bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study
Authors: Solovyeva Olga , Dimairo Munyaradzi , Weir Christopher J. , Hee Siew Wan , Espinasse Aude , Ursino Moreno , Patel Dhrusti , Kightley Andrew , Hughes Sarah , Jaki Thomas , Mander Adrian , Evans Thomas R. Jeffry , Lee Shing , Hopewell Sally , Rantell Khadija Rerhou , Chan An-Wen , Bedding Alun , Stephens Richard , Richards Dawn , Roberts Lesley , Kirkpatrick John , de Bono Johann , Yap Christina 
Published: July 2023

AbstractBackgroundEarly phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE).MethodsThe initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants’ feedback.ResultsThe Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar.ConclusionsBy detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility.Trial registrationSPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network (https://www.equator-network.org/).
CMA mediates resistance in breast cancer models
Authors: Lo Dico Alessia , Martelli C. , Corsi F. , Porro D. , Ottobrini L. , Bertoli G. 
Published: July 2023

Abstract
Background
Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker.

Methods
A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA.

Results
In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours.

Conclusion
Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs.
Novel inflammatory mediator profile observed during pediatric heart surgery with cardiopulmonary bypass and continuous ultrafiltration
Authors: Bierer Joel , Stanzel Roger , Henderson Mark , Sett Suvro , Sapp John , Andreou Pantelis , Marshall Jean S. , Horne David 
Published: July 2023

Abstract
Background
Cardiopulmonary bypass (CPB) is associated with systemic inflammation, featuring increased levels of circulating pro-inflammatory cytokines. Intra-operative ultrafiltration extracts fluid and inflammatory factors potentially dampening inflammation-related organ dysfunction and enhancing post-operative recovery. This study aimed to define the impact of continuous subzero-balance ultrafiltration (SBUF) on circulating levels of major inflammatory mediators.

Methods
Twenty pediatric patients undergoing cardiac surgery, CPB and SBUF were prospectively enrolled. Blood samples were collected prior to CPB initiation (Pre-CPB Plasma) and immediately before weaning off CPB (End-CPB Plasma). Ultrafiltrate effluent samples were also collected at the End-CPB time-point (End-CPB Effluent). The concentrations of thirty-nine inflammatory factors were assessed and sieving coefficients were calculated.

Results
A profound increase in inflammatory cytokines and activated complement products were noted in plasma following CBP. Twenty-two inflammatory mediators were detected in the ultrafiltrate effluent. Novel mediators removed by ultrafiltration included cytokines IL1-Ra, IL-2, IL-12, IL-17A, IL-33, TRAIL, GM-CSF, ET-1, and the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL10. Mediator extraction by SBUF was significantly associated with molecular mass < 66 kDa (Chi2 statistic = 18.8, Chi2 with Yates’ correction = 16.0, p < 0.0001). There was a moderate negative linear correlation between molecular mass and sieving coefficient (Spearman R = − 0.45 and p = 0.02). Notably, the anti-inflammatory cytokine IL-10 was not efficiently extracted by SBUF.

Conclusions
CPB is associated with a burden of circulating inflammatory mediators, and SBUF selectively extracts twenty of these pro-inflammatory factors while preserving the key anti-inflammatory regulator IL-10. Ultrafiltration could potentially function as an immunomodulatory therapy during pediatric cardiac surgery.
Trial registration ClinicalTrials.gov, NCT05154864. Registered retrospectively on December 13, 2021. https://clinicaltrials.gov/ct2/show/record/NCT05154864.
A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Authors: Taccori Asher , Maksoud Rebekah , Eaton-Fitch Natalie , Patel Maharshi , Marshall-Gradisnik Sonya 
Published: July 2023

Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic marker or targeted treatment for ME/CFS. Urine is a non-invasive sample that provides biomarkers that may have the potential to be used in a diagnostic capacity for ME/CFS. While there are several studies investigating urine-based biomarkers for ME/CFS, there are no published systematic reviews to summarise existing evidence of these markers. The aim of this systematic review was to compile and appraise literature on urinary-based biomarkers in ME/CFS patients compared with healthy controls.

