Moderate Confidence Research Articles

Abstract A031: Harnessing the potential of circulating tumour cells for precision diagnostics via multiplexed imaging of the levels and subcellular localizations of over 50 cell identity, state and signaling markers per cell

Abstract Due to their longitudinal accessibility through liquid biopsy, circulating tumour cells (CTCs) hold huge potential as sources of molecular information capable of underpinning precision diagnostics in cancer. Yet key methodological limitations have thus far constrained the practical utility of CTCs as diagnostic analytes, including: a) reliance on positive CTC selection strategies that can bias against distinctive CTC subpopulations (e.g. low EpCAM, low size, low density), and; b) standard fluorescence imaging methods that capture only 4-6 molecular markers per cell. Since 3-4 markers are required to identify CTCs with even moderate confidence, such low marker plexity acutely restricts derivation of additional molecular insights about the cellular states and molecular signals that may be driving disease. Yet these insights are essential to guide selection of optimal therapies, to adapt therapeutic strategies as cycles of resistance arise, and even to stratify patients to the trials needed to expand the therapeutic arsenal. To overcome these challenges and harness the potential of CTCs for precision diagnostics, we have developed a comprehensive pipeline for CTC isolation, storage and batch processing via multiplexed immunofluorescence imaging of 50+ molecular markers per cell. These markers illuminate CTC identity, state (epithelial vs mesenchymal vs stemness), fate (proliferation, death, senescence) and signalling (spanning ∼10 alternate ‘driver’ signalling pathways), providing truly unprecedented molecular insights per CTC, across heterogeneous CTC populations, and regarding potential therapeutic targets. Downstream single-cell quantitative image analyses enable robust but adaptable computational parsing of CTC identity, removing false-positive and false-negative instances otherwise resulting from standard 4-plex CTC definitions (e.g. DAPI, CD45, EpCAM, pan-Cytokeratin) and complementing our upstream use of negative selection methods that capture the full, unbiased diversity of CTCs. The remaining 40+ markers facilitate integrated analyses of relationships between CTC state, fate and signalling pathways, capturing not only protein and phospho-protein expression levels per cell, but also variations in subcellular localisation that constitute additional layers of functional regulation not captured by most omics methods. Excitingly, when combined with machine learning, our approach can discern therapy- resistant cell subpopulations with over 98% accuracy in models of prostate cancer therapy resistance. We are now assessing CTC diversity across patients ranging from treatment naïve to advanced castrate-resistance prostate cancers. Overall, our unique high-plexity analysis now enables interrogation of detailed states, signals and dependencies in each patient CTC, providing the foundations for next-generation precision diagnostics to continuously match individual patients to optimal therapies at each stage of their disease journey. We believe this marks a significant step towards harnessing the true potential of CTCs for precision diagnostics. Citation Format: John G Lock, Tim J Mann, Ye Zheng, Tanzila Khan, Daniel Neumann, Alexander James, Therese Becker, Tara Roberts. Harnessing the potential of circulating tumour cells for precision diagnostics via multiplexed imaging of the levels and subcellular localizations of over 50 cell identity, state and signaling markers per cell [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A031.

Exploration of Reliability and Security of E- Banking: Selected Urban Cooperative banks

The rise of E-banking has introduced unprecedented convenience and accessibility for users, transforming traditional banking operations into efficient online experiences. However, this shift brings challenges, particularly in terms of security and reliability, as users now expect robust protections for their financial data and consistent, dependable service. This study investigates the perceptions of security and reliability in digital banking among 290 urban cooperative banking customers. Using factor analysis, we explore key dimensions of e-banking services, focusing on elements like encryption, biometric security, and trust in transaction reliability. The analysis identified two primary factors: security and reliability, each with distinct contributions to overall user satisfaction. The factor loadings revealed that users had mixed confidence in encryption technologies and data privacy measures, with some expressing high levels of satisfaction, while others indicated significant concerns. Additionally, reliability emerged as a critical factor, with findings indicating that a notable portion of customers were dissatisfied with the timeliness and trustworthiness of e-banking services. For data collection, a structured survey measured responses on a five-point Likert scale, assessing variables such as trustworthiness, encryption effectiveness, privacy maintenance, and personal security practices. Through the use of descriptive and factor analysis, we quantified customer sentiments and identified patterns in user satisfaction. The results suggest that while there is moderate confidence in digital banking security, the reliability of service delivery remains an area for improvement. Banks should consider addressing these findings by enhancing transparency in their security protocols and strengthening service consistency to better meet user expectations in digital banking environments.

Parents' and guardians' experiences of barriers and facilitators in accessing autism spectrum disorder diagnostic services for their children: a qualitative systematic review.

