bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of serum neurofilament light with microglial activation in multiple sclerosis
Authors: Saraste Maija , Matilainen Markus , Vuorimaa Anna , Laaksonen Sini , Sucksdorff Marcus , Leppert David , Kuhle Jens , Airas Laura 
Published: May 2023

BackgroundTranslocator protein (TSPO)-PET and neurofilament light (NfL) both report on brain pathology, but their potential association has not yet been studied in multiple sclerosis (MS) in vivo. We aimed to evaluate the association between serum NfL (sNfL) and TSPO-PET-measurable microglial activation in the brain of patients with MS.MethodsMicroglial activation was detected using PET and the TSPO-binding radioligand [11C]PK11195. Distribution volume ratio (DVR) was used to evaluate specific [11C]PK11195-binding. sNfL levels were measured using single molecule array (Simoa). The associations between [11C]PK11195 DVR and sNfL were evaluated using correlation analyses and false discovery rate (FDR) corrected linear regression modelling.Results44 patients with MS (40 relapsing-remitting and 4 secondary progressive) and 24 age-matched and sex-matched healthy controls were included. In the patient group with elevated brain [11C]PK11195 DVR (n=19), increased sNfL associated with higher DVR in the lesion rim (estimate (95% CI) 0.49 (0.15 to 0.83), p(FDR)=0.04) and perilesional normal appearing white matter (0.48 (0.14 to 0.83), p(FDR)=0.04), and with a higher number and larger volume of TSPO-PET-detectable rim-active lesions defined by microglial activation at the plaque edge (0.46 (0.10 to 0.81), p(FDR)=0.04 and 0.50 (0.17 to 0.84), p(FDR)=0.04, respectively). Based on the multivariate stepwise linear regression model, the volume of rim-active lesions was the most relevant factor affecting sNfL.ConclusionsOur demonstration of an association between microglial activation as measured by increased TSPO-PET signal, and elevated sNfL emphasises the significance of smouldering inflammation for progression-promoting pathology in MS and highlights the role of rim-active lesions in promoting neuroaxonal damage.
Randomised trial of stable chest pain investigation: 3-year clinical and quality of life results from CE-MARC 2
Authors: Everett Colin C. , Berry Colin , McCann Gerry P. , Fernandez Catherine , Reynolds Catherine , Bucciarelli-Ducci Chiara , Dall’Armellina Erica , Prasad Abhiram , Foley James R. , Mangion Kenneth , Bijsterveld Petra , Brown Julia , Stocken Deborah , Walker Simon , Sculpher Mark , Plein Sven , Greenwood John P. 
Published: May 2023

AimsGuidelines for suspected cardiac chest pain have used historical risk stratification tools, advocating invasive coronary angiography (ICA) first-line in those at highest risk. We aimed to determine whether different strategies to manage suspected stable angina affected medium-term cardiovascular event rates and patient-reported quality of life (QoL) measures.MethodsCE-MARC 2, a three-arm parallel group trial, randomised patients with suspected stable cardiac chest pain and a Duke Clinical pretest likelihood of coronary artery disease between 10% and 90%. Patients were randomised to either first-line cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT) or the UK National Institute for Health and Care Excellence (NICE) CG95 (2010) guidelines-directed care. For the three arms, 1-year and 3-year first major adverse cardiovascular event (MACE) rates and QoL assessed by the Seattle Angina Questionnaire, Short Form 12 (V.12) Questionnaire and EuroQol-5 Dimension Questionnaire were recorded.Results1202 patients were randomised to CMR (n=481), SPECT (n=481) and NICE (n=240). Forty-two patients (18 CMR, 18 SPECT, 6 NICE) experienced one or more MACEs. The percentage rates (95% CIs) of MACE in the CMR, SPECT and NICE groups at 3 years were 3.7% (2.4%, 5.8%), 3.7% (2.4%, 5.8%) and 2.1% (0.9%, 4.8%), respectively. QoL scores did not significantly differ across domains.ConclusionDespite a fourfold increase in referrals for ICA, the NICE CG95 (2010) guidelines risk-stratified care strategy did not significantly reduce 3-year MACE or improve QoL, as compared with functional imaging with CMR or SPECT.Trial registration numberClinicalTrials.gov Registry (NCT01664858).
Systematic coronary physiology improves level of agreement in diagnostic coronary angiography
Authors: Bashar Hussein Ali Bashar , Saunders Alec , Alaour Bashir , Gerontitis Dimitrios , Hinton Jonathan , Karamanou Danai , Kechagioglou Georgios , Olsen Sally , Onwordi Eunice , Pope Michael , Zingale Anna , Nicholas Zoe , Golledge Peter , Escaned Javier , Ali Ziad , Curzen Nick 
Published: May 2023