Methods
Three databases: Embase, PubMed, and Scopus were searched for articles pertaining to urinary biomarkers for ME/CFS compared with healthy controls published between December 1994 to December 2022. The final articles included in this review were determined through application of specific inclusion and exclusion criteria. Quality and bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. A meta-analysis according to Cochrane guidelines was conducted on select studies, in particular, those that investigate urinary free cortisol levels in ME/CFS patients compared to healthy controls using the program STATA 17.

Results
Twenty-one studies were included in this review. All of the studies investigated urinary-based markers in ME/CFS patients compared with healthy controls. The reported changes in urinary outputs include urinary free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%). In most cases, there was minimal overlap in the main outcomes measured across the studies, however, differences in urinary free cortisol between ME/CFS patients and healthy controls were commonly reported. Seven studies investigating urinary free cortisol were included in the meta-analysis. While there were significant differences found in urinary free cortisol levels in ME/CFS patients, there was also substantial heterogeneity across the included studies that makes drawing conclusions difficult.

Conclusions
There is limited evidence suggesting a consistent and specific potential urinary-based biomarker for ME/CFS. Further investigations using more standardised methodologies and more stringent case criteria may be able to identify pathophysiological differences with diagnostic potential in ME/CFS patients compared with healthy controls.
The use of alpha 1 thymosin as an immunomodulator of the response against SARS-Cov2
Authors: Espinar-Buitrago M. S. , Tarancon-Diez L. , Vazquez-Alejo E. , Magro-Lopez E. , Genebat M. , Romero-Candau F. , Leal M. , Muñoz-Fernandez M. A. 
Published: July 2023

Abstract
Background
Since the beginning of SARS-CoV2 pandemic, the mortality rate among elderly patients (60–90 years) has been around 50%, so age has been a determining factor of a worse COVID-19 prognosis. Associated with age, the thymic function involution and depletion plays an important role, that could be related to a dysregulated and ineffective innate and adaptive immune response against SARS-CoV2. Our study aims to further in vitro effect of human Thymosin-alpha-1 (α1Thy) treatment on the immune system in population groups with different thymic function levels in the scenario of SARS-CoV2 infection.

Results
Activation markers such as CD40, CD80 and TIM-3 were upregulated in α1Thy presence, especially in plasmacytoid dendritic cells (pDCs) and, with increased TNFα production was observed compared to untreated condition. Co-cultures of CD4 + and CD8 + T cells with DCs treated with α1Thy in response to SARS-CoV2 peptides showed a decrease in the cytokine production compared to the condition without α1Thy pre-treated. A decrease in CD40L activation co-receptor expression in CD8 + LTs was also observed, as well as an increase in PD1 in CD4 + TLs expression in both age groups. In fact, there are no age-related differences in the immunomodulatory effect of the hormone, and it seems that effector memory and terminally differentiated memory T lymphocyte subsets were the most actively influenced by the immunomodulatory α1Thy effect. Finally, the polyfunctionality measured in SARS-CoV2 Specific-T cells response was maintained in α1Thy presence in total and memory subpopulations CD4 + and CD8 + T-cells, despite decreased proinflammatory cytokines production.

Conclusion
The hormone α1Thy could reduce, through the modulation of DCs, the amount of proinflammatory cytokines produced by T cells. Moreover, α1Thy improve lymphocyte functionality and could become a beneficial therapeutic alternative as an adjuvant in SARS-CoV2 treatment either in the acute phase after infection or reinfection. In addition, the effect on the T immune response means that α1Thy can be incorporated into the vaccination regimen, especially in the most immunologically vulnerable individuals such as the elderly.

