Mixed Response Research Articles

Role of traditional healers in the management of microbial keratitis in eastern Nepal

Background Microbial Keratitis (MK) is a leading cause of corneal blindness due to infection and its consequences, with a higher incidence in resource-limited nations. Hospital-based patient records from different parts of Nepal suggest patients often use traditional eye medicine to treat MK. Traditional healers (TH) within the community are often the first point of care for MK management. Little is known of their practice, perceptions, and knowledge around MK management. We aimed to understand the role of traditional healers in the management of MK in south-eastern Nepal. Methods A cross-sectional, mixed method, descriptive study was conducted in the Siraha district of Nepal. A total of 109 traditional healers consented to participate in a survey of knowledge, attitude, and practices. Some participants were also invited to participate in in-depth interviews and focus group discussions. Interviews and focus groups were conducted and recorded in the Maithili language by a native speaking interviewer and transcribed into English. Descriptive analysis was performed for the survey. Data saturation was considered the endpoint for qualitative data collection, and a thematic was analysis applied. Results Traditional healers believe that infection of the eye can be caused by trauma, conjunctivitis, or evil spirits. They were unclear about differentiating MK from other eye conditions. They provided various types of treatment. Some were confident that they could treat severe ulcers that had not responded to medical therapy, while others thought treating larger diameter ulcers would be difficult. Although there were mixed responses in referring patients with MK, the majority of TH were willing to refer. Conclusion In a weak health system, traditional healers may help address barriers to healthcare access and reduce delays to definitive care, upon integration into the formal health system and referral pathway.

I'm a chatbot, ask me anything: building Learning Development for the future

We explored whether artificial intelligence (AI) technologies can aid learning by offering more effective and dynamic ways for students to interact with learning material. Through a survey, we assessed how students perceive and use AI tools, their impressions of the importance of these tools to their future careers and their awareness of AI policies within their universities. Results show mixed responses in terms of students’ familiarity with the tools and what they believe the AI tools could and should not be used for. The results also indicated that students have a thirst to know more about AI tools and their applications. Based on these, we designed customised teaching sessions to teach students those skills that they highlighted in the survey. In addition, we designed an L4 assessment where students need to demonstrate their abilities to critique a ChatGPT output (assessment yet to be submitted by students). These teaching sessions could be rolled out at university level as they are not subject-specific. This conference session shared the design and delivery of the AI-specific teaching sessions and how these were perceived by students. In addition, it demonstrated the design of the L4 assessment with the AI element and how students performed on this. This innovative research on pedagogical methods supports a broader long-term ambition to better understand and improve our teaching, learning, and student engagement through the adoption of AI and the effective use of technology.

Quality of life after stereotactic radiosurgery for brain metastasis: an assessment from a prospective national registry.

Stereotactic radiosurgery (SRS) is frequently used in the management of brain metastasis patients. However, there is an urgent need to evaluate post-treatment outcomes and quality of life metrics for patients undergoing SRS for brain metastases. The NeuroPoint Alliance (NPA) SRS Quality Registry conducted prospective enrollment of patients undergoing SRS from 2017 to 2024. Patients with brain metastases from lung cancer, breast cancer, and melanoma were included in the analysis. Outcomes of interest included quality of life metrics, as captured by the five-dimension Euro-QOL (EQ-5D) at 6-12 months and last record follow-up, overall survival, local progression, out-of-field progression, and overall intracranial progression. 522 patients comprised our analytic cohort, and 315 patients had available EQ-5D data at the time of SRS and final follow-up. 264 (47.8%), 197 (35.7%), and 91 (16.5%) patients had 1, 2-4, and 5-14 lesions pre-SRS, respectively. The median overall survival time from diagnosis was 27.3 months. The median time-to-local progression was not reached. At final follow-up, 107 (34.0%) patients had improvement, 51 (16.2%) patients had stable, and 113 patients (35.9%) had worsening EQ-5D scores when compared to baseline. For 44 (13.9%) patients mixed responses across the EQ-5D indices were reported. Linear regression analysis showed that male sex, smoking status, primary tumor type, time-to-overall progression, cumulative intracranial tumor volume (CITV), and baseline EQ-5D were statistically significantly associated with EQ-5D single index at the final follow-up. Real-world data from the SRS NPA Registry demonstrated that most patients with brain metastasis had no change or improvement in quality of life after SRS. Baseline EQ-5D was predictive of EQ-5D single index at final follow-up, and, as such, EQ-5D at baseline would be a valuable assessment measure for brain metastasis patients undergoing SRS.