ObjectiveThe training of interventional cardiologists (ICs), non-interventional cardiologists (NICs) and cardiac surgeons (CSs) differs, and this may be reflected in their interpretation of invasive coronary angiography (ICA) and management plan. Availability of systematic coronary physiology might result in more homogeneous interpretation and management strategy compared with ICA alone.Methods150 coronary angiograms from patients with stable chest pain were presented independently to three NICs, three ICs and three CSs. By consensus, each group graded (1) coronary disease severity and (2) management plan, using options: (a) optimal medical therapy alone, (b) percutaneous coronary intervention, (c) coronary artery bypass graft or (d) more investigation required. Each group was then provided with fractional flow reserve (FFR) from all major vessels and asked to repeat the analysis.ResultsThere was only ‘fair’ level of agreement of management plan among ICs, NICs and CSs (kappa 0.351, 95% CI 0.295–0.408, p<0.001) based on ICA alone (complete agreement in 35% of cases), which almost doubled to ‘good’ level (kappa 0.635, 95% CI 0.572–0.697, p<0.001) when comprehensive FFR was available (complete agreement in 66% of cases). Overall, the consensus management plan changed in 36.7%, 52% and 37.3% of cases for ICs, NICs and CSs, respectively, when FFR data were available.ConclusionsCompared with ICA alone, the availability of systematic FFR of all major coronary arteries produced a significantly more concordant interpretation and more homogeneous management plan among IC, NIC and CS specialists. Comprehensive physiological assessment may be of value in routine care for Heart Team decision-making.Trial registration numberNCT01070771.
Awareness and use of short-fill e-liquids by youth in England in 2021: findings from the ITC Youth Tobacco and Vaping Survey
Authors: Taylor Eve , East Katherine , Reid Jessica L , Hammond David 
Published: May 2023

Background
Refillable e-cigarettes were popular among youth in England in 2021. The UK Tobacco and Related Products Regulations (TRPR) limits e-liquids to 20 mg/mL of nicotine in a 10 mL bottle. Short-fill e-liquids, which are not covered by TRPR regulations, are typically nicotine-free and come in larger, underfilled bottles allowing customisation with the addition of ‘nicotine shots’. This paper investigates awareness, use, and reasons for use of short-fill e-liquids among youth in England.

Methods
Data are from the online 2021 International Tobacco Control Youth Survey, comprising 4224 youth (aged 16–19 years) in England. Weighted logistic regression models investigated associations between awareness and past 30-day use of short-fills by smoking status, vaping status, nicotine strength vaped and participant demographics. Reasons for use were also reported.

Results
Approximately one-quarter (23.0%) of youth in England reported awareness of short-fill e-liquids. Among youth who had vaped in the past 30 days, 22.1% had used short-fills in the past 30 days; use was most prevalent among those who were also smoking (43.2%) and those who reported usually vaping nicotine concentrations of 2.1% (21 mg/mL) or more (40.8%). ‘Convenience of a bigger bottle’ was the most selected reason for use (45.0%), followed by ‘less expensive than regular e-liquids’ (37.6%).

