bluuebunny/crossref_metadata_2025_split huggingface dataset:
‘I’ve never been so stressed in my life’: a qualitative analysis of young adults’ lived experience amidst pandemic restrictions in Prince Edward Island, Canada
Authors: Postill Gemma , Halpin Michael , Zanin Claire , Ritter Caroline 
Published: March 2024

ObjectivesThis qualitative study aimed to explore how young adults experienced the COVID-19 pandemic in relation to extensive lockdowns, social isolation and psychosocial distress. Specifically, this research focused on how the pandemic impacted those who did not contract COVID-19 and lived in a low-risk geographical location. The focus was young adults given they have large social circles (high risk for disease transmission) and have an increased propensity to mental health conditions. These insights can inform planning for future pandemics.DesignThis paper draws on 30 in-depth semistructured interviews. Data were analysed inductively following the principles of a constructivist grounded theory approach.Setting and participants30 young adults living in Prince Edward Island during the COVID-19 pandemic, a Canadian province with a low number of COVID-19 cases at the time of data collection.ResultsWe developed four themes that describe the experience of young adults during the COVID-19 pandemic: (1) life course disruption, (2) fear and anxiety about the COVID-19 virus, (3) isolation and loss of hope and (4) strategies for managing adversity. Our findings highlight the areas of young adults’ lives that were affected by extensive social changes related to the COVID-19 pandemic. We demonstrate that even individuals who had not contracted the virus were considerably impacted.ConclusionWe provide a detailed description of the comprehensive impact of COVID-19 on low-risk young adults not previously infected with the COVID-19 virus. By reflecting on the biographical disruption experienced by young adults, we highlight the need and opportunity to direct healthcare resources towards identifying and addressing the secondary impacts of pandemics. Consequently, these findings can guide decisions relating to future pandemic restrictions to better account for the experiences of individuals living through them.
Impact of chronic oral glucocorticoid treatment on mortality in patients with COVID-19: analysis of a population-based cohort
Authors: Einarsdottir Margret J , Kibiwott Kirui Brian , Li Huiqi , Olsson Daniel , Johannsson Gudmundur , Nyberg Fredrik , Ragnarsson Oskar 
Published: March 2024

ObjectivesWhile glucocorticoid (GC) treatment initiated for COVID-19 reduces mortality, it is unclear whether GC treatment prior to COVID-19 affects mortality. Long-term GC use raises infection and thromboembolic risks. We investigated if patients with oral GC use prior to COVID-19 had increased mortality overall and by selected causes.DesignPopulation-based observational cohort study.SettingsPopulation-based register data in Sweden.ParticipantsAll patients infected with COVID-19 in Sweden from January 2020 to November 2021 (n=1 200 153).Outcome measuresAny prior oral GC use was defined as ≥1 GC prescription during 12 months before index. High exposure was defined as ≥2 GC prescriptions with a cumulative prednisolone dose ≥750 mg or equivalent during 6 months before index. GC users were compared with COVID-19 patients who had not received GCs within 12 months before index. We used Cox proportional hazard models and 1:2 propensity score matching to estimate HRs and 95% CIs, controlling for the same confounders in all analyses.Results3378 deaths occurred in subjects with any prior GC exposure (n=48 806; 6.9%) and 14 850 among non-exposed (n=1 151 347; 1.3%). Both high (HR 1.98, 95% CI 1.87 to 2.09) and any exposure (1.58, 1.52 to 1.65) to GCs were associated with overall death. Deaths from pulmonary embolism, sepsis and COVID-19 were associated with high GC exposure and, similarly but weaker, with any exposure. High exposure to GCs was associated with increased deaths caused by stroke and myocardial infarction.ConclusionPatients on oral GC treatment prior to COVID-19 have increased mortality, particularly from pulmonary embolism, sepsis and COVID-19.
Effectiveness of a community-based multicomponent lifestyle intervention (the ADA programme) to improve the quality of life of French breast cancer survivors: protocol for a pragmatic cluster randomised trial and embedded qualitative study
Authors: El-Khoury Fabienne , Mino Jean-Christophe , Deschamps Nicolas , Lopez Chloé , Menvielle Gwenn , Dargent-Molina Patricia 
Published: March 2024

