bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults
Authors: Koychev Ivan , Adler Amanda I , Edison Paul , Tom Brian , Milton Joanne E , Butchart Joe , Hampshire Adam , Marshall Charles , Coulthard Elizabeth , Zetterberg Henrik , Hellyer Peter , Cormack Francesca , Underwood Benjamin R , Mummery Catherine J , Holman Rury R 
Published: June 2024

IntroductionGlucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer’s disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD.Methods and analysisISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged ≥55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition. Eligible individuals are randomised in a 1:1 ratio to once-daily oral semaglutide or placebo, starting at 3 mg and up-titrating to 14 mg over 8 weeks. They will attend safety visits and provide blood samples to measure AD biomarkers at weeks 4, 8, 26 and 39. All cognitive assessments are repeated at week 26. The last study visit will be at week 52, when all baseline measurements will be repeated. The primary end point is the 1-year change in tau PET signal.Ethics and disseminationThe study was approved by the West Midlands—Edgbaston Research Ethics Committee (22/WM/0013). The results of the study will be disseminated through scientific presentations and peer-reviewed publications.Trial registration numberISRCTN71283871.
Public preferences and willingness to pay for a net zero NHS: a protocol for a discrete choice experiment in England and Scotland
Authors: Loría-Rebolledo Luis Enrique , Abbott Michael , Antunes Mélanie , Norwood Patricia , Ryan Mandy , Watson Verity , Wu Hangjian 
Published: June 2024

IntroductionClimate change poses a major threat to our health, livelihoods and the planet. In 2020, the UK National Health Service (NHS) committed to reducing its Scope 1, 2 and 3 emissions to reach net zero by 2045. Although a net zero NHS would help to limit the consequences of climate change, little is known about the UK general public’s values and preferences for the proposed service changes needed to reach net zero.MethodsThis study will elicit the public’s preferences for actions to help achieve net zero NHS in England and Scotland using a discrete choice experiment (DCE). The DCE attributes and levels describe actions that can be taken by the NHS across key areas: buildings and estates, outdoor space, travel and transport, provision of care, goods and services and food and catering. The survey was designed using online think-aloud interviews with 17 members of the public. Two versions of the survey will be administered to a sample of up to 2200 respondents. One will include a payment vehicle as income tax increases. We will estimate the relative importance of each attribute and, for the former survey, the monetary trade-offs which individuals are willing to make between attributes. Where possible, we will match both samples to gauge preference robustness with the inclusion of the monetary payment. We will test whether respondents’ preferences differ based on their socioeconomic circumstances and attitudes toward the NHS and climate change.Ethics and disseminationThe University of Aberdeen’s School of Medicine, Medical Sciences and Nutrition Ethics Research Board has approved the study (reference: SERB/690090). All participants will provide informed consent. Results will be submitted to peer-reviewed publications and presented at relevant conferences and seminars. A lay summary of the research will be published on the Health Economics Research Unit website.
Generation Scotland: an update on Scotland’s longitudinal family health study
Authors: Milbourn Hannah , McCartney Daniel , Richmond Anne , Campbell Archie , Flaig Robin , Robertson Sarah , Fawns-Ritchie Chloe , Hayward Caroline , Marioni Riccardo E , McIntosh Andrew M , Porteous David J , Whalley Heather C , Sudlow Cathie 
Published: June 2024

