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Stage at diagnosis and international survival variation in childhood tumors in the BENCHISTA study
No full textImportance: Understanding the reasons for variations in population-level survival differences in childhood cancer is important to guide improvement efforts. Collaboration between population-based cancer registries (CRs) to apply the international consensus Toronto guidelines to record tumor stage at diagnosis is a key first step.
Objective: To test whether survival probabilities by tumor stage vary internationally, using 6 childhood solid tumors as exemplars.
Design, Setting, and Participants: The International Benchmarking of Childhood Cancer Survival by Stage (BENCHISTA) population-based retrospective cohort study included all incident cases of neuroblastoma, Wilms tumor, medulloblastoma, osteosarcoma, Ewing sarcoma of bone, and rhabdomyosarcoma diagnosed between January 1, 2014, and December 31, 2017, with 3-year follow-up for survival. A total of 73 CRs from 27 countries (23 European as well as Australia, Brazil, Canada, and Japan) constituted the dataset. Analyses were conducted from June 2023 to December 2024.
Main Outcomes and Measures: Three-year overall survival (OS) by stage for each tumor type, with comparisons between countries grouped into 5 predefined European areas. Multivariable Cox and logistic models estimated each area’s hazard or odds ratio of death compared with Central Europe (Austria, Belgium, France, Germany, Switzerland, and the Netherlands), adjusted by age group and stage.
Results: A total of 9883 cases were included; 4452 (45%) were girls and overall median (IQR) age was 54 (22-122) months; stage completeness was 93% (9199 of 9883). Three-year OS rates were as follows: Wilms tumor, 95% (95% CI, 94%-96%); neuroblastoma, 83% (95% CI, 81%-84%); medulloblastoma, 79% (95% CI, 77%-81%); Ewing sarcoma, 78% (95% CI, 75%-80%); rhabdomyosarcoma, 77% (95% CI, 74%-79%); and osteosarcoma, 75% (95% CI, 73%-77%). Geographical variations in age-adjusted OS were found for neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdomyosarcoma. Following additional adjustment for stage, differences were no longer significant for neuroblastoma (in the UK and Ireland) and rhabdomyosarcoma (in Eastern Europe) while becoming significant for neuroblastoma in Eastern Europe (hazard ratio, 1.36; 95% CI, 1.05-1.76) and medulloblastoma in Southern Europe (hazard ratio, 1.42; 95% CI, 1.03-1.94). However, no mitigation of survival variation was observed for Ewing sarcoma in the UK and Ireland (hazard ratio, 2.06; 95% CI, 1.39-3.04) and Eastern Europe (hazard ratio, 1.87; 95% CI, 1.22-2.86) as well as for medulloblastoma in Eastern Europe (hazard ratio, 1.68; 95% CI, 1.13-2.49).
Conclusions and Relevance: In this BENCHISTA cohort study of 6 solid tumors, international variation in population-level OS was associated with differences in tumor stage distribution for some cancer types and regions. Additional factors are suggested for further investigation. The results have important implications for national health systems for monitoring early diagnosis efforts and supporting collaboration between CRs and clinicians to sustain standardized use of Toronto guidelines to improve understanding of survival variation in childhood cancer
Factors that influenced the delivery of a community-based continuous mass dog rabies vaccination approach in the Mara region of Tanzania
No full textIntroduction: Mass dog vaccination is the most effective approach for interrupting canine rabies transmission. However, current vaccination strategies are typically centralized and conducted annually, leaving some communities excluded and with few opportunities to vaccinate their dogs. A community-based continuous mass dog vaccination strategy was piloted in the Mara region of Tanzania. We investigate factors that influenced the delivery of this approach and how the processes were sustained over two years.
Methods: We employed mixed methods to explore what influenced vaccination delivery. We conducted in-depth interviews (n = 24) and focus group discussions (n = 12) with implementers and community members, and non-participant observation of vaccinations (n = 172 h). We documented time spent by dog owners attending campaigns (n = 610) and how dogs were handled (n = 696), and audited how components of the community-based continuous approach were delivered (n= 47). Qualitative data was analyzed thematically, and regression and descriptive statistics used to assess factors affecting delivery.