IntroductionBreast cancer survivors (BCSs) are often faced with multiple mental and physical sequelae and are at increased risk of emotional distress, degraded health-related quality of life (HRQoL), chronic pain and fatigue.Physical activity is strongly associated with improved HRQoL and survival rates; however, adherence rates to recommendations for a healthy lifestyle are seldom satisfactory among BCSs. Also, few studies have examined the effectiveness of multicomponent and personalised interventions that integrate physical activity and motivational techniques to improve the HRQoL of BCS.Method and analysis“Activité physique adaptée Doublée d’un Accompagnement d’après cancer” (ADA) is an integrated programme of physical activity enriched with a dietary and supportive care approach targeting BCS in the early post-treatment phase. The effectiveness of the ADA intervention will be evaluated using a cluster randomised controlled trial design with two arms (ADA programme vs usual care; 1:1 ratio).The ADA intervention aims to recruit 160 participants and will be implemented by Siel Bleu, a non-profit association specialised in health prevention via adapted physical activity. Measurements will be performed at baseline, 3, 6 and 12 months after the start of the intervention. The primary outcome will be participants’ HRQoL, at 12 months measured by the Functional Assessment of Chronic Illness Therapy-Fatigue global score. Secondary outcome will include participants’ physical, social, emotional and functional well-being. The effect of the intervention on physical activity level, motivation for physical activity, relation to food and self-efficacy will also be evaluated.Ethics and disseminationThe study was approved by the ‘CPP Paris XI’ Institutional Review Board on 5 May 2022 (Ref no.: 21.04512.000048-22004). The study’s findings will be shared through various channels, including academic publications, simplified reports for wider audiences and active engagement with medical and institutional organisations as well as patients’ associations.Trial registration numberNCT05658341.
UK medical students’ self-reported knowledge and harm assessment of psychedelics and their application in clinical research: a cross-sectional study
Authors: Song-Smith Charlie , Jacobs Edward , Rucker James , Saint Matthew , Cooke James , Schlosser Marco 
Published: March 2024

ObjectiveTo capture UK medical students’ self-reported knowledge and harm assessment of psychedelics and to explore the factors associated with support for changing the legal status of psychedelics to facilitate further clinical research.DesignCross-sectional, anonymous online survey of UK medical students using a non-random sampling method.SettingUK medical schools recognised by the General Medical Council.Participants132 medical students who had spent an average of 3.8 years (SD=1.4; range: 1–6) in medical school.ResultsMost students (83%) reported that they were aware of psychedelic research and only four participants (3%) said that they were not interested in learning more about this type of research. Although medical students’ harm assessment of psychedelics closely aligned with that of experts, only 17% of students felt well-educated on psychedelic research. Teachings on psychedelics were only rarely encountered in their curriculum (psilocybin: 14.1 (SD=19.9), scale: 0 (never) to 100 (very often)). Time spent at medical schools was not associated with more knowledge about psychedelics (r=0.12, p=0.129). On average, this sample of medical students showed strong support for changing the legal status of psychedelics to facilitate further research into their potential clinical applications (psilocybin: 80.2 (SD=24.8), scale: 0 (strongly oppose) to 100 (strongly support)). Regression modelling indicated that greater knowledge of psychedelics (p<0.001), lower estimated harm scores (p<0.001), more time spent in medical school (p=0.024) and lower perceived effectiveness of non-pharmacological mental health treatments (p=0.044) were associated with greater support for legal status change.ConclusionsOur findings reveal a significant interest among UK medical students to learn more about psychedelic research and a strong support for further psychedelic research. Future studies are needed to examine how medical education could be refined to adequately prepare medical students for a changing healthcare landscape in which psychedelic-assisted therapy could soon be implemented in clinical practice.
Association of sildenafil use with age-related macular degeneration: a retrospective cohort study
Authors: Han Ji Eun Diana , Subramanian Anuradhaa , Lee Wen Hwa , Coker Jesse , Denniston Alastair K , Nirantharakumar Krishnarajah , Adderley Nicola Jaime 
Published: March 2024

