Clinical Indications Research Articles

The effectiveness of vedolizumab in advanced therapy-experienced ulcerative colitis patients: Real world data from the Inflammatory Bowel Disease of the Middle East (IBD-ME) Registry group.

Vedolizumab is an approved ulcerative colitis (UC) treatment. Multiple large randomized clinical trials have demonstrated the drug's efficacy and safety. However, real-world data from Middle Eastern countries are spare. The study aims to evaluate the clinical efficacy of vedolizumab (VDZ) therapy in advanced therapy experienced UC patients. A retrospective electronic chart review of a cohort study of 153 moderately to severely active UC patients who failed or were intolerant to TNF antagonists and received vedolizumab from two large tertiary care centers was performed. Rates of clinical response and remission were retrospectively evaluated at 3,6, and 12 months post VDZ therapy using Patient Simple Clinical Colitis Activity Index (P-SCCAI); clinical response was defined as a decrease in P-SCCAI ≥3, and clinical remission was defined as a P-SCCAI score of ≤3 points. Logistic regression analysis was used to identify predictors of response to vedolizumab. A total of 153 UC patients had sufficient data for analysis. Clinical remission rates were 61.9% for patients on vedolizumab every 8 weeks and 89.3% for those receiving every 4 (Q4) weeks dosing. A significant reduction in CRP and improvement of albumin post vedolizumab treatment were observed, and corticosteroids were stopped in most patients. In a multiple logistic regression analysis, several factors were found to influence the clinical effectiveness of VDZ in inducing remission. Female gender was associated with a higher likelihood of remission [OR =3.09, 95% CI = (1.05-9.13), P = 0.04]. Conversely, a greater number of biologics used prior to VDZ treatment was associated with a lower likelihood of remission [OR =0.418, 95% CI = (0.203-0.859), P = 0.017]. Patients with extensive disease (E3) had an increased likelihood of remission [OR =3.81, 95% CI = (1.32-10.97), P = 0.0129]. Additionally, a VDZ dosing frequency of Q4 weeks was associated with a significantly higher likelihood of remission [OR =6.08, 95% CI = (1.73-21.39), P = 0.0049]. No significant safety signals were reported. In this current real-world study, vedolizumab effectively achieved clinical response and remission in most advanced therapy experienced UC patients treated for up to 12 months. Future studies with larger sample sizes and more robust study designs should be conducted to further validate the results of this study.

Histologic healing and clinical outcomes in ulcerative colitis.

Growing evidence suggests histologic healing (HH) improves clinical outcomes in ulcerative colitis (UC) patients beyond endoscopic healing (EH). We hypothesize that HH is associated with better clinical outcomes in Asian UC patients, for whom data is lacking. We performed a retrospective study of UC patients in clinical remission (CR) with a follow-up colonoscopy and minimum 1-year follow-up post-colonoscopy. Primary outcome was clinical relapse (CRL), defined as either a Simple Clinical Colitis Activity Index score of > 2, medication escalation, hospitalization or colectomy. Predictors of CRL and HH were assessed. One hundred patients were included with a median follow-up of 22 months. At index colonoscopy, 80 patients were in EH. On follow-up, 41 patients experienced CRL. Of 80 patients in EH, 34 (42.5%) had persistent histologic activity (Nancy Index ≥ 2) and 29 (36.3%) relapsed during the follow-up period. Amongst patients in CR and EH, those with HH had lower CRL rate (26.1% vs. 50.0%, P= 0.028) and longer CRL-free survival (mean 46.1 months vs. 31.5 months, P= 0.015) than those with persistent histologic activity. On bivariable analysis of 100 patients in CR, HH, and Mayo endoscopic score (MES) of 0 were significantly associated with lower risk of CRL. On multivariable analysis, only MES 0 remained predictive of lower CRL risk. Above and beyond CR and EH, achieving HH improves clinical outcomes in Asian UC patients. However, HH may not confer incremental benefit if MES 0 has been achieved. Further prospective studies evaluating the benefit of histologically guided therapeutic decisions are needed.

Management of vascular access inflow-outflow imbalance: A bimodal approach.

