bluuebunny/crossref_metadata_2025_split huggingface dataset:
Motivations for concurrent use of uppers and downers among people who access harm reduction services in British Columbia, Canada: findings from the 2019 Harm Reduction Client Survey
Authors: Steinberg Abigail , Mehta Amiti , Papamihali Kristi , Lukac Christine D , Young Sara , Graham Brittany , Lock Kurt , Fleury Mathew , Buxton Jane A 
Published: May 2022

IntroductionAn increase in crystal methamphetamine (methamphetamine) use during the overdose epidemic is being observed in British Columbia (BC), Canada, and across North America. Concurrent use (ie, using uppers and downers one after the other or together) can increase the risk of fatal and non-fatal opioid overdose.ObjectivesWe investigated motivations for concurrent use of uppers and downers, specifically how (eg, in what order) and why people use concurrently, to identify potential interventions to prevent overdose and other harms.Setting and participantsThe 2019 Harm Reduction Client Survey was administered across 22 harm reduction supply distribution sites in BC (n=621). This thematic analysis examined 307 responses by people who affirmed concurrent use to classify order and reasons for using uppers and downers concurrently.ResultsOf the 307 people who responded ‘yes’ to concurrent use, 179 (58.3%) used downers then uppers, 76 (24.8%) used uppers then downers and 184 (59.9%) mixed uppers and downers together. Four main reasons for concurrent use emerged: self-medication, availability and preference, drug effects/properties, and financial and life situation. People who mixed drugs together predominantly wanted to achieve desired drug effects/properties, such as a specific high or balancing stimulating and sedating effects.ConclusionsThe ongoing rise in overdoses in BC is multifactorial, and the recent parallel increases in methamphetamine use and concurrent use with opioids may contribute. Qualitative interviews may further elucidate reasons for concurrent use. Addressing reasons for concurrent use identified in this study through harm reduction strategies and education may affect the rates of overdose morbidity and mortality.
Representation of women on editorial boards of ophthalmology journals: protocol for a cross-sectional study
Authors: Park Jeff , Xue Yuanxin , Xue Ryan , Felfeli Tina 
Published: May 2022

IntroductionThere is a notable under-representation of women in leadership positions in ophthalmology despite the increasing number of women as ophthalmologists. Gender inequality in editorial boards of ophthalmology journals has not been investigated on a global scale. This study will aim to evaluate the representation of women as editorial board members in ophthalmology journals across different regions, journal subspecialties and impact factors.Methods and analysisThis will be a cross-sectional study describing the gender composition of editorial boards in ophthalmology journals globally. Ulrich’s Periodicals Directory and SCImago Journal & Country Rank will be used to comprehensively identify journals indexed with the keyword, ‘ophthalmology’. All journals with active websites and lists of editorial boards will be included. Journals will be categorised according to the World Bank’s 2021 classification of countries by income and region, and classified into ophthalmology subspecialties based on publication scope. Impact factors will be obtained from Journal Citation Reports. The gender and academic degrees of each editorial board member will be determined based on journal profiles, institutional websites or name query feature on an online interface. The research impact of each editorial board member will be ascertained from the author records on Web of Science. The gender proportion will be presented for all journals combined, and then for journals grouped by regions, subspecialties and impact factors. Editorial board member characteristics including academic degrees and research productivity measures will be compared between men and women. These comparisons will be made using the χ2 test for categorical variables and the independent samples t-test for continuous variables.Ethics and disseminationThis study did not require research ethics approval given the use of publicly available data and lack of human subjects. The results will be presented at scientific meetings and published in peer-reviewed journals.
Toxicities and outcomes of neoadjuvant treatment in elderly patients with locally advanced rectal cancer: a scoping review protocol
Authors: Hamed Ruba Ahmed , Korpanty Greg , Kelly Dervla 
Published: May 2022

