bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus
Authors: Wong Charis , Gregory Jenna M , Liao Jing , Egan Kieren , Vesterinen Hanna M , Ahmad Khan Aimal , Anwar Maarij , Beagan Caitlin , Brown Fraser S , Cafferkey John , Cardinali Alessandra , Chiam Jane Yi , Chiang Claire , Collins Victoria , Dormido Joyce , Elliott Elizabeth , Foley Peter , Foo Yu Cheng , Fulton-Humble Lily , Gane Angus B , Glasmacher Stella A , Heffernan Áine , Jayaprakash Kiran , Jayasuriya Nimesh , Kaddouri Amina , Kiernan Jamie , Langlands Gavin , Leighton D , Liu Jiaming , Lyon James , Mehta Arpan R , Meng Alyssa , Nguyen Vivienne , Park Na Hyun , Quigley Suzanne , Rashid Yousuf , Salzinger Andrea , Shiell Bethany , Singh Ankur , Soane Tim , Thompson Alexandra , Tomala Olaf , Waldron Fergal M , Selvaraj Bhuvaneish T , Chataway Jeremy , Swingler Robert , Connick Peter , Pal Suvankar , Chandran Siddharthan , Macleod Malcolm 
Published: February 2023

ObjectivesMotor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART:NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.MethodsWe conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.ResultsFrom the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.DiscussionFor future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.
Safety and efficacy of an artificial intelligence-enabled decision tool for treatment decisions in neovascular age-related macular degeneration and an exploration of clinical pathway integration and implementation: protocol for a multi-methods validation study
Authors: Hogg Henry David Jeffry , Brittain Katie , Teare Dawn , Talks James , Balaskas Konstantinos , Keane Pearse , Maniatopoulos Gregory 
Published: February 2023

IntroductionNeovascular age-related macular degeneration (nAMD) management is one of the largest single-disease contributors to hospital outpatient appointments. Partial automation of nAMD treatment decisions could reduce demands on clinician time. Established artificial intelligence (AI)-enabled retinal imaging analysis tools, could be applied to this use-case, but are not yet validated for it. A primary qualitative investigation of stakeholder perceptions of such an AI-enabled decision tool is also absent. This multi-methods study aims to establish the safety and efficacy of an AI-enabled decision tool for nAMD treatment decisions and understand where on the clinical pathway it could sit and what factors are likely to influence its implementation.Methods and analysisSingle-centre retrospective imaging and clinical data will be collected from nAMD clinic visits at a National Health Service (NHS) teaching hospital ophthalmology service, including judgements of nAMD disease stability or activity made in real-world consultant-led-care. Dataset size will be set by a power calculation using the first 127 randomly sampled eligible clinic visits. An AI-enabled retinal segmentation tool and a rule-based decision tree will independently analyse imaging data to report nAMD stability or activity for each of these clinic visits. Independently, an external reading centre will receive both clinical and imaging data to generate an enhanced reference standard for each clinic visit. The non-inferiority of the relative negative predictive value of AI-enabled reports on disease activity relative to consultant-led-care judgements will then be tested. In parallel, approximately 40 semi-structured interviews will be conducted with key nAMD service stakeholders, including patients. Transcripts will be coded using a theoretical framework and thematic analysis will follow.Ethics and disseminationNHS Research Ethics Committee and UK Health Research Authority approvals are in place (21/NW/0138). Informed consent is planned for interview participants only. Written and oral dissemination is planned to public, clinical, academic and commercial stakeholders.
Time trends in caesarean section rates and associations with perinatal and neonatal health: a population-based cohort study of 1 153 789 births in Norway
Authors: Laine Katariina , Pay Aase Devold , Yli Branka M 
Published: February 2023