ObjectiveDespite significant advances in clinical care and understanding of the underlying pathophysiology, age-related macular degeneration (AMD)—a major cause of global blindness—lacks effective treatment to prevent the irreversible degeneration of photoreceptors leading to central vision loss. Limited studies suggest phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may prevent AMD by increasing retinal blood flow. This study explores the potential association between sildenafil use and AMD risk in men with erectile dysfunction using UK data.Methods and analysisUsing the UK’s IQVIA Medical Research Data, the study analysed 31 575 men prescribed sildenafil for erectile dysfunction and no AMD history from 2007 to 2015, matched with a comparator group of 62 155 non-sildenafil users in a 1:2 ratio, over a median follow-up of approximately three years.ResultsThe primary outcome was the incidence of AMD in the two groups. The study found no significant difference in AMD incidence between the sildenafil users and the non-users, with an adjusted hazard ratio (HR) of 0.99 (95% CI 0.84 to 1.16), after accounting for confounders such as age, ethnicity, Townsend deprivation quintile, body mass index category, and diagnosis of hypertension and type 2 diabetes.ConclusionThe study results indicated no significant association between sildenafil use and AMD prevention in UK men with erectile dysfunction, suggesting sildenafil’s protective effect on AMD is likely insignificant.
Bispecific immune cell engager enhances the anticancer activity of CD16+ NK cells and macrophages in vitro, and eliminates cancer metastasis in NK humanized NOG mice
Authors: Khoshtinat Nikkhoi Shahryar , Yang Ge , Owji Hajar , Grizotte-Lake Mayara , Cohen Rick I , Gil Gonzalez Lazaro , Massumi Mohammad , Hatefi Arash 
Published: March 2024

BackgroundIn a prior report, we detailed the isolation and engineering of a bispecific killer cell engager, referred to as BiKE:E5C1. The BiKE:E5C1 exhibits high affinity/specificity for the CD16a activating receptor on natural killer (NK) cells and human epidermal growth factor receptor 2 (HER2) on cancer cells. In vitro studies have demonstrated that BiKE:E5C1 can activate the NK cells and induce the killing of HER2+ ovarian and breast cancer cells, surpassing the performance of the best-in-class monoclonal antibody, Trazimera (trastuzumab). To advance this BiKE technology toward clinical application, the objective of this research was to demonstrate the ability of BiKE:E5C1 to activate CD16+ immune cells such as NK cells and macrophages to kill cancer cells, and eradicate metastatic HER2+ tumors in NK humanized NOG mice.MethodsWe assessed BiKE:E5C1’s potential to activate CD16-expressing peripheral blood (PB)-NK cells, laNK92 cells, and THP-1-CD16A monocyte-macrophages through flowcytometry and antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC) assays. Subsequently, laNK92 cells were selected as effector cells and genetically modified to express the nanoluciferase gene, enabling the monitoring of their viability in NK humanized NOG mice using quantitative bioluminescent imaging (qBLI). To evaluate the functionality of BiKE:E5C1 in vivo, we introduced firefly luciferase-expressing ovarian cancer cells via intraperitoneal injection into hIL-15 and hIL-2 NOG mice, creating a model of ovarian cancer metastasis. Once tumor establishment was confirmed, we treated the mice with laNK92 cells plus BiKE:E5C1 and the response to therapy was assessed using qBLI.ResultsOur data demonstrate that BiKE:E5C1 activates not only laNK92 cells but also PB-NK cells and macrophages, significantly enhancing their anticancer activities. ADCC assay demonstrated that IgG1Fc region had no impact on BiKE:E5C1’s anticancer activity. In vivo results reveal that both hIL-15 and hIL-2 NOG mouse models support the viability and proliferation of laNK92 cells. Furthermore, it was observed that BiKE:E5C1 activates laNK92 cells in mice, leading to eradication of cancer metastasis in both NK humanized hIL-15 and hIL-2 NOG mouse models.ConclusionsCollectively, our in vivo findings underscore BiKE:E5C1’s potential as an immune cell engager capable of activating immune cells for cancer cell elimination, thereby expanding the arsenal of available BiKEs for cancer immunotherapy.
Understanding the Impact of Changes in Application Characteristics on SRGM
Authors: Arora Rajat , Mittal Rubina , Anand Sameer , Kapur P. K. 
Published: March 2024