IntroductionColorectal cancer remains the second leading cause of cancer-related death in 60–79 years old and the third leading cause of death in patients aged 80 and above. Rectal cancer accounts for approximately a third of colorectal cancer diagnoses. The current standard of care for managing locally advanced rectal cancer involves a multimodal combined approach with neoadjuvant treatment, surgery with total mesorectal excision and adjuvant chemotherapy. Neoadjuvant treatment can be in the form of short-course radiotherapy, long-course concurrent radiotherapy with chemotherapy or total neoadjuvant chemotherapy with concurrent chemoradiotherapy followed by chemotherapy. This scoping aims to assess the toxicity and outcome of the different neoadjuvant treatment modalities in elderly patients.Methods and analysisWe will use Arksey and O'Malley’s five scoping review methodology framework stages. Searches will be conducted in Ovid Medline, Embase, Cochrane database and CINAHL. In addition, the researcher will hand search for all registered trials, using a combination of terms such as “locally advanced rectal cancer”, “neoadjuvant treatment”, and “elderly patients.” Two independent reviewers will screen titles and abstracts and then full text based on predefined inclusion and exclusion criteria. Publications will be extracted using a customised data extraction tool to include study characteristics, research topics, exposures and outcomes.Ethics and disseminationEthics approval is not required as the data will be collected from the existing literature. The findings of this study will help with future clinical research on the topic. We will publish the findings of this review in a peer-reviewed journal and present them at academic conferences targeting geriatric oncology service providers.
Transferring neurointerventionalists saves time compared with interhospital transfer of stroke patients for endovascular thrombectomy: a collaborative pooled analysis of 1001 patients (EVEREST)
Authors: Seker Fatih , Fifi Johanna T , Morey Jacob R , Osanai Toshiya , Oki Sogo , Brekenfeld Caspar , Fiehler Jens , Bendszus Martin , Möhlenbruch Markus A 
Published: May 2022

BackgroundInterhospital transfer of stroke patients (drip and ship concept) is associated with longer treatment times compared with primary admission to a comprehensive stroke center (mothership concept). In recent years, studies on a novel concept of performing endovascular thrombectomy (EVT) at external hospitals (EXT) by transferring neurointerventionalists, instead of patients, have been published. This collaborative study aimed at answering the question of whether EXT saves time in the workflow of acute stroke treatment across various geographical regions.MethodsThis was a patient level pooled analysis of one prospective observational study and four retrospective cohort studies, the EVEREST collaboration (EndoVascular thrombEctomy at Referring and External STroke centers). Time from initial stroke imaging to EVT (vascular puncture) was compared in mothership, drip and ship, and EXT concepts.ResultsIn total, 1001 stroke patients from various geographical regions who underwent EVT due to large vessel occlusion were included. These were divided into mothership (n=162, 16.2%), drip and ship (n=458, 45.8%), and EXT (n=381, 38.1%) cohorts. The median time periods from onset to EVT (195 min vs 320 min, p<0.001) and from imaging to EVT (97 min vs 184 min, p<0.001) in EXT were significantly shorter than for drip and ship thrombectomy concept.ConclusionsThis pooled analysis of the EVEREST collaboration adds evidence that performing EVT at external hospitals can save time compared with drip and ship across various geographical regions. We encourage conducting randomized controlled trials comparing both triage concepts.
Lung cancer mortality in the European cohort of titanium dioxide workers: a reanalysis of the exposure–response relationship
Authors: Guseva Canu Irina , Gaillen-Guedy Alan , Antilla Ahti , Charles Sandrine , Fraize-Frontier Sandrine , Luce Danièle , McElvenny Damien Martin , Merletti Franco , Michel Cecile , Pukkala Eero , Schubauer-Berigan Mary K , Straif Kurt , Wild Pascal , Richardson David B 
Published: May 2022

ObjectivesAnimal bioassays have demonstrated convincing evidence of the potential carcinogenicity to humans of titanium dioxide (TiO2), but limitations in cohort studies have been identified, among which is the healthy worker survivor effect (HWSE). We aimed to address this bias in a pooled study of four cohorts of TiO2workers.MethodsWe reanalysed data on respirable TiO2dust exposure and lung cancer mortality among 7341 male workers employed in TiO2production in Finland, France, UK and Italy using the parametric g-formula, considering three hypothetical interventions: setting annual exposures at 2.4 (U.S. occupational exposure limit), 0.3 (German limit) and 0 mg/m3for 25 and 35 years.ResultsThe HWSE was evidenced. Taking this into account, we observed a positive association between lagged cumulative exposure to TiO2and lung cancer mortality. The estimated number of lung cancer deaths at each age group decreased across increasingly stringent intervention levels. At age 70 years, the estimated number of lung cancer deaths expected in the cohort after 35-year exposure was 293 for exposure set at 2.4 mg/m3, 235 for exposure set at 0.3 mg/m3, and 211 for exposure set at 0 mg/m3.ConclusionThis analysis shows that HWSE can hide an exposure–response relationship. It also shows that TiO2epidemiological data could demonstrate an exposure–effects relationship if analysed appropriately. More epidemiological studies and similar reanalyses of existing cohort studies are warranted to corroborate the human carcinogenicity of TiO2. This human evidence, when combined with the animal evidence, strengthens the overall evidence of carcinogenicity of TiO2.
Dark matter effect on the weak deflection angle by black holes at the center of Milky Way and M87 galaxies
Authors: Pantig Reggie C. , Övgün Ali 
Published: May 2022