Root traits of soybeans exposed to polyethylene films, polypropylene fragments, and biosolids

Biosolid use imports microplastics into the rhizosphere where they may interfere with root-soil-microbial interactions and cause morphological adaptations in crop root systems. Few studies have examined the response of crop roots to microplastics at documented soil concentrations, and many studies collect root traits using destructive techniques. Hence, there is little information on when and how microplastics effect the physical structure of root systems. Using the rhizobox method, soybeans (Glycine max) were grown in soil amended with biosolid microplastic mimics (polyethylene film or polypropylene fragments at 2,000 and 15,000 particles/kg dry soil) or biosolids and imaged weekly until maturity (11 weeks) using a custom scanner system. Plant biomass increased in the polyethylene treatments and decreased in the high concentration polypropylene treatment. Relative to the Control, polyethylene treatments had larger root length, reduced root diameters, reached maturity faster, had deeper root systems, and had a greater number of lateral roots. In contrast, polypropylene treatments had a mixed response, with high concentrations eliciting a lower root length, fewer laterals, and a more vertical root orientation. Segmented linear regression revealed that root growth in the Control and Biosolid treatments continued through the course of the experiment, while the microplastic treatments reached maturity up to two weeks earlier. Imagery revealed that microplastics elicited deeper rooting depth within the first week and differences in all root traits were evident by the development of the first trifoliate leaflets. Microplastic effects on root traits at early life stages suggest soil physiological drivers, while increased branching frequency and lower lateral elongation are suggestive of changes in soil nitrogen availability. The minimal difference in root traits in the biosolid treatment may be attributable to differences in microplastic properties or counteractive effects by other biosolid constituents.

Revisiting resistance: student diaries and educational aspirations in Colonial Korea (1920–1945)

ABSTRACT This article examines the intricate interplay of educational enthusiasm, conformity, and resistance amongst Korean students during the Japanese colonial period (1920–1945). It explores how Japan’s governance shift in the 1920s, which extended schooling years and introduced co-education, elicited mixed responses from Korean students, ranging from compliance to various forms of resistance. By examining student diaries, this study unravels the complexities of educational aspirations and resistance and challenges traditional binary views of colonial educational history. The research highlights the heightened educational zeal in the 1920s and 1930s, characterised by increased school enrolment and fierce competition for admissions. The diaries provide insight into students’ reactions to colonial policies, blending aspirations for advancement with subtle forms of resistance. In analysing diary entries, this paper uncovers how increases in student enrolment and rising educational aspirations reflect both conformity with and resistance to colonial policies. Explicit resistance, more prominent in the 1920s, was replaced by implicit forms as militarism intensified in the 1930s. This study categorises resistance into organised (overt) and disorganised (covert) forms, with the latter including subtler forms of opposition, such as disquieting, indirect, and silent resistances. The diaries examined in this study reflect the dual life experiences of students, who adhered to public norms while nurturing private dissent. Manifestations of resistance ranged from disquieting actions to metaphorical defiance and strategic silence, which illustrates students’ complex navigation between external conformity and internal rebellion. This understanding of compliance and resistance, encompassing overt acts and subtle unspoken forms, underscores the need for a comprehensive view of educational aspirations during this historical period.

Acceptability of a remotely delivered sedentary behaviour intervention to improve sarcopenia and maintain independent living in older adults with frailty: a mixed-methods study