PurposeGeneration Scotland (GS) is a large family-based cohort study established as a longitudinal resource for research into the genetic, lifestyle and environmental determinants of physical and mental health. It comprises extensive genetic, sociodemographic and clinical data from volunteers in Scotland.ParticipantsA total of 24 084 adult participants, including 5501 families, were recruited between 2006 and 2011. Within the cohort, 59% (approximately 14 209) are women, with an average age at recruitment of 49 years. Participants completed a health questionnaire and attended an in-person clinic visit, where detailed baseline data were collected on lifestyle information, cognitive function, personality traits and mental and physical health. Genotype array data are available for 20 026 (83%) participants, and blood-based DNA methylation (DNAm) data for 18 869 (78%) participants. Linkage to routine National Health Service datasets has been possible for 93% (n=22 402) of the cohort, creating a longitudinal resource that includes primary care, hospital attendance, prescription and mortality records. Multimodal brain imaging is available in 1069 individuals.Findings to dateGS has been widely used by researchers across the world to study the genetic and environmental basis of common complex diseases. Over 350 peer-reviewed papers have been published using GS data, contributing to research areas such as ageing, cancer, cardiovascular disease and mental health. Recontact studies have built on the GS cohort to collect additional prospective data to study chronic pain, major depressive disorder and COVID-19.Future plansTo create a larger, richer, longitudinal resource, ‘Next Generation Scotland’ launched in May 2022 to expand the existing cohort by a target of 20 000 additional volunteers, now including anyone aged 12+ years. New participants complete online consent and questionnaires and provide postal saliva samples, from which genotype and salivary DNAm array data will be generated. The latest cohort information and how to access data can be found on the GS website (www.generationscotland.org).
Incidence and predictors of diabetic foot ulcer among patients with diabetes mellitus in a diabetic follow-up clinic in Central Ethiopia: a retrospective follow-up study
Authors: Negussie Yohannes Mekuria , Komicha Meyrema Abdo , Abebe Tilaye Workneh 
Published: June 2024

BackgroundDiabetic foot ulcer is a major medical, social, and economic problem, and a leading cause of hospitalisations, increased morbidity, and mortality. Despite a rising occurrence, there is a dearth of data on the incidence and its predictors.ObjectiveTo assess the incidence and predictors of diabetic foot ulcers among patients with diabetes mellitus in a diabetic follow-up clinic in Central Ethiopia.DesignRetrospective follow-up study design.ParticipantsA total of 418 newly diagnosed diabetes mellitus patients from 1 January 2012 to 31 December 2022. A computer-generated simple random sampling method was used to select the study participants. Data were collected using a structured data extraction checklist. The collected data were entered into Epi Info V.7.2 and exported to STATA V.14 for analysis. To estimate survival time, the Kaplan-Meier method was used, and the survival difference was tested using a log-rank test.Outcome measuresThe Cox proportional hazard model was fitted to identify the predictors of diabetic foot ulcer development. The strength of the association was estimated using an adjusted hazard ratio (AHR) with a 95% confidence interval (CI), and statistical significance was proclaimed at a p<0.05.ResultThe overall incidence of diabetic foot ulcer was 1.51 cases (95% CI 1.03 to 2.22) per 100 person-years of observation. The cumulative incidence was 6.2% (95% CI 4.1% to 8.6%) over 10 years. The median time of follow-up was 45 months (IQR 21–73). Diastolic blood pressure of 90 mm Hg or above (AHR 2.91, 95% CI 1.25 to 6.77), taking combined medication (AHR 3.24, 95% CI 1.14 to 9.19) and having a peripheral arterial disease (AHR 5.26, 95% CI 1.61 to 17.18) were statistically significant predictors of diabetic foot ulcer development.ConclusionThe risk of occurrence of diabetic foot ulcer was relatively high. Diastolic blood pressure level, combined medication and peripheral arterial disease were independent predictors of diabetic foot ulcer development. Hence, close monitoring and proper interventions are essential.
Addressing the unmet needs of women with breast cancer in Mexico: a non-randomised pilot study of the digital ePRO intervention
Authors: Contreras Sánchez Saúl Eduardo , Doubova Svetlana V , Martinez Vega Ingrid Patricia , Grajales Álvarez Rocío , Villalobos Valencia Ricardo , Dip Borunda Abdel Karim , Lio Mondragón Lorena , Martínez Pineda Wendy Jazmín , Nuñez Cerrillo Jose Gustavo , Huerta López Alma Diana , Zalapa Velázquez Rita , Mendoza Ortiz Valeria , Vázquez Zamora Víctor Javier , Montiel Jarquín Álvaro José , García Galicia Arturo , Talamantes Gómez Enrique Isay , Sánchez Reyes Roberto , Aguirre Gómez Jaqueline , Ayala Anzures María Eugenia , Zapata Tarrés Marta , Monroy Adriana , Leslie Hannah H. 
Published: June 2024

