bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leptomeningeal Metastasis from Non–Small Cell Lung Cancer and Current Landscape of Treatments
Authors: Ozcan Gonca , Singh Meghana , Vredenburgh James J. 
Published: August 2022

Abstract
Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis (LC), is a devastating complication of metastatic cancer that occurs when neoplastic cells invade the meningeal space. Diagnosis of LM remains challenging given the heterogeneous signs and symptoms at presentation and requires thorough neurological examination, cerebrospinal fluid (CSF) analysis, and MRI of the brain and spine with gadolinium. Detecting neoplastic cells in the CSF is the gold standard for diagnosing leptomeningeal metastases; however, it has low sensitivity and may require multiple CSF samples. New emerging technologies, such as liquid biopsy of CSF, have increased sensitivity and specificity for detecting circulating tumor cells in CSF. The management of LM in patients with NSCLC requires an individualized multidisciplinary approach. Treatment options include surgery for ventricular shunt placement, radiation therapy to bulky or symptomatic disease sites, systemic or intrathecal chemotherapy, molecularly targeted agents, and, more recently, immunotherapy. Targeting actionable mutations in LM from NSCLC, such as EGFR tyrosine kinase inhibitors or anaplastic lymphoma kinase gene rearrangement inhibitors, has shown encouraging results in terms of disease control and survival. Although there are limited data regarding the use of immunotherapy in LM, immunotherapy has produced promising results in several case reports. In this review, we focused on the epidemiology, pathophysiology, clinical presentation, diagnosis, and current treatment strategies, with a special emphasis on novel agents, including targeted therapies and immunotherapy of LM in patients with NSCLC.
Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus–Driven Cancers
Authors: Ghosh Soma , Mazumdar Tuhina , Xu Wei , Powell Reid T. , Stephan Clifford , Shen Li , Shah Pooja A. , Pickering Curtis R. , Myers Jeffery N. , Wang Jing , Frederick Mitchell J. , Johnson Faye M. 
Published: August 2022

Abstract

Purpose:
Human papillomavirus (HPV) causes &gt;5% of cancers, but no therapies uniquely target HPV-driven cancers.

Experimental Design:
We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts. Mitotic pathway components were manipulated with drugs, knockdown, and overexpression.

Results:
Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We hypothesized that the mechanism of sensitivity involves retinoblastoma (Rb) expression because the viral oncoprotein E7 leads to Rb protein degradation, and basal Rb protein expression correlates with Aurora inhibition–induced apoptosis. Manipulating Rb directly, or by inducing E7 expression, altered cells’ sensitivity to Aurora kinase inhibitors. Rb affects expression of the mitotic checkpoint genes MAD2L1 and BUB1B, which we found to be highly expressed in HPV-positive patient tumors. Knockdown of MAD2L1 or BUB1B reduced Aurora kinase inhibition–induced apoptosis, whereas depletion of the MAD2L1 regulator TRIP13 enhanced it. TRIP13 is a potentially druggable AAA-ATPase. Combining Aurora kinase inhibition with TRIP13 depletion led to extensive apoptosis in HPV-positive cancer cells but not in HPV-negative cancer cells.

Conclusions:
Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of Rb. Because it does not affect cells with intact Rb function, this novel combination may have a wide therapeutic window, enabling the effective treatment of Rb-deficient cancers.
Associations Between Adherence to Evidence-Based, Stroke Quality Indicators and Outcomes of Acute Reperfusion Therapy
Authors: Ren Nice , Ogata Soshiro , Kiyoshige Eri , Nishimura Kunihiro , Nishimura Ataru , Matsuo Ryu , Kitazono Takanari , Higashi Takahiro , Ogasawara Kuniaki , Iihara Koji ,   on behalf of Close The Gap-Stroke, J-ASPECT Study Collaborators*
Published: August 2022

Background:
Quality indicators (QIs) are an accepted tool for measuring a hospital’s performance in routine care. We examined national trends in adherence to the QIs developed by the Close The Gap-Stroke program by combining data from the health insurance claims database and electronic medical records, and the association between adherence to these QIs and early outcomes in patients with acute ischemic stroke in Japan.

Methods:
In the present study, patients with acute ischemic stroke who received acute reperfusion therapy in 351 Close The Gap-Stroke-participating hospitals were analyzed retrospectively. The primary outcomes were changes in trends for adherence to the defined QIs by difference-in-difference analysis and the effects of adherence to distinct QIs on in-hospital outcomes at the individual level. A mixed logistic regression model was adjusted for patient and hospital characteristics (eg, age, sex, number of beds) and hospital units as random effects.