Conclusions
Awareness of short-fills was common among youth in 2021, including among those who had never vaped or smoked. Among youth who vaped in the past 30 days, short-fill use was more prevalent among those who also smoked and those who vaped nicotine-containing e-liquids. Integration of short-fill products into existing e-cigarette regulations should be considered.
Minimal Critical Sequences in Model-based Safety and Security Analyses: Commonalities and Differences
Authors: Serru Théo , Nguyen Nga , Batteux Michel , Rauzy Antoine 
Published: May 2023

Discrete event systems are increasingly used as a modeling tool to assess safety and cybersecurity of complex systems. In both cases, the analysis relies on the extraction of critical sequences. This approach proves to be very powerful. It suffers, however, from the combinatorial explosion of the number of sequences to look at. To push the limits of what is feasible with reasonable computational resources, extraction algorithms use cutoffs and minimality criteria.
In this article, we review the principles of extraction algorithms, and we show that there are important differences between critical sequences extracted in the context of safety analyses and those extracted in the context of cybersecurity analyses. Based on this thorough comparison, we introduce a new cutoff criterion, so-called footprint, that aims at capturing the willfulness of an intruder performing a cyberattack. We illustrate our presentation by means of three case studies, one focused on the analysis of failures and two focused on the analysis of cyberattacks and their effects on safety. We show experimentally the interest of the footprint criterion.
Inhibition of ACAA1 Restrains Proliferation and Potentiates the Response to CDK4/6 Inhibitors in Triple-Negative Breast Cancer
Authors: Peng Wen-Ting , Jin Xi , Xu Xiao-En , Yang Yun-Song , Ma Ding , Shao Zhi-Ming , Jiang Yi-Zhou 
Published: May 2023

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with unfavorable outcomes. Developing therapeutic targets for TNBC remains a challenge. Here, we identified that acetyl-CoA acyltransferase 1 (ACAA1) is highly expressed in the luminal androgen receptor (LAR) subtype of TNBC compared with adjacent normal tissues in our TNBC proteomics dataset. Inhibition of ACAA1 restrained TNBC proliferation and potentiated the response to the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib. Mechanistically, ACAA1 interacted with CDK4, and the inhibition of ACAA1 blocked RB transcriptional corepressor 1 (RB1) phosphorylation, resulting in G1–S cell-cycle arrest. Importantly, trimetazidine, a traditional drug for ischemic heart disease, caused a decrease in ACAA1 protein levels and enhanced the efficacy of abemaciclib in preclinical TNBC models. In conclusion, this study identifies that ACAA1 is a therapeutic target in TNBC and suggests the combination of trimetazidine and abemaciclib could be beneficial for ACAA1-high TNBCs.

Significance:
ACAA1 is highly expressed in TNBC, serving as a potential therapeutic target in ACAA1-high tumors and a predictive biomarker of resistance to CDK4/6 inhibitors for RB1-proficient patients.
BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors
Authors: Petrelli Annalisa , Rizzolio Sabrina , Pietrantonio Filippo , Bellomo Sara E. , Benelli Matteo , De Cecco Loris , Romagnoli Dario , Berrino Enrico , Orrù Claudia , Ribisi Salvatore , Moya-Rull Daniel , Migliore Cristina , Conticelli Daniela , Maina Irene M. , Puliga Elisabetta , Serra Violeta , Pellegrino Benedetta , Llop-Guevara Alba , Musolino Antonino , Siena Salvatore , Sartore-Bianchi Andrea , Prisciandaro Michele , Morano Federica , Antista Maria , Fumagalli Uberto , De Manzoni Giovanni , Degiuli Maurizio , Baiocchi Gian Luca , Amisano Marco F. , Ferrero Alessandro , Marchiò Caterina , Corso Simona , Giordano Silvia 
Published: May 2023

Abstract

Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as “benign.” However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer.

