Antibiotic-resistant infections have become a public health crisis that is driven by the inappropriate use of antibiotics. In the USA, antibiotic stewardship programs (ASP) have been established and ...are required by regulatory agencies to help combat the problem of antibiotic resistance. Post-operative antibiotic use in surgical cases deemed low-risk for infection is an area with significant overuse of antibiotics in children. Consensus among leading public health organizations has led to guidelines eliminating post-operative antibiotics in low-risk surgeries. However, the best strategies to de-implement these inappropriate antibiotics in this setting are unknown.
A 3-year stepped wedge cluster randomized trial will be conducted at nine US Children's Hospitals to assess the impact of two de-implementation strategies, order set change and facilitation training, on inappropriate post-operative antibiotic prescribing in low risk (i.e., clean and clean-contaminated) surgical cases. The facilitation training will amplify order set changes and will involve a 2-day workshop with antibiotic stewardship teams. This training will be led by an implementation scientist expert (VRM) and a pediatric infectious diseases physician with antibiotic stewardship expertise (JGN). The primary clinical outcome will be the percentage of surgical cases receiving unnecessary post-operative antibiotics. Secondary clinical outcomes will include the rate of surgical site infections and the rate of Clostridioides difficile infections, a common negative consequence of antibiotic use. Monthly semi-structured interviews at each hospital will assess the implementation process of the two strategies. The primary implementation outcome is penetration, which will be defined as the number of order sets changed or developed by each hospital during the study. Additional implementation outcomes will include the ASP team members' assessment of the acceptability, appropriateness, and feasibility of each strategy while they are being implemented.
This study will provide important information on the impact of two potential strategies to de-implement unnecessary post-operative antibiotic use in children while assessing important clinical outcomes. As more unnecessary medical practices are identified, de-implementation strategies, including facilitation, need to be rigorously evaluated. Along with this study, other rigorously designed studies evaluating additional strategies are needed to further advance the burgeoning field of de-implementation.
NCT04366440. Registered April 28, 2020, https://clinicaltrials.gov/ct2/show/NCT04366440 .
News is a kind of writing style, which is so valuable that many linguists choose it to study. This thesis aims to conduct a systemic analysis of modality type, value and orientation under the ...framework of Halliday’s Systemic-functional Grammar in order to explore the interpersonal meanings of modality in English news discourse. The research data is drawn from micro-blogging official platforms, among which 20 pieces of news discourse in all are selected to establish a small type of corpus. All the 20 pieces of news discourse are taken from the micro-blogging in 1.20 to 2.20 of 2017. All the news is about “Donald Trump’s Muslim Entry Ban” (A ban made by Donald Trump, which claimed that Muslim can’t enter America). Meanwhile, both qualitative and quantitative research methods are adopted to discover the distribution of modality in micro-blogging news discourse and its interpersonal meanings, and hence to deepen people’s cognition and understanding on micro-blogging news discourse. Through a detailed analysis, the study has a lot of findings. We found that modality language is widely used in micro-blogging news. From the perspective of modality type, reporters prefer to use finite modal adjunct such as will in the type of modulation to show their emotional attitude of the target thing. From the perspective of modality value, we can see that median value is the most popular among three values for reporters, and “will” and “would” are the most popular expressions that express the speaker’s expectations, willingness and determination or the reporter’s views, attitudes on the possibility of a certain event. Meanwhile, from the perspective of modality orientation, the speaker or writer tends to use implicit objective orientation in order to show objectiveness of the news discourse and get rid of writers’ responsibilities. This paper attempts to analyze modality in micro-blogging English news discourse from the perspective of interpersonal functions which aims to provide a new method for discourse analysis and acts as a beneficial complementary to modality language analysis.