Due to the increasing reliance on technology in nearly every industry over the past three decades, it has become necessary to evaluate the performance of a software product prior to its formal release in the market. The properties of a software application, such as its complexity and lines of code, are subject to change over time as a result of factors namely the testing environment, allocation of resources, testing efficiency, and testing team’s expertise. The assumption of constant Fault Detection Rate (FDR) may not accurately anticipate the potential number of bugs correctly. Keeping all these considerations in mind, a framework is developed to incorporate change point in the development of a testing effort-based Software Reliability Growth Model (SRGM) that takes into account the effect of application characteristics under both perfect and imperfect debugging settings. In addition, these outcomes are compared to the model without a change point. The proposed model is validated on two real-life software fault datasets. The results demonstrate that the proposed model performs better than the model without a change point.
A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma
Authors: Hwang Grace H. , Pazyra-Murphy Maria F. , Seo Hyuk-Soo , Dhe-Paganon Sirano , Stopka Sylwia A. , DiPiazza Marina , Sutter Nizhoni , Gero Thomas W. , Volkert Alison , Ombelets Lincoln , Dittemore Georgia , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Agar Nathalie Y.R. , Scott David A. , Segal Rosalind A. 
Published: March 2024

Abstract

Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1–38 functioned as an EYA antagonist and opposed SHH signaling. DS-1–38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB.

Significance:
Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain cancer.
Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma
Authors: Dermawan Josephine K. , Chiang Sarah , Singer Samuel , Jadeja Bhumika , Hensley Martee L. , Tap William D. , Movva Sujana , Maki Robert G. , Antonescu Cristina R. 
Published: March 2024

Abstract

Purpose:
Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model.

Experimental Design:
We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least 1-year follow-up.

Results:
In STLMS, French Federation of Cancer Centers (FNCLCC) grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate, and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk: co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk: presence of RB1 mutation, ATRX mutation, or del12q; low risk: lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk: concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk: presence of TP53 mutation, ATRX mutation, or amp20q; low risk: lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression.

Conclusions:
Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.
Small Extracellular Vesicles From Infarcted and Failing Heart Accelerate Tumor Growth
Authors: Caller Tal , Rotem Itai , Shaihov-Teper Olga , Lendengolts Daria , Schary Yeshai , Shai Ruty , Glick-Saar Efrat , Dominissini Dan , Motiei Menachem , Katzir Idan , Popovtzer Rachela , Nahmoud Merav , Boomgarden Alex , D’Souza-Schorey Crislyn , Naftali-Shani Nili , Leor Jonathan 
Published: March 2024

BACKGROUND:
Myocardial infarction (MI) and heart failure are associated with an increased incidence of cancer. However, the mechanism is complex and unclear. Here, we aimed to test our hypothesis that cardiac small extracellular vesicles (sEVs), particularly cardiac mesenchymal stromal cell–derived sEVs (cMSC-sEVs), contribute to the link between post-MI left ventricular dysfunction (LVD) and cancer.