The objectives of this review were to comprehensively identify the best available qualitative evidence about parents' and guardians' experiences of barriers and facilitators in accessing autism spectrum disorder (ASD) diagnostic services for their children; and to develop recommendations based on the review for addressing barriers to timely diagnosis and early intervention. Early identification of ASD is a priority because the best chance for improving symptoms occurs through early and intensive intervention. A definitive ASD diagnosis is often a prerequisite for children to access publicly funded services, yet obtaining a diagnosis in itself can be stressful, frustrating, and time-consuming for many families. It is essential to understand the barriers and facilitators parents and guardians face in accessing ASD diagnostic services for their children. This qualitative systematic review considered studies conducted worldwide that included parents and guardians of children up to 18 years of age who had accessed or who were attempting to access ASD diagnostic services for their children. This review was conducted in accordance with the JBI methodology for systematic reviews of qualitative evidence. A literature search included CINAHL (EBSCOhost), CINAHL Plus (EBSCOhost), MEDLINE (EBSCOhost), APA PsycINFO (EBSCOhost), Social Services Abstracts (ProQuest), ERIC (EBSCOhost), and Embase. Gray literature sources included ProQuest Dissertations and Theses, Google Scholar, Google, OpenGrey, other online resources (government and organizational websites), and reference lists of retrieved records. No language, date, or country limits were applied to the searches. Retrieved records from the academic databases, gray literature, and reference lists of retrieved records were screened, with potentially relevant records examined in full against the inclusion criteria. Eligible studies were critically appraised for methodological quality and those included in this review were subjected to data extraction of descriptive details and study findings relevant to the review question. Study findings were synthesized and assigned confidence scores. All reviewers agreed upon the categories and finalized synthesized findings. The 36 included studies varied in qualitative research designs with high methodological quality. There were approximately 661 eligible participants, and 55 credible and unequivocal research findings. The research findings yielded 6 categories and 3 synthesized findings with moderate confidence scores. Parents' and guardians' ability to access ASD diagnostic services for their children is affected by i) encountering health care providers who actively listened to and addressed parents' and guardians' concerns instead of dismissing them, providing a sense of support and validation; ii) facing extended waiting times and associated financial burdens resulting in frustration and associated financial impact when delays occurred; and iii) encountering health care providers lacking specialized knowledge about ASD contributing to parents' and guardians' confusion due to inaccurate or conflicting diagnoses related to ASD comorbidities. Many parents described their journey in accessing ASD assessment and diagnostic services for their children as cumbersome. Parents' and guardians' experiences were affected by the level of perceived support by and knowledge of health care providers; confusion surrounding inaccurate/mixed diagnoses related to ASD; lengthy delays; and systemic and contextual barriers in navigating the pathway to ASD assessment and diagnosis that included socioeconomic and cultural disparities. PROSPERO CRD42018100127.

Functional status is associated with mean right atrial pressure derived from cardiac MRI

Abstract Background Right atrial pressure (RAP) is a key metric in haemodynamic assessment. Elevated RAP is associated with poor prognosis in heart failure and pulmonary hypertension and physiologically with fluid overload. RAP can be measured invasively or non-invasively, but Cardiac MRI (CMR) currently cannot estimate RAP. Purpose To develop a model to estimate RAP from CMR from paired right heart catheter (RHC) and CMR assessments. Assess correlation to WHO functional status prior to prospective clinical validation studies. Methods Patients were recruited to a registry of those referred for assessment of dyspnoea between 2012 and 2020. Inclusion criteria were age >18 years, signs and symptoms of heart failure and adequate CMR image quality. Patients diagnosed with pulmonary arterial hypertension were excluded. RHC and CMR were performed on the same day. CMR 2- and 4- chamber cines were used to measure chamber dimensions, strain, ejection fraction and stroke volume with operator reviewed AI contours in MASS research software. Pearson’s product-moment correlation coefficient (r ) was used to assess relationships between CMR metrics and invasive mRAP. Variables were then included in stepwise multiple linear regression models to predict mRAP. These were compared with receiver-operator curve analysis and DeLong’s test. Kruskal-Wallis test compared median mRAP between WHO functional class groups. Results The cohort of 672 patients was divided based upon invasive mRAP ≤ 8mmHg (44%) and mRAP > 8mmHg (56%). Higher mRAP was associated with increased age, male sex and a higher diastolic blood pressure but there was no difference in rates of heart failure types although the majority had preserved ejection fraction (51% vs 52%) with few having reduced ejection fraction (4.1% vs 8%). Right atrial (RA) dimensions, strain and ejection fraction had the strongest correlation with mRAP with moderate correlation to right ventricular (RV) measurements. Multivariable models contained simple RA dimensions (model 1), RA dimensions and strain (model 2), RA and RV dimensions (model 3) and RA end systolic volume corrected for body mass index and sex (model 4). All models had similar predictive capability (Figure 1 Panel A). RA end systolic volume was isolated in model 1 as the only variable required for mRAP prediction (coefficient = 0.06, p < 0.001). Using a threshold of mRAP >8mmHg ROC analysis demonstrated an area under the curve of 0.78 (95% Confidence interval 0.75 to 0.81) (Figure 1 Panel B). Worse WHO functional Class at time of assessment was significantly associated with increased CMR derived mRAP (P<0.001) (Figure 2). Conclusions mRAP can be estimated with moderate confidence from CMR RA end systolic volume. Limited available clinical data suggest functional status may be predicted by CMR derived mRAP. Further studies on wider populations are required to validate this model externally, refine it and determine its prognostic clinical significance.

