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Background and objective: Focal therapy (FT) is increasingly recognized as a promising approach for managing localized prostate cancer (PCa), notably reducing treatment-related morbidities. However, post-treatment anatomical changes present significant challenges for surveillance using current imaging techniques. This study aimed to evaluate the inter-reader agreement and efficacy of the Prostate Imaging after Focal Ablation (PI-FAB) scoring system in detecting clinically significant prostate cancer (csPCa) on post-FT multiparametric magnetic resonance imaging (mpMRI). Methods: A retrospective cohort study was conducted involving patients who underwent primary FT for localized csPCa between 2013 and 2023, followed by post-FT mpMRI and a prostate biopsy. Two expert genitourinary radiologists retrospectively evaluated post-FT mpMRI using PI-FAB. The key measures included inter-reader agreement of PI-FAB scores, assessed by quadratic weighted Cohen’s kappa (κ), and the system’s efficacy in predicting in-field recurrence of csPCa, with a PI-FAB score cutoff of 3. Additional diagnostic metrics including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy were also evaluated. Key findings and limitations: Scans from 38 patients were analyzed, revealing a moderate level of agreement in PI-FAB scoring (κ = 0.56). Both radiologists achieved sensitivity of 93% in detecting csPCa, although specificity, PPVs, NPVs, and accuracy varied. Conclusions and clinical implications: The PI-FAB scoring system exhibited high sensitivity with moderate inter-reader agreement in detecting in-field recurrence of csPCa. Despite promising results, its low specificity and PPV necessitate further refinement. These findings underscore the need for larger studies to validate the clinical utility of PI-FAB, potentially aiding in standardizing post-treatment surveillance. Patient summary: Focal therapy has emerged as a promising approach for managing localized prostate cancer, but limitations in current imaging techniques present significant challenges for post-treatment surveillance. The Prostate Imaging after Focal Ablation (PI-FAB) scoring system showed high sensitivity for detecting in-field recurrence of clinically significant prostate cancer. However, its low specificity and positive predictive value necessitate further refinement. Larger, more comprehensive studies are needed to fully validate its clinical utility.

The study assessed the peptidomic profile of in-bag dry-aged (2 °C, RH 75 %, 0.5 m.s−1, n = 30) and wet-aged (-1.5 °C, n = 30) lamb with high and low levels of lipid oxidation. A total of 1056 low molecular weight peptides (< 10 kDa) were identified in aged lamb samples, using LC-MS/MS and label free quantification (data are available via ProteomeXchange with identifier PXD047738). Partial Least Squares – Discriminant analysis highlighted that all discriminating peptides in dry-aged lamb were from titin, whereas discriminating peptides in the wet-aged samples were predominantly from nebulin, myotilin, collagen type IV, LIM domain binding 3, and heat shock protein family B. Comparison of peptides from aged lamb meat with high- and low-levels of lipid oxidation showed that most discriminatory peptides within an ageing method are derived from oxidatively modified peptides from creatine kinase. These peptides could thus potentially be used as signature biomolecules to discriminate ageing techniques and indicate lipid oxidation levels.

Variants in ATP-binding cassette transporter type A4 (ABCA4) have been linked to several forms of inherited retinal diseases (IRDs) besides the classically defined Stargardt disease (STGD), known collectively as ABCA4 retinopathies. ABCA4 is a sizable locus harboring 50 exons; thus, its analysis has revealed over 2,400 variants described, of which more than 2,000 are causal. Due to the clinical and genetic heterogeneity, diagnosing ABCA4 retinopathies is challenging. To date, no ABCA4-related retinopathy has been detected in Lebanon. Using next-generation sequencing, we analyzed our IRDs' cohort retrospectively (61 families) and identified five with ABCA4-related retinopathies, making it a relatively abundant cause of IRDs (about 8 %). Three families were diagnosed with rod-cone dystrophy (RCD), two with STGD, and one with cone-rod dystrophy (CRD). In conclusion, our study showed the presence of ABCA4 variants with a high degree of heterogeneity in Lebanon.