Main findings: Factors that facilitated participation in the campaigns included delivering vaccination free of charge, more frequent availability of vaccinations, and co-implementation with communities. Limiting factors were distance to vaccination points, difficulties in handling dogs and vaccination schedules conflicting with local socioeconomic activities. Sub-village level campaigns were more accessible and required less time from dog owners.
Interpretation: Involving community-based persons facilitated planning and advertising of campaigns. Mass dog vaccination campaigns can achieve and maintain herd immunity if organized at least twice a year and at subvillage levels. Educating vaccinators and communities on dog behavior and handling could improve participation in campaigns
Phase 2, randomized, double-blind, placebo-controlled study of CRD-740, a PDE9 inhibitor, in chronic heart failure
Get PDFBackground:
The beneficial effects of natriuretic peptide receptor activation are mediated by cyclic guanosine monophosphate (cGMP). Phosphodiesterase 9 (PDE9) hydrolyzes cGMP and therefore its inhibition has the potential to increase intracellular cGMP signaling.
Objectives:
The aim of this study is to assess the effects of the oral PDE9 inhibitor CRD-740 on plasma and urinary cGMP in patients with heart failure and reduced ejection fraction (HFrEF).
Methods:
Patients with HFrEF of >6 months, NYHA functional class II/III, ejection fraction ≤40%, and elevated N-terminal pro–B-type natriuretic peptide were randomized 2:1 to CRD-740 (10 mg twice a day for 2 weeks, then 25 mg twice a day for 10 weeks) or placebo. The primary pharmacodynamic endpoint was the change in plasma cGMP to week 4.
Results:
Sixty patients were randomized to CRD-740 (n = 40) or placebo (n = 20). Baseline characteristics included ejection fraction 28% ± 7%, with 73% of patients taking sacubitril/valsartan. The placebo-corrected change in plasma cGMP from baseline at week 4 increased with CRD-740, 19.1% ± 26.9% increase vs 8.8% (31.3%) decrease in area under the curve from 0 to 6 hours, respectively, for a least squared mean difference of 26.5% (95% CI: 7.8-45.1; P = 0.003). There was no interaction with the presence/absence of sacubitril/valsartan (P = 0.47). An increase in urinary cGMP was observed with CRD-740 at day 1 (P = 0.012), week 2 (P = 0.014), and week 4 (P = 0.09). No significant between-group differences in systolic blood pressure, hypotension, or serious adverse events were observed.
Conclusions:
In this initial phase 2 trial, PDE9 inhibition with CRD-740 was well tolerated and resulted in elevations of plasma and urinary cGMP on top of standard care, including sacubitril/valsartan, supporting the potential of PDE9 inhibition to enhance the beneficial effects of the natriuretic peptide receptor-cGMP pathway incremental to existing heart failure treatments. (Effectiveness of CRD-740 in Heart Failure [CARDINAL-HF]; NCT05409183
The concentration grid exercise: effects of silent practice and music distraction on performance, attention, affect, and brain activity
No full textWe conducted two studies using the concentration grid exercise to assess the effects of practice in silence (Study 1) and practice with loud music on the background (Study 2) on performance, attention, core affective states (arousal and pleasantness), and alpha, beta, and theta brain waves. In Study 1, we recruited 12 participants, 6 males and 6 females (M = 27.50, SD = 8.27). In Study 2, we recruited 12 participants, 6 males and 6 females (M = 26.36, SD = 6.67). For both Study 1 and Study 2, no significant effects were observed for performance, attention, and core affect. Marginal significant effects were observed for attention and arousal, suggesting loud music was a distraction to at least some participants. Across both studies, the electroencephalogram data revealed significant differences in alpha, beta, and theta power across pre-test and post-test trials. Collectively, these findings support the neural efficiency hypothesis; in that practice leads to a more quiescent brain state in both silent-practice and music distraction conditions. These findings also suggest that the concentration grid exercise can be an appropriate tool for research and practice
