bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate cancer androgen receptor splice variant 7 biomarker study - a multicentre randomised feasibility trial of biomarker-guided personalised treatment in patients with advanced prostate cancer (the VARIANT trial) study protocol
Authors: Clark Emma , Morton Miranda , Sharma Shriya , Fisher Holly , Howel Denise , Walker Jenn , Wood Ruth , Hancock Helen , Maier Rebecca , Marshall John , Bahl Amit , Crabb Simon , Jain Suneil , Pedley Ian , Jones Rob , Staffurth John , Heer Rakesh 
Published: April 2023

IntroductionProstate cancer is the most common male cancer with one in four developing non-curable metastatic disease. Initial treatment responses to hormonal therapies are transient and further management options lie between (1) further hormone therapy or (2) a non-hormonal approach involving additional chemotherapy or molecular radiotherapy (radium-223). There is no clear rationale for choosing between these mechanistically different treatment approaches. The biology of hormone resistance is driven through abnormal androgen receptor activity and we can assay this through a blood test measuring androgen receptor variant 7 (AR-V7) expression in circulating tumour cells. Despite increasing evidence supporting AR-V7’s role as a prognostic marker, the clinical utility of such measures remains unknown in helping personalise treatment decisions.Methods and designThe VARIANT feasibility trial is a pragmatic design, to be run over 18 months with participants randomised into the intervention arm receiving biomarker (AR-V7) guided clinical treatment and participants randomised into the control arm with conventional standard management (no biomarker guidance). AR-V7 positive participants (likely to be insensitive to further hormone treatment) will receive chemotherapy or in other cases radium-223 (where routinely available). Seventy male ≥18 years old participants with metastatic castrate resistant prostate cancer clinically indicated to proceed to further hormone therapy or chemotherapy, will be recruited from three National Health Service Trusts based in England, Scotland and Wales. The feasibility primary outcome is willingness of patients to be randomised and clinicians to recruit to a biomarker-based treatment strategy, with trial data informing the basis of a definitive and appropriately powered randomised control trial.Ethics and disseminationFormal ethics review was undertaken with a favourable opinion, through Wales NRES Committee 2 18/WA/0419. Findings to be disseminated through patient and professional organisations that have expressed their support, media outlets and peer-reviewed journal publication.Trial registration numberNCT10246848
Duloxetine combined with intra-articular injection versus intra-articular injection alone for pain relief in knee osteoarthritis: a study protocol for a randomised controlled trial
Authors: Li Duo Yi , Han Rong , Zhao Zhi Gang , Luo Fang 
Published: April 2023

IntroductionIntra-articular (IA) injection of hyaluronic acid (HA) and corticosteroid (CS) is a common treatment for osteoarthritis (OA) of the knee. As a drug treatment for patients with depression, duloxetine has been shown in many studies to effectively relieve the pain of OA and improve function of the knee joint. However, evidence regarding the efficacy of IA injection of HA+CS combined with duloxetine for pain management in patients with OA of the knee is lacking. The aim of this study was to test the hypothesis that IA injection of HA+CS combined with duloxetine could achieve pain management superior to that of IA injection of HA+CS alone in patients experiencing knee OA pain.MethodsThis study will adopt a prospective, randomised, open-label blind endpoint study design. In total, 150 patients with OA of the knee will be enrolled in the study. The participants will be randomly allocated to receive either a single IA injection of HA+CS combined with duloxetine or a single IA injection of HA+CS alone, and both groups will complete a 24-week follow-up to assess pain and functional improvements. The primary outcome measure is the change in the weekly mean of the 24 hours average pain scores from baseline to the end of 24 weeks in patients with OA of the knee, and the secondary outcomes include the response to treatment, changes from baseline in the brief pain inventory, improvement in the Western Ontario and McMaster Universities Osteoarthritis index scores, patient global impression of improvement scale, Hospital Anxiety and Depression Scale and adverse events during the 24-week follow-up. The data will be analysed by the intention-to-treat principle.Ethics approval and disseminationThis study was approved by the institutional ethics committee of the Beijing Tiantan Hospital (approval number: KY 2019-086-02). The results of the study will be published in peer-reviewed journals, and the findings will be presented at scientific meetings.Trial registration numberClinicalTrials.gov Identifier:NCT04117893.
Study protocol: evaluation of the 0–5 public health investment in England – a mixed-methods study integrating analyses of national linked administrative data with in-depth case studies
Authors: Harron Katie , Cavallaro Francesca L , Bunting Catherine , Clery Amanda , Kendall Sally , Cassidy Rebecca , Atkins Julie , Saloniki Eirini-Christina , Bedford Helen , Woodman Jenny 
Published: April 2023