BackgroundSarcopenia is a leading cause of functional decline, loss of independence, premature mortality, and frailty in older adults. Reducing and breaking up sedentary behaviour is associated with positive sarcopenia and frailty outcomes. This study aimed to explore the acceptability, engagement and experiences of a remotely delivered sedentary behaviour intervention to improve sarcopenia and independent living in older adults with frailty.MethodsThis was a mixed-methods study. In-depth qualitative semi-structed interviews were conducted with a subset (N = 15) of participants with frailty (aged 74 ± 6 years) who had participated in the Frail-LESS (LEss Sitting and Sarcopenia in Frail older adults) intervention aimed at reducing sedentary behaviour. The interviews explored acceptability of the intervention overall and its individual components (a psychoeducation workbook, wrist-worn activity tracker, health coaching, online peer support and tailored feedback on sitting, standing and stepping). Process evaluation questionnaires with closed and scaled questions explored intervention engagement, fidelity and experiences.ResultsOverall acceptability of the intervention was good with most participants perceiving the intervention to have supported them in reducing and/or breaking up their sedentary behaviour. The wrist-worn activity tracker and health coaching appeared to be the most acceptable and useful components, with high levels of engagement. There was attendance at 104 of 150 health coaching sessions offered and 92% of participants reported using the wrist-worn activity tracker. There was a mixed response regarding acceptability of, and engagement with, the psychoeducation workbook, tailored feedback, and online peer support.ConclusionsThe Frail-LESS intervention had good levels of acceptability and engagement for some components. The findings of the study can inform modifications to the intervention to optimise acceptability and engagement in a future definitive randomised controlled trial.Trial registrationThe trial was registered with ISRCTN (number ISRCTN17158017).

North Carolina head start teachers’ needs, resources, experiences, and priority for science education and professional development

ABSTRACT Early science learning is a part of preschool curriculum that can have positive outcomes for children’s scientific knowledge and interest. Head Start teachers are well positioned to implement quality science lessons. Through an in-depth needs assessment survey, the current study examined North Carolina preschool Head Start teachers’ responses on needs, resources, experiences with professional development, and personal priority levels for science education. Our analysis revealed that Head Start teachers mostly utilized informal teaching methods and used curricular and organizational resources, but utilizing mealtimes for teaching science had mixed responses. Teachers reported their access to resources and connections to community partnerships. Teachers preferred asynchronous or online PD formats and were motivated by compensation and continuing education credits while accessing PD. Most teachers rated science to be a very or extremely important personal priority. Differences in teacher education, experience, and position levels also influenced the findings of the study. The implication section delineates steps that can be taken toward strengthening science education within Head Start settings along with support that can be provided to teachers.

7911 High Dose Serial Radioactive Iodine Therapies Facilitated byAutologous Stem Cell Cryopreservation in a Patient with Exceptionally Avid Metastatic FTC

Abstract Disclosure: S. Paknikar: None. D. Toro Tobon: None. J. Durski: None. H. Alkhateeb: None. M.M. Ryder: None. Introduction: Radioactive iodine (RAI) therapy-induced myelosuppression is a dose-limiting toxicity for RAI avid metastatic differentiated thyroid cancers. We describe a patient with exceptionally RAI avid metastatic follicular thyroid cancer (FTC) who underwent autologous stem cell cryopreservation (ASCC) to enable high dose I-131 treatments. Case: A 60-year-old woman with T1bN0M0 FTC underwent two-stage thyroidectomy and three doses of I-131 between 2002-2007 (434 mCi cumulative activity) due to incomplete biochemical response. She presented to our institution in 2015 with rising thyroglobulin (Tg) levels and lung nodules that were intensely RAI avid. She enrolled in a clinical trial of selumetinib versus placebo (for 1 month) followed by 150 mci I-131. She had a profound response with an 80% reduction in Tg and 50% tumor shrinkage. The following year her Tg rose to 8381 ng/mL and she developed biopsy proven, well differentiated metastatic FTC in the hip and liver. Lenvatinib treatment resulted in partial tumor and Tg response but was halted due to grade 3/4 toxicities. Tumor genomic interrogation revealed NRAS, PIK3CA, and TSH-R activating mutations, providing a causal explanation of her intensely RAI avid and responsive disease. Repeat I-131 therapy was facilitated by GM-CSF stimulated ASCC (8.57 x10(6) CD34+ cells/kg for two cycles) as a tool to help mitigate future potential RAI-induced myelosuppression. The patient received 295 mci I-131 followed by a 98% decrease in Tg and 20-25% shrinkage of liver metastases. Transient pancytopenia ensued but did not require autologous stem cell transplantation (ASCT). Due to insurance issues, the patient was lost to follow-up for two years. She returned with cachexia from severe, untreated thyrotoxicosis due to widespread functional, thyroxine producing metastatic disease. Anti-thyroid drug therapy (ATD) restored euthyroid status with significant clinical improvement. A non-stimulated I-123 whole body scan showed diffuse RAI avid disease with 88% whole body radioiodine retention at 48h. She received 125 mci I-131 with initial tumor response but with progression of bone marrow, calvaria, and retinal metastases. Six months later, a final dose of 253 mCi I-131 (cumulative activity 1,370 mCi) resulted in mixed tumor responses. Unfortunately, resection of a RAI refractory calvaria lesion postoperatively resulted in serious complications. ASCT and salvage treatments could not be pursued due to her impaired functional status. The patient pursued hospice care and passed away 20 years after her diagnosis. Conclusion: We characterize a patient with NRAS, PIK3CA and TSH-R mutant metastatic, thyroxine-producing FTC whose recurrences over 20 years retained intense RAI avidity and response to I-131 therapy. In cases with potential benefit from multiple high dose RAI therapies, ASCT may be a tool to mitigate I-131-induced myelosuppression. Presentation: 6/1/2024