Background: Distinct molecular subtypes of muscle-invasive bladder cancer (MIBC) have been identified via gene expression profiling. Objective: We investigated the feasibility of a simple immunohistochemistry (IHC)-based Lund subtyping method and the association of MIBC subtypes with oncological outcomes for patients after bladder-preserving radiation-based therapy. Design, setting, and participants: Transurethral resected tumor tissues from 104 patients treated with radiation-based therapy were sampled on tissue microarray blocks. Outcome measurements and statistical analysis: The expression of KRT5, GATA3, and p16 proteins was scored via digital image analysis. Hierarchical clustering was used to classify tumors as the basal subtype or one of two luminal subtypes: genomically unstable (GU) or urothelial-like (URO). Subtypes were evaluated for association with complete response (CR), recurrence-free survival (RFS), and overall survival (OS). Results and limitations: The median OS was 43 mo (95% confidence interval 19–77) and median follow-up was 55 mo (interquartile range 39–75). Age and clinical stage had a significant impact on OS (p

Multiple randomized controlled trials have extensively examined the therapeutic effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors, ushering in a transformative approach to treating individuals with type 2 diabetes mellitus (DM). Notably, emerging reports have drawn attention to the potential positive impacts of SGLT2 inhibitors in nondiabetic patients. In an effort to delve into this phenomenon, a comprehensive systematic literature review spanning PubMed (NLM), Medline (Ovid), and Cochrane Library, covering publications from 2000 to 2024 was undertaken. This systematic review encompassed twenty-six randomized control trials (RCTs) involving 35,317 participants. The findings unveiled a multifaceted role for SGLT2 inhibitors, showcasing their ability to enhance metabolic control and yield cardioprotective effects through a reduction in cardiovascular death (CVD) and hospitalization related to heart failure (HF). Additionally, a renalprotective effect was observed, evidenced by a slowdown in chronic kidney disease (CKD) progression and a decrease in albuminuria. Importantly, these benefits were coupled with an acceptable safety profile. The literature also points to various biological plausibility and underlying mechanistic pathways, offering insights into the association between SGLT2 inhibitors and these positive outcomes in nondiabetic individuals. Current research trends indicate a continual exploration of additional role for SGLT2 inhibitors in. Nevertheless, further research is imperative to fully elucidate the mechanisms and long-term outcomes associated with the nondiabetic use of SGLT2 inhibitors.

Solid tumors account for approximately 90% of all adult human cancers. As such, the development of novel cellular therapies has become of increasing importance to target solid tumor malignancies, such as prostate, lung, breast, bladder, colon, and liver cancers. One such cellular therapy relies on the use of chimeric antigen receptor T cells (CAR-T cells). CAR-T cells are engineered to target specific antigens on tumor cells. To date, there are six FDA-approved CAR-T cell therapies that have been utilized for hematologic B cell malignancies. Immune cell trafficking and immunosuppressive factors within the tumor microenvironment increase the relative difficulty in developing a robust CAR-T cell therapy against solid tumors. Therefore, it is critical to develop novel methodologies for high-throughput phenotypic and functional assays using 3D tumor spheroid models to assess CAR-T cell products against solid tumors. In this manuscript, we discuss the use of CAR-T cells targeted towards PSMA, an antigen that is found on prostate cancer tumor cells, the second most common cause of cancer deaths among men worldwide. We demonstrate the use of high-throughput, plate-based image cytometry to characterize CAR-T cell-mediated cytotoxic potency against 3D prostate tumor spheroids. We were able to kinetically evaluate the efficacy and therapeutic value of PSMA CAR-T cells by analyzing the cytotoxicity against prostate tumor spheroids. In addition, the CAR-T cells were fluorescently labeled to visually identify the location of the T cells as cytotoxicity occurs, which may provide more meaningful information for assessing the functionality of the CAR-T cells. The proposed image cytometry method can overcome limitations placed on traditional methodologies to effectively assess cell-mediated 3D tumor spheroid cytotoxicity and efficiently generate time- and dose-dependent results.