IntroductionHealth visiting is a long-established, nationally implemented programme that works with other services at a local level to improve the health and well-being of children and families. To maximise the impact and efficiency of the health visiting programme, policy-makers and commissioners need robust evidence on the costs and benefits of different levels and types of health visiting, for different families, in different local contexts.Methods and analysisThis mixed-methods study will analyse individual-level health visiting data for 2018/2019 and 2019/2020 linked with longitudinal data from children’s social care, hospitals and schools to estimate the association of number and type of health visiting contacts with a range of children and maternal outcomes. We will also use aggregate local authority data to estimate the association between local models of health visiting and area-level outcomes. Outcomes will include hospitalisations, breast feeding, vaccination, childhood obesity and maternal mental health. Where possible, outcomes will be valued in monetary terms, and we will compare total costs to total benefits of different health visiting service delivery models. Qualitative case studies and extensive stakeholder input will help explain the quantitative analyses and interpret the results in the context of local policy, practice and circumstance.Ethics and disseminationThe University College London Research Ethics Committee approved this study (ref 20561/002). Results will be submitted for publication in a peer-reviewed journal and findings will be shared and debated with national policy-makers, commissioners and managers of health visiting services, health visitors and parents.
Development and testing of the QDis-MH checklist for discharge letters from specialised mental healthcare: a stakeholder-centred study
Authors: Biringer Eva , Helgeland J , Hellesen H B , Aβmus Jörg , Hartveit M 
Published: April 2023

BackgroundThe ‘discharge letter’ is the mandatory written report sent from specialists in the specialist services to general practitioners (GPs) on patient discharge. Clear recommendations from relevant stakeholders for contents of discharge letters and instruments to measure the quality of discharge letters in mental healthcare are needed. The objectives were to (1) detect which information relevant stakeholders defined as important to include in discharge letters from mental health specialist services, (2) develop a checklist to measure the quality of discharge letters and (3) test the psychometric properties of the checklist.MethodsWe used a stepwise multimethod stakeholder-centred approach. Group interviews with GPs, mental health specialists and patient representatives defined 68 information items with 10 consensus-based thematic headings relevant to include in high-quality discharge letters. Information items rated as highly important by GPs (n=50) were included in the Quality of Discharge information-Mental Health (QDis-MH) checklist. The 26-item checklist was tested by GPs (n=18) and experts in healthcare improvement or health services research (n=15). Psychometric properties were assessed using estimates of intrascale consistency and linear mixed effects models. Inter-rater and test–retest reliability were assessed using Gwet’s agreement coefficient (Gwet’s AC1) and intraclass correlation coefficients.ResultsThe QDis-MH checklist had satisfactory intrascale consistency. Inter-rater reliability was poor to moderate, and test–retest reliability was moderate. In descriptive analyses, mean checklist scores were higher in the category of discharge letters defined as ‘good’ than in ‘medium’ or ’poor’ letters, but differences did not reach statistical significance.ConclusionsGPs, mental health specialists and patient representatives defined 26 information items relevant to include in discharge letters in mental healthcare. The QDis-MH checklist is valid and feasible. However, when using the checklist, raters should be trained and the number of raters kept to a minimum due to questionable inter-rater reliability.
Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort
Authors: Stoltze Ulrik Kristoffer , Hildonen Mathis , Hansen Thomas Van Overeem , Foss-Skiftesvik Jon , Byrjalsen Anna , Lundsgaard Malene , Pignata Laura , Grønskov Karen , Tumer Zeynep , Schmiegelow Kjeld , Brok Jesper Sune , Wadt Karin A W 
Published: April 2023

