bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors affecting the feasibility of post-authorisation RCTs for conditionally authorised anticancer medicines: a multistakeholder perspective from a qualitative focus group study
Authors: van Hattem Christine C , de Jong Amos J , de Groot Jolien S , Hoekman Jarno , Broekman K Esther , Sonke Gabe S , van Hennik Paula B , Bloem Lourens T 
Published: November 2024

ObjectiveThe collection of comprehensive data from post-authorisation trials for conditionally authorised anticancer medicines is frequently delayed. This raises questions about the feasibility of post-authorisation randomised controlled trials (RCTs) that aim to address remaining uncertainties. Therefore, this study explored factors that facilitate or impede the feasibility of post-authorisation RCTs from the perspective of stakeholders directly involved in the design, medical-ethical approval, and conduct of these RCTs.DesignWe conducted four qualitative focus groups (FGs).SettingFG discussions focused on the oncology setting in European context.ParticipantsTwenty-eight European patients, physicians, medical ethicists and pharmaceutical industry representatives participated in the FGs.InterventionRespondents were informed about the topic and the purpose of the FGs before and at the start of FG discussions. An FG script was used to guide the discussion, which was informed by 14 semi-structured interviews with various stakeholders.ResultsWe identified factors with the potential to impact feasibility related to trial design, trial conduct, factors external to a trial and post-authorisation interaction with regulators. Factors that may be particularly relevant for the post-authorisation setting include the choice of relevant endpoints and the inclusion of a fair comparator (trial design), strategies to increase patients’ and physicians’ willingness to participate (trial conduct), and external factors relating to a medicine’s commercial availability, the presence of competing medicines and trials and the perceptions about clinical equipoise. Post-authorisation interaction with regulators about how to obtain comprehensive data was deemed necessary in cases where a post-authorisation RCT seems infeasible.ConclusionsBased on the identified factors, our findings suggest that patient recruitment and retention could be assessed more in-depth during regulatory feasibility assessments at the time of granting conditional marketing authorisation and that sponsors and regulators should better inform patients and physicians about the remaining uncertainties for conditionally authorised medicines and the necessity for post-authorisation RCTs. By enhancing the evaluation of trial feasibility, timely completion of post-authorisation RCTs may be facilitated to resolve the remaining uncertainties within a reasonable timeframe.
Association between a healthy lifestyle and the prevalence of depression in radiology residents in China: findings from a nationwide survey
Authors: Peng Yuting , Chen Jiashen , Jiang Maoqing , Han Li-Yuan , Yang Zhenghan , Wang Zhenchang , Wang Peicheng , Li Hange , Zhu Jiming , Zhang Jingfeng , Zheng Jianjun 
Published: November 2024

ObjectiveThe relationship between a healthy lifestyle and depression in radiology residents remains poorly understood. This study aims to investigate the relationship between a healthy lifestyle and depressive symptoms in radiology residents in a nationwide survey.DesignCross-sectional study.SettingThe survey was conducted among radiology residents undergoing training in China between December 2020 and April 2021. This encompassed a total of 215 municipalities and 406 training centres.Participants3677 radiology residents in 31 provinces of China.Primary and secondary outcome measuresThe primary outcome was Healthy Lifestyle Score (HLS). A multiple logistic regression analysis was performed to evaluate the association between lifestyle factors and depressive symptoms. Additionally, the weighted quantile sum (WQS) index was utilised to identify the lifestyle factor that had the greatest impact on depressive symptoms.ResultsThe study sample consisted of 3677 participants, among whom the prevalence of depression was 34.7%. Participants were categorised based on their Health Lifestyle Score (HLS) into three groups: low HLS (LHLS), moderate HLS (MHLS) and high HLS (HHLS), with proportions of 8.0%, 79.8% and 12.2%, respectively. Those with LHLS were found to have a significantly higher risk of depression (OR: 5.21, 95% CI: 3.72 to 7.30) and a more severe level of depression (p for trend<0.001) compared with those with HHLS. Furthermore, the Well-being Quality of Life Index (WQS) showed a significant association with depression (OR: 0.34, 95% CI: 0.28 to 0.40), with sleep being identified as the most significant factor contributing to a healthy lifestyle.ConclusionThe study establishes a significant association between an LHLS (long and irregular work hours) and an elevated risk of depressive symptoms among the participants, emphasising the crucial role of sleep in this relationship. These findings underline the importance of promoting a healthy lifestyle, specifically emphasising the need for adequate sleep, among radiology residents.
Systematic review and meta-analysis assessing the status of carotid intima–media thickness and lipid profiles in type 2 diabetes mellitus
Authors: Mashaba Reneilwe Given , Phoswa Wendy , Maimela Eric , Lebelo Sogolo , Modjadji Perpetua , Mokgalaboni Kabelo 
Published: November 2024