Recovery and Recidivism: The Aftermath of Helping the Organization Unethically

AbstractThis research draws from moral self-regulation and moral disengagement theories to examine how employees react to their own unethical pro-organizational behavior (UPB). We hypothesize that UPB will elicit mixed moral-based cognitive responses among employees that promote both recovery and recidivism. Results of two studies show that, on the one hand, engaging in UPB damaged perpetrators' moral self-concept, captured by an increase in perceived loss of moral credits; this prompted them to perform customer-directed helping behaviors to recover their damaged moral self-concept; on the other hand, UPB also elicited a cognitive justification process, which was related to an increase in subsequent UPB. This nuanced reaction helps explain why individuals' moral self-regulation does not necessarily remedy for moral failings, while also suggesting practical steps that leaders can take to prevent a "slippery slope" pattern of UPB from taking hold in the organization.

Preclinical Models of Atopic Dermatitis Suitable for Mechanistic and Therapeutic Investigations.

Atopic dermatitis (AD) is a complex immune-mediated abnormality of the skin characterized by impaired barrier function, eczematous dermatitis, chronic pruritus and itch. The immunological response in AD is mediated by a Th2-dominated immune response in the early acute phase followed by a Th1/ Th2 mixed immune response in the chronic phase. AD is the first step of the "atopic march" that progresses into food allergy, allergic rhinitis, and asthma. Different models are indispensable for studying AD pathogenesis and for designing pre-clinical studies for therapeutic discovery. They reflect the characteristic morphological features of typical human AD with regard to epidermal thickening, hyperkeratosis, acanthosis, and spongiosis and help understand the immunopathogenesis of the disease with respect to IgE levels and cellular infiltration of eosinophils, mast cells, and lymphocytes. Although it is difficult to replicate all human AD clinical features in a model, several AD in vivo models comprising spontaneous, induced, transgenic, and humanized and in vitro models, including 2D, co-culture, and 3D, have been described previously. However, several questions remain regarding whether these models satisfactorily reflect the complexity of human AD. Therefore, this review comprehensively highlights the diversity of currently available models and provides insights into the selection of suitable models based on research questions. It also summarizes the diverse mechanisms associated with each model, which may be valuable for better study design to test new therapeutic options.

Salvia officinalis L. resilience under chromium stress: An integrated study of growth, physiology, biochemical changes and rosmarinic acid production

Medicinal plants are increasingly challenged by rising chromium (Cr) levels in agricultural soil and water bodies due to industrialization and human activities. This research examines the impact of various chromium concentrations on Salvia officinalis L., a medicinal herb, over 3 specific time periods: 30, 60 and 90 days. As the duration of Cr exposure increases, various growth parameters showed an upward trend at the lowest concentrations, with the most robust growth observed in the 20 ppm Cr treatment group after 90 days. However, higher chromium concentrations resulted in reduced plant growth compared to untreated plants. Chromium primarily accumulates in the roots, stems and leaves, with the highest accumulation observed at 100 ppm. However, chlorophyll content declined with prolonged Cr exposure, particularly at higher concentrations. Carbohydrate levels initially increased at lower Cr concentrations but decreased with greater exposure, while protein content consistently decreased with elevated Cr levels. Proline levels exhibited mixed responses, rising at lower concentrations and declining at higher ones. Malondialdehyde (MDA) content increased with higher Cr levels and extended exposure. The enzymatic antioxidant system showed an initial increase followed by a decline with prolonged exposure. Rosmarinic acid content increased with chromium (Cr) exposure upto 60 ppm but subsequently decreased beyond that threshold. In the first 30 days, plants treated with Cr demonstrated a 17 % increase in rosmarinic acid production compared to the control (48.9 mg/g DW). However, with continued Cr exposure, there was a decline in rosmarinic acid production ranging from 10 % to 20 % compared to the control level (67.02 mg/g DW) at 90 days post-treatment. These findings underscore the complex and contrasting responses of Salvia officinalis to Cr toxicity, highlighting the necessity for extended study into the core mechanisms governing these responses and the development of strategies to alleviate heavy metal stress in plants.

