Conectar
Combined vascular endothelial growth factor/programmed death-ligand 1 blockade through atezolizumab/bevacizumab (A/B) is the current standard of care in advanced hepatocellular carcinoma (HCC). A/B substantially improved objective response rates compared with tyrosine kinase inhibitor sorafenib; however, a majority of patients will still not respond to A/B. Strong scientific rationale and emerging clinical data suggest that faecal microbiota transfer (FMT) may improve antitumour immune response on PD-(L)1 blockade. Early trials in melanoma with FMT and reinduction of immune checkpoint blockade (ICI) therapy in patients with anti-PD-1-refractory metastatic melanoma were reported in 2021 and demonstrated reinstatement of response to ICI therapy in many patients. Due to anatomical vicinity and the physiological relevance of the gut-liver axis, we hypothesise HCC to be a particularly attractive cancer entity to further assess a potential benefit of FMT in combination with ICI towards increased antitumour immunity. Additionally, HCC often occurs in patients with liver cirrhosis, where liver function is prognostically relevant. There is evidence that FMT may increase hepatic function and therefore could positively affect outcome in this patient population.
This prospective, multicentre, randomised, placebo-controlled, double-blind phase II clinical trial has been designed to assess immunogenicity and safety of FMT via INTESTIFIX 001 combined with A/B in advanced HCC in comparison to A/B with placebo. Primary endpoints are measured as tumour CD8+ T cell infiltration after 2 cycles of treatment with vancomycin, A/B+INTESTIFIX 001 in comparison to vancomycin-placebo, A/B+INTESTIFIX 001-placebo and safety of the therapeutic combination in advanced HCC. INTESTIFIX 001 is an encapsulated FMT preparation by healthy donors with a high alpha-diversity in their gut microbiome for oral administration, manufactured by the Cologne Microbiota Bank (CMB). Sample size was calculated to achieve a specific expected accuracy for the primary immunological endpoint. 48 subjects will be randomised to reach a goal of 42 usable measurements in the modified intention-to-treat set. Subjects will be randomised in a 2:1 ratio to A/B or placebo (28 A/B, 14 placebo).
The study was approved by ethics committee review and the German Federal Ministry of Drugs and Medical Devices. The trial is registered under EU CT no. 2023-506887-15-00. The outcome of the study will be disseminated via peer-reviewed publications and at international conferences.
Neoadjuvant (chemo)radiotherapy (n(C)RT) followed by resection with total mesorectal excision (TME) constitutes the standard treatment for patients with locally advanced rectal cancer of the middle and lower third. However, n(C)RT has demonstrated no significant impact on overall survival but is associated with adverse effects, including impaired sphincter and sexual function. We hypothesise that omitting n(C)RT in selected patients with a clear circumferential resection margin (CRM) >1 mm as determined through preoperative MRI is not inferior regarding local recurrence rate within 3 years after surgery. That treatment approach may show fewer adverse effects and be more cost-effective.
Selective neoadjuvant therapy of rectal cancer patients (SELREC) is a randomised controlled, parallel-group, open, multicentre, non-inferiority trial. The experimental intervention involves performing TME surgery without n(C)RT. In contrast, the control intervention adheres to German S3-guidelines, incorporating neoadjuvant radiotherapy (nRT) with a dosage of 5x5 Gy or a total of 50.4 Gy. Additionally, if applicable, concomitant chemotherapy (CT) based on 5-fluorouracil is administered, followed by TME surgery within less than 12 weeks. Adjuvant treatment according to guidelines is allowed depending on the (y)pTNM stage.
The inclusion criteria for this study encompass adult patients with primary adenocarcinoma of the rectum in whom the main tumour mass is located less than 12 cm away from the anal verge, as assessed via proctoscopy. Additionally, eligible participants are required to have a preoperative tumour stage determined by MRI of either T1 or T2 with lymph node involvement (N1) or T3 with no lymph node involvement (N0) or with lymph node involvement (N1) and no distant metastases (M0). The assessment of a clear CRM >1 mm, based on MRI, is another prerequisite for inclusion. A total of 1074 patients in approximately 35 centres are planned to be allocated to the trial.
The primary endpoint of the trial is local recurrence within 3 years after surgery. The primary estimand is based on the full analysis set using a logistic mixed model (margin 3%). The first secondary endpoint is no/minor low anterior resection syndrome (LARS) score at 2 years after surgery, and further secondary endpoints include survival outcomes and quality of life. Safety analysis involves describing the frequencies of major intervention-specific complications, such as the acute toxicity of n(C)RT according to CTCAE and perioperative morbidity and mortality according to Clavien-Dindo criteria.
SELREC is financially supported by the German Federal Ministry of Education and Research.
This trial has been prospectively registered in the German Clinical Trials Register.