ObjectivesTo study caesarean section (CS) rates and associations with perinatal and neonatal health in Norway during 1999–2018.DesignPopulation-based cohort study.SettingMedical Birth Registry of Norway.Participants1 153 789 births and 1 174 066 newborns.MethodsCS, intrapartum, perinatal and neonatal mortality rates expressed as percentages (%) or per mille (‰) with 95% CIs.Primary and secondary outcome measuresCS rates in the Robson Ten-Group Classification System; intrapartum, perinatal and neonatal mortality rates.ResultsThe overall CS rate increased from 12.9% in 1999 to 16.7% in 2008 (p<0.001), and then reduced to 15.8% in 2018 (p<0.001). The largest reductions were observed in Robson groups 2 and 4. In Robson group 2, the planned CS rate decreased from 9.6% in 2007–2008 to 4.6% in 2017–2018, the intrapartum CS rate decreased from 26.6% in 2007–2008 to 22.3% in 2017–2018. In Robson group 4, the planned CS rate decreased from 16.1% in 2007–2008 to 7.6% in 2017–2018, and the intrapartum CS rate decreased from 7.8% in 2007–2008 to 5.2% in 2017–2018.The intrapartum fetal mortality rate decreased from 0.51 per 1000 (‰) in 1999–2000 to 0.14‰ in 2017–2018. Neonatal mortality decreased from 2.52‰ to 1.58‰.ConclusionsCS rates in Norway increased between 1999 and 2008, followed by a significant reduction between 2008 and 2018. At the same time, fetal and neonatal mortality rates decreased. Norwegian obstetricians and midwives have contributed to maintaining a low CS rate under 17%. These findings indicate that restricting the use of CS is a safe option for perinatal health.
Observational prospective study of social media, smartphone use and self-harm in a clinical sample of young people: study protocol
Authors: Bye Amanda , Carter Ben , Leightley Daniel , Trevillion Kylee , Liakata Maria , Branthonne-Foster Stella , Williamson Grace , Zenasni Zohra , Dutta Rina 
Published: February 2023

IntroductionYoung people are the most frequent users of social media and smartphones and there has been an increasing speculation about the potential negative impacts of their use on mental health. This has coincided with a sharp increase in the levels of self-harm in young people. To date, studies researching this potential association are predominantly cross-sectional and reliant on self-report data, which precludes the ability to objectively analyse behaviour over time. This study is one of the first attempts to explore temporal patterns of real-world usage prior to self-harm, to identify whether there are usage patterns associated with an increased risk.Methods and analysisTo study the mechanisms by which social media and smartphone use underpin self-harm in a clinical sample of young people, the Social media, Smartphone use and Self-harm in Young People (3S-YP) study uses a prospective, observational study design. Up to 600 young people aged 13–25 years old from secondary mental health services will be recruited and followed for up to 6 months. Primary analysis will compare real-world data in the 7 days leading up to a participant or clinician recorded self-harm episode, to categorise patterns of problematic usage. Secondary analyses will explore potential mediating effects of anxiety, depression, sleep disturbance, loneliness and bullying.Ethics and disseminationThis study was approved by the National Research Ethics Service, London - Riverside, as well as by the Joint Research and Development Office of the Institute of Psychiatry, Psychology and Neuroscience and South London and Maudsley NHS Foundation Trust (SLaM), and the SLaM Clinical Research Interactive Search (CRIS) Oversight Committee. The findings from this study will be disseminated through peer-reviewed scientific journals, conferences, websites, social media and stakeholder engagement activities.Trial registration numberNCT04601220.
Factor analysis of community-ranked built environment factors contributing to pedestrian injury risk in Kampala city, Uganda
Authors: Bayiga-Zziwa Esther , Nsubuga Rogers , Mutto Milton 
Published: February 2023