The anodic voltammetric behavior of methotrexate was studied at glassy carbon electrode in acetate buffer (pH
=
3.6) solution using cyclic, square-wave voltammetric and chronocoulometric techniques. ...The oxidation of methotrexate is an irreversible diffusion-controlled process. The oxidation mechanism was proposed and discussed in this work. The dependence of the current on pH, the concentration and nature of buffer, and instrumental parameters were investigated to optimize the experimental conditions for the determination of methotrexate. It was found that in the range of 8.0
×
10
−7–2.0
×
10
−5
mol/L, the currents measured by square-wave voltammetry presented a good linear property as a function of the concentrations of methotrexate. In addition, validation parameters, such as reproducibility, sensitivity and recovery were evaluated as well. The proposed method was also successfully applied for the determination of methotrexate in diluted human urine with good satisfactory.
Interest in understanding the roles of white matter (WM) inflammation and damage in the pathophysiology of Alzheimer disease (AD) has been growing significantly in recent years. However, in vivo ...magnetic resonance imaging (MRI) techniques for imaging inflammation are still lacking. An advanced diffusion-based MRI method, neuro-inflammation imaging (NII), has been developed to clinically image and quantify WM inflammation and damage in AD. Here, we employed NII measures in conjunction with cerebrospinal fluid (CSF) biomarker classification (for β-amyloid (Aβ) and neurodegeneration) to evaluate 200 participants in an ongoing study of memory and aging. Elevated NII-derived cellular diffusivity was observed in both preclinical and early symptomatic phases of AD, while disruption of WM integrity, as detected by decreased fractional anisotropy (FA) and increased radial diffusivity (RD), was only observed in the symptomatic phase of AD. This may suggest that WM inflammation occurs earlier than WM damage following abnormal Aβ accumulation in AD. The negative correlation between NII-derived cellular diffusivity and CSF Aβ
level (a marker of amyloidosis) may indicate that WM inflammation is associated with increasing Aβ burden. NII-derived FA also negatively correlated with CSF t-tau level (a marker of neurodegeneration), suggesting that disruption of WM integrity is associated with increasing neurodegeneration. Our findings demonstrated the capability of NII to simultaneously image and quantify WM cellularity changes and damage in preclinical and early symptomatic AD. NII may serve as a clinically feasible imaging tool to study the individual and composite roles of WM inflammation and damage in AD.
Background Many patients with resectable non-small cell lung cancer (NSCLC) are unfit for lobectomy owing to comorbidity. Surgical outcomes are biased by preoperative selection factors and upstaging ...that occurs during surgery. This study compares outcomes between sublobar pulmonary resection and traditional external beam radiation therapy. Methods This cohort study utilizes Surveillance, Epidemiology, and End Results–Medicare data (1998 to 2005). Patients with stage IA NSCLC treated with either radiotherapy or sublobar resection were compared. The bias of clinical staging in the radiation group versus pathologic staging in the surgical group was addressed by including only sublobar resections without lymph node sampling. Medicare claims data were used to calculate a modified Charlson comorbidity score for each patient. Results In all, 878 patients received radiotherapy and 657 underwent sublobar resection without lymph node sampling. Radiation patients were older (77.0 versus 75.5 years, p < 0.0001) and had larger tumors (22.8 versus 17.9 mm, p < 0.0001). There was no difference in comorbidity scores between groups ( p = 0.21). Three-year overall survival favored sublobar resection (56% versus 35%; p < 0.0001). Predictors of earlier death were radiation, age, comorbidity score, tumor size, male sex, and prior malignancy (all p < 0.05). Propensity analysis matched 319 radiation patients and 319 sublobar resection patients. In this subgroup, 3-year overall survival favored sublobar resection (52% versus 41%; p < 0.001). Conclusions Sublobar resection without lymph node sampling appears to be superior to radiotherapy for clinical stage IA NSCLC. For patients with prohibitive risk for lobectomy, sublobar resection may be preferable to radiotherapy. Radiotherapy results in current and future patients are likely to be better.