Screening of rice cultivars against Scirpophaga incertulas Walker : utilising cluster analysis as a tool to identify resistant cultivars

The field experiment was conducted in the Boro season from December 2022 to April 2023 at the Institutional research farm, Institute of Agriculture, Palli Siksha Bhavana, Visva-Bharati, Sriniketan, Birbhum, West Bengal, for the screening of thirty-three rice cultivars for their resistance to yellow stem borer, Scirpophaga incertulas Walker. The experiment utilized modified percent damage values to grade these cultivars during both vegetative and reproductive stages. Early-duration cultivars displayed varied reactions, with Jaldi 13 (2) exhibiting consistent resistance (2.53% DH, 12.65% D), while others showed moderate resistance or susceptibility with deadheart percentages ranging from 4.73% to 8.51% and corresponding damage percentages between 23.65% and 42.55%. This trend extended to reproductive stages, where all early-duration cultivars demonstrated moderate to high susceptibility, with damage percentages between 30.8% and 54.5%. The mid-early duration cultivars displayed mixed responses, with Sahabhagi (4) demonstrating moderate resistance (4.92% DH) and Sukumar (3) exhibiting moderate susceptibility (8.21% DH) during the vegetative stage. These diverse reactions continued into the reproductive stage, providing a comprehensive understanding of their responses to the pest. Additionally, in medium and late-duration cultivars, a range of reactions persisted, with cultivars like Pratiksha (20) showing moderate resistance (6.63% DH) in the mid-duration category and Ajith (25) displaying moderate resistance (6.33% DH) in the late-duration category. Cluster analysis categorized the cultivars into distinct groups, showcasing a mix of resistant, moderately resistant, and susceptible types across all growth durations. Notably, cultivars like Gotra 1 (10), Parijat (14), Pushpa (17), PNR 546 (19), Pravat (23) and Gotra 2 (31) consistently demonstrated resistance or moderate resistance across different growth stages, suggesting their potential suitability in tailoring resistant breeding programs and pest management strategies against the stem borer in rice cultivation.

Fully Synthetic TF-Based Self-Adjuvanting Vaccine Simultaneously Triggers iNKT Cells and Mincle and Protects Mice against Tumor Development.

The Thomsen-Friedenreich (TF) antigen has proven to be a promising target for developing novel therapeutic cancer vaccines. Here, a new strategy that TF antigen covalently coupled with KRN7000 and vizantin was developed. The resulting three-component vaccine KRN7000-TF-vizantin simultaneously triggers invariant natural killer T (iNKT) cells and macrophage-inducible C-type lectin (Mincle) signaling pathways, eliciting much stronger TF-specific immune responses than glycoprotein vaccine TF-KLH/alum and the corresponding two-component conjugate vaccines TF-KRN7000 and TF-vizantin. The analysis of IgG isotypes and the secretion of cytokines revealed that KRN7000-TF-vizantin induced Th1/Th2 mixed immune responses, where Th1 was dominant. In vivo experiments demonstrated that KRN7000-TF-vizantin increased the survival rate and survival time of tumor-challenged mice, and surviving mice rejected further tumor attacks without any additional treatment. This work demonstrates that covalently coupled KRN7000 and vizantin could serve as a promising TF-based vaccine carrier for antitumor immune therapy, and KRN7000-TF-vizantin features great potential to be a vaccine candidate.

Effects of GABA on Oxidative Stress and Metabolism in High-Glucose Cultured Mongolian Sheep Kidney Cells.