AbstractIn this paper, we investigated the effect of dark matter on the weak deflection angle by black holes at the galactic center. We consider three known dark matter density profiles such as the Cold Dark Matter, Scalar Field Dark Matter, and the Universal Rotation Curve from the Burkert profile. To achieve this goal, we used how the positional angles are measured by the Ishihara et al. method based on the Gauss–Bonnet theorem on the optical metric. With the help of the non-asymptotic form of the Gauss-Bonnet theorem, the longitudinal angle difference is also calculated. First, we find the emergence of apparent divergent terms on the said profiles, which indicates that the spacetime describing the black hole-dark matter combination is non-asymptotic. We showed that these apparent divergent terms vanish when the distance of the source and receiver are astronomically distant from the black hole. Using the current observational data in the Milky Way and M87 galaxies, we find interesting behaviors of how the weak deflection angle varies with the impact parameter, which gives us some hint on how dark matter interacts with the null particles for each dark matter density profile. We conclude that since these deviations are evident near the dark matter core radius, the weak deflection angle offers a better alternative for dark matter detection than using the deviation from the black hole shadow. With the dark matter profiles explored in this study, we find that the variation of the values for weak deflection angle strongly depends on the dark matter mass on a particular profile.
Restricted Delaunay Triangulation for Explicit Surface Reconstruction
Authors: Wang Pengfei , Wang Zixiong , Xin Shiqing , Gao Xifeng , Wang Wenping , Tu Changhe 
Published: May 2022

The task of explicit surface reconstruction is to generate a surface mesh by interpolating a given point cloud. Explicit surface reconstruction is necessary when the point cloud is required to appear exactly on the surface. However, for a non-perfect input, such as lack of normals, low density, irregular distribution, thin and tiny parts, and high genus, a robust explicit reconstruction method that can generate a high-quality manifold triangulation is missing.
We propose a robust explicit surface reconstruction method that starts from an initial simple surface mesh, alternately performs a Filmsticking step and a Sculpting step of the initial mesh, and converges when the surface mesh interpolates all input points (except outliers) and remains stable. The Filmsticking is to minimize the geometric distance between the surface mesh and the point cloud through iteratively performing a restricted Voronoi diagram technique on the surface mesh, whereas the Sculpting is to bootstrap the Filmsticking iteration from local minima by applying appropriate geometric and topological changes of the surface mesh.
Our algorithm is fully automatic and produces high-quality surface meshes for non-perfect inputs that are typically considered to be challenging for prior state of the art. We conducted extensive experiments on simulated scans and real scans to validate the effectiveness of our approach.
A Phase III Multicenter Randomized Clinical Trial of 60 Gy versus 50 Gy Radiation Dose in Concurrent Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma
Authors: Xu Yujin , Dong Baiqiang , Zhu Weiguo , Li Jiancheng , Huang Rong , Sun Zongwen , Yang Xinmei , Liu Liping , He Han , Liao Zhongxing , Guan Ni , Kong Yue , Wang Wanwei , Chen Jianxiang , He Huijuan , Qiu Guoqin , Zeng Ming , Pu Juan , Hu Wangyuan , Bao Yong , Liu Zhigang , Ma Jun , Jiang Hao , Du Xianghui , Hu Jin , Zhuang Tingting , Cai Jing , Huang Jin , Tao Hua , Liu Yuan , Liang Xiaodong , Zhou Juying , Tao Guangzhou , Zheng Xiao , Chen Ming 
Published: May 2022

Abstract

Purpose:
In this multicenter phase 3 trial, the efficacy and safety of 60 Gy and 50 Gy doses delivered with modern radiotherapy technology for definitive concurrent chemoradiotherapy (CCRT) in patients with inoperable esophageal squamous cell carcinoma (ESCC) were evaluated.