Background p38-Alpha mitogen-activated protein kinase (p38-MAPK) is a tumor suppressor often mutated in human cancers, but its specific role in colorectal cancer is not completely understood. ...Previous studies have found that p38-MAPK activity inhibits epithelial proliferation and promotes apoptosis in the intestine. Therefore, we sought to test the hypothesis that intestinal disruption of p38-MAPK would lead to increased tumorigenesis in the colon. Methods p38-MAPK was deleted in mice within the intestinal epithelium using a tamoxifen-inducible Cre system under control of the villin promoter villin-Cre ERT2(+), MAPK14(f/f) . An azoxymethane and dextran sodium sulfate protocol was used to drive intestinal tumor development. Tumor measurements were made using computer software from photographs of excised colon specimens. Results The number of mice that developed tumors was not statistically different when comparing wild-type mice (7/14) to inducible, intestine epithelial-deleted p38-MAPK (9/11) mice after azoxymethane/dextran sodium sulfate treatment ( P = .21). However, the epithelial-deleted p38-MAPK mice developed significantly more tumors (3.7 vs 1.1; P = .008) and nearly 4 times the total tumor burden as wild-type mice (17.4 vs 4.8 mm2 ; P = .03). Wild-type and epithelial-deleted p38-MAPK groups demonstrated a similar degree of colon inflammation. Conclusion Deletion of p38-MAPK within the colonic mucosa leads to a hyperplastic state promoting greater tumor development. Because the severity of colitis was not augmented in mice with p38-MAPK deficiency, tumor development is likely mediated by impaired cell cycle regulation within the colonic epithelium. Manipulation of p38-MAPK activity may provide a novel treatment and/or prevention strategy in the management of colorectal cancer, particularly in the setting of inflammatory bowel disease.
BackgroundVEGF, a key mediator of angiogenesis and resistance to immunotherapy, is overexpressed in head and neck squamous-cell carcinoma (HNSCC). The primary aims of this trial were to determine the ...recommended phase 2 dose (RP2D) of ramucirumab, a potent inhibitor of VEGF receptor-2, given with pembrolizumab, and the objective response rate (ORR) of this combination as first-line treatment for recurrent or metastatic (RM)-HNSCC.MethodsStudy participants provided written informed consent. Eligible patients had incurable HNSCC originating in the oral cavity, oropharynx, larynx, or hypopharynx. RM disease within 6 months of curative-intent systemic therapy and programmed death ligand (PD-L1) negative disease were permitted. In a dose de-escalation phase 1 design, patients received ramucirumab (level one: 10 mg/kg; then 8 and 6 mg/kg) and pembrolizumab (200 mg) on day 1 of each 21-day cycle until discontinuation criteria were met. Each dose level included three patients. The RP2D of ramucirumab was defined as the highest dose level at which one or fewer patients experienced a dose-limiting toxicity (DLT) during cycle one. In a Simon two-stage phase 2 design, patients with measurable, previously untreated RM-HNSCC received ramucirumab at the RP2D with pembrolizumab. Tumor response was assessed by RECIST1.1. When the trial was developed, the ORR of pembrolizumab given as first-line treatment wasn’t known; however, the ORR for platinum pre-treated disease was 13–18%. Therefore, an ORR of <13% was deemed unacceptable and an ORR of >32% was of clinical interest. In stage one, two or more responses among ten patients were required to enroll to stage two. Eight or more responses among 33 evaluable patients (those with at least one response assessment) was evidence for efficacy (80% power; one-sided α= 0.05).ResultsThree patients were treated in phase 1 and 37 in phase 2. Eleven patients (28%) had recurrent disease within 6 months of curative-intent systemic therapy. In phase 1, no DLT occurred at the starting dose of ramucirumab. Tumor response occurred in 2 of these 3 patients. In phase 2, tumor response occurred in 19 of 33 evaluable patients (ORR 57.6%, 95%CI: 39.2–74.5). Tumor response by PD-L1 CPS is shown in the table below (table 1). No unexpected safety concerns were identified.Abstract 358 Table 1ConclusionsThe RP2D of ramucirumab given with pembrolizumab was 10 mg/kg on day 1 of each 21-day cycle. The primary hypothesis was accepted: the ORR with ramucirumab and pembrolizumab was higher than expected with pembrolizumab monotherapy when given as first-line treatment for RM-HNSCC.Trial RegistrationThis trial is registered with ClinicalTrials.gov (NCT03650764).Ethics ApprovalThis study was approved by Washington University’s Ethics Board; approval number 201809094.