Results:
Between 2013 and 2017, 21 651 patients (median age, 77 years; 43.0% female) were assessed. Of the 25 defined measures, marked and sustainable improvement in the adherence rates was observed for door-to-needle time, door-to-puncture time, proper use of endovascular thrombectomy, and successful revascularization. The in-hospital mortality rate was 11.6%. Adherence to 14 QIs lowered the odds of in-hospital mortality (odds ratio [95% CI], door-to-needle <60 min, 0.80 [0.69–0.93], door-to-puncture <90 min, 0.80 [0.67–0.96], successful revascularization, 0.40 [0.34–0.48]), and adherence to 11 QIs increased the odds of functional independence (modified Rankin Scale score 0–2) at discharge.

Conclusions:
We demonstrated national marked and sustainable improvement in adherence to door-to-needle time, door-to-puncture time, and successful reperfusion from 2013 to 2017 in Japan in patients with acute ischemic stroke. Adhering to the key QIs substantially affected in-hospital outcomes, underlining the importance of monitoring the quality of care using evidence-based QIs and the nationwide Close The Gap-Stroke program.
Cardiometabolic Disease Results in Sex‐ and Age‐Dependent Cerebrovascular Degeneration and Arteriolar Morphological Changes
Authors: Jestus Jack , Kondrasov Sasha , Yager Brock , McMullen Nate , Contillo Nicholas , Ryalat Fatima , Xiang Zhidan , Diz Debra I. , Wolfe Stacey Q. 
Published: August 2022

ABSTRACT
In the past 20 years, no drug therapies have been successfully translated into human use for intracerebral hemorrhage (ICH), the most devastating stroke subset. One likely factor is lack of effective animal models of human disease including common comorbidities, such as hypertension and diabetes. We evaluated the cardiometabolic rodent model, (mRen2)27, where overexpression of Ren2 results in extreme hypertension, glucose intolerance and obesity, as an appropriate ICH model. Methods: Sprague Dawley (SD) and (mRen2)27 rats were sacrificed at 14‐, 32‐, and 52‐weeks. Brains were sectioned sagittally at 5 μm. Whole‐brain sections were stained using Hematoxylin & Eosin (H&E) and Van Geison (VG) collagen staining to visualize the pial blood vessels. Wall‐to‐lumen ratios for vessels were calculated and compared using a student t‐test to determine significance. Results: There was no significant difference in arteriolar morphology at 14‐weeks between male SD and mRen animals (SD, n=16 and mRen, n=16). At 32‐weeks, there was a significant difference in mRen male rats (SD, n=13 and mRen, n=17; p<0.0001), with significantly increased wall thickness and decreased Lumen size in the mRen animals (increased W:L ratio). However, at this timeframe, there was no significant difference between the female SD and mRen cohorts (SD, n=6 and mRen, n=8). At 52‐weeks, there was a significant increase in W:L ratios in both male (SD, n=4 and mRen, n=7; p<0.01) and female (SD, n=9 and mRen, n=8; p<0.05) mRen animals compared to control. Conclusion: The (mRen2)27 cardiometabolic animal model demonstrates age‐related sex changes in the wall:lumen ratio of cerebral vasculature consistent with cerebrovascular disease seen in ischemic and hemorrhagic stroke patients. Males develop these vascular changes earlier than females, but both sexes in this model develop cerebral vascular changes by 1 year of age. The (mRen2)27 model appears to recapitulate human disease and sex differences, and may serve as an appropriate translational model of ICH.
Imaging Indicators for Parenchymal Hemorrhage After Mechanical Thrombectomy in Acute Stroke
Authors: Kimura Ryutaro , Shoda Sotaro , Saito Tomonari , Suzuki Kentaro , Kutsuna Akihito , Kanamaru Takuya , Katano Takehiro , Nakagami Toru , Numao Shinichiro , Suda Satoshi , Nishiyama Yasuhiro , Kimura Kazumi 
Published: August 2022

Background
In patients with acute ischemic stroke with large vessel occlusion, the presence of hyperintense lesions on fluid‐attenuated inversion recovery (FLAIR‐positive) before mechanical thrombectomy (MT) and that of hyperdense lesions on noncontrast computed tomography (CT‐positive) after MT are associated with parenchymal hemorrhage, but the significance of these findings is unclear.

