bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective cohort analysis of prescription patterns of cancer medications during periods of drug stockouts in Botswana
Authors: Davey Sonya , Grover Surbhi , Bilker Warren B , Setlhako Dipho I , Ralefala Tlotlo B , Manshimba Patrick , Gross Robert , DeMichele Angela , Shulman Lawrence N , Martei Yehoda M 
Published: July 2021

ObjectiveCancer drug stockouts occur at high frequencies globally, however, their effects on treatment are understudied in sub-Saharan Africa (SSA). We aimed to determine whether causes of suboptimal cancer treatment prescriptions differed between periods of stockout and full treatment supply.DesignA retrospective cohort study of systemic therapy prescriptions for patients diagnosed with the twelve most common solid tumour cancers treated in 2016.SettingPrincess Marina Hospital in Gaborone, Botswana.ParticipantsPatients in the retrospective cohort who experienced any suboptimal treatment events, defined as ≥7 days delay or switch from guideline-concordant initiated therapy.Primary and secondary outcome measuresFrequency of delays and patterns of prescription changes for specific regimens and cancer types.Results167/378 patients contributed to 320 suboptimal events (115 therapy switches, 167 delays and 38 events with both), over 1452 total chemotherapy cycles received. Events during stockout were 43% delays, 43% switches and 14% both during stockout periods and 67.2% delays, 24.4% switches and 8.4% both during non-stockout periods (p<0.001). Majority of switches involved de-escalation of initially prescribed guideline-recommended regimens in patients with breast cancer, Kaposi sarcoma and patients with colorectal cancer, which occurred more frequently during periods of drug stockouts. Among patients with breast cancer, substitution of docetaxel for paclitaxel event occurred exclusively during paclitaxel drug stockout. Delays of ≥7 days events were most frequent in breast cancer patients receiving paclitaxel during stockout, and combination doxorubicin and cyclophosphamide even during periods of non-stockout.ConclusionsThe aetiology of suboptimal events differed during stockout and non-stockout periods. Prescription patterns that involved de-escalation of initiated therapy and substitution of paclitaxel with docetaxel occurred frequently during periods of drug stockout. Further research needs to be conducted to understand the impact of stockout on survival and barriers to maintaining essential cancer medicines supplies in SSA, and the factors driving frequent delays in therapy delivery.
Topological analysis of hepatocellular carcinoma tumour microenvironment based on imaging mass cytometry reveals cellular neighbourhood regulated reversely by macrophages with different ontogeny
Authors: Sheng Jianpeng , Zhang Junlei , Wang Lin , Tano Vincent , Tang Jianghui , Wang Xun , Wu Jiangchao , Song Jinyuan , Zhao Yaxing , Rong Jingxia , Cheng Fei , Wang Jianfeng , Shen Yinan , Wen Liang , He Junjun , Zhang Hui , Li Taohong , Zhang Qi , Bai Xueli , Lu Zhimin , Liang Tingbo 
Published: July 2021

ObjectiveHepatocellular carcinoma (HCC) tumour microenvironment (TME) is highly complex with diverse cellular components organising into various functional units, cellular neighbourhoods (CNs). And we wanted to define CN of HCC while preserving the TME architecture, based on which, potential targets for novel immunotherapy could be identified.DesignA highly multiplexed imaging mass cytometry (IMC) panel was designed to simultaneously quantify 36 biomarkers of tissues from 134 patients with HCC and 7 healthy donors to generate 562 highly multiplexed histology images at single-cell resolution. Different function units were defined by topological analysis of TME. CN relevant to the patients’ prognosis was identified as specific target for HCC therapy. Transgenic mouse models were used to validate the novel immunotherapy target for HCC.ResultsThree major types of intratumour areas with distinct distribution patterns of tumorous, stromal and immune cells were identified. 22 cellular metaclusters and 16 CN were defined. CN composed of various types of cells formed regional function units and the regional immunity was regulated reversely by resident Kupffer cells and infiltrating macrophages with protumour and antitumour function, respectively. Depletion of Kupffer cells in mouse liver largely enhances the T cell response, reduces liver tumour growth and sensitises the tumour response to antiprogrammed cell death protein-1 treatment.ConclusionOur findings reveal for the first time the various topological function units of HCC TME, which also presents the largest depository of pathological landscape for HCC. This work highlights the potential of Kupffer cell-specific targeting rather than overall myeloid cell blocking as a novel immunotherapy for HCC treatment.
Work-related and personal predictors of COVID-19 transmission: evidence from the UK and USA
Authors: Anand Paul , Allen Heidi L , Ferrer Robert L , Gold Natalie , Gonzales Martinez Rolando Manuel , Kontopantelis Evangelos , Krause Melanie , Vergunst Francis 
Published: July 2021

