bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of surfactant dose on outcomes in preterm infants with respiratory distress syndrome: the OPTI-SURF study protocol
Authors: Goss Kevin Colin William , Gale Chris , Malone Rachel , Longford Nicholas , Ratcliffe Kirsty , Modi Neena 
Published: April 2023

IntroductionRespiratory distress syndrome is a condition seen in preterm infants primarily due to surfactant insufficiency. European guidelines recommend the dose and method of surfactant administration. However, in routine practice, clinicians often use a ‘whole vial’ approach to surfactant dosing. The aim of this study is to assess whether in preterm infants of gestational age 36+6weeks+daysor less, a low first dose of surfactant (100–130 mg/kg) compared with a high first dose (170–200 mg/kg) affects survival with no mechanical ventilation on either on postnatal days 3 and 4, and other outcomes.Methods and analysisIn this prospective, observational study, we will use the National Neonatal Research Database as the main data source. We will obtain additional information describing the dose and method of surfactant administration through the neonatal EPR system. We will use propensity scores to form matched groups with low first dose and high first dose for comparison.Ethics and disseminationThis study was approved by the West Midlands—Black Country Research Ethics Committee (REC reference: 18/WM/0132; IRAS project ID: 237111). The results of the research will be made publicly available through presentations at local, national or international conferences and will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT03808402.
Design and development of the Pediatric Urology Recovery After Surgery Endeavor (PURSUE) multicentre pilot and exploratory study
Authors: Rove Kyle O , Strine Andrew C , Wilcox Duncan T , Vricella Gino J , Welch Timothy P , VanderBrink Brian , Chu David I , Chaudhry Rajeev , Zee Rebecca S , Brockel Megan A 
Published: April 2023

IntroductionLower urinary tract reconstruction in paediatric urology represents a physiologically stressful event that is associated with high complication rates, including readmissions and emergency room visits. Enhanced recovery after surgery (ERAS) protocol is a set of multidisciplinary, perioperative strategies designed to expedite surgical recovery without adversely impacting readmission or reoperation rates. Early paediatric urology data demonstrated ERAS reduced complications in this population.Methods and analysisIn 2016, a working group of paediatric urologists and anaesthesiologists convened to develop an ERAS protocol suitable for patients undergoing lower urinary tract reconstruction and define study process measures, patient-reported outcomes and clinically relevant outcomes in paediatric and adolescent/young adult patients. A multicentre, prospective, propensity-matched, case–control study design was chosen. Each centre will enrol five pilot patients to verify implementation. Subsequent enrolled patients will be propensity matched to historical controls. Eligible patients must be aged 4–25 years and undergoing planned operations (bladder augmentation, continent ileovesicostomy or appendicovesicostomy, or urinary diversion). 64 ERAS patients and 128 controls will be needed to detect a decrease in mean length of stay by 2 days. Pilot phase outcomes include attainment of ≥70% mean protocol adherence per patient and reasons for protocol deviations. Exploratory phase primary outcome is ERAS protocol adherence, with secondary outcomes including length of stay, readmissions, reoperations, emergency room visits, 90-day complications, pain scores, opioid usage and differences in Quality of Recovery 9 scores.Ethics and disseminationThis study has been registered with authors’ respective institution review boards and will be published in peer-reviewed journals. It will provide robust insight into the feasibility of ERAS in paediatric urology, determine patient outcomes and allow for iteration of ERAS implementations as new best practices and evidence for paediatric surgical care arise. We anticipate this study will take 4 years to fully accrue with completed follow-up.Trial registration numberNCT03245242.
Effect of the VivaSight double-lumen tube on the incidence of hypoxaemia during one-lung ventilation in patients undergoing thoracoscopic surgery: a study protocol for a prospective randomised controlled trial
Authors: Long Si , Li Yuhang , Guo Junying , Hu Rong 
Published: April 2023