METHODS:
We purified and characterized sEVs from post-MI hearts and cultured cMSCs. Then, we analyzed cMSC-EV cargo and proneoplastic effects on several lines of cancer cells, macrophages, and endothelial cells. Next, we modeled heterotopic and orthotopic lung and breast cancer tumors in mice with post-MI LVD. We transferred cMSC-sEVs to assess sEV biodistribution and its effect on tumor growth. Finally, we tested the effects of sEV depletion and spironolactone treatment on cMSC-EV release and tumor growth.

RESULTS:
Post-MI hearts, particularly cMSCs, produced more sEVs with proneoplastic cargo than nonfailing hearts did. Proteomic analysis revealed unique protein profiles and higher quantities of tumor-promoting cytokines, proteins, and microRNAs in cMSC-sEVs from post-MI hearts. The proneoplastic effects of cMSC-sEVs varied with different types of cancer, with lung and colon cancers being more affected than melanoma and breast cancer cell lines. Post-MI cMSC-sEVs also activated resting macrophages into proangiogenic and protumorigenic states in vitro. At 28-day follow-up, mice with post-MI LVD developed larger heterotopic and orthotopic lung tumors than did sham-MI mice. Adoptive transfer of cMSC-sEVs from post-MI hearts accelerated the growth of heterotopic and orthotopic lung tumors, and biodistribution analysis revealed accumulating cMSC-sEVs in tumor cells along with accelerated tumor cell proliferation. sEV depletion reduced the tumor-promoting effects of MI, and adoptive transfer of cMSC-sEVs from post-MI hearts partially restored these effects. Finally, spironolactone treatment reduced the number of cMSC-sEVs and suppressed tumor growth during post-MI LVD.

CONCLUSIONS:
Cardiac sEVs, specifically cMSC-sEVs from post-MI hearts, carry multiple protumorigenic factors. Uptake of cMSC-sEVs by cancer cells accelerates tumor growth. Treatment with spironolactone significantly reduces accelerated tumor growth after MI. Our results provide new insight into the mechanism connecting post-MI LVD to cancer and propose a translational option to mitigate this deadly association.
Association of Blood Pressure With Brain White Matter Microstructural Integrity Assessed With MRI Diffusion Tensor Imaging in Healthy Young Adults
Authors: Won Junyeon , Maillard Pauline , Shan Kevin , Ashley John , Cardim Danilo , Zhu David C. , Zhang Rong 
Published: March 2024

BACKGROUND:
High blood pressure (BP) in middle-aged and older adults is associated with a brain white matter (WM) microstructural abnormality. However, little evidence is available in healthy young adults. We investigated the associations between high BP and WM microstructural integrity in young adults.

METHODS:

This study included 1015 healthy young adults (542 women, 22–37 years) from the Human Connectome Project. Brachial systolic and diastolic BP were measured using a semiautomatic or manual sphygmomanometer. Diffusion-weighted magnetic resonance imaging was acquired to obtain diffusion tensor imaging metrics of free water (FW) content, FW-corrected WM fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity. Using whole-brain voxel-wise linear regression models and ANCOVA, we examined associations of BP and hypertension stage with diffusion tensor imaging metrics after adjusting for age, sex, education, body mass index, smoking status, alcohol consumption history, and differences in the
b
value used for diffusion magnetic resonance imaging.

RESULTS:
Systolic and diastolic BP of the sample (mean±SD) were 122.8±13.0 and 76.0±9.9 mm Hg, respectively. Associations of BP with diffusion tensor imaging metrics revealed regional heterogeneity for FW-corrected fractional anisotropy. High BP and high hypertension stage were associated with higher FW and lower FW-corrected axial diffusivity, FW-corrected radial diffusivity, and FW-corrected mean diffusivity. Moreover, associations of high diastolic BP and hypertension stage with high FW were found only in men not in women.

CONCLUSIONS:
High BP in young adults is associated with altered brain WM microstructural integrity, suggesting that high BP may have damaging effects on brain WM microstructural integrity in early adulthood, particularly in men.