Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy

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Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Contemporary Epidemiology of and Risk Factors Associated with Removal of a Pathologically Normal Appendix in Children with Suspected Appendicitis

BackgroundThe goal of this study was to characterize contemporary performance benchmarks and risk factors associated with negative appendectomy (NA) in children with suspected appendicitis.MethodsA multicenter retrospective cohort analysis of children undergoing appendectomy for suspected appendicitis was performed using data from the 2016–2021 NSQIP-Pediatric Appendectomy Targeted Public Use Files. Multivariable regression was used to evaluate the influence of year, age, sex, and WBC count on NA rate, and to generate rate estimates for NA based on different combinations of demographic characteristics and WBC profiles.Results100,322 patients were included from 140 hospitals. The overall NA rate was 2.4%, and rates decreased significantly during the study period (2016: 3.1% vs. 2021: 2.3%, p < 0.001). In adjusted analyses, the highest risk for NA was associated with a normal WBC (<9000/mm³; OR 5.31 [95% CI: 4.87–5.80]), followed by female sex (OR 1.55 [95% CI: 1.42–1.68]) and age <5 years (OR 1.64 [95% CI 1.39, 1.94]). Model-estimated risk for NA varied significantly across demographic and WBC strata, with a 14.4-fold range in rates between subgroups with the lowest and highest predicted risk (males 13–17 years with elevated WBC [1.1%] vs. females 3–4 years with normal WBC [15.8%]).ConclusionsContemporary NA rates have decreased over time, however NA risk remains high in children without a leukocytosis, particularly for girls and children <5 years of age. These data provide contemporary performance benchmarks for NA in children with suspected appendicitis and identify high-risk populations where further efforts to mitigate NA risk should be targeted.Level of EvidenceIII.     

主动脉出口血压对左心室血流特性的影响

采用Mimics对心脏进行三维重构，用3-matic进行模型优化以及模型误差分析，对左心室室壁运动做速度分布假设，基于UDF宏文件对左心室室壁运动编写程序，将血液视为非牛顿流体，采用动网格技术研究不同血压对左心室血液流动的影响。模拟发现当左心室收缩时，压力梯度明显，内部压力减小。当左心室舒张时，内部压力逐渐增高。二尖瓣口处的速率先增大后减小。血压升高，左心室内剪切应力持续增大，极易破坏红细胞结构，产生溶血现象，导致心脏功能紊乱。     

Contribution of different somatosensory afferent input to subcortical somatosensory evoked potentials in humans

ObjectivesTo investigate the subcortical somatosensory evoked potentials (SEPs) to electrical stimulation of either muscle or cutaneous afferents.MethodsSEPs were recorded in 6 patients suffering from Parkinson’s disease (PD) who underwent electrode implantation in the pedunculopontine (PPTg) nucleus area. We compared SEPs recorded from the scalp and from the intracranial electrode contacts to electrical stimuli applied to: 1) median nerve at the wrist, 2) abductor pollicis brevis motor point, and 3) distal phalanx of the thumb. Also the high-frequency oscillations (HFOs) were analysed.ResultsAfter median nerve and pure cutaneous (distant phalanx of the thumb) stimulation, a P1-N1 complex was recorded by the intracranial lead, while the scalp electrodes recorded the short-latency far-field responses (P14 and N18). On the contrary, motor point stimulation did not evoke any low-frequency component in the PPTg traces, nor the N18 potential on the scalp. HFOs were recorded to stimulation of all modalities by the PPTg electrode contacts.ConclusionsStimulus processing within the cuneate nucleus depends on modality, since only the cutaneous input activates the complex intranuclear network possibly generating the scalp N18 potential.SignificanceOur results shed light on the subcortical processing of the somatosensory input of different modalities.     

Glycaemic control for patients with severe acute brain injury: Protocol for a systematic review

Background

Hyperglycaemia is common in patients with acute brain injury admitted to an intensive care unit (ICU). Many studies have found associations between development of hyperglycaemia and increased mortality in hospitalised patients. However, the optimal target for blood glucose control is unknown. We want to conduct a systematic review with meta-analysis and trial sequential analysis to explore the beneficial and harmful effects of restrictive versus liberal glucose control on patient outcomes in adults with severe acute brain injury.

Methods

We will systematically search medical databases including CENTRAL, Embase, MEDLINE and trial registries. We will search the following websites for ongoing or unpublished trials: http://www.controlled-trials.com/ , http://www.clinicaltrials.gov/ , www.eudraCT.com , http://centerwatch.com/ , The Cochrane Library's CENTRAL, PubMed, EMBASE, Science Citation Index Expanded and CINAHL. Two authors will independently review and select trials and extract data. We will include randomised trials comparing levels of glucose control in our analyses and observational studies will be included to address potential harms. The primary outcomes are defined as all-cause mortality, functional outcome and health-related quality of life. Secondary outcomes include serious adverse events including hypoglycaemia, length of ICU stay and duration of mechanical ventilation, and explorative outcomes including intracranial pressure and infection. Trial Sequential Analysis will be used to investigate the risk of type I error due to repetitive testing and to further explore imprecision. Quality of trials will be evaluated using the Cochrane Risk of Bias tool, and quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.

Discussion

The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice.     

Midterm Outcomes of Angioplasty for Pediatric Renovascular Hypertension

PurposeTo evaluate the midterm outcomes of percutaneous transluminal renal angioplasty (PTRA) for pediatric renovascular hypertension (RVH).Materials and MethodsThe clinical data of patients who underwent PTRA for RVH in the authors’ hospital from 2012 to 2019 were retrospectively analyzed. Postprocedural blood pressure, glomerular filtration rate (GFR) of the affected kidney, restenosis, and complications were closely monitored.ResultsPTRA was performed in a total of 30 children (20 boys and 10 girls), with a mean age of 7.3 years ± 0.7 (range, 40 days to 13.9 years) and a mean weight of 25.0 kg ± 2.3 (range, 3.4–53 kg). The median follow-up period was 26.5 months (range, 1 month to 7.5 years). Technical success was achieved in 26 (86.7%) of the 30 patients. Restenosis developed in 3 patients (10.0%). Only 1 patient underwent stent implantation, and the stent fractured 8 months later, requiring further intervention. There were no other complications. In terms of clinical benefit of blood pressure control after the initial PTRA procedure, 15 patients (50%) were cured and 7 patients (23.3%) showed improvement. There was no significant difference in the etiology, lesion location, and lesion length between patients with clinical benefit and failure (P = .06, P = .202, and P = .06, respectively). GFR of the affected kidney was significantly improved from 19.9 mL/min ± 11.2 to 38.1 mL/min ± 11.9 at the 6-month follow-up after PTRA (P < .001).ConclusionsThe overall results of PTRA for pediatric RVH caused by different etiologies are promising. PTRA not only provided a clinical benefit of blood pressure control in 73.3% of the patients but also significantly improved the function of the affected kidney.