IntroductionA double-lumen tube (DLT) is a traditional one-lung ventilation tool that needs to be positioned under the guidance of a fibreoptic bronchoscope or auscultation. The placement is complex, and poor positioning often causes hypoxaemia. In recent years, VivaSight double-lumen tubes (v-DLTs) have been widely used in thoracic surgery. Because the tubes can be continuously observed during intubation and the operation, malposition can be corrected at any time. However, the effect of v-DLT on perioperative hypoxaemia has been rarely reported. The aim of this study was to observe the incidence of hypoxaemia during one-lung ventilation with v-DLT and to compare the perioperative complications between v-DLT and conventional double-lumen tube (c-DLT).Methods and analysisOne hundred patients planning to undergo thoracoscopic surgery will be randomised into the c-DLT group and the v-DLT group. During one-lung ventilation, both groups of patients will receive low tidal volume for volume control ventilation. When the blood oxygen saturation falls below 95%, the DLT will be repositioned and the oxygen concentration will be increased to improve the respiratory parameters (5 cm H2O Positive end-expiratory pressure (PEEP) on the ventilation side and 5 cm H2O CPAP (continuous airway positive pressure) on the operation side), and double lung ventilation measures will be taken in sequence to prevent a further decline in blood oxygen saturation. The primary outcomes are the incidence and duration of hypoxaemia and the number of intraoperative hypoxaemia treatments, and the secondary outcomes will be postoperative complications and total hospitalisation expenses.Ethics and disseminationThe study protocol was approved by the Clinical Research Ethics Committee of The First Affiliated Hospital, Sun Yat-sen University (2020–418) and registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn). The results of the study will be analysed and reported.Trial registration numberChiCTR2100046484.
Older adults’ experiences and perceived impacts of the Aging, Community and Health Research Unit-Community Partnership Program (ACHRU-CPP) for diabetes self-management in Canada: a qualitative descriptive study
Authors: Yous Marie-Lee , Ganann Rebecca , Ploeg Jenny , Markle-Reid Maureen , Northwood Melissa , Fisher Kathryn , Valaitis Ruta , Chambers Tracey , Montelpare William , Légaré France , Beleno Ron , Gaudet Gary , Giacometti Luisa , Levely Deborah , Lindsay Craig , Morrison Allan , Tang Frank ,   On behalf of the ACHRU-CPP Research Team
Published: April 2023

ObjectivesTo assess the experiences and perceived impacts of the Aging, Community and Health Research Unit-Community Partnership Program (ACHRU-CPP) from the perspectives of older adults with diabetes and other chronic conditions. The ACHRU-CPP is a complex 6-month self-management evidence-based intervention for community-living older adults aged 65 years or older with type 1 or type 2 diabetes and at least one other chronic condition. It includes home and phone visits, care coordination, system navigation support, caregiver support and group wellness sessions delivered by a nurse, dietitian or nutritionist, and community programme coordinator.DesignQualitative descriptive design embedded within a randomised controlled trial was used.SettingSix trial sites offering primary care services from three Canadian provinces (ie, Ontario, Quebec and Prince Edward Island) were included.ParticipantsThe sample was 45 community-living older adults aged 65 years or older with diabetes and at least one other chronic condition.MethodsParticipants completed semistructured postintervention interviews by phone in English or French. The analytical process followed Braun and Clarke’s experiential thematic analysis framework. Patient partners informed study design and interpretation.ResultsThe mean age of older adults was 71.7 years, and the mean length of time living with diabetes was 18.8 years. Older adults reported positive experiences with the ACHRU-CPP that supported diabetes self-management, such as improved knowledge in managing diabetes and other chronic conditions, enhanced physical activity and function, improved eating habits, and opportunities for socialisation. They reported being connected to community resources by the intervention team to address social determinants of health and support self-management.ConclusionsOlder adults perceived that a 6-month person-centred intervention collaboratively delivered by a team of health and social care providers helped support chronic disease self-management. There is a need for providers to help older adults connect with available health and social services in the community.Trial registration numberClinicalTrials.gov ID:NCT03664583; Results.
Cross-sectional study to assess depression among healthcare workers in Lusaka, Zambia during the COVID-19 pandemic
Authors: Simbeza Sandra , Mutale Jacob , Mulabe Musunge , Jere Lazarus , Bukankala Chama , Sikombe Kombatende , Sikazwe Izukanji , Bolton-Moore Carolyn , Mody Aaloke , Geng Elvin H , Sharma Anjali , Beres Laura K , Pry Jake M 
Published: April 2023