ObjectivesThis study aimed to explore the acceptability, feasibility, usability, and preliminary effect of an electronic patient-reported outcome (ePRO) intervention for patients with breast cancer in Mexico.DesignWe conducted a multimethod non-randomised pilot study. We used a pre-test/post-test design for quantitative assessment of the intervention’s effect on patients’ supportive care needs and quality of life. We conducted in-depth interviews (IDIs) with participants and healthcare workers to explore the intervention’s benefits and barriers and understand its feasibility.Participants50 women aged 20–75 diagnosed with stage I–III breast cancer were enrolled within 2 weeks of starting neoadjuvant or adjuvant treatment with chemotherapy or radiotherapy. We excluded illiterate women and those with visual impairment, cognitive disability or severe depression. IDIs were conducted with 18 participants and 10 healthcare providers.SettingOncology services in three public hospitals of the Mexican Social Security Institute.InterventionThe ePRO intervention consisted of a responsive web application for weekly symptom reporting combined with proactive follow-up by nurses guided by predefined clinical algorithms for 6 weeks.Results50 women were enrolled out of 66 eligible patients approached (75.8%). All 50 completed the 4-week follow-up assessment (100% retention). Completion of the symptom registry declined from 100% in week 1 to 66% in week 6. Participants experienced decreases in supportive care needs and increased quality of life. The ePRO application was rated highly usable. Participants and health professionals both perceived intervention benefits. Drawbacks included poor fit for women receiving radiotherapy and challenges using the application for women with low digital literacy or experiencing severe symptoms.ConclusionsThis pilot study provided evidence of the high usability and potential efficacy of a web-based ePRO intervention. We revised recruitment during the pilot to include multiple facilities, and we will further revise for the randomised trial to address barriers to successful ePRO implementation.Trial registration numberClinicalTrials.gov ID:NCT05925257.
Single-arm study of camrelizumab plus apatinib for patients with advanced mucosal melanoma
Authors: Zhao Lianjun , Ren Yu , Zhang Guiying , Zheng Kelin , Wang Jiayu , Sha Huizi , Zhao Mengke , Huang Rong , Kang Donglin , Su Xinyu , Wu Yirong , Zhang Wangling , Lai Ruihe , Li Lin , Mei Rui , Wang Yitao , Tian You , Wang Fufeng , Liu Baorui , Zou Zhengyun 
Published: June 2024

BackgroundPrevious studies have suggested the potential synergistic antitumor activity when combining immune checkpoint inhibitors with anti-angiogenic agents in various solid tumors. We aimed to assess the efficacy and safety of camrelizumab (a humanized programmed cell death-1 antibody) plus apatinib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor) for patients with advanced mucosal melanoma (MM), and explore-related biomarkers.MethodsWe conducted a single-center, open-label, single-arm, phase II study. Patients with unresectable or recurrent/metastatic MM received camrelizumab and apatinib. The primary endpoint was the confirmed objective response rate (ORR).ResultsBetween April 2019 and June 2022, 32 patients were enrolled, with 50.0% previously received systemic therapy. Among 28 patients with evaluable response, the confirmed ORR was 42.9%, the disease control rate was 82.1%, and the median progression-free survival (PFS) was 8.05 months. The confirmed ORR was 42.9% (6/14) in both treatment-naïve and previously treated patients. Notably, treatment-naïve patients had a median PFS of 11.89 months, and those with prior treatment had a median PFS of 6.47 months. Grade 3 treatment-related adverse events were transaminase elevation, rash, hyperbilirubinemia, proteinuria, hypertension, thrombocytopenia, hand-foot syndrome and diarrhea. No treatment-related deaths were observed. Higher tumor mutation burden (TMB), increased T-cell receptor (TCR) diversity, and altered receptor tyrosine kinase (RTK)/RAS pathway correlated with better tumor response.ConclusionCamrelizumab plus apatinib provided promising antitumor activity with acceptable toxicity in patients with advanced MM. TMB, TCR diversity and RTK/RAS pathway genes were identified as potential predictive biomarkers and warrant further validation.Trial registration numberChinese Clinical Trial Registry, ChiCTR1900023277.
Integrated analysis of tertiary lymphoid structures and immune infiltration in ccRCC microenvironment revealed their clinical significances: a multicenter cohort study
Authors: Wang Yu-Qi , Chen Wen-Jin , Zhou Wang , Dong Ke-Qin , Zuo Li , Xu Da , Chen Jia-Xin , Chen Wei-Jie , Li Wen-Yan , Liu Zi-Chang , Jiang Zheng-Yu , Tang Yi-Fan , Qin Yu-Xuan , Wang Lin-Hui , Pan Xiu-Wu , Cui Xin-Gang 
Published: June 2024