Patients and Methods:
Patients with pathologically confirmed stage IIA‒IVA ESCC were randomized 1:1 to receive conventional fractionated 60 Gy or 50 Gy to the tumor and regional lymph nodes. Concurrent weekly chemotherapy (docetaxel 25 mg/m2; cisplatin 25 mg/m2) and two cycles of consolidation chemotherapy (docetaxel 70 mg/m2; cisplatin 25 mg/m2 days 1‒3) were administered.

Results:
A total of 319 patients were analyzed for survival, and the median follow-up was 34.0 months. The 1- and 3-year locoregional progression-free survival (PFS) rates for the 60 Gy group were 75.6% and 49.5% versus 72.1% and 48.4%, respectively, for the 50 Gy group [HR, 1.00; 95% confidence interval (CI), 0.75‒1.35; P = 0.98]. The overall survival rates were 83.7% and 53.1% versus 84.8% and 52.7%, respectively (HR, 0.99; 95% CI, 0.73‒1.35; P = 0.96), whereas the PFS rates were 71.2% and 46.4% versus 65.2% and 46.1%, respectively (HR, 0.97; 95% CI, 0.73‒1.30; P = 0.86). The incidence of grade 3+ radiotherapy pneumonitis was higher in the 60 Gy group (nominal P = 0.03) than in the 50 Gy group.

Conclusions:
The 60 Gy arm had similar survival endpoints but a higher severe pneumonitis rate compared with the 50 Gy arm. Fifty Gy should be considered as the recommended dose in CCRT for ESCC.
Neuroendocrine and Rare Tumor Advances: A New and Promising TRAIL Emerges
Authors: Owen Dwight H. , Trikalinos Nikolaos A. 
Published: May 2022

SummaryONC201 is an oral selective antagonist of the dopamine D2 receptor and direct activator of caseinolytic protease P. In a phase II study, ONC021 was shown to be well tolerated with notable efficacy in patients with the rare neuroendocrine neoplasms pheochromocytomas-paragangliomas, although biomarkers for activity remain to be elucidated.See related article by Anderson et al., p. 1773
Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab, or Nivolumab in Patients with Advanced Solid Tumors
Authors: Davar Diwakar , Zappasodi Roberta , Wang Hong , Naik Girish S. , Sato Takami , Bauer Todd , Bajor David , Rixe Olivier , Newman Walter , Qi Jingjing , Holland Aliya , Wong Phillip , Sifferlen Lianna , Piper Diane , Sirard Cynthia A. , Merghoub Taha , Wolchok Jedd D. , Luke Jason J. 
Published: May 2022

Abstract

Purpose:
TRX518 is a mAb engaging the glucocorticoid-induced TNF receptor−related protein (GITR). This open-label, phase I study (TRX518-003) evaluated the safety and efficacy of repeated dose TRX518 monotherapy and in combination with gemcitabine, pembrolizumab, or nivolumab in advanced solid tumors.

Patients and Methods:
TRX518 monotherapy was dose escalated (Part A) and expanded (Part B) up to 4 mg/kg loading, 1 mg/kg every 3 weeks. Parts C–E included dose-escalation (2 and 4 mg/kg loading followed by 1 mg/kg) and dose-expansion (4 mg/kg loading) phases with gemcitabine (Part C), pembrolizumab (Part D), or nivolumab (Part E). Primary endpoints included incidence of dose-limiting toxicities (DLT), serious adverse events (SAE), and pharmacokinetics. Secondary endpoints were efficacy and pharmacodynamics.

Results:
A total of 109 patients received TRX518: 43 (Parts A+B), 30 (Part C), 26 (Part D), and 10 (Part E), respectively. A total of 67% of patients in Parts D+E had received prior anti–PD(L)1 or anti–CTLA-4. No DLTs, treatment-related SAEs, and/or grade 4 or 5 AEs were observed with TRX518 monotherapy. In Parts C–E, no DLTs were observed, although TRX518-related SAEs were reported in 3.3% (Part C) and 10.0% (Part E), respectively. Objective response rate was 3.2%, 3.8%, 4%, and 12.5% in Parts A+B, C, D, and E, respectively. TRX518 affected peripheral and intratumoral regulatory T cells (Treg) with different kinetics depending on the combination regimen. Responses with TRX518 monotherapy+anti–PD1 combination were associated with intratumoral Treg reductions and CD8 increases and activation after treatment.