Subjects
Thymosin alpha 1, Dendritic cells, SARS-CoV2-specific T cells response, Immunomodulation
Target volume delineation for radiotherapy of meningiomas: an ANOCEF consensus guideline
Authors: Martz Nicolas , Salleron Julia , Dhermain Frédéric , Vogin Guillaume , Daisne Jean-François , Mouttet-Audouard Raphaelle , Tanguy Ronan , Noel Georges , Peyre Matthieu , Lecouillard Isabelle , Jacob Julian , Attal Justine , Charissoux Marie , Veresezan Ovidiu , Hanzen Chantal , Huchet Aymeri , Latorzeff Igor , Coutte Alexandre , Doyen Jérôme , Stefan Dinu , Feuvret Loic , Garcia Gabriel C. T. E. , Royer Philippe 
Published: July 2023

Abstract
Purpose
Radiotherapy is, with surgery, one of the main therapeutic treatment strategies for meningiomas. No prospective study has defined a consensus for the delineation of target volumes for meningioma radiotherapy. Therefore, target volume definition is mainly based on information from retrospective studies that include heterogeneous patient populations. The aim is to describe delineation guidelines for meningioma radiotherapy as an adjuvant or definitive treatment with intensity-modulated radiation therapy and stereotactic radiation therapy techniques. This guideline is based on a consensus endorsed by a multidisciplinary group of brain tumor experts, members of the Association of French-speaking Neuro-oncologists (ANOCEF).

Materials and methods
A 3-step procedure was used. First, the steering group carried out a comprehensive review to identify divergent issues on meningiomas target volume delineation. Second, an 84-item web-questionnaire has been developed to precisely define meningioma target volume delineation in the most common clinical situations. Third, experts members of the ANOCEF were requested to answer. The first two rounds were completed online. A third round was carried out by videoconference to allow experts to debate and discuss the remaining uncertain questions. All questions remained in a consensus.

Results
Limits of the target volume were defined using visible landmarks on computed tomography and magnetic resonance imaging, considering the pathways of tumor extension. The purpose was to develop clear and precise recommendations on meningiomas target volumes.

Conclusion
New recommendations for meningiomas delineation based on simple anatomic boundaries are proposed by the ANOCEF. Improvement in uniformity in target volume definition is expected.
Extended prone positioning for intubated ARDS: a review
Authors: Walter Thaïs , Ricard Jean-Damien 
Published: July 2023

AbstractDuring the COVID-19 pandemic, several centers had independently reported extending prone positioning beyond 24 h. Most of these centers reported maintaining patients in prone position until significant clinical improvement was achieved. One center reported extending prone positioning for organizational reasons relying on a predetermined fixed duration. A recent study argued that a clinically driven extension of prone positioning beyond 24 h could be associated with reduced mortality. On a patient level, the main benefit of extending prone positioning beyond 24 h is to maintain a more homogenous distribution of the gas–tissue ratio, thus delaying the increase in overdistention observed when patients are returned to the supine position. On an organizational level, extending prone positioning reduces the workload for both doctors and nurses, which might significantly enhance the quality of care in an epidemic. It might also reduce the incidence of accidental catheter and tracheal tube removal, thereby convincing intensive care units with low incidence of ARDS to prone patients more systematically. The main risk associated with extended prone positioning is an increased incidence of pressure injuries. Up until now, retrospective studies are reassuring, but prospective evaluation is needed.
Graphical Abstract
A new reservoir-based CPAP with low oxygen consumption: the Bag-CPAP
Authors: de Beaufort Eloïse , Carteaux Guillaume , Morin François , Lesimple Arnaud , Haudebourg Anne-Fleur , Fresnel Emeline , Duval Damien , Broc Alexandre , Mercat Alain , Brochard Laurent , Savary Dominique , Beloncle François , Mekontso Dessap Armand , Richard Jean-Christophe 
Published: July 2023

Abstract
Background
Several noninvasive ventilatory supports rely in their design on high oxygen consumption which may precipitate oxygen shortage, as experienced during the COVID-19 pandemic. In this bench-to-bedside study, we assessed the performance of a new continuous positive airway pressure (CPAP) device integrating a large reservoir (“Bag-CPAP”) designed to minimize oxygen consumption, and compared it with other CPAP devices.

Methods
First, a bench study compared the performances of Bag-CPAP and four CPAP devices with an intensive care unit ventilator. Two FiO2 targets (40–60% and 80–100%) at a predefined positive end expiratory pressure (PEEP) level between 5 and 10 cm H2O were tested and fraction of inspired oxygen (FiO2) and oxygen consumption were measured. Device-imposed work of breathing (WOB) was also evaluated. Second, an observational clinical study evaluated the new CPAP in 20 adult patients with acute respiratory failure in two hospitals in France. Actual FiO2, PEEP, peripheral oxygen saturation, respiratory rate, and dyspnea score were assessed.