Significance:
PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.
Updated Review of Major Cancer Risk Factors and Screening Test use in the United States, with a Focus on Changes During the COVID-19 Pandemic
Authors: Star Jessica , Bandi Priti , Nargis Nigar , Islami Farhad , Yabroff K. Robin , Minihan Adair K. , Smith Robert A. , Jemal Ahmedin 
Published: May 2023

Abstract
We present national and state representative prevalence estimates of modifiable cancer risk factors, preventive behaviors and services, and screening, with a focus on changes during the COVID-19 pandemic. Between 2019 and 2021, current smoking, physical inactivity, and heavy alcohol consumption declined, and human papillomavirus vaccination and stool testing for colorectal cancer screening uptake increased. In contrast, obesity prevalence increased, while fruit consumption and cervical cancer screening declined during the same timeframe. Favorable and unfavorable trends were evident during the second year of the COVID-19 pandemic that must be monitored as more years of consistent data are collected. Yet disparities by racial/ethnic and socioeconomic status persisted, highlighting the continued need for interventions to address suboptimal levels among these population subgroups.
Monitoring Sarcoma Response to Immune Checkpoint Inhibition and Local Cryotherapy with Circulating Tumor DNA Analysis
Authors: Bui Nam Q. , Nemat-Gorgani Neda , Subramanian Ajay , Torres Ileana A. , Lohman Marta , Sears Timothy J. , van de Rijn Matt , Charville Gregory W. , Becker Hans-Christoph , Wang David S. , Hwang Gloria L. , Ganjoo Kristen N. , Moding Everett J. 
Published: May 2023

Abstract

Purpose:
Immune checkpoint inhibition has led to promising responses in soft tissue sarcomas (STS), but the majority of patients do not respond and biomarkers of response will be crucial. Local ablative therapies may augment systemic responses to immunotherapy. We evaluated circulating tumor DNA (ctDNA) as a biomarker of response in patients treated on a trial combining immunotherapy with local cryotherapy for advanced STS.

Patients and Methods:
We enrolled 30 patients with unresectable or metastatic STS to a phase II clinical trial. Patients received ipilimumab and nivolumab for four doses followed by nivolumab alone with cryoablation performed between cycles 1 and 2. The primary endpoint was objective response rate (ORR) by 14 weeks. Personalized ctDNA analysis using bespoke panels was performed on blood samples collected prior to each immunotherapy cycle.

Results:
ctDNA was detected in at least one sample for 96% of patients. Pretreatment ctDNA allele fraction was negatively associated with treatment response, progression-free survival (PFS), and overall survival (OS). ctDNA increased in 90% of patients from pretreatment to postcryotherapy, and patients with a subsequent decrease in ctDNA or undetectable ctDNA after cryotherapy had significantly better PFS. Of the 27 evaluable patients, the ORR was 4% by RECIST and 11% by irRECIST. Median PFS and OS were 2.7 and 12.0 months, respectively. No new safety signals were observed.

Conclusions:
ctDNA represents a promising biomarker for monitoring response to treatment in patients with advanced STS, warranting future prospective studies. Combining cryotherapy and immune checkpoint inhibitors did not increase the response rate of STS to immunotherapy.
NL-201 Upregulates MHC-I Expression and Intratumoral T-cell Receptor Diversity, and Demonstrates Robust Antitumor Activity as Monotherapy and in Combination with PD-1 Blockade
Authors: Mortales Christie , Dutzar Benjamin , Chen Jerry , Chen Alex , Huard Justin , Walkey Carl , Swanson Ryan 
Published: May 2023