BackgroundTertiary lymphoid structures (TLSs) serve as organized lymphoid aggregates that influence immune responses within the tumor microenvironment. This study aims to investigate the characteristics and clinical significance of TLSs and tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC).MethodsTLSs and TILs were analyzed comprehensively in 754 ccRCC patients from 6 academic centers and 532 patients from The Cancer Genome Atlas. Integrated analysis was performed based on single-cell RNA-sequencing datasets from 21 ccRCC patients to investigate TLS heterogeneity in ccRCC. Immunohistochemistry and multiplex immunofluorescence were applied. Cox regression and Kaplan-Meier analyses were used to reveal the prognostic significance.ResultsThe study demonstrated the existence of TLSs and TILs heterogeneities in the ccRCC microenvironment. TLSs were identified in 16% of the tumor tissues in 113 patients. High density (>0.6/mm2) and maturation of TLSs predicted good overall survival (OS) (p<0.01) in ccRCC patients. However, high infiltration (>151) of scattered TILs was an independent risk factor of poor ccRCC prognosis (HR=14.818, p<0.001). The presence of TLSs was correlated with improved progression-free survival (p=0.002) and responsiveness to therapy (p<0.001). Interestingly, the combination of age and TLSs abundance had an impact on OS (p<0.001). Higher senescence scores were detected in individuals with immature TLSs (p=0.003).ConclusionsThe study revealed the contradictory features of intratumoral TLSs and TILs in the ccRCC microenvironment and their impact on clinical prognosis, suggesting that abundant and mature intratumoral TLSs were associated with decreased risks of postoperative ccRCC relapse and death as well as favorable therapeutic response. Distinct spatial distributions of immune infiltration could reflect effective antitumor or protumor immunity in ccRCC.
Sprinting performance and behavior of adult shortnose sturgeon (Acipenser brevirostrum)
Authors: Castro-Santos Theodore , Kieffer Micah , Goerig Elsa 
Published: June 2024

Swimming ability and performance are central to the ecology of aquatic species and to the design of structures intended to promote access to habitat. This is particularly important for migratory species traveling over significant distances. Here, we present results of a study of swimming behaviors of adult shortnose sturgeon ( Acipenser brevirostrum). Sturgeon were presented with velocity challenges of 0.5–2.5 m·s‒1 in a 35 m long flume that they were allowed to enter and ascend volitionally. Attempt rate was greatest among large sturgeon, at warm temperatures, and at low flow velocities. Sturgeon swam for shorter distances and durations against high-velocity flows; larger sturgeon had greater overall performance and endurance, but when velocities were standardized to body lengths the relative performance was reduced with increased body size. Overall, however, sturgeon were able to swim at much greater speeds than previously predicted, consistent with other studies showing that volitional performance exceeds that of data collected in common laboratory apparatus.
Cosmic microwave background in a non-Archimedean world
Authors: Postavaru Octavian 
Published: June 2024