Navigating the rise of artificial intelligence and imposter participants in qualitative health research
Get PDFArtificial intelligence enables people to create convincing online identities and narratives, which poses a growing threat to qualitative health research conducted online. We report on a UK-wide interview study on financial insecurity and serious illness that, during open recruitment across three university sites, received hundreds of false expressions of interest generated or assisted by large language models. Suspected false expressions of interest and screening call notes were retained and anonymised for qualitative content analysis, following Schreier’s (2012) approach. Analysis of emails and screening calls exposed repetitive templated phrasing, vague accounts of serious illnesses, postcode anomalies, and resistance to brief video verification. A layered authentication workflow, postcode checks, UK telephone confirmation, and short introductory calls helped to filter suspected imposters while maintaining accessibility for participants at risk of digital exclusion. This experience highlights the ethical tension between vigilance and trust, and demonstrates the hidden labour and time costs of mitigating imposter participants. By sharing observable red flags, practical screening steps, and their resource implications, we contribute methodological guidance to emerging debates on protecting data integrity in the face of AI-assisted imposter participants. Our case demonstrates that proportionate, manual checks can safeguard authenticity without imposing undue barriers, provided teams remain reflexive about inclusivity and communicate checks clearly in study materials. We outline decision points that researchers and research governance teams can adapt to context, including when to escalate from email screening to telephone or video, how to document anomalies, and how to record exclusions. We argue that journals and funders should recognise verification effort in methods reporting and budgets. The article offers immediate, implementable safeguards for qualitative researchers, and sets priorities for benchmarking detection tools and integrating AI literacy into qualitative methods training
TWEAK is increased in ulcerative colitis and contributes to fibroblast-mediated monocyte activation via heterologous non-canonical NF-kB/STAT3 signaling
Get PDFBackground and Aims:
Interactions between fibroblasts and monocytes have emerged as a contributing factor in inflammatory bowel disease (IBD) pathogenesis and therapy resistance, owing to the ability of both cell types to participate in tissue inflammation and repair. We have previously shown that the tumor necrosis factor superfamily member TWEAK (TNFSF12) can induce an ulcerative colitis (UC)-like inflammatory profile in colonic fibroblasts in vitro, in turn promoting monocyte adhesion and activation. However, the mechanisms underlying fibroblast–monocyte communication and its dysregulation in ulcerative colitis are incompletely understood.
Methods:
Here we use co-culture models, human biopsies from UC patients and healthy donors, and public single-cell transcriptomics to characterize the mechanisms underlying fibroblast-mediated monocyte activation.
Results:
We show that TWEAK-treated inflammatory fibroblasts induce a transcriptional program that resembles early monocyte/macrophage intermediates in UC and is enriched for genes associated with resistance to anti-TNF (TREM1, OSM, IL1B) and susceptibility to IBD (NOD2, ATG16L1). We find that conditioned media from TWEAK-treated fibroblasts causes a sustained activation of STAT3 phosphorylation in monocytes, and that inhibition of the NF-κB inducing kinase (NIK) impairs the ability of inflammatory fibroblasts to activate STAT3 phosphorylation in monocytes, resulting in reduced expression of inflammatory mediators. Using tissues from UC patients, we show that the expansion of CD90+/PDPN+ inflammatory fibroblasts and increased FN14 in UC correlates with the accumulation of TWEAK+ myeloid cells in the colonic mucosa, and that these fibroblasts co-localize with infiltrating monocytes in sites of active inflammation.