Previously, the study had been approved by the responsible ethics committee of Heidelberg and the local ethics committees of the collaborating institutions before patient enrolment. Any protocol deviation that has an impact on relevant parameters such as study design, endpoints or patient safety will be reported to the responsible ethics committees.
The results will be published in a peer-reviewed scientific journal and on institutional websites.
German Clinical Trials Register DRKS00030567.
Psychosis, characterised by chronic symptoms often emerging in youth, imposes a substantial burden on individuals and healthcare systems. While early detection and intervention can mitigate this burden, there is limited evidence on the cost-effectiveness of such approaches. To address this lack of evidence, this study protocol outlines the health economic implications of an artificial intelligence (AI)-based intervention, the Computer-Assisted Risk-Evaluation (CARE), designed to prevent psychosis. The intervention uses AI technologies to enhance the diagnosis and treatment quality for individuals at high risk of psychosis.
The health economic evaluation has been designed alongside a 12-month multicentre randomised controlled trial comparing CARE with treatment as usual from both payer and societal perspectives. An implementation cost analysis will complement the evaluation, and long-term consequences beyond the trial will be explored descriptively. Based on a literature review, an initial economic logic model will guide subsequent analyses by depicting CARE’s programme theory.
The cost-effectiveness assessment will include averted cases of manifest psychosis and quality-adjusted life-years using the EuroQol 5-Dimensions 3-Level instrument. Other effectiveness outcomes will also be incorporated into a cost–consequence analysis. Cost-effectiveness acceptability curves reflecting statistical uncertainty will be constructed, incorporating various payer and societal willingness-to-pay values. The implementation cost analysis will follow a mixed-methods approach to capture facility-specific costs.
A dark logic model, emphasising negative outcomes, will be developed to investigate long-term consequences. Further, the initial economic logic model will be refined using trial data and expert interviews. This comprehensive approach aims to provide decision-makers not only with evidence on the cost-effectiveness of CARE, but also with a broader understanding of the implications of the intervention.
The study has received ethical approval and plans to disseminate its findings through publication in a peer-reviewed journal and conference presentations.
To explore the types of barriers that midwives face when practicing or attempting to practice in rural and remote locations.
An integrative review using the Ecological Systems Theory.
The review was guided by Whitmore and Knafl. Included studies were appraised using the Mixed Methods Appraisal tool.
In January 2024, searches were undertaken in CINHAL, MEDLINE, Science Direct, and Google Scholar.
A total of 470 articles were screened after searches. Fourteen articles published between 1990 and 2023 met all inclusion criteria. They were thematically analysed to explore barriers present at the micro-, macro-, and meso-levels. The mico-level barriers included isolation, financial insecurity due to low volume, and challenges in separating personal and professional life. Barriers at the meso level included discord in interprofessional relationships and challenges in attending continuing education. Lack of midwifery representation, overt medical dominance, and policy acted as barriers at the macro level.
Rural midwives face complex challenges that demand multi-faceted and multi-level solutions. The findings highlight the need for an increase in midwifery representation in healthcare planning, improved policies related to midwifery, and the adoption of a rural model of healthcare planning that accounts for the unique social realities of living and practicing in rural communities.
By illuminating the challenges faced by rural midwives, efforts can be directed toward sustainable solutions to support rural midwifery practices and decrease rural health disparities.
Increasing midwifery access in rural communities can help reduce maternity care disparities for rural families. By identifying and addressing the barriers experienced by rural midwives, it can strengthen advocacy for targeted policies and support systems that empower midwives.
This review is reported according to the PRISMA guidelines for scoping reviews.
No Patient or Public Contribution.
by Alexandra R. van den Berg, Pieter R. Roelfsema, Sander M. Bohte
The acquisition of knowledge and skills does not occur in isolation but learning experiences amalgamate within and across domains. The process through which learning can accelerate over time is referred to as learning-to-learn or meta-learning. While meta-learning can be implemented in recurrent neural networks, these networks tend to be trained with architectures that are not easily interpretable or mappable to the brain and with learning rules that are biologically implausible. Specifically, these rules have often employed backpropagation-through-time, which relies on information that is unavailable at synapses that are undergoing plasticity in the brain. Previous studies that exclusively used local information for their weight updates had a limited capacity to integrate information over long timespans and could not easily learn-to-learn. Here, we propose a novel gated memory network named RECOLLECT, which can flexibly retain or forget information by means of a single memory gate and is trained with a biologically plausible trial-and-error-learning that requires only local information. We demonstrate that RECOLLECT successfully learns to represent task-relevant information over increasingly long memory delays in a pro-/anti-saccade task, and that it learns to flush its memory at the end of a trial. Moreover, we show that RECOLLECT can learn-to-learn an effective policy on a reversal bandit task. Finally, we show that the solutions acquired by RECOLLECT resemble how animals learn similar tasks.
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