ObjectiveTo develop evidence of work-related and personal predictors of COVID-19 transmission.Setting and respondentsData are drawn from a population survey of individuals in the USA and UK conducted in June 2020.Background methodsRegression models are estimated for 1467 individuals in which reported evidence of infection depends on work-related factors as well as a variety of personal controls.ResultsThe following themes emerge from the analysis. First, a range of work-related factors are significant sources of variation in COVID-19 infection as indicated by self-reports of medical diagnosis or symptoms. This includes evidence about workplace types, consultation about safety and union membership. The partial effect of transport-related employment in regression models makes the chance of infection over three times more likely while in univariate analyses, transport-related work increases the risk of infection by over 40 times in the USA. Second, there is evidence that some home-related factors are significant predictors of infection, most notably the sharing of accommodation or a kitchen. Third, there is some evidence that behavioural factors and personal traits (including risk preference, extraversion and height) are also important.ConclusionsThe paper concludes that predictors of transmission relate to work, transport, home and personal factors. Transport-related work settings are by far the greatest source of risk and so should be a focus of prevention policies. In addition, surveys of the sort developed in this paper are an important source of information on transmission pathways within the community.
PD-1+CXCR5−CD4+ Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma
Authors: Li Jiang-Ping , Wu Chang-You , Chen Ming-Yuan , Liu Shang-Xin , Yan Shu-Mei , Kang Yin-Feng , Sun Cong , Grandis Jennifer R , Zeng Mu-Sheng , Zhong Qian 
Published: July 2021

BackgroundA major current challenge is to exploit tertiary lymphoid structures (TLSs) to promote the lymphocyte infiltration, activation and differentiation by tumor antigens to increase antitumor immune responses. The mechanisms that underlie the role of TLS formation in the adaptive immune responses against nasopharyngeal carcinoma (NPC) remain largely unknown.MethodsCell populations and the corresponding markers were identified by single-cell RNA sequencing and fluorescence-activated cell sorting analysis. In vitro differentiation experiments were used to simulate the generation, regulation and function of the Th-CXCL13 cell subset in the tumor microenvironment of NPC. These were followed by histological evaluation of the colocalization of tumor-associated B cells (TABs) and Th-CXCL13 cells within TLSs, and statistical analysis of the relationship between the cells in TLSs and overall survival.ResultsA PD-1+CXCR5−CD4+ Th-CXCL13 cell subset was identified in NPC. This subset was a major source of CXCL13, representing the majority of the CD4+ T cells at levels comparable with Th1 and Tfh cells present in the TLSs. Monocytes activated by toll-like receptor 4 agonists served as the antigen-presenting cells that most efficiently triggered the expansion of Th-CXCL13 cells. Transforming growth factor beta 1 (TGF-β1) stimulation and activation of Sox4 were critical for the induction and polarization of Th-CXCL13 cells in this process. The potential functional contributions of TABs recruited by Th-CXCL13 cells which induced plasma cell differentiation and immunoglobulin production via interleukin-21 and CD84 interactions in the TLSs demonstrated improved survival.ConclusionsInduction of Th-CXCL13 cells links innate inflammation to immune privilege in tumor-associated TLSs and might predict better survival.
Combining C reactive protein and serum albumin to predict 90-day mortality in systemic lupus erythematosus with serious community-acquired infections
Authors: He Shuangjun , Tang Chao , Yu Jie , Ma Jun , Qiao Minjie , Zhou Wei , Chen Yi , Zhang Xingyu 
Published: July 2021

