bluuebunny/crossref_metadata_2025_split huggingface dataset:
Durable responses in patients with genitourinary cancers following immune checkpoint therapy rechallenge after moderate-to-severe immune-related adverse events
Authors: Siddiqui Bilal A , Gheeya Jinesh S , Goswamy Rohit , Bathala Tharakeswara K , Surasi Devaki Shilpa , Gao Jianjun , Shah Amishi , Campbell Matthew T , Msaouel Pavlos , Goswami Sangeeta , Wang Jennifer , Zurita Amado J , Jonasch Eric , Corn Paul G , Aparicio Ana M , Siefker-Radtke Arlene O , Sharma Padmanee , Subudhi Sumit K , Tannir Nizar 
Published: July 2021

BackgroundImmune checkpoint therapy (ICT) prolongs survival in subsets of patients with cancer but can also trigger immune-related adverse events (irAEs) requiring treatment discontinuation. Recent studies have investigated safety of ICT rechallenge after irAEs, and evidence suggests that rechallenge may be associated with improved antitumor responses. However, data are limited on response duration after ICT rechallenge, particularly after severe irAEs.ObjectiveTo evaluate safety and efficacy of ICT rechallenge after moderate-to-severe irAEs in patients with renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer.MethodsIn this retrospective cohort study, medical records from September 25, 2013, to June 1, 2020, for patients with genitourinary (GU) cancers at MD Anderson Cancer Center who were rechallenged with the same or different ICT following irAEs were reviewed. Demographics, ICT exposure, irAEs (grade and treatment), ICT discontinuation or rechallenge, rates of subsequent irAEs (new or recurrent) and antitumor activity (objective response rates and response duration) were reviewed.ResultsSixty-one patients with RCC, UC, and prostate cancer were rechallenged with ICT after experiencing 105 total irAEs. Objective response rates after rechallenge, that is, upgrade in response, were 14% in RCC (4/28), 21% in UC (3/14), and 0% in prostate cancer. All seven patients who achieved upgrade in response had initial grade 2 or 3 irAEs. Responses were durable among these seven patients, with median radiographic progression-free survival not reached (range: 3.7–66.4 months) as of the March 8, 2021, data cut-off (median follow-up 40.9 months (95% CI 35.3 to 46.5)). All achieved complete response except one patient who was lost to follow-up. The rate of subsequent grade 3 or 4 irAEs after rechallenge was 30%, with no fatal irAEs. The rate of recrudescence of the same irAE was 26% (16/61). 54% of patients received corticosteroids (33/61), and 21% received targeted immunosuppression (13/61) for the initial irAEs.Conclusions and relevanceICT rechallenge after moderate-to-severe irAEs was associated with deep and durable responses in a subset of patients with RCC and UC, with acceptable safety and no fatal events. Strategies to enable ICT resumption after moderate-to-severe irAEs, such targeted immunosuppression, warrant further study.
Thromboelastography predicts dual antiplatelet therapy-related hemorrhage in patients with acute ischemic stroke
Authors: He Dan , Guo Yinping , Zhang Yi , Zhao Jing , Wu Lingshan , Yu Zhiyuan , Qu Wensheng , Luo Xiang 
Published: July 2021