ObjectivesCarotid intima–media thickness (CIMT) is a measurement for subclinical atherosclerosis and has been associated with overall cardiovascular diseases, especially in type 2 diabetes mellitus (T2DM). We aimed to assess the status of carotid health and lipid profile in T2DM.DesignThis systematic review and meta-analysis synthesised data published from clinical studies.Data sourcesGoogle Scholar, PubMed and Scopus were searched from inception to 18 January 2024.Eligibility criteria for selecting studiesStudies conducted in patients with T2DM and those without T2DM were included. Studies conducted in T2DM adults evaluating carotid status and lipid profile were considered.Data extraction and synthesisTwo authors independently used standardised methods to comprehensively search, screen and extract data from all relevant studies. The risk of bias was assessed using the Newcastle-Ottawa checklist. Meta-analysis was conducted using Review Manager and metaHun through random effects models. The random effect model was used due to high heterogeneity.ResultsEvidence was analysed from 57 studies with a sample size of 29 502 (8254 T2DM and 21 248 people without T2DM). There was a significantly higher CIMT, with a standardised mean difference (SMD) of 1.01 (95% CI 0.75, 1.26, p<0.00001). Additionally, there was an elevated triglyceride (TG) (SMD=1.12, 95% CI 0.82, 1.41, p<0.00001), total cholesterol (TC), (SMD=0.24, 95% CI 0.02, 0.46, p=0.03) and low-density lipoprotein-cholesterol (LDL-C), (SMD=0.35, 95% CI 0.11, 0.59, p=0.004) in patients with T2DM compared with those without T2DM. Furthermore, a significant decrease in high-density lipoprotein cholesterol (HDL-C) was observed in the T2DM compared with people without T2DM, SMD=−0.79, 95% CI−0.96, –0.62, p<0.00001). Age, body mass index and hypertension were associated with increased CIMT and TG and decreased HDL-C in T2DM. Additionally, age, gender and hypertension were associated with an increased LDL-C in T2DM.ConclusionOur findings suggest that an increased CIMT is accompanied by increased TG, TC, LDL-C and HDL-C reduction in patients with T2DM.PROSPERO registration numberCRD42023451731.
Current and potential contributions of large-scale food fortification to meeting micronutrient requirements in Senegal: a modelling study using household food consumption data
Authors: Adams Katherine P , Engle-Stone Reina , Wibberley Brent , Tsang Becky L , Tarini Ann , Beye Maguette , Rowe Laura A 
Published: November 2024

IntroductionMicronutrient deficiencies are common among women of reproductive age (WRA) and children in Senegal. Large-scale food fortification (LSFF) can help fill gaps in dietary intake.MethodsWe used household food consumption data to model the contributions of existing LSFF programmes (vitamin A-fortified refined oil and iron and folic acid-fortified wheat flour) and the potential contributions of expanding these programmes to meeting the micronutrient requirements of WRA (15–49 7 years) and children (6–59 months).ResultsWithout fortification, apparent inadequacy of household diets for meeting micronutrient requirements exceeded 70% for vitamin A, thiamin, riboflavin, folate and zinc, was 61% for iron among WRA (43% among children) and was ~25% for vitamin B12. At estimated current compliance, fortified refined oil was predicted to reduce vitamin A inadequacy to ~35% and could further reduce inadequacy to ~25% if compliance with the standard improved. Fortified wheat flour at estimated current compliance reduced iron and, especially, folate inadequacy, but improvements in compliance would be necessary to achieve the full potential. Beyond existing programmes, expanding wheat flour fortification to include additional micronutrients was predicted to have a modest impact on thiamin and riboflavin inadequacies and larger impacts on vitamin B12and, especially, zinc inadequacies. Adding a programme to import fortified rice could further reduce inadequacies of multiple micronutrients (generally by >10 percentage points), although potential risk of high intake of vitamin A, folic acid and zinc among children should be carefully considered. With both wheat flour and rice fortification, predicted prevalence of vitamin A, iron and zinc inadequacy remained above 25% in some regions, pointing to the potential need for coordinated, targeted micronutrient interventions to fully close gaps.ConclusionsWhen considered alongside evidence on the cost and affordability of these programmes, this evidence can help inform the development of a comprehensive micronutrient intervention strategy in Senegal.
Depletion of conventional CD4+T cells is required for robust priming and dissemination of tumor antigen-specific CD8+T cells in the setting of anti-CD4 therapy
Authors: Ramirez Delaney E , Dragnev Christo P C , Searles Tyler G , Spicer Nathaniel , Chen Tiffany , Lines J Louise , Hawkes Aaron R , Davis Wilson L , Mohamed Asmaa , Shirai Keisuke , Phillips Joseph D , Rosato Pamela C , Huang Yina H , Turk Mary Jo 
Published: November 2024