The Mongolian sheep, emblematic of the Inner Mongolian grasslands, is renowned for its exceptional stress resistance and adaptability to harsh environments, drawing considerable attention. Recent research has unveiled the novel role of γ-aminobutyric acid (GABA) in combating oxidative stress. This investigation examined how GABA impacts renal-cortex and medulla cells from Mongolian sheep exposed to high-glucose stress conditions, utilizing gene expression analysis and non-targeted metabolomics. Elevated glucose levels significantly reduced the viability of Mongolian sheep renal cells and increased reactive oxygen species (ROS) levels. Conversely, the introduction of GABA notably enhanced cell viability, reduced ROS production, and stimulated the expression of antioxidant genes (e.g., Gpx, SOD, CAT) in the renal cortex. In the renal medulla, CAT expression increased, while Gpx gene expression showed mixed responses. Metabolomics analysis indicated that high-glucose exposure altered various metabolites, whereas GABA alleviated the metabolic stress induced by high glucose through modulating glycolysis and the tricarboxylic acid cycle. In Mongolian sheep renal cells, GABA effectively mitigated oxidative damage triggered by high-glucose stress by upregulating antioxidant genes and regulating metabolic pathways, revealing insights into its potential mechanism for adapting to extreme environments. This finding offers a fresh perspective on understanding the stress resilience of Mongolian sheep and may provide valuable insights for research across diverse disciplines.

Abstract A004: A Phase 1B/2 trial of second line immunotherapy with pepinemab and avelumab for patients with metastatic pancreatic adenocarcinoma

Abstract Background: Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor prognosis despite maximal therapy and is recalcitrant to approved immunotherapies. In PDAC, Semaphorin 4D (SEMA4D) expression is prognostic in patients who have undergone surgical resection and correlates with tumor infiltration of activated CD8+ T-cells. Furthermore, preclinical studies suggest that monoclonal blockade of SEMA4D supports CD8+T cells tumoral infiltration and activation, sensitizing PDAC to immune checkpoint blockade (ICB). Thus, we hypothesized that a humanized anti-SEMA4D antibody (pepinemab) may improve disease control and responsiveness to ICB in patients with PDAC. Methods: We designed a phase Ib/II single-arm clinical trial to evaluate the safety, tolerability, and efficacy of pepinemab with anti-PD-L1 (avelumab) in patients with chemotherapy-refractory PDAC (NCT05102721). The study follows a dose de-escalation schema starting at a dose combination of 20mg/kg pepinemab and 800mg avelumab every two weeks. Patient accrual for phase 1b utilizes the Bayesian Optimal Interval design targeting a dose-limiting toxicity rate of 30% or less. After 16 subjects receive a given combination dose, a Simon’s two stage assessment of futility will be undertaken with expansion to phase 2 if 2 or more subjects demonstrate response. Treatment response is assessed via RECIST 1.1 criteria with surveillance CT prior to enrollment and after completion of two cycles (8 weeks). Baseline and on-treatment tumor biopsies (after completion of one cycle, 4 weeks) are performed to analyze changes in immune, stromal, and genomic profiles to elucidate mechanisms of treatment response and failure. Patient reported outcomes are incorporated (FACT-Hep and FAACT subdomains) to assess disease-specific symptoms. Results: A total of 14 patients have been enrolled to date. Three subjects withdrew from the study prior to completing the evaluable period (four weeks of treatment) and nine subjects terminated treatment due to disease progression. Two subjects continue to receive combination treatment pending evaluation of tumor response. Baseline and on-treatment biopsies have been obtained and stored for correlative analysis from 8 evaluable subjects. One treatment-related adverse event occurred though the patient was able to complete treatment without further events. No treatment-related toxicities have been encountered. Conclusions: Combining pepinemab with avelumab appears to be safe and tolerable to date. Nine of eleven patients demonstrated disease progression, though 1 of these 9 demonstrated mixed response with some lesions showing radiologic partial and even complete response. Overall treatment response, survival data, and correlative science forthcoming. Citation Format: Luis I Ruffolo, Matthew Byrne, Bailey Hilty, Brian A Belt, Yatee Dave, Paul Burchard, Terrence Fisher, Elizabeth E. Evans, Crystal Mallow, Megan Boise, Darren Carpizo, Jen Jen Yeh, David C Linehan, Daniel Mulkerin. A Phase 1B/2 trial of second line immunotherapy with pepinemab and avelumab for patients with metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A004.