BackgroundStratification of the risk of hemorrhage in patients with acute ischemic stroke following dual antiplatelet therapy (DAPT) is challenging. It remains unclear whether thromboelastography (TEG) can be used to predict DAPT-related hemorrhagic events.ObjectiveThe present study aims to discover predictors for hemorrhage events after DAPT based on parameters such as TEG.MethodsA total of 859 patients with acute ischemic stroke who received DAPT were recruited consecutively. Demographic, clinical, and neuroimaging characteristics were evaluated at baseline; TEG parameters were obtained 7 days later after DAPT. Hemorrhagic events were monitored about 1 month after the stroke.ResultsOf the patients, 61 (7.1%) had hemorrhagic events. Patients in the hemorrhage group had a lower adenosine diphosphate (ADP)-induced platelet-fibrin clot maximum amplitude and a higher ADP inhibition rate (ADP%) than those in the non-hemorrhage group (p<0.05). ADP% was confirmed as an independent predictor of hemorrhagic events with an optimal cut-off point of 83.3% (area under the curve (AUC) = 0.665, 95% CI 0.573 to 0.767, p<0.01). We constructed a logistic model based on D-dimer, National Institutes of Health Stroke Scale scores, and ADP% to predict hemorrhagic events in patients with acute ischemic stroke during DAPT (AUC=0.720, 95% CI 0.625 to 0.858, p<0.01), with a sensitivity of 72.1% and a specificity of 76.5%.ConclusionsMonitoring changes of TEG parameters helps to guide personalized DAPT for patients with ischemic stroke. A 30–82.3% range of ADP% is recommended for DAPT treatment.
'Drip-and-ship' intravenous thrombolysis and outcomes for large vessel occlusion thrombectomy candidates in a hub-and-spoke telestroke model
Authors: Regenhardt Robert W , Rosenthal Joseph A , Awad Amine , Martinez-Gutierrez Juan Carlos , Nolan Neal M , McIntyre Joyce A , Whitney Cynthia , Alotaibi Naif M , Dmytriw Adam A , Vranic Justin E , Stapleton Christopher J , Patel Aman B , Rost Natalia S , Schwamm Lee H , Leslie-Mazwi Thabele M 
Published: July 2021

BackgroundRandomized trials have not demonstrated benefit from intravenous thrombolysis among patients undergoing endovascular thrombectomy (EVT). However, these trials included primarily patients presenting directly to an EVT capable hub center. We sought to study outcomes for EVT candidates who presented to spoke hospitals and were subsequently transferred for EVT consideration, comparing those administered alteplase at spokes (i.e., ‘drip-and-ship’ model) versus those not.MethodsConsecutive EVT candidates presenting to 25 spokes from 2018 to 2020 with pre-transfer CT angiography defined emergent large vessel occlusion and Alberta Stroke Program CT score ≥6 were identified from a prospectively maintained Telestroke database. Outcomes of interest included adequate reperfusion (Thrombolysis in Cerebral Infarction (TICI) 2b–3), intracerebral hemorrhage (ICH), discharge functional independence (modified Rankin Scale (mRS) ≤2), and 90 day functional independence.ResultsAmong 258 patients, median age was 70 years (IQR 60–81), median National Institutes of Health Stroke Scale (NIHSS) score was 13 (6-19), and 50% were women. Ninety-eight (38%) were treated with alteplase at spokes and 113 (44%) underwent EVT at the hub. Spoke alteplase use independently increased the odds of discharge mRS ≤2 (adjusted OR 2.43, 95% CI 1.08 to 5.46, p=0.03) and 90 day mRS ≤2 (adjusted OR 3.45, 95% CI 1.65 to 7.22, p=0.001), even when controlling for last known well, NIHSS, and EVT; it was not associated with an increased risk of ICH (OR 1.04, 95% CI 0.39 to 2.78, p=0.94), and there was a trend toward association with greater TICI 2b–3 (OR 3.59, 95% CI 0.94 to 13.70, p=0.06).ConclusionsIntravenous alteplase at spoke hospitals may improve discharge and 90 day mRS and should not be withheld from EVT eligible patients who first present at alteplase capable spoke hospitals that do not perform EVT. Additional studies are warranted to confirm and further explore these benefits.
Was the implementation of standardised tobacco packaging legislation in England associated with changes in smoking prevalence? A segmented regression analysis between 2006 and 2019
Authors: Opazo Breton Magdalena , Britton John , Brown Jamie , Beard Emma , Bogdanovica Ilze 
Published: July 2021