Lived and care experiences of young people with chronic musculoskeletal pain and mental health conditions. A systematic review with qualitative evidence synthesis.

Chronic musculoskeletal pain (CMP) and coexisting mental health conditions impact young people; however, little is known about their lived and care experiences. In a prospectively registered systematic review with qualitative evidence synthesis (PROSPERO: CRD42022369914), we explored the following: (1) lived physical, psychological, and social experiences; and (2) care experiences/preferences of young people living with CMP and mental health conditions. Inclusion criteria: studies using qualitative methods; participants aged 16 to 24 years with CMP and coexisting mental health condition(s); phenomenon explored included lived and/or care experiences. Seven databases were searched (inception to 19-May-2024), study quality was assessed, data were extracted and analysed thematically, and GRADE-CERQual was used to assess confidence in findings. Twenty-two studies (23 reports) were included (>239 participants, 82% women). Lived experiences yielded 4 themes (9 findings): 2-way relationship between CMP and mental health (2 findings, low to moderate confidence); psychosocial implications of CMP (3 findings, very low-moderate confidence); uncertainty about future (2 findings, low-moderate confidence); coping with CMP and mental health conditions (2 findings, low-moderate confidence). Care experiences/preferences yielded 3 themes (8 findings): navigating healthcare systems (2 findings, moderate confidence); receiving appropriate care (3 findings, very low-moderate confidence); point-of-care experiences and care preferences (3 findings, very low-moderate confidence). Chronic musculoskeletal pain and mental health conditions are interconnected, significantly impacting young people's lives, identities, and socialisation, yet services for CMP and mental health are often inadequate and poorly integrated. The mechanisms and interplay of CMP and mental health require deeper exploration, including how young people may be better supported with personalised, holistic, developmentally and/or life-stage-appropriate integrated care.

It Helps with Crap Lecturers and Their Low Effort: Investigating Computer Science Students’ Perceptions of Using ChatGPT for Learning

This study explores how computing science students (n = 335) use ChatGPT, their trust in its information, their navigation of plagiarism issues, and their confidence in addressing plagiarism and academic integrity. A mixed-methods approach was used, combining quantitative survey data with a qualitative thematic analysis of student comments to provide a comprehensive understanding of these issues. The findings reveal that ChatGPT has become integral to students’ academic routines, with 87.8% using it weekly with variable frequency. Most students (70.3%) believe the university should allow ChatGPT use, and 66.6% think it is fair to use it for academic purposes despite 57.4% distrusting its information. Additionally, 53.8% worry about accidentally plagiarising when using ChatGPT. Overall, students have moderate confidence in addressing these academic integrity issues, with no differences between undergraduate and postgraduate students. Male students reported higher confidence in handling plagiarism and academic integrity issues than female students, suggesting underlying differences in how students perceive and interact with generative AI technologies. A thematic analysis of 74 student comments on their ChatGPT experience revealed four themes: (a) Usage and Role of ChatGPT, (b) Ethical and Responsible Use, (c) Limitations and Accuracy, and (d) Impact on Education and Need for Clear Guidelines. This study contributes to the ongoing debate on accepting and using ChatGPT, highlighting the need for institutions to provide clear guidelines and ethical considerations to ensure responsible use within educational contexts.

Home use of mifepristone for medical abortion: a systematic review

BackgroundIn many countries, persons seeking medical abortion with mifepristone followed by misoprostol can self-administer the second drug, misoprostol, at home, but self-administration of the first drug, mifepristone, is not allowed...

The efficacy of ciprofol versus propofol on anesthesia in patients undergoing endoscopy: a systematic review and meta-analysis of randomized controlled trials.