A more accurate descriptive and clinically useful diagnosis based upon pathophysiology for what is commonly referred to as venous outflow stenosis is inflow-outflow imbalance. In these cases, the total outflow capacity of the AV access is inadequate to handle the inflow volume (Qa) without an increase in pressure. The relative inadequacy of the access outflow capacity in comparison to Qa results in increased outflow resistance and a proportional increase in intraluminal pressure. The clinical indicators associated with venous stenosis are the resulting manifestations of this imbalance. The point at which this occurs is dependent upon variations in these two parameters-Qa and outflow resistance. The variations in these two parameters are considerable and reciprocal. Excessive Qa results in or can lead to an entire list of serious problems that adversely affect patient morbidity and mortality. Most studies dealing with AV access Qa reduction have been for the treatment of an existing condition rather than its prevention; however, prevention of disease rather than waiting for its development is an important tenet of medical practice. The resulting clinical picture of inflow-outflow imbalance is taken as an indication for corrective treatment. In the past, in most cases this has meant angioplasty to open the outflow if it is reduced; however, this clinical picture may be associated with an excessive Qa and angioplasty in these cases creates the risk for a further increase in Qa. It is the authors' opinion that access flow measurements should be a part of the evaluation of these cases prior to planning treatment. Using this information, a bimodal approach to primary treatment should be adopted involving either angioplasty for cases with a low or normal Qa or flow reduction in cases with an elevated Qa.

Validity of Wrist-Worn Activity Tracker Heart Rate Detection in Fontan Patients During Exercise.

Physical activity and a healthy lifestyle play an essential role in optimizing long-term health in patients with Fontan physiology. Wrist-worn activity trackers may be useful in medically directed exercise programs for patients with Fontan physiology. The objective of this study was to measure the validity of Garmin and Fitbit activity tracker heart rate detection in patients with Fontan circulation when compared to electrocardiogram (ECG) during cardiopulmonary exercise testing (CPET). 47 Fontan patients undergoing CPET for clinical indications were included and wore activity trackers during CPET. Heart rate via the activity tracker was collected at baseline, maximal exercise, and recovery. Patient heart rates, peak VO2, and peak respiratory exchange ratio (RER) were collected using standard CPET protocols and equipment. Heart rate at each time point was compared between the activity trackers and CPET ECG. Median age of participants was 17.1 years, 15.1 years since Fontan completion. Mean percent of predicted peak VO2 was 56.8%, z-score -3.2 with 61.7% of participants completing a maximal CPET (RER ≥ 1.09). Baseline oxygen saturation mean was 92.9%, 90.0% at maximal exercise. Activity trackers demonstrated mean absolute percentage error < 10% at most time points, comparable with other studies. Demographics, Fontan-associated comorbidities, and echocardiogram findings did not impact the accuracy. Consumer-oriented wrist-worn activity trackers show promising accuracy for heart rate monitoring in medically directed exercise programs for adolescents and young adults with Fontan physiology. Further validation across different exercise modalities is needed.

Recommended procedures for managing carious lesions in primary teeth with pulp involvement—a scoping review

BackgroundManaging dental caries in primary teeth with pulp involvement is a significant challenge. Clinical guidelines offer recommendations for effective management.AimTo identify and analyze policies, guidelines, and recommendations for treating primary teeth with pulp-involved carious lesions, highlighting existing research gaps and setting the foundation for future research.MethodsA comprehensive search was conducted across databases (PubMed, Scopus, Embase, GIN, and LILACS) and grey literature sources (Trip and ProQuest) to identify guidelines, consensus, policy, and position statements on primary teeth pulp therapy and extraction thresholds. Two independent reviewers screened the abstracts and titles, followed by full-text screening.ResultsAfter removing duplication, of the 1098 records, 14 were selected for analysis. This review examined various treatments for deep caries lesions in primary teeth, including indirect/direct pulp capping, pulpotomy, pulpectomy, lesion sterilization/tissue restoration, and extraction. Time search was restricted to documents published from 30th January 2008 to 30th January 2024, offering insights into evolving clinical practices.ConclusionTreatment for carious lesions in primary teeth involving the pulp depends on clinical indications and may involve minimally invasive techniques. Recommended options are indirect pulp capping, pulpotomy, and pulpectomy, while direct capping and tooth removal are discouraged. Further research is needed to address gaps, improve guideline development, and enhance consistency of recommendations.