Background and aimIn 2016, England initiated the implementation of standardised tobacco packaging, introduced in conjunction with minimum pack sizes and other measures included in the 2014 European Tobacco Products Directive, over the course of a 1-year sell-off period ending in May 2017. These measures have been shown to have been associated with increases in tobacco prices and product diversity. We now investigate the association between implementation of the new legislation and smoking status in England.DesignSegmented regression analysis of repeated cross-sectional surveys using a generalised linear model with individual-level data to test for a change in trend and immediate step change.SettingEngland.ParticipantsParticipants in the Smoking Toolkit Study, which involves repeated, cross‐sectional household surveys of individuals aged 16 years and older in England. The sample included 278 219 individual observations collected between November 2006 and December 2019.InterventionImplementation of standardised packaging legislation (May 2016 and May 2017).MeasurementsIndividual-level current smoking status adjusted for implementation of tobacco control policies, cigarette price, seasonality and autocorrelation.FindingsThe implementation of standardised packaging was associated with a significant step reduction in the odds of being a smoker after May 2017 (OR: 0.93; 95% CI 0.87 to 0.99). The magnitude of the association was similar when modelling the step change in May 2016 at the start of the 1-year policy implementation period (OR: 0.90; 95% CI: 0.83 to 0.97).ConclusionsThis is the first independent study demonstrating that implementation of standardised packaging was associated with a reduction in smoking in England which occurred in anticipation of, rather than after, full policy implementation. It appears that the odds of being a smoker were affected by the prospect of the move to standardised packs and accompanying legislation.
Where next for the design, delivery, and evaluation of community-based physical activity prescription? Emerging lessons from the United Kingdom
Authors: Oliver E.J. , Buckley B. , Dodd-Reynolds C.J. , Downey J. , Hanson C. , Henderson H. , Hawkins J. , Steele J. , Wade M. , Watson P.M. 
Published: July 2021

Despite widespread use, community-based physical activity prescription is controversial. Data limitations have resulted in a lack of clarity about what works, under what circumstances, and for whom, reflected in conservative policy recommendations. In this commentary we challenge a predominantly negative discourse, using contemporary research to highlight promising findings and “lessons learnt” for design, delivery, and evaluation. In doing so, we argue for the importance of a more nuanced approach to future commissioning and evaluation. Novelty: Amalgamating learning from multiple research teams to create recommendations for advancing physical activity prescription.
Antimicrobial and Antibiofilm Effects of Silver Nanoparticles Produced byYarrowia lipolyticaAgainst Vegetative and StarvedShigella
Authors: Chourabi Kalthoum , Elleuch Lobna , Kloula Salma , Landoulsi Ahmed , Chatti Abdelwaheb 
Published: July 2021

Silver nanoparticles have attracted much interest from scientists to develop nanosilver-based disinfectant products due to their unique properties of high antimicrobial activity. This study focused on biosynthesis, characterization, antimicrobial and antibiofilm effects of silver nanoparticles against vegetative and starved Shigella strains. The silver nanoparticles were synthesized using the yeast Yarrowia lipolytica and characterized by ultraviolet–visible spectroscopy, X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. The antimicrobial and antibiofilm activities of silver nanoparticles were tested against the growth of vegetative and starved Shigella strains. After the addition of silver nitrate solution to the supernatant of Y. lipolytica, we noticed the appearance of a brown-black coloration that suggested the formation of silver nanoparticles. The presence of silver nanoparticles was manifested by a maximum absorption in the ultraviolet–visible range, precisely at the wavelength 420[Formula: see text]nm. The crystalline nature and the stability of silver nanoparticles were confirmed, respectively, by XRD and FTIR analysis. The antibacterial activity of silver nanoparticles showed significant toxicity on Shigella strains indicating that the starved cells were more sensitive to treatment with silver nanoparticles than vegetative cells. Surprisingly, the biofilm formation had not been inhibited by silver nanoparticles for both vegetative and starved cells. In conclusion, a new class of nanosilver containing disinfectant nanoproducts will be promising for advanced environmental treatments including air disinfection, water disinfection, surface disinfection and personal hygiene that will help to prevent the further outbreak of diseases.
Location of Gastrointestinal Stromal Tumor (GIST) in the Stomach Predicts Tumor Mutation Profile and Drug Sensitivity
Authors: Sharma Ashwyn K. , de la Torre Jorge , IJzerman Nikki S. , Sutton Thomas L. , Zhao Beiqun , Khan Tahsin M. , Banerjee Sudeep , Cui Christina , Nguyen Vi , Alkhuziem Maha , Snaebjornsson Petur , van Boven Hester , Bruining Annemarie , Tang Chih-Min , Yoon Hyunho , De la Fuente Alexa , Kato Shumei , Patel Hitendra , Heinrich Michael C. , Corless Christopher L. , Horgan Santiago , Burgoyne Adam M. , Fanta Paul , Mesirov Jill P. , Blakely Andrew M. , Davis Jeremy L. , Mayo Skye C. , van Houdt Winan J. , Steeghs Neeltje , Sicklick Jason K. 
Published: July 2021

Abstract

Purpose:
Gastrointestinal stromal tumors (GIST) commonly arise in different regions of the stomach and are driven by various mutations (most often in KIT, PDGFRA, and SDHx). We hypothesized that the anatomic location of gastric GIST is associated with unique genomic profiles and distinct driver mutations.