Ciprofol is a new intravenous anesthetic with a similar chemical structure to propofol. We aimed to compare the incidence of adverse actions like injection pain and time indexes of ciprofol versus propofol on anesthesia in patients undergoing endoscopy. We also compared anesthetists' satisfaction during the procedure. Two independent researchers (Liu and Zeng) searched the Cochrane Library, Embase databases, and PubMed for controlled clinical trials. This meta-analysis of randomized controlled trials (RCTs) was performed with the Review Manager, Stata and the Cochrane Risk-of-Bias 2 tool to evaluate methodological quality. Relative risks with 95% confidence interval (CI) were calculated for outcomes. Ten trials, including 1545 patients, were examined in the current meta-analysis. During anesthesia in patients undergoing endoscopy, the incidence of injection pain was significantly reduced in the research group. Compared with propofol, the pooled risk difference (RD) with the use of ciprofol for injection pain for all the procedures was - 0.34 (95% confidence interval [CI], -0.48 to 0.19), and RR for hypotension was 0.73(95% CI:0.58 to 0.92). GRADE showed this meta-analysis has moderate or low confidence. Trial sequential analysis for mortality indicated insufficient sample size for a definitive judgment for lower incidence of hypotension. In painless endoscopy, compared with propofol, ciprofol exhibited non-inferiority anesthesia/sedation in patients, and had a good safety profile with a lower incidence of pain on injection and may reduce the chance of hypotension. Trial sequential analysis suggested the need for more cases, and GRADE highlighted moderate certainty, emphasizing the necessity for further targeted RCTs. PROSPERO, CRD42023433627.

Barriers and facilitators to the uptake of electronic collection and use of patient-reported measures in routine care of older adults: a systematic review with qualitative evidence synthesis.

The aims of this systematic review were to (1) synthesize the available qualitative evidence on the barriers and facilitators influencing implementation of the electronic collection and use of patient-reported measures (PRMs) in older adults' care from various stakeholder perspectives and (2) map these factors to the digital technology implementation framework Non-adoption, Abandonment, challenges to the Scale-up, Spread, Sustainability (NASSS) and behavior change framework Capability, Opportunity, Motivation, Behaviour (COM-B). A search of MEDLINE, CINAHL Plus, and Web of Science databases from 1 January 2001 to 27 October 2021 was conducted and included English language qualitative studies exploring stakeholder perspectives on the electronic collection and use of PRMs in older adults' care. Two authors independently screened studies, conducted data extraction, quality appraisal using the Critical Appraisal Skills Programme (CASP), data coding, assessed confidence in review findings using Grading of Recommendations Assessment, Development, and Evaluation Confidence in the Evidence from Reviews of Qualitative Research (GRADE CERQual), and mapped the findings to NASSS and COM-B. An inductive approach was used to synthesize findings describing the stakeholder perspectives of barriers and facilitators. Twenty-two studies were included from the 3368 records identified. Studies explored older adult, caregiver, healthcare professional, and administrative staff perspectives. Twenty nine of 34 review findings (85%) were graded as having high or moderate confidence. Key factors salient to older adults related to clinical conditions and socio-cultural factors, digital literacy, access to digital technology, and user interface. Factors salient to healthcare professionals related to resource availability to collect and use PRMs, and value of PRMs collection and use. Future efforts to implement electronic collection and use of PRMs in older adults' care should consider addressing the barriers, facilitators, and key theoretical domains identified in this review. Older adults are more likely to adopt electronic completion of PRMs when barriers associated with digital technology access, digital literacy, and user interface are addressed. Future research should explore the perspectives of other stakeholders, including those of organizational leaders, digital technology developers and implementation specialists, in various healthcare settings and explore factors influencing implementation of PREMs. CRD42022295894.

Low-dose immunotherapy for patients with cancer in low- and middle-income countries (LMIC): A needs assessment.

112 Background: Immune checkpoint inhibitors are unavailable or unaffordable to many patients in LMIC, including Mexico. Some proposed strategies to improve access include weight-based dosing, vial sharing, or using low-dose IO (immunotherapy) schedules. Despite the potential advantages of low-dose IO to increase access and improve outcomes, there is limited information regarding the use of low-dose IO in real-world clinical practice in LMICs. Methods: We conducted a cross-sectional online survey of medical oncologists and hematologists practicing in Mexico. The survey was distributed via email using databases from the Mexican Society of Oncology and the Mexican Society of Hematology, and through physician Whatsapp groups in April and May 2024. The primary objective was to examine the prevalence and reasons of low-dose IO use in real-world clinical practice across Mexico. The survey assessed provider characteristics, prevailing attitudes, and potential barriers to low-dose IO adoption. Results: A total of 154 specialists answered the online survey, of which 77 completed it. The median age was 41 years (range 30-73); forty-five (58.4%) were men, thirty-one were women (40.2%), and two were non-binary. Fifty-nine (77%) were medical oncologists and 18 (23%) were hematologists. Twenty-two (29.3%) worked in private practice, nine (12%) in public institutions, and forty-four (58.7%) practiced in both. Seventy-two percent of respondents reported barriers in acquiring IO and forty-eight percent reported utilizing low-dose IO. For low-dose IO users, nivolumab was the most frequently prescribed drug (76%), followed by pembrolizumab (43%). The most frequent reason for using low-dose IO was reducing treatment-related cost (83% of respondents). Common barriers to low-dose IO use included concerns regarding the efficacy and safety of lower doses and a lack of knowledge about dosing protocols. Fifty respondents (67%) reported complete or moderate confidence in the efficacy of low-dose IO for patients with advanced disease, while only 36 respondents (49%) reported confidence on its efficacy for patients with localized disease. Conclusions: Despite its potential benefits of low-dose IO and a need to improve access to treatment, there are concerns about the efficacy and safety of this strategy among Mexican cancer specialists. Addressing these barriers and identifying facilitators could improve the acceptability of prospective trials studying low-dose IO in Mexico.