ObjectiveSerious infections in SLE are common and have emerged as the major cause of death. However, effective methods to identify poor prognosis are still lacking. Therefore, we aimed to determine the predictive value of C reactive protein (CRP) plus albumin (ALB) in SLE with serious infections.MethodsFrom May 2015 to December 2018, consecutive patients with SLE presenting with serious infections in our emergency department were prospectively recruited. Serum CRP and ALB were measured within 24 hours of admission. The outcome was defined as mortality rate at 90 days. A CRP plus ALB score (2–6) was assigned based on the CRP and ALB concentrations. We performed univariate and multivariate regression analyses to detect the independent effects of CRP plus ALB on 90-day mortality (all-cause and infection-related). Subgroup analyses were used to show the effects stratified by lupus nephritis.ResultsA total of 150 patients were included, and the all-cause 90-day mortality rate was 38% (n=57), 41 of which was infection-related. The predominant infection sites were pulmonary (79.3%) and bloodstream infection (20.7%). Serum CRP and ALB levels were significantly different in non-surviving patients compared with those in surviving patients (p=0.002 and p<0.001, respectively). In the fully adjusted logistic regression model, the CRP plus ALB score was associated with decreased 90-day survival (adjusted OR 1.52; 95% CI 1.08 to 2.13; p=0.017).ConclusionsCRP plus ALB was associated with the risk of all-cause and infection-related 90-day mortality in SLE with serious infections. Although this finding requires further verification, the two parameters may be useful for predicting poor outcomes in such patients.
LUPUS-BEST—treat-to-target in systemic lupus erythematosus: study protocol for a three-armed cluster-randomised trial
Authors: Mucke Johanna , Kuss Oliver , Brinks Ralph , Schanze Sabine , Schneider Matthias 
Published: July 2021

IntroductionAs chronic systemic autoimmune disease, which can affect every organ, SLE is creating significant burden and increased mortality. Despite better outcomes over the past decades by optimising standard of care, new interventions are needed for further improvements. Changing strategy to ‘treat-to-target’ (T2T) may be a promising concept proven successful in other chronic diseases.Methods and analysisIn this cluster-randomised trial, SLE centres will be assigned 1:1:1 to standard of care (SoC), remission (no clinical disease activity+prednisolone ≤5 mg/day+Physician Global Assessment (PGA 0–3) <0.5±immunomodulatory treatment) or and Lupus Low Disease Activity State (LLDAS, low disease activity+prednisolone ≤7.5 mg/day+PGA ≤1+no new disease activity). Per arm, 424 patients will be included. Intervention centres receive a standardised training on T2T and shared decision-making (SDM). In intervention centres, patients not in target enter a phase of tight control with six weekly visits and treatment adjustments (at least four visits) or until the target is reached and maintained. Patients in target are reassessed every 12 weeks. In case of flare, they can enter tight control based on SDM. In the SoC arm, patients receive their usual three to six monthly controls and treatment adjustments according to the physician’s discretion. Study duration is 120 weeks using change in damage and health-related quality of life (HRQoL) as major outcomes. The primary endpoint will be damage accrual at 120 weeks as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index and will by analysed by a mixed model.ConclusionsThis is the first trial to assess if the implementation of a T2T concept in clinical care minimises damage accrual and improves HRQoL in patients with SLE. Comparison of remission and LLDAS will help to identify the target with the best benefit–risk ratio concerning attainability, adverse events and damage. The emphasis on SDM will strengthen patient autonomy and will improve both their satisfaction and medical condition.
A multianalyte assay panel with cell-bound complement activation products demonstrates clinical utility in systemic lupus erythematosus
Authors: Alexander Roberta Vezza , Rey Daniel Scott , Conklin John , Domingues Vinicius , Ahmed Mansoor , Qureshi Jazibeh , Weinstein Arthur 
Published: July 2021