Experimental Design:
We compared KIT versus non-KIT status with tumor location within the National Cancer Database (NCDB) for 2,418 patients with primary gastric GIST. Additionally, we compiled an international cohort (TransAtlantic GIST Collaborative, TAGC) of 236 patients and reviewed sequencing results, cross-sectional imaging, and operative reports. Subgroup analyses were performed for tumors located proximally versus distally. Risk factors for KIT versus non-KIT tumors were identified using multivariate regression analysis. A random forest machine learning model was then developed to determine feature importance.

Results:
Within the NCDB cohort, non-KIT mutants dominated distal tumor locations (P &lt; 0.03). Proximal GIST were almost exclusively KIT mutant (96%) in the TAGC cohort, whereas 100% of PDGFRA and SDH-mutant GIST occurred in the distal stomach. On multivariate regression analysis, tumor location was associated with KIT versus non-KIT mutations. Using random forest machine learning analysis, stomach location was the most important feature for predicting mutation status.

Conclusions:
We provide the first evidence that the mutational landscape of gastric GIST is related to tumor location. Proximal gastric GIST are overwhelmingly KIT mutant, irrespective of morphology or age, whereas distal tumors display non-KIT genomic diversity. Anatomic location of gastric GIST may therefore provide immediate guidance for clinical treatment decisions and selective confirmatory genomic testing when resources are limited.
Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma
Authors: Ribas Antoni , Medina Theresa , Kirkwood John M. , Zakharia Yousef , Gonzalez Rene , Davar Diwakar , Chmielowski Bartosz , Campbell Katie M. , Bao Riyue , Kelley Heather , Morris Aaron , Mauro David , Wooldridge James E. , Luke Jason J. , Weiner George J. , Krieg Arthur M. , Milhem Mohammed M. 
Published: July 2021

AbstractPatients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti–PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10.Significance:In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response.See related commentary by Sullivan, p. 2960.This article is highlighted in the In This Issue feature, p. 2945
Intracranial Bleeding After Percutaneous Coronary Intervention: Time‐Dependent Incidence, Predictors, and Impact on Mortality
Authors: Lee Pil Hyung , Park Sojeong , Nam Hyewon , Kang Do‐Yoon , Kang Soo‐Jin , Lee Seung‐Whan , Kim Young‐Hak , Park Seong‐Wook , Lee Cheol Whan 
Published: July 2021

Background
Limited data are available on intracranial hemorrhage (ICH) in patients undergoing antithrombotic therapy after percutaneous coronary intervention (PCI).

Methods and Results

Using the Korean National Health Insurance Service database, we identified 219 274 patients without prior ICH and who underwent a first PCI procedure between 2007 and 2016 and analyzed nontraumatic ICH and all‐cause mortality. ICH after PCI occurred in 4171 patients during a median follow‐up of 5.6 years (overall incidence rate: 3.32 cases per 1000 person‐years). The incidence rate of ICH showed an early peak of 21.66 cases per 1000 person‐years within the first 30 days, followed by a sharp decrease to 3.68 cases per 1000 person‐years between 30 days and 1 year, and to <1 case per 1000 patient‐years from the second year until 10 years after PCI. The 1‐year mortality rate was 38.2% after ICH, with most deaths occurring within 30 days (n=999, mortality rate: 24.2%). No significant difference in mortality risk was observed between patients who had ICH within and after 1 year following PCI (adjusted hazard ratio, 1.04; 95% CI, 0.95–1.14;
P
=0.43). The predictors of post‐PCI ICH were age ≥75 years, hypertension, atrial fibrillation, end‐stage renal disease, history of stroke or transient ischemic attack, dementia, and use of vitamin K antagonists.