ObjectivesWe sought to assess depression among healthcare workers (HCWs) in the context of COVID-19 in Lusaka Province, Zambia.DesignThis cross-sectional study is nested within a larger study, the Person-Centred Public Health for HIV Treatment in Zambia (PCPH), a cluster-randomised trial to assess HIV care and outcomes.SettingThe research was conducted in 24 government-run health facilities from 11 August to 15 October 2020 during the first wave of the COVID-19 pandemic in Lusaka, Zambia.ParticipantsWe used convenience sampling to recruit HCW participants who were previously enrolled in the PCPH study, had more than 6 months’ experience working at the facility and were voluntarily willing to participate.Primary outcome measuresWe implemented the well-validated 9-question Patient Health Questionnaire (PHQ-9) to assess HCW depression. We used mixed-effects, adjusted Poisson regression to estimate the marginal probability of HCWs experiencing depression that may warrant intervention (PHQ-9 score ≥5) by healthcare facility.ResultsWe collected PHQ-9 survey responses from 713 professional and lay HCWs. Overall, 334 (46.8%, 95% CI 43.1%, 50.6%) HCWs recorded a PHQ-9 score ≥5, indicating the need for further assessment and potential intervention for depression. We identified significant heterogeneity across facilities and observed a greater proportion of HCWs with symptoms of depression in facilities providing COVID-19 testing and treatment services.ConclusionsDepression may be a concern for a large proportion of HCWs in Zambia. Further work to understand the magnitude and aetiologies of depression among HCWs in the public sector is needed to design effective prevention and treatment interventions to meet the needs for mental health support and to minimise poor health outcomes.
Factors predicting the transition from acute to persistent pain in people with ‘sciatica’: the FORECAST longitudinal prognostic factor cohort study protocol
Authors: Schmid Annina B , Ridgway Lucy , Hailey Louise , Tachrount Mohamed , Probert Fay , Martin Kathryn R , Scott Whitney , Crombez Geert , Price Christine , Robinson Claire , Koushesh Soraya , Ather Sarim , Tampin Brigitte , Barbero Marco , Nanz Daniel , Clare Stuart , Fairbank Jeremy , Baskozos Georgios 
Published: April 2023

IntroductionSciatica is a common condition and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared with low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. It remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (eg, symptom severity, routine MRI) are consistent prognostic factors.The FORECAST study (factors predicting the transition from acute to persistent pain in people with ‘sciatica’) will take a different approach by exploring mechanism-based subgroups in patients with sciatica and investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica.Methods and analysisWe will perform a prospective longitudinal cohort study including 180 people with acute/subacute sciatica. N=168 healthy participants will provide normative data. A detailed set of variables will be assessed within 3 months after sciatica onset. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will determine outcome with the Sciatica Bothersomeness Index and a Numerical Pain Rating Scale for leg pain severity at 3 and 12 months.We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small data sets will be used to identify the most powerful predictors and model selection/accuracy.The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and may identify prognostic factors of pain persistence.Ethics and disseminationThe FORECAST study has received ethical approval (South Central Oxford C, 18/SC/0263). The dissemination strategy will be guided by our patient and public engagement activities and will include peer-reviewed publications, conference presentations, social media and podcasts.Trial registration numberISRCTN18170726; Pre-results.
Engineering second-generation TCR-T cells by site-specific integration of TRAF-binding motifs into theCD247locus
Authors: Lah Sangjoon , Kim Segi , Kang In , Kim Hyojin , Hupperetz Cedric , Jung Hyuncheol , Choi Hyeong Ryeol , Lee Young-Ho , Jang Hyeon-Ki , Bae Sangsu , Kim Chan Hyuk 
Published: April 2023

BackgroundThe incorporation of co-stimulatory signaling domains into second-generation chimeric antigen receptors (CARs) significantly enhances the proliferation and persistence of CAR-T cells in vivo, leading to successful clinical outcomes.MethodsTo achieve such functional enhancement in transgenic T-cell receptor-engineered T-cell (TCR-T) therapy, we designed a second-generation TCR-T cell in which CD3ζ genes modified to contain the intracellular domain (ICD) of the 4-1BB receptor were selectively inserted into theCD247locus.ResultsThis modification enabled the simultaneous recruitment of key adaptor molecules for signals 1 and 2 on TCR engagement. However, the addition of full-length 4-1BB ICD unexpectedly impaired the expression and signaling of TCRs, leading to suboptimal antitumor activity of the resulting TCR-T cells in vivo. We found that the basic-rich motif (BRM) in the 4-1BB ICD was responsible for the undesirable outcomes, and that fusion of minimal tumor necrosis factor receptor-associated factor (TRAF)-binding motifs at the C-terminus of CD3ζ (zBBΔBRM) was sufficient to recruit TRAF2, the key adaptor molecule in 4-1BB signaling, while retaining the expression and proximal signaling of the transgenic TCR. Consequently, TCR-T cells expressing zBBΔBRMexhibited improved persistence and expansion in vitro and in vivo, resulting in superior antitumor activity in a mouse xenograft model.ConclusionsOur findings offer a promising strategy for improving the intracellular signaling of TCR-T cells and their application in treating solid tumors.
Targeting Mutated p53: Naivete and Enthusiasm to Attempt the Impossible
Authors: El-Deiry Wafik S. 
Published: April 2023