Methods
Patients with acute stroke with large vessel occlusion underwent magnetic resonance imaging, including diffusion‐weighted imaging and FLAIR, before MT. Noncontrast CT was obtained within 60 minutes after MT. The occurrence of parenchymal hemorrhage type 2 (PH2) was assessed on CT within 7 days after MT. FLAIR and CT‐positive were defined as a case with hyperintense and hyperdense lesions immediately before and after MT, respectively. Clinical and imaging factors associated with PH2 were evaluated by multivariate regression analysis.

Results

Enrolled were 412 patients (median age, 76 years; men, 58.3%; median National Institutes of Health Stroke Scale score, 16). The site of occlusion was the internal carotid artery (n=122, 29.6%), M1 (n=180, 43.7%), and M2 (n=96, 23.3%). FLAIR‐positive, CT‐positive, and PH2 were found in 149 (36.2%), 223 (54.1%), and 34 patients (8.3%), respectively. PH2 was significantly more frequent in CT‐positive than CT‐negative patients (14.3% versus 1.1%;
P
<0.001), but not in FLAIR‐positive than FLAIR‐negative patients (10.7% versus 6.8%;
P
=0.193). Regardless of FLAIR status, PH2 was significantly more frequent in CT‐positive than CT‐negative patients (12.8% versus 0.8% [
P
<0.001] for FLAIR‐negative, and 16.7% versus 1.7% [
P
=0.003] for FLAIR‐positive). Multivariate regression analysis demonstrated that CT‐positive was the only independent factor associated with PH2 (odds ratio, 12.699 [95% CI, 2.964–54.416];
P
<0.001). Sensitivity, specificity, positive predictive value, and negative predictive values of CT‐positive for predicting PH2 occurrence were 94.1%, 49.5%, 14.3%, and 98.9%, respectively.

Conclusion
In patients with acute ischemic stroke with large vessel occlusion, CT‐positive immediately after MT was strongly predictive of PH2, but no such relationship was found for FLAIR‐positive before MT.
“Human vs Machine” Validation of a Deep Learning Algorithm for Pediatric Middle Ear Infection Diagnosis
Authors: Crowson Matthew G. , Bates David W. , Suresh Krish , Cohen Michael S. , Hartnick Christopher J. 
Published: August 2022

AbstractObjectiveWe compared the diagnostic performance of human clinicians with that of a neural network algorithm developed using a library of tympanic membrane images derived from children taken to the operating room with the intent of performing myringotomy and possible tube placement for recurrent acute otitis media (AOM) or otitis media with effusion (OME).Study DesignRetrospective cohort study.SettingTertiary academic medical center from 2018 to 2021.MethodsA training set of 639 images of tympanic membranes representing normal, OME, and AOM was used to train a neural network as well as a proprietary commercial image classifier from Google. Model diagnostic prediction performance in differentiating normal vs nonpurulent vs purulent effusion was scored based on classification accuracy. A web‐based survey was developed to test human clinicians’ diagnostic accuracy on a novel image set, and this was compared head to head against our model.ResultsOur model achieved a mean prediction accuracy of 80.8% (95% CI, 77.0%‐84.6%). The Google model achieved a prediction accuracy of 85.4%. In a validation survey of 39 clinicians analyzing a sample of 22 endoscopic ear images, the average diagnostic accuracy was 65.0%. On the same data set, our model achieved an accuracy of 95.5%.ConclusionOur model outperformed certain groups of human clinicians in assessing images of tympanic membranes for effusions in children. Reduced diagnostic error rates using machine learning models may have implications in reducing rates of misdiagnosis, potentially leading to fewer missed diagnoses, unnecessary antibiotic prescriptions, and surgical procedures.
Characteristics of clinical trials related to hip fractures and factors associated with completion
Authors: Wang Shengjie , Xiong Fan , Gao Yanzheng , Lei Mingxing , Zhang Xianlong 
Published: August 2022

Abstract
Background
This study aimed at investigating the characteristics of clinical trials related to hip fractures that were registered at ClinicalTrials.gov. It also aimed to identify potential risk factors associated with completion.