Results
All six systems tested in the bench study reached the minimal FiO2 target of 40% and four reached at least 80% FiO2 while maintaining PEEP in the predefined range. Device-delivered FiO2/consumed oxygen ratio was the highest with the new reservoir-based CPAP irrespective of FiO2 target. WOB induced by the device was higher with Bag-CPAP. In the clinical study, Bag-CPAP was well tolerated and could reach high (> 90%) and moderate (> 50%) FiO2 with an oxygen flow rate of 15 [15–16] and 8 [7–9] L/min, respectively. Dyspnea score improved significantly after introduction of Bag-CPAP, and SpO2 increased.

Conclusions
In vitro, Bag-CPAP exhibited the highest oxygen saving properties albeit had increased WOB. It was well accepted clinically and reduced dyspnea. Bag-CPAP may be useful to treat patients with acute respiratory failure in the field, especially when facing constraints in oxygen delivery.
Why is it so hard to identify (consistent) predictors of treatment outcome in psychotherapy? – clinical and research perspectives
Authors: Eilertsen Silje Elisabeth Hasmo , Eilertsen Thomas Hasmo 
Published: July 2023

Abstract
Background
Anxiety and depression are two of the most debilitating psychological disorders worldwide today. Fortunately, effective treatments exist. However, a large proportion of patients do not recover from treatment, and many still have symptoms after completing treatment. Numerous studies have tried to identify predictors of treatment outcome. So far, researchers have found few or no consistent predictors applicable to allocate patients to relevant treatment.

Methods
We set out to investigate why it is so hard to identify (consistent) predictors of treatment outcome for psychotherapy in anxiety and depression by reviewing relevant literature.

Results
Four challenges stand out; a) the complexity of human lives, b) sample size and statistical power, c) the complexity of therapist-patient relationships, and d) the lack of consistency in study designs. Together these challenges imply there are a countless number of possible predictors. We also consider ethical implications of predictor research in psychotherapy. Finally, we consider possible solutions, including the use of machine learning, larger samples and more realistic complex predictor models.

Conclusions
Our paper sheds light on why it is so hard to identify consistent predictors of treatment outcome in psychotherapy and suggest ethical implications as well as possible solutions to this problem.
Are inner nuclear layer ischemic lesions hidden indicators of retinal vein occlusion risk? A case-control study
Authors: Nourinia Ramin , Mashhadi Seyed Mohammadjavad , Abtahi Seyed-Hossein , Nouri Hosein 
Published: July 2023

Abstract
Purpose
To investigate the association between retinal vein occlusion (RVO) and evidence of previous, unnoticed inner nuclear layer (INL) infarction in the fellow eye.

Methods
This prospective case-control study compared the prevalence of INL lesions in the fellow eye of consecutive people with hypertension (PwHTN) with unilateral RVO versus a randomly chosen eye of an age-matched control group of PwHTN without RVO. En face slabs above the outer plexiform layer (OPL) were generated from 6 × 6 fovea-centered optical coherence tomography scans. Cross-sectional scans and en face slabs were surveyed for evidence of active/resolved ischemic INL lesions.

Results
69 PwHTN were included and assigned to two groups, i.e., the RVO group (n = 37; 22 BRVO and 15 CRVO) and the control group (n = 32). There was no inter-group difference regarding age, gender distribution, and background diseases. Resolved INL lesions were more frequent in the RVO group (n = 26) than in the control group (n = 4) (70.3% vs. 12.5%, p < 0.001). BRVO and CRVO cases had similar prevalence of INL lesions in their fellow eyes. Unlike diabetes, ischemic heart disease, and gender, INL lesions were associated with RVO (in the fellow eye) with an odds ratio of 15.7 (95%CI: 4.17–76.73, p < 0.001).

Conclusion
We identified a substantially higher prevalence of INL lesions in PwHTN with RVO compared to PwHTN without RVO. The atrophic appearance of lesions suggests they may serve as early markers of increased RVO risk in individuals with systemic or cardiovascular predisposing factors.