BackgroundOvercoming immune suppression is a major barrier to eliciting potent CD8+T cell responses against cancer. Treatment with anti-CD4 monoclonal antibody is an effective means for eliminating CD4+Foxp3+regulatory (Treg) cells in preclinical models and has also demonstrated efficacy in early clinical trials. However, the underlying basis for treatment efficacy, more specifically the implications of codepleting other CD4-expressing cell compartments in tumor-bearing hosts, is not well understood.MethodsTumor-bearing mice were treated with anti-CD4 versus other therapies that preserve helper T cell function, and the priming, tissue distribution, and maintenance of tumor antigen-specific CD8 T cells were assessed. Antibody blockade and transgenic mouse models were used to determine the mechanisms of CD8 T cell priming. Single-cell RNA-sequencing (scRNAseq) was used to further characterize CD8 T cells that are primed by anti-CD4 therapy and to identify immunosuppressive CD4 T cell subsets in human melanoma following immune checkpoint blockade (ICB).ResultsComparing anti-CD4 to dual ICB therapy, we show that anti-CD4 facilitates more robust priming of TCF-1+, IL-2-producing, tumor-specific CD8+T cells that disseminate to tissues and form memory. By decoupling priming from homeostatic proliferation and associated cytokines, we find that anti-CD4 functions independently of creating homeostatic space for CD8+T cells. We also show that depletion of CD4-expressing antigen-presenting cell subsets is not required for anti-CD4 efficacy. Instead, robust tumor-specific CD8+T cell priming and memory generation required the removal of total antigen-specific CD4+T cells, including both Tregs and CD4+Foxp3-negative conventional (Tconv) cells. In particular, the elimination of CD4+Tconv cells was necessary for the accumulation and maturation of conventional type-1 dendritic cells in tumor-draining LNs, which were required for CD8+T cell priming. Accordingly, anti-CD4 treatment restored CD8+T cell responses in mice cotreated with dual ICB. scRNAseq of melanoma tumors from patients who received ICB revealed the presence of Tr1 and Treg subsets, as well as CD4+Tconv subsets that lacked clear transcriptional evidence of helper differentiation.ConclusionsThese findings underscore the underappreciated benefit of depleting CD4+Tconv cells to promote systemic primary and memory CD8+T cell responses against cancer.
Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression
Authors: Roerden Malte , Castro Andrea B , Cui Yufei , Harake Noora , Kim Byungji , Dye Jonathan , Maiorino Laura , White Forest M , Irvine Darrell J , Litchfield Kevin , Spranger Stefani 
Published: November 2024

BackgroundIntratumoral heterogeneity (ITH) and subclonal antigen expression blunt antitumor immunity and are associated with poor responses to immune-checkpoint blockade immunotherapy (ICB) in patients with cancer. The underlying mechanisms however thus far remained elusive, preventing the design of novel treatment approaches for patients with high ITH tumors.MethodsWe developed a mouse model of lung adenocarcinoma with defined expression of different neoantigens (NeoAg), enabling us to analyze how these impact antitumor T-cell immunity and to study underlying mechanisms. Data from a large cancer patient cohort was used to study whether NeoAg architecture characteristics found to define tumor immunogenicity in our mouse models are linked to ICB responses in patients with cancer.ResultsWe demonstrate that concurrent expression and clonality define NeoAg architectures which determine the immunogenicity of individual NeoAg and drive immune evasion of tumors with heterogenous NeoAg expression. Mechanistically, we identified concerted interplays between concurrent T-cell responses induced by cross-presenting dendritic cells (cDC1) mirroring the tumor NeoAg architecture during T-cell priming in the lymph node. Depending on the characteristics and clonality of respective NeoAg, this interplay mutually benefited concurrent T-cell responses or led to competition between T-cell responses to different NeoAg. In tumors with heterogenous NeoAg expression, NeoAg architecture-induced suppression of T-cell responses against branches of the tumor drove immune evasion and caused resistance to ICB. Therapeutic RNA-based vaccination targeting immune-suppressed T-cell responses synergized with ICB to enable control of tumors with subclonal NeoAg expression. A pan-cancer clinical data analysis indicated that competition and synergy between T-cell responses define responsiveness to ICB in patients with cancer.ConclusionsNeoAg architectures modulate the immunogenicity of NeoAg and tumors by dictating the interplay between concurrent T-cell responses mediated by cDC1. Impaired induction of T-cell responses supports immune evasion in tumors with heterogenous NeoAg expression but is amenable to NeoAg architecture-informed vaccination, which in combination with ICB portrays a promising treatment approach for patients with tumors exhibiting high ITH.
Magnitude of antigen-specific T-cell immunity the month after completing vaccination series predicts the development of long-term persistence of antitumor immune response
Authors: Liao John B , Dai James Y , Reichow Jessica L , Lim Jong-Baeck , Hitchcock-Bernhardt Katie M , Stanton Sasha E , Salazar Lupe G , Gooley Theodore A , Disis Mary L 
Published: November 2024