Effectiveness of solution-focused brief therapy: An umbrella review of systematic reviews and meta-analyses

Objective This umbrella review of systematic reviews and meta-analyses evaluates the effectiveness of Solution-Focused Brief Therapy (SFBT) across various populations and settings. Method A total of 25 systematic reviews, including 15 meta-analyses, were analyzed. Reviews were included if they used systematic search methods and quality assessments and focused on the effectiveness of SFBT as a therapeutic approach. Results SFBT demonstrated significant positive outcomes across different issues, settings, and cultural contexts, with no evidence of harm. High confidence in evidence of effectiveness was established for depression, overall mental health, and progress towards individual goals for the adult population. In addition, findings indicated mainly moderate confidence in evidence of SFBT effectiveness for a wide variety of outcomes for all age groups. No difference was found in the confidence in the evidence by world region, though Western and Eastern studies researched some different aspects. Conclusion SFBT is an effective therapeutic approach for various psychological, social, school, medical, couple, or self-related issues. Further research with rigorous methodologies and comprehensive reporting is needed to strengthen the confidence in these findings and provide evidence for the brevity of the intervention.

The Impact of Antidepressants on COVID-19 and Post-Acute COVID-19 Syndrome: A Scoping-Review Update

On May 20, 2024, this systematic scoping review in PUBMED identified 1016 articles related to AD and COVID-19, Long COVID and SARS-COV-2. These included 10 retrospective "large scale" studies (> 20000 chart reviews), 8 prospective clinical trials (plus 4 regarding Long COVID), 11 placebo-controlled randomized (RCT) (plus 2 regarding Long COVID) and 15 meta-analyses. COVID-19: Retrospective studies with cohorts taking AD primarily for psychiatric comorbidities or chronic pain conditions directly prior to SARS-COV-2 infection described that this substance class (most studied: Selective Serotonin Re-Uptake Inhibitors (SSRI) and Selective Serotonin Noradrenaline Re-Uptake Inhibitors (SSNRI)) were associated with (i) significantly fewer SARS-COV-2 infections and (ii) a milder course of COVID-19 ("COVID-19 protection"). Ten of the 11 RCTs found regarding COVID-19 tested fluvoxamine, as this old AD appeared suitable as a prophylactic agent against severe COVID-19, taking into account its in vitro potency against the progression of intracellular sepsis cascades. Therefore, most (12 out of 15) meta-analyses also referred to fluvoxamine. They found (iii) a significant (40-70% reduction) in mortality, intubation and hospitalization rates when fluvoxamine was used as an add-on to standard therapy for mild to moderate COVID-19. When this AD was used in the early stages of the disease, it was more successful than when it was given later in advanced, severe COVID-19 (e.g. severe pneumonia, final sepsis stages). A dose dependency was observed: 2x50 mg fluvoxamine over 15 days was less effective than 2x100 or even 3x100 mg with an adverse event profile still at the placebo level. Direct comparisons with drugs approved for COVID-19 do not yet exist. A first indirect meta-analytical comparison showed an advantage of paxlovid or molnupiravir versus fluvoxamine against the development of severe COVID-19: risk reduction of 95% (I2 = N/A, but only one study) or 78% (I2=0) versus 5+-5% (I2=48). However, an add-on of fluvoxamine was still significantly more efficacious than symptom-oriented standard therapy alone. Long COVID: A common Long COVID phenotype with dominant anxiety and depression symptoms, which responds to AD, relaxation therapy and/or psychotherapy, has now been identified. Casuistics report positive effects of AD on fatigue, cognitive and autonomic dysfunctions. A first large prospective open-label RCT has just shown significantly more favourable courses, less viral load and less pro-inflammatory cytokines in the treatment of mild to moderate COVID-19 with fluvoxamine versus standard treatment, also with regard to the subsequent development of neuropsychiatric and pulmonary Long COVID or fatigue. Overall, there is promising evidence of a preventive effect of AD (especially fluvoxamine) against progression to severe COVID-19 and against the development of Long COVID. It is likely, that the entire AD substance class could be effective here. This assumption is based on the results of retrospective large scale studies, but awaits verification by better controlled studies. The potential effectiveness/efficacy (currently low and moderate confidence of the evidence for the entire substance class and specifically fluvoxamine, respectively) of fluvoxamine as an add-on against COVID-19 and possibly also directly against Long COVID could stimulate similar projects in other infectious diseases that also have the potential to pose a lasting threat to the health of those affected. We consider the evidence to date to be sufficient to be able to emphasize a possible positive effect of these substances in the psychoeducation of patients with COVID-19 or Long COVID who are already receiving AD for other conditions - especially also against the symptoms associated with the viral disease or its consequences. In regions where neither vaccines nor antiviral agents currently approved for the prevention or treatment of COVID-19 are available, AD and in particular fluvoxamine would be a cost-effective alternative to protect against a severe course, even if this AD appears to have a smaller effect against COVID-19 than the currently approved antiviral agents, but with presumably better tolerability. A direct comparative clinical trial with approved antiviral agents is still pending and should be positive to further open the door for a guideline-based recommendation of fluvoxamine (or perhaps even AD) for COVID-19 or its aftermath.