Evaluating the Knowledge of Radiation Exposure Parameters Among CT Technologists in Saudi Arabia: A Survey-Based Study on Adherence to ALARA Principles and Dose Optimization

Computed tomography is a crucial tool in modern healthcare, offering non-invasive imaging for diagnosis and monitoring. However, its widespread use raises concerns about radiation exposure. Adhering to the ALARA principle is vital to minimize risks while maintaining diagnostic quality. This study evaluates the knowledge of CT technologists in Saudi Arabia regarding radiation exposure parameters. A questionnaire-based survey was conducted, covering demographics, perceptions, and understanding of CT parameters. Statistical analysis revealed gaps in knowledge, particularly regarding dose optimization strategies and diagnostic reference levels. While most participants recognized the importance of adjusting parameters based on patient characteristics and clinical indications, deficiencies were observed in understanding specific parameters' effects on dose and image quality. Furthermore, a notable proportion of participants were unfamiliar with DRLs, indicating a need for improved education in this area. The study emphasizes the importance of interdisciplinary collaboration between radiologists, physicists, and technologists in protocol development and optimization.

Oral Fecal Microbiota Transplantation in Dogs with Tylosin-Responsive Enteropathy—A Proof-of-Concept Study

A clinical trial was conducted to evaluate the effect of fecal microbiota transplantation (FMT) on the canine chronic enteropathy clinical activity index (CCECAI), fecal consistency, and microbiome of dogs with tylosin-responsive enteropathy (TRE). The trial consisted of four phases: (1) screening with discontinuation of tylosin for 4 weeks, (2) inclusion with re-introduction of tylosin for 3–7 days, (3) treatment with FMT/placebo for 4 weeks, and (4) post-treatment with follow-up for 4 weeks after treatment cessation. The study found that the treatment efficacy of FMT (71.4%) was slightly higher than that of placebo (50%), but this difference was not statistically significant due to underpowering. The most abundant bacterial species detected in the fecal microbiomes of dogs with TRE before FMT or placebo treatment were Blautia hansenii, Ruminococcus gnavus, Escherichia coli, Clostridium dakarense, Clostridium perfringens, Bacteroides vulgatus, and Faecalimonas umbilicata. After FMT, the microbiomes exhibited increases in Clostridium dakarense, Clostridium paraputrificum, and Butyricicoccus pullicaecorum. The microbiome alpha diversity of TRE dogs was lower when on tylosin treatment compared to healthy dogs, but it increased after treatment in both the FMT and placebo groups. Comparisons with the stool donor showed that, on average, 30.4% of donor strains were engrafted in FMT recipients, with the most common strains being several Blautia sp., Ruminococcus gnavus, unclassified Lachnoclostridium, Collinsella intestinalis, and Fournierella massiliensis.

State of the art medical devices for fluorescence-guided surgery (FGS): technical review and future developments.

Medical devices for fluorescence-guided surgery (FGS) are becoming available at a fast pace. The main challenge for surgeons lies in the lack of in-depth knowledge of optical imaging, different technical specifications and poor standardisation, and the selection of the best device based on clinical application. This manuscript aims to provide an up-to-date description of the commercially available fluorescence imaging platforms by comparing their mode of use, required settings, image types, compatible fluorophores, regulatory approval, and cost. We obtained this information by performing a broad literature search on PubMed and by contacting medical companies directly. The data for this review were collected up to November 2023. Thirty-two devices made by 19 medical companies were identified. Ten systems are surgical microscopes, 5 can be used for both open and minimally invasive surgery (MIS), 6 can only be used for open surgery, and 10 only for MIS. One is a fluorescence system available for the Da Vinci robot. Nineteen devices can provide an overlay between fluorescence and white light image. All devices are compatible with Indocyanine Green, the most common fluorescence dye used intraoperatively. There is significant variability in the hardware and software of each device, which resulted in different sensitivity, fluorescence intensity, and image quality. All devices are CE-mark regulated, and 30 were FDA-approved. There is a prolific market of devices for FGS and healthcare professionals should have basic knowledge of their technical specifications to use it at best for each clinical indication. Standardisation across devices must be a priority in the field of FGS, and it will enhance external validity for future clinical trials in the field.