AbstractThe universe begins its expansion from dimensions below the Planck scale, where the uncertainty principle reigns. If at these dimensions the Archimedean geometry is useless, the p-adic non-Archimedean world creates an environment conducive to phenomenological modeling. The standard description of the cosmological density contrast is made by the Fourier decomposition of plane waves in the field of p-adic numbers $$\mathbb {Q}_p$$

Q
p

. The coupling of the primordial perturbations is done by coupling the phases. Since the phases are the stars of this article, we represent them in the hue-saturation-brightness color space both in $$\mathbb {R}$$
R
and in $$\mathbb {Q}_p$$

Q
p

. If the primordial perturbations interact weakly with each other, with their growth they become important enough from an energetic point of view to gravitationally interact with each other. We identify the coupling using the phase gradient operator, and extract the coupled points from the spectrum. We use pseudoentropy for the quantitative analysis of the information generated by the phases.
Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11
Authors: Parker Gregory S. , Toth Julia I. , Fish Sarah , Blanco Gabrielle , Kampert Taylor , Li Xiaoming , Yang Linette , Stumpf Craig R. , Steadman Kenneth , Jamborcic Aleksandar , Chien Stephen , Daniele Elizabeth , Dearie Alejandro , Leriche Geoffray , Bailey Simon , Thompson Peggy A. 
Published: June 2024

Abstract
Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent “direct” degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extraterminal protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent antitumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein–protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent antitumor activity in vivo.
Designing and Implementing Experiments within Local Bureaucratic Systems: A Cautionary Tale from an Educator Incentive Program
Authors: Asad Saher , Habib Masooma , Karachiwalla Naureen , Kosec Katrina , Leaver Clare , ur Rehman Attique 
Published: June 2024

Abstract
Partnering with governments to co-design pilot interventions and embed them in local bureaucratic systems is increasingly seen as “best practice” on grounds of scalability and sustainability. This paper reports on a pilot program that was co-designed with, and embedded within, the Elementary and Secondary Education Department in Pakistan's Khyber Pakhtunkhwa province that offers a cautionary tale. The over-arching desire to work within existing bureaucratic systems, while laudable, constrained the design of the randomized controlled trial. This paper presents findings on some of the institutional factors which resulted in failed implementation of the randomized controlled trial and a lost opportunity to learn about the efficacy of key design features. The paper briefly outlines the design of the pilot—promotion-based incentives for educators—and summarizes the largely null results. It then turns to implementation, discussing what went wrong, how this was uncovered, and lessons learned for co-designing and embedding future pilot studies with(in) government.
Rare coincidence: Macro-thyroid-stimulating hormone and multiple manufacturer-specific interferences in thyroid hormone immunoassays
Authors: Mrosewski Ingo , Dannheim Viola , Klett Robert , Urbank Matthias , Stobbe Silvia , Ittner Jochen R , Bidlingmaier Martin 
Published: June 2024

Immunoassays are widely used for laboratory assessment of endocrine functions including thyroid hormones. While usually adequate for patient evaluation, they are known to potentially suffer from interference from a variety of factors. We report the case of a 44 year-old male patient without clinical symptoms of thyroid disease who presented for specialist evaluation after pathological thyroid function tests prompted a transferal by his primary care practitioner. Thyroid function tests showed discrepant results across immunoassays and platforms of different manufacturers. Polyethylene glycol precipitation prompted the diagnosis of macro-thyroid-stimulating hormone, while heterophilic and non-specific antibody blocking reagents proved ineffective in eliminating the interference in thyroid-stimulating hormone, free triiodothyronine and free thyroxine measurements. Further assessment ruled out a diagnosis of familial dysalbuminemic hyperthyroxinemia, leaving an exclusion diagnosis of manufacturer-specific interference in free triiodothyronine and free thyroxine assays due to unknown factors. Both clinicians and laboratory specialists must be aware of potential interference in immunoassays which otherwise might be misleading, potentially triggering unnecessary (invasive) follow-up procedures or therapeutic interventions. Close communication is required for successful troubleshooting. To our knowledge, no other case of both macro-thyroid-stimulating hormone and manufacturer-specific interference in a single patient has been documented thus far.