Conclusions:
TRX518 showed an acceptable safety profile with pharmacodynamic activity. Repeated dose TRX518 monotherapy and in combination resulted in limited clinical responses associated with immune activation.
See related commentary by Hernandez-Guerrero and Moreno, p. 3905
HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC that Overcomes Osimertinib-Resistant EGFR Triple Mutations
Authors: Du Yong , Chen Yongfeng , Wang Yuxia , Chen Jinju , Lu Xiaorong , Zhang Li , Li Yan , Wang Zhaofu , Ye Guozhong , Zhang George 
Published: May 2022

Abstract
The EGFR C797S mutation is the most common on-target resistance mechanism to osimertinib in patients with advanced non–small cell lung cancer (NSCLC). Currently there are no effective treatment options for patients with NSCLC harboring EGFR C797S triple mutants (Del19/T790M/C797S and L858R/T790M/C797S). Herein, we report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades the EGFR C797S-containing triple mutants. HJM-561 potently inhibits the proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells while sparing cells expressing wild-type EGFR. Oral administration of HJM-561 shows robust antitumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 CDX and PDX models that were resistant to osimertinib treatment. Taken together, our results suggest that HJM-561 is a promising therapeutic option for overcoming EGFR triple mutation-mediated drug resistance in NSCLC.
Watch the interview with George Zhang, PhD, recipient of the 2024 Molecular Cancer Therapeutics Award for Outstanding Journal Article: https://vimeo.com/992990122
Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors
Authors: Tomar Sakshi , Zhang Jingli , Khanal Manakamana , Hong Jessica , Venugopalan Abhilash , Jiang Qun , Sengupta Manjistha , Miettinen Markku , Li Nan , Pastan Ira , Ho Mitchell , Hassan Raffit 
Published: May 2022

Abstract
Mesothelin targeting CAR T cells have limited activity in patients. In this study, we sought to determine if efficacy of anti-mesothelin CAR T cells is dependent on the mesothelin epitopes that are recognized by them. To do so, we developed hYP218 (against membrane-proximal epitope) and SS1 (against membrane-distal epitope) CAR T cells. Their efficacy was assessed in vitro using mesothelin-positive tumor cell lines and in vivo in NSG mice with mesothelin-expressing ovarian cancer (OVCAR-8), pancreatic cancer (KLM-1), and mesothelioma patient-derived (NCI-Meso63) tumor xenografts. Persistence and tumor infiltration of CAR T cells was determined using flow cytometry. hYP218 CAR T cells killed cancer cells more efficiently than SS1 CAR T cells, with a two- to fourfold lower ET50 value (effector-to-target ratio for 50% killing of tumor cells). In mice with established tumors, single intravenous administration of hYP218 CAR T cells lead to improved tumor response and survival compared with SS1 CAR T cells, with complete regression of OVCAR-8 and NCI-Meso63 tumors. Compared with SS1 CAR T cells, there was increased peripheral blood expansion, persistence, and tumor infiltration of hYP218 CAR T cells in the KLM-1 tumor model. Persistence of hYP218 CAR T cells in treated mice led to antitumor immunity when rechallenged with KLM-1 tumor cells. Our results show that hYP218 CAR T cells, targeting mesothelin epitope close to cell membrane, are very effective against mesothelin-positive tumors and are associated with increased persistence and tumor infiltration. These results support its clinical development to treat patients with mesothelin-expressing cancers.
A new topology of multilevel inverter with switches count reducing at symmetrical/asymmetrical mode
Authors: Albakhait Mohammed D. , Abdulkareem Arwa Amer 
Published: May 2022

The <span>multi-level inverter (MLI) has an important role in modern technologies due to its advantages. On the other hand, its circuits need a large number of switches, capacitors and direct current (DC) sources. This paper introduces a new topology for a MLI with a reduction in number of switches, no need for capacitors in exchange for an increase in number of levels in the output. The proposed model is operated in symmetric and asymmetric modes with the presence of resistive and inductive loads. Whereas, (5 and 9) output levels were obtained in symmetric and asymmetric modes, respectively. In contrast, the number of switches was halved and without need for capacitors, compared to the conventional MLI topologies not a secret that reducing the number of switches has the effect of reducing cost and complexity, in addition to the problems of balancing the voltage on capacitors. The programming environment used to build the proposed model of the MLI was MATLAB/Simulink, where the validity of the hypotheses contained in this paper were proved and the obtained results are identical to what was planned under different loads and different operation modes. In addition, the paper included a comparison study among the proposed topology and conventional topologies in terms of the number of switches, capacitors and </span>sources.