ObjectiveTo evaluate the clinical utility of the multianalyte assay panel (MAP), commercially known as AVISE Lupus test (Exagen Inc.), in patients suspected of SLE.MethodsA systematic review of medical records of ANA-positive patients with a positive (>0.1) or negative (<−0.1) MAP score was conducted when the MAP was ordered (T0), when the test results were reviewed (T1) and at a later time (T2, ≥8 months after T1). Confidence in the diagnosis of SLE and initiation of hydroxychloroquine (HCQ) were assessed.ResultsA total of 161 patient records from 12 centres were reviewed at T0 and T1. T2 occurred for 90 patients. At T0, low, moderate and high confidence in SLE diagnosis was reported for 58%, 30% and 12% patients, respectively. Confidence in SLE diagnosis increased for the MAP positive, while MAP negative made SLE less likely. Odds of higher confidence in SLE diagnosis increased by 1.74-fold for every unit of increase of the MAP score (p<0.001). Using the MAP-negative/anti-double-stranded DNA-negative patients as reference, the HR of assigning an International Classification of Diseases, Tenth Revision lupus code was 7.02-fold, 11.2-fold and 14.8-fold higher in the low tier-2, high tier-2 and tier-1 positive, respectively (p<0.001). The HR of initiating HCQ therapy after T0 was 2.90-fold, 4.22-fold and 3.98-fold higher, respectively (p<0.001).ConclusionThe MAP helps increase the confidence in ruling-in and ruling-out SLE in patients suspected of the disease and informs on appropriate treatment decisions.
Direct oral anticoagulants versus vitamin K antagonists in patients with antiphospholipid syndrome: systematic review and meta-analysis
Authors: Koval Nazariy , Alves Mariana , Plácido Rui , Almeida Ana G , Fonseca João Eurico , Ferreira Joaquim J , Pinto Fausto J , Caldeira Daniel 
Published: July 2021

BackgroundDespite vitamin K antagonists (VKA) being the gold standard in the prevention of thromboembolic events in antiphospholipid syndrome (APS), non-vitamin K antagonists oral anticoagulants/direct oral anticoagulants (DOACs) have been used off-label.ObjectiveWe aimed to perform a systematic review comparing DOACs to VKA regarding prevention of thromboembolic events, occurrence of bleeding events and mortality in patients with APS.MethodsAn electronic database search was performed through MEDLINE, CENTRAL and Web of Science. After data extraction, we pooled the results using risk ratio (RR) and 95% CI. Heterogeneity was assessed using the I². The outcomes considered were all thromboembolic events as primary, and major bleeding, all bleeding events and mortality as secondary. Evidence confidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology.ResultsWe included 7 studies and a total of 835 patients for analyses. Thromboembolic events were significantly increased in DOACs arm, compared with VKA—RR 1.69, 95% CI 1.09 to 2.62, I²—24%, n=719, 6 studies. In studies using exclusively rivaroxaban, which was the most representative drug in all included studies, the thromboembolic risk was increased threefold (RR 3.36, 95% CI 1.53 to 7.37). The risks of major bleeding, all bleeding events and mortality were not significantly different from control arm. The grade of certainty of our results is very low.ConclusionsCurrent evidence suggests DOACs use, particularly rivaroxaban, among patients with APS, is less effective than VKA since it is associated with 69% increased risk of thromboembolic events.Trial registration numberCRD42020216178.
Performance and luminosity models for heavy-ion operation at the CERN Large Hadron Collider
Authors: Bruce R. , Jebramcik M. A. , Jowett J. M. , Mertens T. , Schaumann M. 
Published: July 2021