Prediction model for poor short-term prognosis in patients with chronic subdural hematoma after burr hole drainage: a retrospective cohort study.

Chronic subdural hematoma (CSDH) is a common condition in neurosurgery. With an aging population, there is increasing attention on the prognosis of patients following surgical intervention. We developed a postoperative short-term prognostic prediction model using preoperative clinical indicators, aiming to assist in perioperative medical decision-making and management. The dataset was randomly divided into training and validation cohorts. An mRS score greater than 2 one month after discharge was considered indicative of a poor prognosis. In the training cohort, the least absolute shrinkage and selection operator (LASSO) regression analysis was used for multivariate analysis to identify independent risk factors and construct a prediction nomogram for poor prognosis one month after discharge. The performance of the nomogram was assessed using the Receiver Operating Characteristic (ROC) curve and calibration curve. A Decision Curve Analysis (DCA) was also conducted to determine the net benefit threshold of the prediction model. Among the 505 participants, 18.8% (95/505) had a poor prognosis one month after discharge. The baseline characteristics did not significantly differ between the training cohort and the validation cohort. LASSO regression analysis in the training cohort reduced the predictors to four potential factors. Further multivariate logistic analyses in the training cohort identified four independent predictors: age, admission Glasgow Coma Scale (GCS) score, hemiparesis, and hemoglobin count. These predictors were incorporated into the nomogram prediction model. Internal validation using ROC analysis, calibration curves, and other methods demonstrated a strong correlation between the observed and predicted likelihood of poor prognosis one month after discharge. The visualized nomogram prediction model we developed for short-term postoperative prognosis of chronic subdural hematoma after burr hole drainage aids in predicting short-term outcomes and guiding clinical treatment decisions. Further external validation is needed in the future to confirm its effectiveness.

Characteristic changes in the mRNA expression profile of plasma exosomes from patients with MPO-ANCA-associated vasculitis and its possible correlations with pathogenesis

To explore the expression patterns and potential roles of mRNAs in exosomes from patients with myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). Plasma exosomes were isolated from MPO-AAV patients and healthy controls (HCs) to screen for differential mRNA expression via exosomal mRNA sequencing. The differentially expressed mRNAs in exosomes from the 2 groups were comparatively explored by bioinformatics analysis. The six most differentially expressed mRNAs were selected and validated in larger groups of MPO-AAV patients and HCs by real-time quantitative polymerase chain reaction (RT‒qPCR). The relationships between these selected mRNAs and patient characteristics were statistically analyzed. Compared with HCs, a total of 1077 mRNAs in exosomes from MPO-AAV patients were found to be significantly upregulated, including DEPDC1B and TPST1, while NSUN4 and AK4 were significantly downregulated. Statistical analysis did not reveal any correlation between the six selected mRNAs and clinical indicators, including disease activity. GO enrichment analysis revealed that these differentially expressed genes participate in various enzyme activities, protein synthesis, etc. KEGG pathway analysis revealed that metabolic pathways, cell adhesion molecules, epithelial signaling, and mitogen-activated protein kinase (MAPK) signaling pathways were significantly enriched in the exosomal mRNAs. There were significant differences in the expression of exosomal mRNAs between MPO-AAV patients and HCs, which may be related to the occurrence and development of MPO-AAV. These findings provide clues for further investigations of MPO-AAV pathogenesis and the identification of new potential therapeutic targets.

Selenium alleviates dextran sulfate sodium-induced colitis and inhibits ferroptosis of intestinal epithelial cells via upregulating glutathione peroxidase 4.