Understanding mediated sports consumption by Irish children: a qualitative study exploring their exposure and understanding of gambling marketing, risks and harms

BackgroundGambling marketing communications create a public health risk by increasing the normalisation of gambling in sports. In a context where broad level studies report significant underage gambling, currently no evidence exists on how these communications are received by children in the Republic of Ireland (hereafter Ireland) and Northern Ireland. To build this evidence base and provide granular detail below broad level data, this study explored the sport consumption habits and views of Irish children (aged 14–17 years) on their exposure, awareness and perceptions of the relationship between sport and gambling.MethodsDrawing on a constructivist approach to data collection, 6 face-to-face focus groups were staged with a total of 51 youth sport consumers from both sides of the border region on the island of Ireland.ResultsFour main themes were established. First, mediated sport consumption was predominantly via mobile social media. Second, we found that their exposure to gambling marketing was high and while frequently seen through social media channels it was also prevalent in peer-to-peer conversations and on the main street. Third, we found mixed responses on their perceptions about gambling and sport. While many felt that sport and gambling were a good fit, they were aware of the financial risks involved. Few children understood the wider social risks with gambling harm. Fourth, children were sceptical of claims made in gambling communications. These findings highlight concerns about how exposure to gambling marketing is impacting children’s views on sport and on gambling. These views need to be taken into consideration when broadcasters and sport organizations are entering into commercial associations.ConclusionsGambling marketing is noticed by children watching mass and social media, and in the towns in the border regions of the island of Ireland. Our study provides children’s viewpoints on this topic which complements the larger quantitative studies in Ireland and Northern Ireland that highlight the growing prevalence of children and gambling. This study not only extends the literature on the exposure, awareness and perceptions of children on the island of Ireland but provides crucial evidence to public health advocates in this region demonstrating the pervasiveness of gambling communications in and around children’s spaces.

Joint modeling of mixed skewed longitudinal responses using convolution of normal and log-normal distributions: a Bayesian approach

This paper investigates the joint modeling of mixed ordinal and continuous longitudinal responses using a random effects model and applying a conditional approach. For the ordinal responses, a latent variable model with a logistic distribution is employed. To address skewness in the data, the model incorporates normal and log-normal convolution (NLNC) for both the error term and the random effects in the longitudinal model. Parameter estimation is carried out within a Bayesian framework using Gibbs sampling. The performance of the proposed model is evaluated through simulation studies, comparing it to joint models of mixed ordinal and continuous longitudinal responses assuming skew-normal or normal distributions. The results indicate that joint models using skew-normal or normal distributions can lead to biased parameter estimates, whereas the NLNC joint model performs better overall. Additionally, the proposed method is applied to analyze data from the British Household Panel Survey (BHPS), using life satisfaction and annual income as the correlated ordinal and continuous longitudinal responses, respectively, with annual income showing significant skewness. The results demonstrate that the proposed model provides the best fit for capturing the substantial skewness in the data.

Effects of Schistosoma haematobium infection and treatment on the systemic and mucosal immune phenotype, gene expression and microbiome: A systematic review.

Urogenital schistosomiasis caused by Schistosoma haematobium affects approximately 110 million people globally, with the majority of cases in low- and middle-income countries. Schistosome infections have been shown to impact the host immune system, gene expression, and microbiome composition. Studies have demonstrated variations in pathology between schistosome subspecies. In the case of S. haematobium, infection has been associated with HIV acquisition and bladder cancer. However, the underlying pathophysiology has been understudied compared to other schistosome species. This systematic review comprehensively investigates and assimilates the effects of S. haematobium infection on systemic and local host mucosal immunity, cellular gene expression and microbiome. We conducted a systematic review assessing the reported effects of S. haematobium infections and anthelmintic treatment on the immune system, gene expression and microbiome in humans and animal models. This review followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42022372607). Randomized clinical trials, cohort, cross-sectional, case-control, experimental ex vivo, and animal studies were included. Two reviewers performed screening independently. We screened 3,177 studies and included 94. S. haematobium was reported to lead to: (i) a mixed immune response with a predominant type 2 immune phenotype, increased T and B regulatory cells, and select pro-inflammatory cytokines; (ii) distinct molecular alterations that would compromise epithelial integrity, such as increased metalloproteinase expression, and promote immunological changes and cellular transformation, specifically upregulation of genes p53 and Bcl-2; and (iii) microbiome dysbiosis in the urinary, intestinal, and genital tracts. S. haematobium induces distinct alterations in the host's immune system, molecular profile, and microbiome. This leads to a diverse range of inflammatory and anti-inflammatory responses and impaired integrity of the local mucosal epithelial barrier, elevating the risks of secondary infections. Further, S. haematobium promotes cellular transformation with oncogenic potential and disrupts the microbiome, further influencing the immune system and genetic makeup. Understanding the pathophysiology of these interactions can improve outcomes for the sequelae of this devastating parasitic infection.