BackgroundStudies suggest that Wilms tumours (WT) are caused by underlying genetic (5%–10%) and epigenetic (2%–29%) mechanisms, yet studies covering both aspects are sparse.MethodsWe performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes.ResultsOf 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1andREST). Only one patient had a family history of WT (3 cases), segregating with theRESTvariant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1,FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01).ConclusionWe find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.
Abstract 3868: Aurora kinase A inhibition overcome adaptive resistance to KRAS G12C inhibitor by G1-checkpoint induced apoptosis in KRAS non-small cell lung cancer
Authors: Li Chendi , Chang Jeremy , Syed Mohammed U. , Nimbalkar Anahita , Shen Yi , Altschuler Steve , Wu Lani , Gong Xueqian , Hata Aaron 
Published: April 2023

Abstract
Cancer cells gain drug-tolerant states and evade therapy. In response to KRAS G12C inhibitor (G12Ci), KRAS mutant non-small cell lung cancer (NSCLC) cells maintain a drug-tolerant state by aurora kinase A (AURKA). AURKA can phosphorylate c-Raf to maintain new KRAS signaling, however, how AURKA becomes activated to cause KRAS G12Ci resistance is unclear. We show here that KRAS G12C + AURKA inhibition cause synthetic lethality in KRAS G12C NSCLC cells. LY3499446 (KRAS G12Ci) and LSN3321213 (aurora kinase A inhibitor) induced apoptosis that is independent of inhibited MAPK reactivation. Using high-content imaging that tracks single-cell fate during treatment, we observed that single-agent KRAS G12Ci induces G1 arrest in a sub-population of cells. Upon co-treatment with G12C + AURKAi, cells that are halted in G1 phase undergo early apoptosis, while those that initially evade G1 arrest and proceed through G2/M undergo apoptosis in subsequent G1. These data suggest the hypothesis that AURKA inhibition may increase the probability of G1 checkpoint-induced apoptosis by facilitating chromosomal misalignment and genomic instability. In summary, we provide clinical rationale for clinical testing of KRAS G12C + AURKA inhibitors. We also suggest a novel mechanism explaining the dependency of KRAS G12C resistant subpopulations on AURKA, leading to the opportunity to investigate the role of genomic instability in conferring KRAS G12Ci adaptive resistance.
Citation Format: Chendi Li, Jeremy Chang, Mohammed U. Syed, Anahita Nimbalkar, Yi Shen, Steve Altschuler, Lani Wu, Xueqian Gong, Aaron Hata. Aurora kinase A inhibition overcome adaptive resistance to KRAS G12C inhibitor by G1-checkpoint induced apoptosis in KRAS non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3868.
Abstract 4305: Germline structural variants shape prostate cancer clinical and molecular evolution
Authors: Wang Nicholas K. , Rouette Alexandre , Houlahan Kathleen E. , Yamaguchi Takafumi N. , Livingstone Julie , Jung Chol-Hee , Georgeson Peter , Fraser Michael , Shiah Yu-Jia , Yao Cindy Q. , Huang Vincent , Fox Natalie S. , Kurganovs Natalie , Kasaian Katayoon , Sabelnykova Veronica Y. , Jayalath Jay , Weke Kenneth , Zhu Helen , van der Kwast Theodorus , Papenfuss Tony , He Housheng H. , Corcoran Niall M. , Bristow Robert G. , Zlotta Alexandre R. , Hovens Christopher , Boutros Paul C. 
Published: April 2023