Selenium, an essential micronutrient for humans, has been shown to be protective against ulcerative colitis (UC), but the exact mechanism remains unclear. The role of selenium, protecting against ferroptosis of intestinal epithelial cells (IECs) in colitis, was investigated in this current study. Serum selenium level and ferroptosis-related gene expression in the colonic mucosa were measured in UC patients and healthy controls. The effects of sodium selenite supplementation on experimental colitis were investigated in dextran sulfate sodium (DSS)-treated mice. The influence of sodium selenite on IEC ferroptosis was evaluated through assessing cell death rate, intracellular ferrous iron content, lipid reactive oxygen species level, and mitochondrial membrane damage of DSS-treated Caco-2 cells. Moreover, glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4, ferroptosis-related genes, were detected in Caco-2 cells and mouse intestines. Serum selenium was decreased in UC patients in comparison with healthy individuals. Additionally, serum selenium level was negatively correlated with disease activity and was associated with clinical inflammation and nutrition indicators. The expression of GPX4 in the mucosa of UC was positively correlated with serum selenium level. The in vivo experiments showed that selenium treatment ameliorated DSS-induced colitis and inhibited ferroptosis in IECs. The in vitro results suggested that selenium supplementation inhibited DSS-induced ferroptosis in Caco-2 cells. GPX4 was upregulated after selenium supplementation both in vivo and in vitro. Serum selenium level was associated with IEC ferroptosis in UC patients. Selenium supplementation alleviates DSS-induced colitis and inhibits ferroptosis in IECs by upregulating the expression of GPX4.

Magnetic resonance imaging-based radiomics model for preoperative assessment of risk stratification in endometrial cancer.

Preoperative risk stratification is significant for the management of endometrial cancer (EC) patients. Radiomics based on magnetic resonance imaging (MRI) in combination with clinical features may be useful to predict the risk grade of EC. To construct machine learning models to predict preoperative risk stratification of patients with EC based on radiomics features extracted from MRI. The study comprised 112 EC patients. The participants were randomly separated into training and validation groups with a 7:3 ratio. Logistic regression analysis was applied to uncover independent clinical predictors. These predictors were then used to create a clinical nomogram. Extracted radiomics features from the T2-weighted imaging and diffusion weighted imaging sequences of MRI images, the Mann-Whitney U test, Pearson test, and least absolute shrinkage and selection operator analysis were employed to evaluate the relevant radiomic features, which were subsequently utilized to generate a radiomic signature. Seven machine learning strategies were used to construct radiomic models that relied on the screening features. The logistic regression method was used to construct a composite nomogram that incorporated both the radiomic signature and clinical independent risk indicators. Having an accuracy of 0.82 along with an area under the curve (AUC) of 0.915 [95% confidence interval (CI): 0.806-0.986], the random forest method trained on radiomics characteristics performed better than expected. The predictive accuracy of radiomics prediction models surpassed that of both the clinical nomogram (AUC: 0.75, 95%CI: 0.611-0.899) and the combined nomogram (AUC: 0.869, 95%CI: 0.702-0.986) that integrated clinical parameters and radiomic signature. The MRI-based radiomics model may be an effective tool for preoperative risk grade prediction in EC patients.

Real-world Effectiveness of Sarilumab in RA: Results from the Open-label, Prospective, Single-arm Observational PROFILE Study.

The 1-year PROspective sarilumab (preFILled syringe/pen) multinational, obsErvational (PROFILE) study evaluated the real-world effectiveness and safety of sarilumab in patients with moderate-to-severe rheumatoid arthritis (RA). Safety endpoints included adverse events (AEs) and lab abnormalities. Effectiveness endpoints included the ACR core set. The primary endpoint was the change from baseline in Clinical Disease Activity Index (CDAI). All statistics are descriptive and pvalues were nominal. In total, 595 patients were treated, of whom 223 (37.5%) received sarilumab monotherapy and 372 (62.5%) received combination therapy. Upon initiation of sarilumab, an improvement in the mean (SD) CDAI score was observed at week 24 [11.4 (10.3)] and was maintained through week 52 [10.0 (10.5)], resulting in a mean [SD] reduction of -14.9 (12.7) and -14.4 (12.9), respectively. There were consistent improvements in disease activity that were similar for patients on monotherapy vs. combination therapy. An increase in the proportion of patients achieving remission and low disease activity was reported. By week 52, both groups had improved physical function and quality of life. There were no new safety signals. The proportions of any patients reporting a treatment-emergent adverse event (TEAE) or serious treatment-emergent AE (SAE) was 66.2% and 5.9%, respectively, and were similar between both treatment groups. Overall, 15.6% of patients discontinued sarilumab treatment due to TEAEs. The most commonly reported TEAE of interest was neutropenia (14.1%). In this 1-year, observational real-world study, sarilumab therapy resulted in improved clinical outcomes. The safety profile was consistent with that observed in sarilumab randomized clinical trials. This study was entered on the German website (Paul Ehrlich Institute) on January 11, 2018, with NIS No.: 423.

Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study.

To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.

Association between lipid accumulation products and gallstones: an analysis of the National Health and Nutrition Examination Survey 2017–2020

AimsThe aim of the research was to look into the connection between the occurrence of gallstones in adult US citizens and lipid accumulation products (LAP).MethodsWe conducted a cross-sectional study of 3,582 U.S. adults with relevant indicators collected from the 2017–2020 National Health and Nutrition Examination Survey (NHANES) database. Multifactorial logistic regression was used to investigate the linear relationship between LAP and gallstone incidence, while smoothed curve fitting was used to describe the nonlinear relationship, and subgroup and interaction analyses were used to evaluate the potential differences between groups.ResultsAmong the 3582 participants aged ≥ 20 years included, there was a positive association between LAP and gallstones. Following adjustments for all covariates, the likelihood of getting gallstones rose by 29% for each unit rise in log2-LAP (OR = 1.29, 95% CI: 1.13‒1.49). Compared to those in the lowest tertile, those in the highest LAP tertile had a significantly higher risk of developing gallstones (OR = 1.97, 95% CI: 1.31‒2.95). Subgroup analyses indicated that the association between LAP and gallstones was not affected by the stratification of the variables examined.ConclusionGallstones and LAP exhibited a positive association in our investigation, indicating that LAP may be utilized as a clinical indicator to determine the occurrence of gallstones.

Regulatory cell therapy for kidney transplantation and autoimmune kidney diseases.

Regulatory cell therapies, including regulatory T cells and mesenchymal stromal cells, have shown promise in early clinical trials for reducing immunosuppression burden in transplantation. While regulatory cell therapies may also offer potential for treating autoimmune kidney diseases, data remains sparse, limited mainly to preclinical studies. This review synthesises current literature on the application of regulatory cell therapies in these fields, highlighting the safety and efficacy shown in existing clinical trials. We discuss the need for further clinical validation, optimisation of clinical and immune monitoring protocols, and the challenges of manufacturing and quality control under Good Manufacturing Practice conditions, particularly for investigator-led trials. Additionally, we explore the potential for expanding clinical indications and the unique challenges posed in paediatric applications. Future directions include scaling up production, refining protocols to ensure consistent quality across manufacturing sites, and extending applications to other immune-mediated diseases.

Abstract A057: Investigating Fibroblast-Epithelial crosstalk in pre-malignant and cancerous microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDAC) originates from precursor lesions, the most common of which are known as pancreatic intraepithelial neoplasia (PanIN). PanIN formation and progression is accompanied by accumulation of a precursor microenvironment (PME) composed of desmoplastic stroma that plays an important role in promoting tumor growth and immune evasion. The crosstalk between tumor cells and stromal cells is an area of active investigation. While PanIN and the PME have been extensively studied in mouse models, their nature in humans have remained elusive as there is no clinical indication to sample healthy pancreas. Through a unique collaboration with the Gift of Life Organ and Tissue donation program, we performed transcriptomic analysis on normal pancreata declined for transplant. We noted that epithelial cells in the PanIN and cancer microenvironment were transcriptomically similar; however, their surrounding stromal fibroblasts were markedly distinct. Given that most precursor lesions remain quiescent while some progress to tumor, we sought out to elucidate how the transcriptional programs in epithelial cells influence fibroblast cell fate. To do so, we developed a 3D ex-vivo organoid-fibroblast coculture system using primary organoid and fibroblast cultures successfully derived from Gift of Life pancreata or PDAC patients undergoing surgical resection. Our coculture system retains histological features of heterogeneity observed in vivo. Using single cell RNA-sequencing analysis of matched fibroblast-organoid cocultures we identified factors that were highly expressed in fibroblasts in tumor cocultures, but not in normal cocultures. We are currently interrogating candidate ligand/receptor interactions in our cocultures to determine the mediators of this epithelial-mediated fibroblast polarization. This model will allow us to gain an understanding about how components of the microenvironment restrain or promote malignant transformation and serve as a great tool to study therapies targeting tumor and stromal cells in a patient specific manner. Citation Format: Padma Kadiyala, Ahmed Elhossiny, Jianhua Liu, Alexander Bray, Katelyn Donahue, Arvind Rao, Jiaqi Shi, Yaqing Zhang, Filip Bednar, Timothy Frankel, Eileen Carpenter, Marina Pasca Di Magliano. Investigating Fibroblast-Epithelial crosstalk in pre-malignant and cancerous microenvironment [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 A057.

