premaxillary–maxillary suture.

To evaluate the diagnostic value of serum Brain-derived neurotrophic factor (BDNF) levels for discriminating PD with depression from without depression, and to investigate whether serum BDNF levels were associated with motor severity and gender in depressed PD patients. Demographic and clinical data were collected from 122 PD patients with depression, 137 without depression and 110 healthy controls. All participants’ serum BDNF concentrations were measured. Their motor abilities and activity were assessed by the Unified PD Rating Scale Part III (UPDRS III) score and the Hoehn and Yahr (H–Y) stage. Depression was scored using the 17-item Hamilton Rating Scale for Depression (HAMD-17). Associations were analyzed with multivariate regression. The serum BDNF levels were lower in depressed PD patients compared to non-depressed PD patients and controls (p

Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of α-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson’s disease. The purpose of this study was therefore to establish an α-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed α-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the α-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined α-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel α-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson’s disease in this animal model.

Identifying determinants of human immunodeficiency virus (HIV) reservoir levels may inform novel viral eradication strategies. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) coinfections were assessed as predictors of HIV proviral DNA level in 26 HIV RNA–suppressed Kenyan children starting antiretroviral therapy before 7 months of age. Earlier acquisition of CMV and EBV and higher cumulative burden of systemic EBV DNA viremia were each associated with higher HIV DNA level in the reservoir after 24 months of antiretroviral therapy, independent of HIV RNA levels over time. These data suggest that delaying or containing CMV and EBV viremia may be novel strategies to limit HIV reservoir formation.

Background. Estrogen is involved in the pathophysiological process of benign prostatic hyperplasia (BPH), in which epithelial-mesenchymal transition (EMT) plays an important role. Upregulation of aquaporin (AQP) 5, which is directly activated by estrogen, has been reported to promote EMT in multiple cells. This study aimed to examine the effects of AQP5 on estrogen-induced EMT in the prostate. Methods. Normal prostate (NP) tissue samples without any histopathological changes and BPH tissue samples with pathologically confirmed hyperplasia were obtained. An EMT cell model was subsequently established by adding estradiol (E2) to RWPE-1 cells, after which AQP5 knockdown was performed. Tissue morphological and immunohistochemical features were examined using hematoxylin-eosin and immunohistochemical staining. Western blot analysis was performed to determine the expression of AQPs, estrogen receptors, and EMT-related proteins. Cell proliferation was assessed and supernatants were collected for enzyme-linked immunosorbent assay to determine transforming growth factor-β1 (TGF-β1) concentrations. Immunofluorescence staining was performed to assess protein expressions in RWPE-1 cells. Results. BPH tissues exhibited greater EMT (TGF-β1: 1.362 ± 0.196 vs. 0.107 ± 0.067, P = 0.003; vimentin: 1.581 ± 0.508 vs. 0.221 ± 0.047, P