Efficacy and safety of rechallenge with [177Lu]Lu-PSMA-I&T radioligand therapy in metastatic castration resistant prostate cancer.

The purpose of this study was to evaluate the safety and outcome of rechallenge [177Lu]Lu-PSMA-I&T in newly progressed mCRPC patients after response to initial [177Lu]Lu-PSMA radioligand therapy(PRLT). We retrospectively included 18 patients who underwent rechallenge with [177Lu]Lu-PSMA-I&T. All patients presented with (i) newly progressed disease after response to initial PRLT; (ii) a [68Ga]Ga-PSMA-11 PET/CT confirming the presence of PSMA-positive metastases; iii)ECOG performance status 0-1.Adverse events were graded according to CTCAE v5.0. Response was assessed by PSA and classified according to PCWG3 recommendations. For patients who underwent restaging with [68Ga]Ga-PSMA-11 PET/CT, imaging response was categorised according to adapted PERCIST v1.0. In patients with discordant [68Ga]Ga-PSMA-11 PET/CT and PSA, other available imaging modalities were evaluated to confirm disease status. Overall survival (OS) was calculated from the first cycle of initial PRLT and rechallenge PRLT, respectively, until last patient contact or death. Patients were initially treated with a median of 5 cycles (range 4-7) and were rechallenged after a median of 9 months (range 3-13). Each patient received a median of 4 (range 2-7) rechallenge cycles (median cumulative activity 26.1GBq). None of the patients experienced life-threatening G4 adverse events during either treatment period. Grade 3 adverse events included one case of anaemia, one case of thrombocytopenia, and one case of renal failure. In 8/18 patients long-term toxicities were evaluated. Serious toxicities (≥ Grade 3) occurred in 3/8 patients (n = 1 G4 thrombocytopenia, n = 1 G4 renal failure and n = 1 pancytopenia and G4 renal failure). Best PSA50%-response was observed in 44% of patients and PSA-disease control was confirmed in 56% of patients at the last cycle. Of the 12/18 patients restaged by imaging, 6/12 (50%) patients had disease control (partial response/stable disease), 1/12 had a mixed response, and 5/12 had progression. After a median follow-up time of 25 months (range 14-44), 10 patients had died, 7 were still alive, and one patient was lost at follow-up. The median OS was 29 months (95%CI,14.3-43.7 months) for the initial treatment and 11 months (95%CI,8.1-13.8 months) for the first rechallenge course. More than half of patients benefit from rechallenge PRLT. Our analysis suggests that rechallenge may prolong survival in selected patients, with an acceptable safety profile.

Enhancing protective immunity against bacterial infection via coating nano-Rehmannia glutinosa polysaccharide with outer membrane vesicles.

With the coming of the post-antibiotic era, there is an increasingly urgent need for safe and efficient antibacterial vaccines. Bacterial outer membrane vesicles (OMVs) have received increased attention recently as a potential subunit vaccine. OMVs are non-replicative and contain the principle immunogenic bacterial antigen, which circumvents the safety concerns of live-attenuated vaccines. Here, we developed a novel nano-vaccine by coating OMVs onto PEGylated nano-Rehmannia glutinosa polysaccharide (pRL) in a structure consisting of concentric circles, resulting in a more stable vaccine with improved immunogenicity. The immunological function of the pRL-OMV formulation was evaluated in vivo and in vitro, and the underlying mechanism was studied though transcriptomic analysis. The pRL-OMV formulation significantly increased dendritic cell (DC) proliferation and cytokine secretion. Efficient phagocytosis of the formulation by DCs was accompanied by DC maturation. Further, the formulation demonstrated superior lymph node targeting, contributing to a potent mixed cellular response and bacterial-specific antibody response against Bordetella bronchiseptica infection. Specifically, transcriptomic analysis revealed that the immune protection function correlated with T-cell receptor signalling and Th1/Th2/Th17 differentiation, among other markers of enhanced immunological activity. These findings have implications for the future application of OMV-coated nano-carriers in antimicrobial immunotherapy.