AbstractTumor suppressor TP53 is an important gene in human cancer because it is mutated in the majority of tumors, leading to loss-of-function or gain-of-function phenotypes. Mutated TP53 acts like an oncogene, driving cancer progression and causing poor patient outcomes. The role of mutated p53 in cancer has been known for over three decades, yet there is no FDA-approved drug to address the problem. This brief historical perspective highlights some of the insightful advances as well as challenges in therapeutic targeting of p53, especially the mutated forms. The article focuses on a functional p53 pathway restoration approach to drug discovery that years ago was not mainstream, encouraged by anyone, taught in textbooks, or embraced by medicinal chemists. With some knowledge, a clinician scientist's interest, and motivation, the author pursued a unique line of investigation leading to insights for functional bypass of TP53 mutations in human cancer. Like mutated Ras proteins, mutant p53 is fundamentally important as a therapeutic target in cancer and probably deserves a "p53 initiative" like the NCI's "Ras initiative.” There is a link between naivete and enthusiasm for pursuing difficult problems, but important solutions are discovered through hard work and persistence. Hopefully, some benefit comes to patients with cancer from such drug discovery and development efforts.
CD73 Is a Critical Immune Checkpoint in a Molecular Subtype of Pancreatic Cancer
Authors: DelGiorno Kathleen 
Published: April 2023

AbstractMolecular stratification of patients with pancreatic ductal adenocarcinoma (PDAC) has the potential to guide clinical decision-making for therapeutic intervention. Investigating mechanisms by which different molecular subtypes of PDAC form and progress will improve patient responses to existing therapies and aid in identifying new, more specific therapeutic approaches. In this issue of Cancer Research, Faraoni and colleagues identified CD73/Nt5e-generated adenosine as a mechanism of immunosuppression specifically in pancreatic ductal–derived basal/squamous-type PDAC. Using genetically engineered mouse models targeting key genetic mutations to pancreatic acinar or ductal cells and an array of experimental and computational biology approaches, the authors found that adenosine signaling through receptor ADORA2B induces immunosuppression and tumor progression in ductal cell–derived tumors. These data demonstrate how molecular stratification of PDAC in combination with targeted approaches may enhance patient responses to therapy in this deadly cancer.See related article by Faraoni et al., p. 1111
Proteostasis Modulation in Germline Missense von Hippel Lindau Disease
Authors: Chittiboina Prashant , Mandal Debjani , Bugarini Alejandro , Asuzu David T. , Mullaney Dustin , Mastorakos Panagiotis , Stoica Stefan , Alvarez Reinier , Scott Gretchen , Maric Dragan , Elkahloun Abdel , Zhuang Zhengping , Chew Emily Y. , Yang Chunzhang , Linehan Marston , Lonser Russell R. 
Published: April 2023

Abstract

Purpose:
Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL.

Patients and Methods:
We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002).

Results:
Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90–pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell–specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling.

Conclusions:
We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.
Abstract 1901: Analysis of the survivin expression in breast tumor tissue from black and white cancer patients
Authors: Brown Kerrie , Fang Yisheng V. , Sankpal Umesh T. 
Published: April 2023

Abstract
Breast cancer is the most common cancer diagnosed and the leading cause of cancer-related deaths in women. Breast cancer disproportionately affects Black women who have significantly higher mortality rates compared to White women with breast cancer. Although factors like access to healthcare and socioeconomic status contribute significantly to this disparity, there is a need to understand the underlying biological mechanisms that might play an important role. Survivin is a protein that belongs to the inhibitor of apoptosis family. Along with its anti-apoptotic function, it is also involved in the progression of the cell cycle. Survivin is normally expressed during development with no expression detected in most adult differentiated tissues. However, high expression of this protein is found in many cancers which correlates with poor prognosis. The goal of this study was to determine the expression of survivin in tumor tissue from Black and White breast cancer patients. Our first approach was to analyze the TCGA database to confirm our hypothesis that there is differential expression of survivin between the two racial groups and within different subtypes of breast cancer. Secondly, we used immunohistochemical analysis to investigate the expression of survivin in patient tumor tissue samples obtained from Black and White breast cancer patients. Results from the analysis of the TCGA database indicate significantly higher expression of survivin in tumors from Black patients compared to White. High survivin expression is also correlated with higher mortality rates. Immunohistochemical analysis of breast tumors also demonstrated higher expression of survivin in tumor tissue from Black patients. We also observed higher nuclear expression in Black patients compared to White patients. Differential expression was also observed between different subgroups of breast cancer. High expression was seen in the most aggressive triple negative (TNBC) form of breast cancer, which is known to disproportionately occur at higher rates in Black women. Our results along with data available in literature, suggest that survivin plays an important role in breast cancer progression (in correlation to race) and could be a useful diagnostic and/or prognostic marker or a therapeutic target.
Citation Format: Kerrie Brown, Yisheng V. Fang, Umesh T. Sankpal. Analysis of the survivin expression in breast tumor tissue from black and white cancer patients [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 1901.