Primary brain tumors are composed of tumor cells, neural/glial tissues, edema, and vasculature tissue. Conventional MRI has a limited ability to evaluate heterogeneous tumor pathologies. We developed ...a novel diffusion MRI-based method-Heterogeneity Diffusion Imaging (HDI)-to simultaneously detect and characterize multiple tumor pathologies and capillary blood perfusion using a single diffusion MRI scan.
Seven adult patients with primary brain tumors underwent standard-of-care MRI protocols and HDI protocol before planned surgical resection and/or stereotactic biopsy. Twelve tumor sampling sites were identified using a neuronavigational system and recorded for imaging data quantification. Metrics from both protocols were compared between World Health Organization (WHO) II and III tumor groups. Cerebral blood volume (CBV) derived from dynamic susceptibility contrast (DSC) perfusion imaging was also compared with the HDI-derived perfusion fraction.
The conventional apparent diffusion coefficient did not identify differences between WHO II and III tumor groups. HDI-derived slow hindered diffusion fraction was significantly elevated in the WHO III group as compared with the WHO II group. There was a non-significantly increasing trend of HDI-derived tumor cellularity fraction in the WHO III group, and both HDI-derived perfusion fraction and DSC-derived CBV were found to be significantly higher in the WHO III group. Both HDI-derived perfusion fraction and slow hindered diffusion fraction strongly correlated with DSC-derived CBV. Neither HDI-derived cellularity fraction nor HDI-derived fast hindered diffusion fraction correlated with DSC-derived CBV.
Conventional apparent diffusion coefficient, which measures averaged pathology properties of brain tumors, has compromised accuracy and specificity. HDI holds great promise to accurately separate and quantify the tumor cell fraction, the tumor cell packing density, edema, and capillary blood perfusion, thereby leading to an improved microenvironment characterization of primary brain tumors. Larger studies will further establish HDI's clinical value and use for facilitating biopsy planning, treatment evaluation, and noninvasive tumor grading.
The use of biomarkers for the early detection of Alzheimer’s disease (AD) is crucial for developing potential therapeutic treatments. Positron Emission Tomography (PET) is a well-established tool ...used to detect β-amyloid (Aβ) plaques in the brain. Previous studies have shown that cross-sectional biomarkers can predict cognitive decline (Schindler et al.,2021). However, it is still unclear whether longitudinal Aβ-PET may have additional value for predicting time to cognitive impairment in AD. The current study aims to evaluate the ability of baseline- versus longitudinal rate of change in-11C-Pittsburgh compound B (PiB) Aβ-PET to predict cognitive decline. A cohort of 153 participants who previously underwent PiB-PET scans and comprehensive clinical assessments were used in this study. Our analyses revealed that baseline Aβ is significantly associated with the rate of change in cognitive composite scores, with cognition declining more rapidly when baseline PiB Aβ levels were higher. In contrast, no signification association was identified between the rate of change in PiB-PET Aβ and cognitive decline. Additionally, the ability of the rate of change in the PiB-PET measures to predict cognitive decline was significantly influenced by APOE ε4 carrier status. These results suggest that a single PiB-PET scan is sufficient to predict cognitive decline and that longitudinal measures of Aβ accumulation do not improve the prediction of cognitive decline once someone is amyloid positive.
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