BackgroundExamining community perspective on an issue is not only a key consideration in research on road safety but also on other topics. There is substantial theoretical and empirical knowledge on built environment factors that contribute to pedestrian injury but how the community views these factors is least studied and constitutes the focus of this study. Our study investigated how respondents ranked the relative importance of selected built environment factors that contribute to pedestrian injury risk in Kampala city, Uganda and examined the underlying pattern behind the rankings.MethodsEight hundred and fifty-one pedestrians selected from 14 different road sections in Kampala city were asked to rank each of the 27 built environment variables on a 4-point Likert scale. Point score analysis was used to calculate scores for the different built environment variables and rank them in order of perceived contribution while factor analysis was used to determine the pattern underlying the responses.ResultsFactor analysis isolated two factors that explained 92% of the variation in respondents’ rankings: ‘road adjacent trip generators and attractors’ and ‘structure of traffic flows’. This finding implies that pedestrians in Kampala city perceived trip generators and attractors adjacent to the road and the structure of traffic flows as major explanations of the influence of the built environment on pedestrian injury risk.ConclusionWhile these rankings and factors identified may not necessarily equate to actual risk, they are important in providing an understanding of pedestrian injury risk from the perspective of the community.
First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817
Authors: Ready Neal E , Audigier-Valette Clarisse , Goldman Jonathan W , Felip Enriqueta , Ciuleanu Tudor-Eliade , Rosario García Campelo María , Jao Kevin , Barlesi Fabrice , Bordenave Stéphanie , Rijavec Erika , Urban Laszlo , Aucoin Jean-Sébastien , Zannori Cristina , Vermaelen Karim , Arén Frontera Osvaldo , Curioni Fontecedro Alessandra , Sánchez-Gastaldo Amparo , Juan-Vidal Oscar , Linardou Helena , Poddubskaya Elena , Spigel David R , Ahmed Samreen , Maio Michele , Li Sunney , Chang Han , Fiore Joseph , Acevedo Angelic , Paz-Ares Luis 
Published: February 2023

BackgroundCheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0–1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection).MethodsCohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3–4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory.ResultsThe most common grade 3–4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3–4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively.ConclusionsFlat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0–1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate.Trial registration numberNCT02869789.
Gene–environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures
Authors: Nasr Zahra , Schoeps Vinicius Andreoli , Ziaei Amin , Virupakshaiah Akash , Adams Cameron , Casper T Charles , Waltz Michael , Rose John , Rodriguez Moses , Tillema Jan-Mendelt , Chitnis Tanuja , Graves Jennifer S , Benson Leslie , Rensel Mary , Krupp Lauren , Waldman Amy T , Weinstock-Guttman Bianca , Lotze Tim , Greenberg Benjamin , Aaen Gregory , Mar Soe , Schreiner Teri , Hart Janace , Simpson-Yap Steve , Mesaros Clementina , Barcellos Lisa F , Waubant Emmanuelle 
Published: February 2023

BackgroundWe previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis.MethodsUsing a case–control paediatric multiple sclerosis study, gene–environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence ofDRB1*15and the absence ofA*02,and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, includingIL-6(rs2069852),BCL-2(rs2187163) andNFKB1(rs7665090).Results490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products andNFKB1SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence ofHLA-A*02(AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products andNFKB1SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found withIL-6andBCL-2SNP GG genotypes.ConclusionsThe presence of gene–environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.
Macroeconomic impact of tobacco taxation in Indonesia
Authors: Bella Adrianna , Swarnata Arya , Vulovic Violeta , Nugroho Dhanie , Meilissa Yurdhina , Usman Usman , Dartanto Teguh 
Published: February 2023

BackgroundA significant tobacco tax increase has long been advocated to reduce Indonesia’s high smoking prevalence. However, implementing such a policy remains challenging due to the tobacco industry’s argument that it would negatively impact the economy.ObjectiveThis study aims to provide a comprehensive estimate of the net impact of tobacco taxation on Indonesia’s economy.MethodThe impact of the tax hike on the economy is simulated through a change in cigarette demand and reallocation of household’s budget and allocation government spending from additional tobacco tax revenue. Input-output analysis is employed to estimate the net effect of the tobacco tax rise on the total economic output, income and employment in Indonesia.FindingIncreasing the tobacco tax would generate a net positive impact on the economy as it would increase economic output, household income and employment. The positive impact is mainly driven by government spending from additional revenue from increased tobacco taxes. Spending tax revenue using the current structure of government spending has the potential to generate the optimal economic effect. Increasing tobacco tax by 45% from the 2019 tax level would increase economic output, household income and employment by Rp84.2 trillion, Rp24.1 trillion and 400.3 thousand jobs, respectively.
SHRIMP U–Pb geochronology of Mesoproterozoic basement and overlying Ocoee Supergroup, NC–TN: dating diagenetic xenotime and monazite overgrowths on detrital minerals to determine the age of sedimentary deposition
Authors: Aleinikoff John N. , Southworth Scott , Fanning C. Mark 
Published: February 2023