High-throughput drug screening identifies novel therapeutics for Low Grade Serous Ovarian Carcinoma

Low grade serous carcinoma (LGSOC) is a rare epithelial ovarian cancer with unique molecular characteristics compared to the more common tubo-ovarian high-grade serous ovarian carcinoma. Pivotal clinical trials guiding the management of epithelial ovarian cancer lack sufficient cases of LGSOC for meaningful subgroup analysis, hence overall findings cannot be extrapolated to rarer chemo-resistant subtypes such as LGSOC. Furthermore, there is a need for more effective therapies for the treatment of relapsed disease, as treatment options are limited. To address this, we conducted the largest quantitative high-throughput drug screening effort (n = 3436 compounds) in 12 patient-derived LGSOC cell lines and one normal ovary cell line to identify unexplored therapeutic avenues. Using a combination of high-throughput robotics, high-content imaging and novel data analysis pipelines, our data set identified 60 high and 19 moderate confidence hits which induced cancer cell specific cytotoxicity at the lowest compound dose assessed (0.1 µM). We also revealed a series of known (mTOR/PI3K/AKT) and novel (EGFR and MDM2-p53) drug classes in which LGSOC cell lines showed demonstrable susceptibility to.

Construction of an adverse outcome pathway for the cardiac toxicity of bisphenol a by using bioinformatics analysis

Bisphenol A (BPA), a common endocrine disruptor, has shown cardiovascular toxicity in several epidemiological studies, as well as in vivo and in vitro experimental studies. However, the related adverse outcome pathway (AOP) of BPA toxicity remains unraveled. This study aimed to develop an AOP for the cardiac toxicity of BPA through bioinformatics analysis. The interactions among BPA, genes, phenotypes, and cardiac toxicity were retrieved from several databases, including the Comparative Toxicogenomics Database, Computational Toxicology, DisGeNet, and MalaCards. The target genes and part of target phenotypes were obtained by Venn analysis and literature screening. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed for target genes by using the DAVID online analysis tool to obtain other target phenotypes. AOP hypotheses from BPA exposure to heart disease were established and evaluated comprehensively by a quantitative weight of evidence (QWOE) method. The target genes included ESR2, MAPK1, TGFB1, and ESR1, and the target phenotypes included heart contraction, cardiac muscle contraction, cellular Ca2+ homeostasis, cellular metabolic process, heart development, etc. Overall, the AOP of BPA cardiac toxicity was deduced to be as follows. Initially, BPA bound with ERα/β and then activated the MAPK, AKT, and IL-17 signaling pathways, leading to Ca2+ homeostasis disorder and increased inflammatory response. Subsequently, cardiac function was impaired, causing coronary heart disease, arrhythmia, cardiac dysplasia, and other heart diseases. According to the Bradford–Hill causal considerations, the score of AOP by QWOE was 69, demonstrating a moderate confidence and providing clues on cardiotoxicity-assessment procedure and further studies on BPA.

Postpartum thromboprophylaxis with enoxaparin: a prospective cohort study on patients' adherence, injection experience, and information retention after counselling by pharmacists.

This research aimed to determine postpartum females' self-reported adherence to and experience with short-term thromboprophylaxis using enoxaparin injection, after counselling by pharmacists. It also sought to assess their knowledge of thromboprophylaxis, injection techniques, and confidence in self-injecting. This prospective cohort study was conducted at a public tertiary hospital in Malaysia from March to June 2023. Self-injection-naïve postpartum females who were initiated on thromboprophylaxis and counselled by a pharmacist were conveniently sampled. Knowledge regarding thromboprophylaxis, injection readiness, and technique were assessed one day after the counselling session. A telephonic interview was conducted at the end of the 10-day therapy to determine adherence and adverse effects experienced. A total of 259 subjects were successfully followed up, with 87.6% (n = 227) adherent to the therapy. Nonadherence was predominantly due to forgetfulness; four had their treatment withheld due to bleeding. One-third of subjects experienced localised pain and bruising. Subjects answered a median of 5/7 knowledge questions and recalled a median of 8/10 injection steps correctly, with those who read the information leaflet provided after counselling scoring significantly higher (P = .02). The majority declared moderate confidence in their ability to self-inject. Subjects who intended to self-inject (P < .01) and were more confident (P = .02) demonstrated better injection technique. Postpartum females counselled by pharmacists largely adhered to short-term enoxaparin for thromboprophylaxis. The impact of the counselling session may be enhanced by addressing their psychological readiness to self-inject, awareness of adverse effects identification, mitigation, and management, as well as setting reminders to prevent forgetfulness to inject.