Main body
We obtained 733 clinical studies related to hip fractures from the ClinicalTrials.gov database and included 470 studies in the analysis. These clinical trials were divided into behavioral, drug/biological, device, procedure, and other categories based on intervention types. Clinical trials investigating drugs or biologics were categorized based on the specific agents administered in each trial. Multiple logistic and Cox regression models were used to test the ability of 24 potential risk factors in predicting recruitment status and completion time, respectively. Among the included clinical trials, 44.89% (211/470) had complete recruitment status. The overall median completion time was 931.00 days (95% confidence interval [CI]: 822.56–1039.44 days). The results of only 8.94% (42/470) of clinical trials were presented on the ClinicalTrials.gov website. Bupivacaine (a local anesthetic) was most commonly investigated (in 25 clinical trials); this was followed by ropivacaine (another local anesthetic, 23 clinical trials) and tranexamic acid (a hemostatic, 21 clinical trials). Multivariate analysis showed that trials including children (P = 0.03) and having National Institutes of Health funds (P < 0.01) had significantly higher rates of complete recruitment. Higher enrollment (P < 0.01), National Institutes of Health funding (P < 0.01), location in the United States (P = 0.04), and location in Europe (P = 0.03) predisposed to longer completion time, while studies involving drugs/biologics (P < 0.01) had shorter completion times.

Conclusions
A considerable proportion of clinical trials related to hip fractures were completed, but the results of only a small fraction were presented on the ClinicalTrials.gov website. The commonly investigated drugs focused on anesthesia, pain relief, and hemostasis. Several independent risk factors that affect recruitment status and completion time were identified. These factors may guide the design of clinical trials relating to hip fractures.
A qualitative exploration of the provision and prioritisation of smoking cessation support to patient carers in a paediatric ward in Australia
Authors: Moyo Sukoluhle , Hefler Marita , Carson-Chahhoud Kristin V. , Thomas David P 
Published: August 2022

Abstract
Background
Hospitalisation of a child is a unique opportunity for health staff to offer smoking cessation support; that is screening for carer smoking status, discussing cessation and providing interventions to carers who smoke. This has the potential to reduce the child’s exposure to second-hand smoke, and in turn tobacco related illnesses in children. However, these interventions are not always offered in paediatric wards. The aim of this study was to explore the provision and prioritisation of smoking cessation support to patient carers in a paediatric ward with a high proportion of Aboriginal patients and carers in a regional area of Australia’s Northern Territory.

Methods
This is a qualitative descriptive study of data collected through semi-structured interviews with 19 health staff. The interviews were audio recorded and transcribed verbatim. Thematic analysis was performed on the transcripts.

Results
We found low prioritisation of addressing carer smoking due to, a lack of systems and procedures to screen for smoking and provide quitting advice and unclear systems for providing more detailed cessation support to carers. Staff were demotivated by the lack of clear referral pathways. There were gaps in skills and knowledge, and health staff expressed a need for training opportunities in smoking cessation.

Conclusion
Health staff perceived they would provide more cessation support if there was a systematic approach with evidence-based resources for smoking cessation. These resources would include guidelines and clinical record systems with screening tools, clear action plans and referral pathways to guide clinical practice. Health staff requested support to identify existing training opportunities on smoking cessation.
Automated, image-based disease measurement for phenotyping resistance to soybean frogeye leaf spot
Authors: McDonald Samuel C. , Buck James , Li Zenglu 
Published: August 2022

Abstract
Background
Frogeye leaf spot is a disease of soybean, and there are limited sources of crop genetic resistance. Accurate quantification of resistance is necessary for the discovery of novel resistance sources, which can be accelerated by using a low-cost and easy-to-use image analysis system to phenotype the disease. The objective herein was to develop an automated image analysis phenotyping pipeline to measure and count frogeye leaf spot lesions on soybean leaves with high precision and resolution while ensuring data integrity.

Results
The image analysis program developed measures two traits: the percent of diseased leaf area and the number of lesions on a leaf. Percent of diseased leaf area is calculated by dividing the number of diseased pixels by the total number of leaf pixels, which are segmented through a series of color space transformations and pixel value thresholding. Lesion number is determined by counting the number of objects remaining in the image when the lesions are segmented. Automated measurement of the percent of diseased leaf area deviates from the manually measured value by less than 0.05% on average. Automatic lesion counting deviates by an average of 1.6 lesions from the manually counted value. The proposed method is highly correlated with a conventional method using a 1–5 ordinal scale based on a standard area diagram. Input image compression was optimal at a resolution of 1500 × 1000 pixels. At this resolution, the image analysis method proposed can process an image in less than 10 s and is highly concordant with uncompressed images.