Exploiting the mechanical effects of ultrasound for noninvasive therapy.

Focused ultrasound is a platform technology capable of eliciting a wide range of biological responses with high spatial precision deep within the body. Although focused ultrasound is already in clinical use for focal thermal ablation of tissue, there has been a recent growth in development and translation of ultrasound-mediated nonthermal therapies. These approaches exploit the physical forces of ultrasound to produce a range of biological responses dependent on exposure conditions. This review discusses recent advances in four application areas that have seen particular growth and have immense clinical potential: brain drug delivery, neuromodulation, focal tissue destruction, and endogenous immune system activation. Owing to the maturation of transcranial ultrasound technology, the brain is a major target organ; however, clinical indications outside the brain are also discussed.

Pharmaceutical innovativeness index: methodological approach for assessing the value of medicines – a case study of oncology drugs

ABSTRACT Background We propose a framework to assess the value of pharmaceutical innovations, with explicit clinical and methodological parameters, based on the therapeutic value and health needs. Research design and methods The study was based on the adaptation of health technology assessment methods documented in the literature, which was applied to a sample of oncological drugs. Difficulties and issues during the application of those tools were identified and addressed to develop a new framework with new and revised domains and clear classification criterion for each domain. Scores were assigned to each level and domain according to their relevance to generate the final score of innovativeness. Results The Pharmaceutical Innovation Index (PII) includes four domains, two related to clinical and social dimensions – Therapeutic Need and Added Therapeutic Value – and other two about methodological features – Study Design and Quality (risk of bias). The scores combined after assigned to each domain results Index of the Innovativeness of the medicines represents the degree of pharmaceutical innovation. Conclusion This work proposes a transparent methodology with well-defined criteria and script; the algorithm developed with authors’ weightings and criteria may be switched to best adjust to other applications, perspective or clinical indications, while keeping the transparency and objectiveness.

Clinical Validation of the Nursing Diagnosis 'Inadequate Health Self-Efficacy' in People With Hypertension.

To test the clinical validity of clinical indicators and causal relationships of aetiological factors of the new nursing diagnosis of inadequate health self-efficacy in people with hypertension. The diagnosis of inadequate health self-efficacy has both theoretical and content validity. However, a clinical validation study is needed to establish an appropriate framework for distinguishing individuals who manifest this unique human response. The study adopts a cross-sectional clinical validation approach, adhering strictly to the STROBE guidelines throughout its design and implementation. Naturalistic sampling was used to identify 302 adults diagnosed with hypertension. Their data were subjected to latent class analysis, which facilitated the identification of a comprehensive set of clinical indicators that demonstrated better diagnostic accuracy and established posterior probabilities to guide the inference of inadequate health self-efficacy. In addition, logistic regression analysis was used to assess the magnitude of the impact of aetiological factors. The prevalence of inadequate health self-efficacy was 76.61%. Among the 13 indicators examined, seven demonstrated notable sensitivity: 'risk-prone health behaviour', 'failure to take action that prevents health problems', 'inadequate self-control', 'avoidance behaviours', 'negative health self-perception', 'inadequate health-related quality of life' and 'difficulty feeling good about adopting a healthy lifestyle'. Additionally, two indicators showed high specificity: 'difficulty feeling good about adopting a healthy lifestyle' and 'inadequate adherence to treatment regimen'. Notably, 15 aetiological factors were identified as significantly associated with an increased risk of inadequate health self-efficacy. A clinical framework consisting of eight clinical indicators and 15 aetiological factors was developed to characterise inadequate health self-efficacy in individuals with hypertension. Clinical validation provides insight into the precision of clinical indicators and the magnitude of the effect of putative causal elements, thereby facilitating identification and tailored intervention for individuals with hypertension and inadequate health self-efficacy.