Patterns of Use of e-Cigarettes and Their Respiratory Effects: Protocol for an Umbrella Review.

Electronic nicotine delivery systems (ENDS)-e-cigarettes or vapes-have been shown to substantially reduce or eliminate many toxins compared with cigarette smoke, but simultaneously ENDS use also produces their own unique toxins. Yet the patterns of use among people who use ENDS are not homogeneous. Some people who use ENDS also smoke cigarettes (dual use). Other people who formerly smoked cigarettes are completely substituting ENDS (exclusive use). A small number of people who have never smoked cigarettes are using ENDS (naïve use of nicotine). Each of these patterns of use results in different exposures to toxins. Unfortunately, epidemiological studies routinely group together any ENDS use regardless of other tobacco use. This umbrella review primarily aims to present all the evidence available on the respiratory effects of ENDS use by adults based on their pattern of use: dual use, exclusive use, and naïve use. With each of these patterns of use, are there benefits, no changes, or harmful effects on respiratory functioning? Our objective is to provide clinicians with a detailed analysis of how different patterns of ENDS use impact respiratory functioning and to point to the best sources of evidence. This umbrella review follows the Methods for Overviews of Reviews framework and the PRIOR (Preferred Reporting Items for Overviews of Reviews) statement. Systematic reviews published since 2019 will be searched across 4 databases and 3 gray literature sources. Additional searches will include citation chasing, references lists, and referrals from respiratory specialists. The quality of included reviews will be evaluated using the AMSTAR2 (A Measurement Tool to Assess Systematic Reviews) checklist. We will document biases in 3 areas: protocol deviations, biases from the Oxford Catalogue of Bias, and internal data discrepancies. Two reviewers will independently conduct the search and quality assessments. Our analysis will focus on reviews rated as moderate or high confidence by AMSTAR2. We will use the Vote Counting Direction of Effect method to manage expected data heterogeneity, assessing whether ENDS use is beneficial or detrimental, or has no effect on respiratory functions based on the pattern of use. The review is expected to be completed by December 2024. The database search was concluded in April 2024, and data extraction and bias assessment were completed in June 2024. The analysis phase is planned to be completed by October 2024. A thorough and comprehensive assessment of the evidence will better inform the contentious debate over the respiratory effects of ENDS providing much needed clarity by linking their effects to specific usage patterns. This analysis is particularly crucial in understanding the risks associated with continued cigarette smoking. PROSPERO CRD42024540034; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=540034. DERR1-10.2196/60325.

Topical Anti-Inflammatory Treatments for Eczema: A Cochrane Systematic Review and Network Meta-Analysis.

Eczema is the most burdensome skin condition worldwide and topical anti-inflammatory treatments are commonly used to control symptoms. The relative effectiveness and safety of different topical anti-inflammatory treatments is uncertain. Network meta-analysis performed within a Cochrane systematic review to compare and statistically rank efficacy and safety of topical anti-inflammatory eczema treatments. Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to June 2023. Included trials were within-participant or between-participant randomised controlled trials. Participants had eczema that was not clinically infected and was not contact dermatitis, seborrheic eczema or hand eczema. Interventions were topical anti-inflammatory treatments but not complementary treatments, antibiotics alone, wet wraps, phototherapy or systemic treatments. Comparators were no treatment/vehicle or another topical anti-inflammatory. We identified 291 trials (45,846 participants), mainly in high-income countries. Most were industry-funded with median 3 weeks treatment duration. Risk of bias assessed using the Cochrane Risk of Bias 2.0 tool was high in 89% of trials, mainly due to risk of selective reporting. Network meta-analysis of binary outcomes ranked potent and/or very potent topical steroids, tacrolimus 0.1% and ruxolitinib 1.5% among the most effective treatments for improving patient-reported symptoms (40 trials, all low confidence) and clinician-reported signs (32 trials, all moderate confidence). For investigator global assessment, the Janus kinas inhibitors ruxolitinib 1.5%, delgocitinib 0.5% or 0.25%, very potent/potent topical steroids and tacrolimus 0.1% were ranked as most effective (140 trials, all moderate confidence). Continuous outcome data were mixed. Local application site reactions were most common with tacrolimus 0.1% (moderate confidence) and crisaborole 2% (high confidence) and least common with topical steroids (moderate confidence). Skin thinning was not increased with short-term use of any topical steroid potency (low confidence) but skin thinning was reported in 6/2044 (0.3%) participants treated with longer-term (6-60 months) topical steroids. Potent topical steroids, Janus kinase inhibitors and tacrolimus 0.1% were consistently ranked as among the most effective topical anti-inflammatory treatments for eczema.