AbstractA good understanding of the luminosity performance in a collider, as well as reliable tools to analyse, predict, and optimise the performance, is of great importance for the successful planning and execution of future runs. In this article, we present two different models for the evolution of the beam parameters and the luminosity in heavy-ion colliders. The first, Collider Time Evolution is a particle tracking code, while the second, the Multi-Bunch Simulation is based on the numerical solution of ordinary differential equations for beam parameters. As a benchmark, we compare simulations and data for a large number of physics fills in the 2018 Pb–Pb run at the CERN Large Hadron Collider (LHC), finding excellent agreement for most parameters, both between the simulations and with the measured data. Both codes are then used independently to predict the performance in future heavy-ion operation, with both Pb–Pb and p–Pb collisions, at the LHC and its upgrade, the high-luminosity LHC. The use of two independent codes based on different principles gives increased confidence in the results.
Analysing Mission-critical Cyber-physical Systems with AND/OR Graphs and MaxSAT
Authors: Barrère Martín , Hankin Chris 
Published: July 2021

Cyber-Physical Systems (CPS) often involve complex networks of interconnected software and hardware components that are logically combined to achieve a common goal or mission; for example, keeping a plane in the air or providing energy to a city. Failures in these components may jeopardise the mission of the system. Therefore, identifying the minimal set of critical CPS components that is most likely to fail, and prevent the global system from accomplishing its mission, becomes essential to ensure reliability. In this article, we present a novel approach to identifying the
Most Likely Mission-critical Component Set (MLMCS)
using AND/OR dependency graphs enriched with independent failure probabilities. We address the MLMCS problem as a Maximum Satisfiability (MaxSAT) problem. We translate probabilities into a negative logarithmic space to linearise the problem within MaxSAT. The experimental results conducted with our open source tool LDA4CPS indicate that the approach is both effective and efficient. We also present a case study on complex aircraft systems that shows the feasibility of our approach and its applicability to mission-critical cyber-physical systems. Finally, we present two MLMCS-based security applications focused on system hardening and forensic investigations.
Selective Inhibition of the Second Bromodomain of BET Family Proteins Results in Robust Antitumor Activity in Preclinical Models of Acute Myeloid Leukemia
Authors: Zhang Lu , Cai Tianyu , Lin Xiaoyu , Huang Xiaoli , Bui Mai H. , Plotnik Joshua P. , Bellin Richard J. , Faivre Emily J. , Kuruvilla Vinitha M. , Lam Lloyd T. , Lu Xin , Zha Zheng , Feng Weiguo , Hessler Paul , Uziel Tamar , Zhang Qi , Cavazos Antonio , Han Lina , Ferguson Debra C. , Mehta Gaurav , Shanmugavelandy Sriram S. , Magoc Terrance J. , Rowe Jenny , Goodwin Neal C. , Dorritie Kathleen A. , Boyiadzis Michael , Albert Daniel H. , McDaniel Keith F. , Kati Warren M. , Konopleva Marina , Shen Yu 
Published: July 2021

AbstractDual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins. In contrast to the broad antiproliferative activities observed with dual bromodomain BET inhibitors, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from acute myeloid leukemia and androgen receptor positive prostate cancer. Studies in acute myeloid leukemia xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable with the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced antitumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared with monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).
WNK1 Enhances Migration and Invasion in Breast Cancer Models
Authors: Jaykumar Ankita B. , Jung Ji-Ung , Parida Pravat Kumar , Dang Tuyen T. , Wichaidit Chonlarat , Kannangara Ashari Rashmi , Earnest Svetlana , Goldsmith Elizabeth J. , Pearson Gray W. , Malladi Srinivas , Cobb Melanie H. 
Published: July 2021

Abstract
Metastasis is the major cause of mortality in patients with breast cancer. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase with no lysine (K) 1 (WNK1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here, we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype, and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.