Abstract
Inherited genetic variation profoundly influences cancer risk and outcome. While the impact of germline single nucleotide polymorphisms has been well-studied in several cancer types, the effects of germline structural variants (gSVs) on cancer biology and clinical outcomes is largely unknown. From our cohort of 300 men with localized, intermediate risk prostate cancer, we identified 6,003 gSVs present in at least 3% of patients; 48 were associated with recurrent somatic alterations or clinical outcome. Of these, approximately 50% were associated with expression of nearby genes or intersected with exons or regulatory regions. Using external cohorts, we validated three gSVs that were strongly associated with poor clinical outcomes, including an inversion at chr14q24.1 present in ~20% of patients. Notably, a strong synergistic effect on outcome was observed in patients with somatic TP53 alterations or high genomic instability, defining a new aggressive prostate cancer subtype with chr14INV as a novel, recurrent biomarker.
Citation Format: Nicholas K. Wang, Alexandre Rouette, Kathleen E. Houlahan, Takafumi N. Yamaguchi, Julie Livingstone, Chol-Hee Jung, Peter Georgeson, Michael Fraser, Yu-Jia Shiah, Cindy Q. Yao, Vincent Huang, Natalie S. Fox, Natalie Kurganovs, Katayoon Kasaian, Veronica Y. Sabelnykova, Jay Jayalath, Kenneth Weke, Helen Zhu, Theodorus van der Kwast, Tony Papenfuss, Housheng H. He, Niall M. Corcoran, Robert G. Bristow, Alexandre R. Zlotta, Christopher Hovens, Paul C. Boutros. Germline structural variants shape prostate cancer clinical and molecular evolution. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4305.
Abstract 5800: Anti-metastatic potential of pitavastatin in triple-negative breast cancer via targeting breast cancer stem-like properties and STAT3 signaling
Authors: Ko Dongmi , Seo Juyeon , Kim Seongjae , Park Soeun , Park Minsu , Nam Kee Dal , Kang Yong koo , Seock Sora , Jung Eunsun , Kim Yoon-Jae , Park Jaeyoun , Kim Ji Young , Seo Jae Hong 
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) is the most deadly and aggressive phenotype, with a higher rate of metastatic recurrence. TNBC does yet have a suitable treatment option other than cytotoxic anticancer drugs. Although pitavastatin has been shown to exert anti-proliferative effects and cytotoxicity in various types of cancer cells, the precise mechanisms underlying pitavastatin’s anti-cancer effects in TNBC have not been fully elucidated. We sought to investigate the mechanism of pitavastatin-induced apoptosis and its effects on cancer stem cell (CSC)-like characteristics in TNBC. Exposure to pitavastatin induced mitochondria-mediated apoptotic cell death in BT549 and 4T1 cells. Mitochondrial dysfunction was accompanied with a robust production of reactive oxygen species (ROS) and collapse of mitochondrial membrane potential (MMP), resulting in subsequent activation of caspase-3/-7 and PARP cleavage. Pitavastatin effectively suppressed CSC-like properties in TNBC via targeting CD44+/CD24- and CD49f+/CD24- phenotypes, as well as impediment of mammosphere formation in vitro. This phenomenon was accompanied with dysregulation of STAT3 survival pathway, concomitant with significant downregulation of cyclin D1, survivin and vimentin. Pitavastatin effectively targets both the proliferating TNBC tumor cells and CSCs via the dysregulation of STAT3 and suppression of CSC-like properties, markedly reducing angiogenesis and tumor growth, coinciding with decreased Ki-67 expression. It is noteworthy that pitavastatin considerably suppressed metastasis, coinciding with significant reduction of MMP-2, MMP-9 and VEGF in the circulating blood of mice. Our findings highlight that pitavastatin may be potentially effective for the treatment of metastatic TNBC.
Citation Format: Dongmi Ko, Juyeon Seo, Seongjae Kim, Soeun Park, Minsu Park, Kee Dal Nam, Yong koo Kang, Sora Seock, Eunsun Jung, Yoon-Jae Kim, Jaeyoun Park, Ji Young Kim, Jae Hong Seo. Anti-metastatic potential of pitavastatin in triple-negative breast cancer via targeting breast cancer stem-like properties and STAT3 signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5800.
Annual Cycle in Upper-Ocean Heat Content and the Global Energy Budget
Authors: Pan Yuying , Cheng Lijing , von Schuckmann Karina , Trenberth Kevin E. , Li Guancheng , Abraham John , Liu Yuanxin , Gouretski Viktor , Yu Yongqiang , Liu Hailong , Liu Chunlei 
Published: April 2023