Conclusion:
Together, our findings suggest that the TWEAK/NF-κB/STAT3 axis represents an attractive target to tune inflammatory stroma/monocyte crosstalk
24-Hour ambulatory blood pressure and C-reactive protein: a systematic review and meta-analysis
Get PDFBackground
Inflammation plays a key role in pathophysiology of hypertension; however the relevance of specific inflammatory mediators, such as C-reactive protein (CRP) is uncertain. We conducted a systematic literature review and meta-analysis to assess the associations between CRP levels and 24-hour blood pressure (BP) values in adult patients.
Methods
We performed a systematic search of PubMed/MEDLINE, Embase, Web of Science, and Scopus for human studies published between January 2013 and June 2023. We included cross-sectional and cohort studies. We excluded studies reporting clinically significant inflammation. We calculated the Pearson’s correlation coefficients between 24-hour BP indices and the CRP levels weighted by the inverse of their variances.
Results
Of 716 reports identified, 20 met eligibility criteria (10,799 participants, mean age ± standard deviation [SD] 56.1 ± 9.5 years, mean ± SD 24-hour systolic BP [SBP] 132.2 ± 14.3 mmHg, and diastolic BP [DBP] 79.3 ± 9.8 mmHg). CRP ranged from 0.14 to 10.6 mg/L, median 2.66 mg/L (interquartile range, 1.13–5.13 mg/L). In the subgroup of studies where CRP levels were ≥ 3 mg/L, a significant positive association between CRP and average 24-hour SBP (r = 0.79, P < 0.001) and DBP (r = 0.83, P < 0.001) was observed. When all studies were analyzed however, there was no correlation between CRP and neither 24-hour SBP (r = 0.18, P = 0.29), nor DBP (r = 0.27, P = 0.94).
Conclusions
CRP may be an important biomarker of the relationship between inflammation and hypertension. However, the relation may not be linear throughout the entire range of CRP values.
Trial Registration
International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD4202346260
Early prediction of adverse stroke outcomes using non-clinical factors and missing data: a machine learning study
Get PDFIntroduction Early prediction of stroke outcomes using prognostic tools may help clinical decision making and inform resource allocation. However, clinical information required to inform prediction tools is often missing. We evaluated the performance of machine learning (ML) prediction models of adverse stroke outcome at 90 days post-admission that exploit non-clinical data, and missingness, alongside traditional clinical and demographic predictors. Methods We used routine hospital data from UK clinical sites (NHS SafeHaven) to train three Gradient Boosted (GBM) models. We compared baseline clinical features with non-clinical features and missingness to predict a composite 90-day adverse stroke outcome: mortality, stroke recurrence or new care-home discharge. Model validation used 10% of the data. Model performance was evaluated by accuracy (correct predictions/total predictions) and Area Under the Receiver Operating Characteristics (ROC) Curve (AUC) while DeLong’s test was used to compare performance of the three models. We used Brier score to evaluate model calibration. SHapley Additive exPlanations (SHAP) analyses determined the contribution of each model feature in predicting adverse stroke outcome. Results The final sample included 3530 stroke patients with 51% males (mean age=72 years; SD=14). Clinical data were incomplete with five clinical features having >63% missing values. The performance of the three models was not significantly different (p=0.5 to 0.9). The model with non-clinical and missingness features demonstrated 71% accuracy and AUC of 0.76 with Brier score of 0.19. Non-clinical factors, such as time to clinical assessment and time to admission, were amongst the five most important predictors of adverse stroke outcome (mean |SHAP|=0.03 and 0.05), alongside Glasgow Coma Scale (0.08), age (0.03) and temperature (0.02). Missing clinical values (pulse and LDL) predicted adverse stroke outcome (mean |SHAP|=0.02 and 0.02) and were correlated with age (ρ=0.2), arrival by ambulance (ρ=0.3), length of stay (ρ=-0.3) and Transient Ischemic Attack (ρ=0.3). Conclusion We demonstrate that non-clinical factors and missingness of data can assist in early predictions of 90-day adverse stroke outcomes. As these factors are often well documented in electronic health systems they could complement or supplement traditional clinical predictive factors
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