Conclusion
Image analysis provides improved resolution over conventional methods of frogeye leaf spot disease phenotyping. This method can improve the precision and resolution of phenotyping frogeye leaf spot, which can be used in genetic mapping to identify QTLs for crop genetic resistance and in breeding efforts for resistance to the disease.
Therapeutic material basis and underling mechanisms of Shaoyao Decoction-exerted alleviation effects of colitis based on GPX4-regulated ferroptosis in epithelial cells
Authors: Li Juan , Tian Xiangge , Liu Jinming , Mo Yuying , Guo Xiaoyi , Qiu Yang , Liu Yuejian , Ma Xiaochi , Wang Yan , Xiong Yongjian 
Published: August 2022

AbstractBackgroundShaoyao Decoction (SYD) is a canonical herbal medicine prescription formulated by Liu Wan-Su in AD 1186. SYD has been widely used to treat inflammatory bowel disease by clearing heat and damp, removing stasis toxin in the intestine; however, the precise mechanisms and therapeutic material basis remain largely unclear. In the present study, we measured the effects of SYD on colitis symptom, epithelial barrier function, epithelial ferroptosis, colonic protein and mRNA expression of glutathione peroxidase 4 (GPX4) in colitis model, and determined whether SYD restored barrier loss in colitis by modulation of GPX4-regulated ferroptosis pathway.MethodsColitis was established by infusion with 1 mL 2,4,6-trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol (40% v/v) in rats at a 125 mg/kg dose. Ferroptosis in epithelial cells was determined by flow cytometer. GPX4 promoter-firefly luciferase fusion construct was transfected to Caco-2 cell to determine GPX4 transcription. MS analysis was used to identified ingredients in SYD.ResultsDifferent doses of SYD significantly alleviated colitis, decreased ferroptosis in epithelial cells, knockout of GPX4 significantly reversed SYD-induced alleviation effects on colitis, restoration of epithelial barrier function, and epithelial ferroptosis. Wogonoside, wogonin, palmatine, paeoniflorin and liquiritin were identified as active ingredients of SYD-exerted alleviation effects of colitis based on GPX4 agonistic transcription.ConclusionSYD alleviated chemically induced colitis by activation of GPX4, inhibition of ferroptosis in epithelial cells and further restoration of barrier function. Wogonoside, wogonin, palmatine, paeoniflorin and liquiritin were identified as the key therapeutic material basis of SYD-exerted anti-colitis effects. The findings provide a scientific basis for the therapeutic effect of SYD on colitis.
MAFLD associated with COPD via systemic inflammation independent of aging and smoking in men
Authors: Tsutsumi Tsubasa , Nakano Dan , Kawaguchi Machiko , Hashida Ryuki , Yoshinaga Shinobu , Takahashi Hirokazu , Anzai Keizo , Kawaguchi Takumi 
Published: August 2022

Abstract
Background and aim
Metabolic dysfunction and associated systemic inflammation are risk factors for chronic obstructive pulmonary disease (COPD) and COPD is highly prevalent in men. We investigated the impact of metabolic-associated fatty liver disease (MAFLD) and MAFLD-related systemic inflammation on COPD in men.

Methods
We enrolled 2,041 men with fatty liver. Patients were classified into the COPD (n = 420/2041) and non-COPD (n = 1621/2041) groups. COPD and its high-risk group were diagnosed using the Japanese Respiratory Society Disease statement. Systemic inflammation was evaluated using the C-reactive protein (CRP)/albumin ratio. Independent factors for COPD were investigated by multivariate analysis and decision-tree analysis.

Results
The prevalence of MAFLD was significantly higher in the COPD group than in the non-COPD group. In multivariable analysis, in addition to heavy smoking and aging, MAFLD was identified as an independent factor for COPD (OR 1.46, 95% CI 1.020–2.101, P = 0.0385). Decision-tree analysis showed that MAFLD, rather than heavy smoking, was the most influential classifier for COPD in non-elderly men (14% in MAFLD vs 6% in non-MAFLD groups). MAFLD was also the second most influential factor in elderly men who were not heavy smokers. In both groups, the CRP/albumin ratio was the first classifier for COPD (16% in the high CRP/albumin ratio group vs 3% in the low CRP/albumin ratio group of non-elderly men).

Conclusions
MAFLD is an independent predictor of COPD in men. MAFLD had a significant impact on COPD through systemic inflammation in men of all ages who were not heavy smokers. MAFLD may be useful to broadly identify COPD in men.