Perceived factors influencing the success of pain neuroscience education in chronic musculoskeletal pain: a meta-synthesis of qualitative studies

Purpose We aimed to identify the factors influencing the success of Pain Neuroscience Education (PNE) in chronic musculoskeletal (MSK) pain from the perspective of those experiencing PNE first-hand. Materials and Methods We conducted a meta-synthesis of qualitative studies. Articles were found on MEDLINE via Pubmed, EMBASE, Cochrane Library, CINHAL, and PsycINFO up to April 2023. Eligible qualitative studies focussed on adults (>16 years old) with a diagnosis of chronic primary or secondary MSK pain who performed PNE. Thematic synthesis by Thomas and Harden was followed. The Critical Appraisal Skills Programme (CASP) tool ensured the quality of the studies, while the Confidence in Evidence from the Reviews of Qualitative Research (CERQual) approach facilitated data confidence assessment. Results Nine studies were included (188 participants). Three analytical themes were developed: (i) “Efficient Communication of Information”, emphasising the importance of accurate content transmission; (ii) “Emotional Support and Well-being”, recognising emotional aspects as integral to treatment; and (iii) “Empowerment Promotion”, focusing on information retention and personal transformation. The studies showed good quality, with moderate confidence in the evidence. Conclusions The perceived factors influencing the success of PNE are intricately related to the domain of communication, the emotional dimension of personal experience, and the capacity to be empowered.

Exploring Funeral Directors' Experience and Perceived Impact of Providing Funeral Services During COVID-19 Restrictions.

The importance of ritual/ceremony following bereavement is well documented, however restrictions during the COVID-19 pandemic impacted the freedom to bury loved ones according to beliefs/traditions. This study explores the experiences of staff providing funeral services during COVID-19 and considers the implications for supporting bereaved families. Fifty-eight staff (male, 72.4%; n = 42) from 17 counties in Ireland, completed a self-report survey assessing perceived impact of COVID-19, confidence providing services, and challenges and supports for practice during this time. Quantitative findings suggest moderate confidence in service provision and low perception of negative impact from COVID-19, while qualitative results highlight a contrast between a feeling of under-recognition at a policy level and a sense of being appreciated by the public. This study highlights the evolving role of the funeral sector in Ireland in supporting the bereaved, and the potential to capitalise on a genuine interest in contributing more to support beyond the funeral.

Combat Medics' Preparedness to Serve as Behavioral Health Extenders in Forward Environments.

Future multidomain operational combat environments will require combat medics to play a larger role in managing behavioral health (BH) conditions in forward environments, as soldiers in small teams may have them as their sole medical support for extended periods of time. Previously they were not expected to serve in this role, and thus, they receive minimal BH training. It is unknown to what extent combat medics consider BH tasks as falling within their scope of practice and how often they engage with their soldiers currently related to BH. Qualitative research suggests that many medics feel inadequately prepared to handle BH problems. Our aim is to further assess medic attitudes and behaviors related to BH to better understand the landscape of medic preparedness to fill an expanded role. Data from 292 medics were collected before their participation in the BH Guidelines for mEdic Assessment and Response training, a day-long training for medics expected to deploy to far-forward environments. We investigated whether combat medics engage with their soldiers in areas related to BH, the extent to which they consider BH-related tasks as part of their scope of practice, and how confident they feel engaging in various BH-related tasks. We explored associations between medics' attitudes related to BH scope of practice and confidence performing BH tasks with gender, rank, component (National Guard vs. Active Duty), work-related BH experience, having suicide training in the past year, and having ever sought help for BH. Results indicated that in the past month, 61.4% of medics discussed BH issues, 48.3% assessed BH problems, and 41.3% provided interventions for BH problems with at least one soldier in their unit. Assessment tasks were more frequently endorsed as falling within medic's scope of practice (75%-95%) than intervention tasks (62%-83%). More medics felt confident doing assessments (39%-49% moderately confident or greater) than providing interventions (31%-37% moderately confident or greater). Medics expressed highest confidence in assessing for suicide risk (49% moderate confidence or greater). Medics with a lot of prior BH work experience and non-commissioned officers (as compared to junior enlisted) reported greater confidence in most tasks. Receiving suicide training in the past year was associated with greater confidence assessing for suicide, as well as providing interventions for suicide, general BH problems, and substance abuse. Most medics agreed that numerous BH tasks fell within the scope of their work, but few felt confident engaging in those tasks. These findings support a need for additional training in BH-related tasks across the force. Exploring ways to provide medics BH-related work rotations would augment their general proficiency as first-line treatment providers for soldiers in combat units, and increased training in BH-related tasks should be studied to determine its ability to increase competency and confidence. If medics can learn to assess and recognize BH concerns before they escalate to needing specialty BH care, this could potentially reduce the burden on BH clinics, as well as strengthen the overall force.