Abstract
Cytokine engineering has shown promise as a means to create novel immunomodulatory agents or to improve upon the therapeutic potential of natural cytokines. NL-201, a de novo, hyperstable, IL2 receptor alpha (IL2Rα)–independent agonist of the receptors for IL2 and IL15, elicits robust preclinical activity in syngeneic murine cancer models, including those resistant to immune checkpoint inhibitors (ICI). Here, we report that NL-201 monotherapy converts ‘cold’ tumor microenvironments (TME) to immunologically ‘hot’ states by driving pro-inflammatory gene expression, enhancing IFNγ-dependent MHC-I expression, and expanding both T-cell number and clonal diversity. In addition, the combination of NL-201 and anti–PD-1 resulted in complementary antitumor activity in the immunologically ‘cold’ and ICI resistant B16F10, EMT6, and Renca syngeneic models. In the B16F10 model, treatment with NL-201 plus anti–PD-1 increased the abundance of CD4+ and CD8+ effector T cells in the TME. These findings reveal an important mechanistic basis for the antitumor activity of NL-201 both as a monotherapy and in combination with PD-1 antagonists, and provide further context for the role of IL2Rα-based signaling in ICI-resistant tumors.
The “Nuts and Bolts” of Doing Coproduction: Exploring Implementation Decisions in Climate Adaptation Research with Stakeholders
Authors: Clifford K. R. , Henderson J. , McAlear Z. , Dilling L. , Duncan B. , Ehert S. , Arens S. , Page R. , Rick U. 
Published: May 2023

Abstract
Developing local climate adaptation strategies that respond to weather and climate extremes is increasingly salient. Coproducing knowledge and climate adaptation strategies can be an important approach to ensuring that they are context specific, meet community needs, and are deemed usable by local decision-makers. Most of the guidance for coproduction has focused on important, overarching themes and ethical considerations like trust, iteration, and flexibility; these are incredibly valuable, but little attention has been focused on specific, highly consequential research decisions that researchers must make that shape project outcomes. Here, we reflect on our experience in a pilot project coproducing climate adaptation knowledge and strategies in six rural communities. We identify eight questions that researchers coproducing science with communities will need to grapple with when designing and conducting research and discuss some of the related trade-offs of each. Topics include community recruitment, champion selection, participant makeup, geography, clarifying expectations, timing, prioritization, and next steps. The questions are broadly applicable to knowledge coproduction and important especially as greater attention is being given to the ethics of doing this work, the power relations, and the potential risk associated with it. We hope that these questions can guide a dialogue for others and motivate explicit discussions of trade-offs involved in planning research that is coproduced with communities. We call for more of this type of self-reflection and sharing across our research community to deepen our knowledge and hopefully lead to a more rapid improvement in outcomes across the many efforts underway today to cocreate climate knowledge for adaptation.
‘It’s tough. It is hard’: A qualitative interview study of staff and volunteers caring for hospice in-patients with delirium
Authors: Featherstone Imogen , Siddiqi Najma , Jones Lesley , Coppo Eleonora , Sheldon Trevor , Hosie Annmarie , Wolkowski Anna , Bush Shirley H , Taylor Johanna , Teodorczuk Andrew , Johnson Miriam J 
Published: May 2023

Background: Delirium is a distressing condition often experienced by hospice in-patients. Increased understanding of current multidisciplinary care of delirium is needed to develop interventions in this setting. Aim(s): To explore hospice staff and volunteers’ practice, its influences and what may need to change to improve hospice delirium care. Design: Qualitative interview study using behaviour change theory from a critical realist stance. Setting/participants: Thirty-seven staff, including different professional groups and roles, and volunteers were purposively sampled from two in-patient hospices. Results: We found that participants’ practice focus was on managing hyperactive symptoms of delirium, through medication use and non-pharmacological strategies. Delirium prevention, early recognition and hypoactive delirium received less attention. Our theoretically-informed analysis identified this focus was influenced by staff and volunteers’ emotional responses to the distress associated with hyperactive symptoms of delirium as well as understanding of delirium prevention, recognition and care, which varied between staff groups. Non-pharmacological delirium management was supported by adequate staffing levels, supportive team working and a culture of person-centred and family-centred care, although behaviours that disrupted the calm hospice environment challenged this. Conclusions: Our findings can inform hospice-tailored behaviour change interventions that develop a shared team understanding and engage staff’s emotional responses to improve delirium care. Reflective learning opportunities are needed that increase understanding of the potential to reduce patient distress through prevention and early recognition of delirium, as well as person-centred management. Organisational support for adequate, flexible staffing levels and supportive team working is required to support person-centred delirium care.