Sedimentary rocks of the Ocoee Supergroup crop out in the Appalachian Blue Ridge of western North Carolina and eastern Tennessee. This ∼12 km thick sequence of strata was mapped as nonconformably overlying Mesoproterozoic crystalline basement (about 1.20–1.02 Ga) and beneath the lower Cambrian Chilhowee Group, leading to the traditional interpretation that the Ocoee Supergroup was deposited between about 1.02 and 0.54 Ga. This interpretation was challenged by Unrug and Unrug (1990, Geology, 18: 1041–1045) and Unrug et al. (2000, Geological Society of America Bulletin. Vol. 112, pp. 982–996), who claimed that Paleozoic fossils were recovered from rocks of the Walden Creek Group (upper Ocoee), and thereby created a new tectonic model for the origin of Laurentia. To resolve the age controversy concerning the time of deposition of the Ocoee Supergroup, diagenetic xenotime overgrowths on detrital zircon and diagenetic monazite on detrital monazite were dated by the U–Pb method. Sensitive High Resolution Ion Microprobe ages of diagenetic xenotime from three samples of sandstone (Thunderhead Sandstone, Cades Sandstone, and Shields Formation) indicate that the Ocoee Supergroup was deposited in the interval of about 580–550 Ma. A sample of Sandsuck Formation (uppermost Ocoee) yielded xenotime overgrowths of about 410 Ma, probably related to post-depositional low-grade metamorphism. Various origins of xenotime overgrowths may be distinguished by trace element distributions. Ages and trace element concentrations of monazite overgrowths support the xenotime age results, although concordia systematics are complicated by high concentrations of common Pb and inheritance of ages (∼1.2 and 0.6 Ga). These age data support the observed field relations for a late Neoproterozoic depositional age of the Ocoee Supergroup.
PRP19 Enhances Esophageal Squamous Cell Carcinoma Progression by Reprogramming SREBF1-Dependent Fatty Acid Metabolism
Authors: Zhang Guang-Cong , Yu Xiang-Nan , Guo Hong-Ying , Sun Jia-Lei , Liu Zhi-Yong , Zhu Ji-Min , Liu Tao-Tao , Dong Ling , Shen Xi-Zhong , Yin Jie 
Published: February 2023

AbstractLipid metabolism reprogramming is a recognized hallmark of cancer cells. Identification of the underlying regulators of metabolic reprogramming in esophageal squamous cell carcinoma (ESCC) could uncover potential therapeutic targets to improve treatment. Here, we demonstrated that pre-mRNA processing factor 19 (PRP19) mediates reprogramming of lipid metabolism in ESCC. Expression of PRP19 was significantly upregulated in multiple ESCC cohorts and was correlated with poor clinical prognosis. PRP19 promoted ESCC proliferation in vitro and in vivo. Upregulation of PRP19 enhanced fatty acid synthesis through sterol regulatory element-binding protein 1 (SREBF1), a major transcription factor of lipid synthase. Moreover, PRP19 enhanced the stability of SREBF1 mRNA in an N6-methyladenosine–dependent manner. Overall, this study shows that PRP19-mediated fatty acid metabolism is crucial for ESCC progression. Targeting PRP19 is a potential therapeutic approach to reverse metabolic reprogramming in patients with ESCC.Significance:Upregulation of pre-mRNA processing factor 19 (PRP19) contributes to esophageal squamous cell carcinoma progression by reprogramming SREBF1-dependent fatty acid metabolism, identifying PRP19 as a potential prognostic biomarker and therapeutic target.