Abstract
As a major component of Earth’s energy budget, ocean heat content (OHC) plays a vital role in buffering climate change. The annual cycle is the most prominent change in OHC but has always been removed to study variations and changes in Earth’s energy budget. Here, we investigate the annual cycle of the upper-2000-m OHC at regional to global scales and assess the robustness of the signals using the spread of multiple observational products. The potential drivers are also investigated by comparing the annual OHC signal with the corresponding change in top-of-atmosphere radiation, surface heat flux, ocean heat divergence, and meridional heat transport. Results show that the robust signal of annual OHC change is significant down to a 1000-m depth globally and can reach down to 1500 m in some areas such as the tropical ocean. The global OHC (0–1500 m) changes from positive anomalies within September–February to negative anomalies within March–August, mainly because of the larger ocean area in the Southern Hemisphere and the seasonal migration of solar irradiance. Owing to the huge ocean heat capacity, the annual cycle of OHC dominates that of the global energy budget. The difference among the OHC annual cycles in the three major ocean basins is mainly attributed to ocean heat transport, especially in the tropics. In the upper 1500 m at mid- and high latitudes and in the upper 50 m of the tropics, the net sea surface heat flux dominates the OHC annual cycle, while in the tropics below 50 m, wind-driven Ekman heat transport associated with the geostrophic flow is the main driver.
Otolaryngologic Presentations to Emergency Departments During the COVID-19 Pandemic: A Systematic Review and Meta-Analysis
Authors: Munhall Christopher C. , Shah Sunny , Nguyen Shaun A. , Meyer Ted A. , Schlosser Rodney J. , White David R. 
Published: April 2023

Objectives: To perform a systematic review of otolaryngologic presentation rates to emergency department settings before and after lockdown due to the COVID-19 pandemic. Sources: PubMed, Scopus, and CINAHL. Methods: A systematic search was conducted following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses) for studies describing otolaryngologic presentations to emergency department and rapid access clinic settings both in the before-lockdown and after-lockdown periods. The start of after-lockdown period varied based on initiation of lockdown, ranging from March 1st to June 1st of 2020 across general emergency department studies. Results: A total of 14 studies were included in this review. About 10 were general emergency departments, 3 were specifically pediatric emergency departments, and 1 study focused on the geriatric population (>65 years). A total of 13 790 patients were included, with 9446 in the before-lockdown period (68.5%) and 4344 in the after-lockdown period (31.5%). Meta-analysis of proportions for otolaryngologic presentations across general emergency departments was performed. Comparison of weighted proportions found significant differences between before-lockdown and after-lockdown presentation rates for infectious etiologies, tonsillitis specifically, foreign bodies, non-infectious airway issues, and epistaxis among these studies. Conclusions: The increased proportions of various non-infectious presentations (eg, epistaxis, foreign bodies, and airway issues) following lockdown might be associated with proportional decreases in infectious pathologies, given decreased social contact to prevent SARS-CoV-2 transmission. Overall, it is important for otolaryngologists to recognize what presentations might more commonly be seen and require evaluation and potential intervention in light of a global pandemic.