BackgroundFor best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the immune response must rely on T cells. The magnitude and differentiation of effective, durable immune responses depend on antigen-specific precursor frequencies. However, development of vaccines that induce durable T-cell responses for cancer treatment has remained elusive.MethodsTo address long-lasting immunity, patients with HER2+ (human epidermal growth factor receptor 2) advanced stage cancer received HER2/neu targeted vaccines. Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot measuring HER2/neu IFN-γ T cells were analyzed from 86 patients from three time points: baseline, 1 month after vaccine series, and long-term follow-up at 1 year, following one in vitro stimulation. The baseline and 1-month post-vaccine series responses were correlated with immunity at long-term follow-up by logistic regression. Immunity was modeled by non-linear functions using generalized additive models.ResultsAntigen-specific T-cell responses at baseline were associated with a 0.33-log increase in response at long-term follow-up, 95% CI (0.11, 0.54), p=0.003. 63% of patients that had HER2/neu specific T cells at baseline continued to have responses at long-term follow-up. Increased HER2/neu specific T-cell response 1 month after the vaccine series was associated with a 0.47-log increase in T-cell response at long-term follow-up, 95% CI (0.27, 0.67), p=2e-5. 74% of patients that had an increased IFN-γ HER2 response 1 month after vaccines retained immunity long-term. As the 1-month post-vaccination series precursor frequency of HER2+IFN-γ T-cell responses increased, the probability of retaining these responses long-term increased (OR=1.49 for every one natural log increase of precursor frequency, p=0.0002), reaching an OR of 20 for a precursor frequency of 1:3,000ConclusionsPatients not destined to achieve long-term immunity can be identified immediately after completing the vaccine series. Log-fold increases in antigen-specific precursor frequencies after vaccinations correlate with increased odds of retaining long-term HER2 immune responses. Further vaccine boosting or immune checkpoint inhibitors or other immune stimulator therapy should be explored in patients that do not develop antigen-specific T-cell responses to improve overall response rates.
Comparison of a voclosporin-based triple immunosuppressive therapy to high-dose glucocorticoid-based immunosuppressive therapy: a propensity analysis of the AURA-LV and AURORA 1 studies and ALMS
Authors: Dall'Era Maria , Kalunian Kenneth , Solomons Neil , Truman Matt , Hodge Lucy S , Yap Ernie , Askanase Anca D 
Published: November 2024

IntroductionHigh-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy.MethodsPropensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months.ResultsThere were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months.ConclusionsCompared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.
Biomechanical validation of the field-expedient pelvic splint
Authors: Savakus Jonathan C , Skacel T , Jindia M , Al-Madani Y , Spoletini L , C Ross R , Gehring A , J Stinner D 
Published: November 2024

IntroductionMorbidity and mortality from pelvic ring injuries can be mitigated by early and effective external pelvic stabilisation. The field-expedient pelvic splint (FEPS) is a recently described technique to improvise an effective pelvic binder for an austere environment. This technique has not been biomechanically validated. We hypothesise that the FEPS will be biomechanically equivalent to a commercially available pelvic binder routinely used in the austere environment.MethodsCompressive force generation of the FEPS was measured using a commercial load frame. A SAM Pelvic Sling was used as a control. The FEPS was tested for initial force generation, persistence of force generation over a 6-hour longitudinal test period and force generation after repeated assembly/disassembly.ResultsThe FEPS generated 203N (±7N) with one windlass turn and 420N (±34N) with two windlass turns. The SAM Pelvic Sling generated 197N (±11N) of force. There was no significant difference between FEPS after one windlass crank and the SAM Pelvic Sling but the force generated by the FEPS with two windlass cranks was significantly higher than the SAM Pelvic Sling. Longitudinal testing showed that after 6 hours of continuous compression, the FEPS generated 189N (±19N) and the force generated at hour 6 was not significantly different from the initial force generated by SAM Pelvic Sling. Reusability testing showed no significant difference with force generation by the FEPS after repeated assembly/disassembly with one crank of the windlass but there was a significantly increased force generation by FEPS after repeated use trials with two cranks of the windlass.ConclusionThe FEPS exerted equivalent pelvic compressive forces to its commercial equivalent and this force generation persists at effective levels over a 6-hour time course. The FEPS remained effective after repeated use. The FEPS is a viable alternative in the austere or resource-limited environment for temporary pelvic stabilisation.