Conclusions
New ICH most frequently occurs in the early period after PCI and is associated with a high risk of early death, regardless of the occurrence time of ICH. Careful implementation of antithrombotic strategies is needed in patients at an increased risk for ICH, particularly in the peri‐PCI period.
Effect of Alteplase Use on Outcomes in Patients With Atrial Fibrillation: Analysis of the Initiation of Anticoagulation After Cardioembolic Stroke Study
Authors: Yaghi Shadi , Mistry Eva , de Havenon Adam , Leon Guerrero Christopher R. , Nouh Amre , Liberman Ava L. , Giles James , Liu Angela , Nagy Muhammad , Kaushal Ashutosh , Azher Idrees , Mac Grory Brian , Fakhri Hiba , Brown Espaillat Kiersten , Asad Syed Daniyal , Pasupuleti Hemanth , Martin Heather , Tan Jose , Veerasamy Manivannan , Esenwa Charles , Cheng Natalie , Moncrieffe Khadean , Moeini‐Naghani Iman , Siddu Mithilesh , Scher Erica , Trivedi Tushar , Wu Teddy , Khan Muhib , Keyrouz Salah , Furie Karen , Henninger Nils 
Published: July 2021

Background
Intravenous alteplase improves outcome after acute ischemic stroke without a benefit in 90‐day mortality. There are limited data on whether alteplase is associated with reduced mortality in patients with atrial fibrillation (AF)‐related ischemic stroke whose mortality rate is relatively high. We sought to determine the association of alteplase with hemorrhagic transformation and mortality in patients with AF.

Methods and Results
We retrospectively analyzed consecutive patients with acute ischemic stroke between 2015 and 2018 diagnosed with AF included in the IAC (Initiation of Anticoagulation After Cardioembolic Stroke) study, which pooled data from stroke registries at 8 comprehensive stroke centers across the United States. For our primary analysis, we included patients who did not undergo mechanical thrombectomy (MT), and secondary analyses included patients who underwent MT. We used binary logistic regression to determine whether alteplase use was associated with risk of hemorrhagic transformation and 90‐day mortality. There were 1889 patients (90.6%) who had 90‐day follow‐up data available for analyses and were included; 1367 patients (72.4%) did not receive MT, and 522 patients (27.6%) received MT. In our primary analyses we found that alteplase use was independently associated with an increased risk for hemorrhagic transformation (odds ratio [OR], 2.23; 95% CI, 1.57–3.17) but reduced risk of 90‐day mortality (OR, 0.58; 95% CI, 0.39–0.87). Among patients undergoing MT, alteplase use was not associated with a significant reduction in 90‐day mortality (OR, 0.68; 95% CI, 0.45–1.04).

Conclusions
Alteplase reduced 90‐day mortality of patients with acute ischemic stroke with AF not undergoing MT. Further study is required to assess the efficacy of alteplase in patients with AF undergoing MT.
The Application of the Law of Occupation in Maritime Zones and Rights to ‘Occupied’ Marine Resources
Authors: Friedman Shani 
Published: July 2021

Abstract
This article seeks to contribute to the emerging literature concerning the application of belligerent occupation in maritime zones of the occupied State. It supports the approach that the law of occupation and the law of the sea apply simultaneously in case of occupation of coastal States, offering a new perspective on the jurisdiction of the occupying power to exploit marine resources in the occupied State’s continental shelf and exclusive economic zone. This perspective highlights some issues that have been ignored in the literature thus far to better understand the rights and obligations of the relevant Parties with respect to maritime zones of the occupied State.
Africa, the International Criminal Court and the Law-Diplomacy Nexus
Authors: Spies Yolanda Kemp 
Published: July 2021

Summary
The pioneering diplomatic role of African states in the establishment of the ICC, with its unprecedented legal mandate, was a triumph for a continent with a recent history of legal — diplomatic subjugation. However, the Court’s perceived Afro-centric bias since its inception, contradiction of sovereign immunity custom, and blatant manipulation by the UN Security Council has prompted the African Union to recommend en masse withdrawal. By contrast, this article makes the case that the continent, rather than being a victim of selective, politicised justice, has capitalised on its ICC membership. The Court has become ‘Africanised’ in its substantive specialisation, its executive profile has assumed an African identity and Africa’s penchant for collective diplomacy is facilitated by quantitative advantage in ICC membership. Maximising its diplomatic agency and using the ICC’s principle of complementarity, Africa now has a unique opportunity to insert itself instrumentally at the law — diplomacy nexus in international relations.