Introduction: Rituximab monotherapy represents the main therapeutic option for cryoglobulinemic vasculitis (CV) with severe organ involvement. However, initial worsening of the CV, known as rituximab-associated CV flare (=CV flare), has been described and are associated with high mortality rates. The aim of the present study is to evaluate the outcomes of plasmapheresis initiated before or during rituximab treatment, as prevention of CV flare. Methods: We conducted a retrospecttive study in our tertiary referral center from 2001 to 2020. We have included all patients with CV receiving rituximab and divided them in two groups whether they had flare prevention by plasmapheresis or not. We evaluated rituximab-related CV flare incidence in both groups. CV flare was defined as the onset of a new organ involvement or worsening of the initial manifestations within 4 weeks following rituximab. Results: Among the 71 patients included, 44 received rituximab without plasmapheresis (control = CT cohort) and 27 received plasmapheresis before or during rituximab treatment (preventive plasmapheresis = PP cohort). PP was given to patients thought to have a high risk of CV flare, with significantly more severe diseases than patients in the CT cohort. Despite this, no CV flare was observed in the PP group. In the other hand, 5 flares occurred in the CT cohort. Conclusion: Our results show that plasmapheresis is efficient and well tolerated to prevent rituximab-associated CV flare. We believe that our data support the use of plasmapheresis in this indication, especially in patients with high risk of CV flare.

Background: Cardiac implantable electronic devices (CIED)—ie, pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy devices—have recently been designed to allow for patients to safely undergo magnetic resonance imaging (MRI) when specific programming is implemented. MRI AutoDetect is a feature that automatically switches CIED’s programming into and out of an MR safe mode when exposed to an MRI environment. Objective: The purpose was to analyze de-identified daily remote transmission data to characterize the utilization of the MRI AutoDetect feature. Methods: Home Monitoring transmission data collected from MRI AutoDetect–capable devices were retrospectively analyzed to determine the workflow and usage in patients experiencing an MRI using the MRI AutoDetect feature. Results: Among 48,756 capable systems, 2197 devices underwent an MRI using the MRI AutoDetect feature. In these 2197 devices, the MRI AutoDetect feature was used a total of 2806 times with an average MRI exposure of 40.83 minutes. The majority (88.9%) of MRI exposures occurred on the same day as the MRI AutoDetect programming. A same day post-MRI exposure follow-up device interrogation was performed 8.6% of the time. A device-related complaint occurred within 30 days of the MRI exposure in 0.25% of MRI exposures using MRI AutoDetect but with no adverse clinical outcome. Conclusion: As a result of automation in device programming, the MRI AutoDetect feature eliminated post-MRI device reprogramming in 91.4% of MRI exposures and, while less frequent, allowed for pre-MRI interrogations prior to the day of the MRI exposure—reducing resource utilization and creating workflow flexibility.

Biospecimen collection in the Adolescent Brain Cognitive Development (ABCD) study – of hair samples, shed deciduous (baby) teeth, and body fluids – will serve dual functions of screening for study eligibility, and providing measures of biological processes thought to predict or correlate with key study outcomes on brain and cognitive development. Biosamples are being collected annually to screen for recency of drug use prior to the neuroimaging or cognitive testing visit, and to store for the following future studies: (1) on the effects of exposure to illicit and recreational drugs (including alcohol and nicotine); (2) of pubertal hormones on brain and cognitive developmental trajectories; (3) on the contribution of genomics and epigenomics to child and adolescent development and behavioral outcomes; and (4) with pre- and post-natal exposure to environmental neurotoxicants and drugs of abuse measured from novel tooth analyses. The present manuscript describes the rationales for inclusion and selection of the specific biospecimens, methodological considerations for each measure, future plans for assessment of biospecimens during follow-up visits, and preliminary ABCD data to illustrate methodological considerations. Keywords: Biospecimens, ABCD study, Substance use, Gonadal hormones, Genetics, Environmental exposures

Novel approaches to project evaluations are needed to document the outcomes and lessons to be learned from the numerous and diverse investments international donor organizations, national governments, and regional institutions are making in climate services. This paper describes an elaborated logic model to structure the evaluation of a climate services program, which we demonstrate in a case study of the Caribbean Agrometeorological Initiative (CAMI). Moving beyond the “loading dock” model of scientific information application, this logic model helps evaluators to address all elements of the provision of climate services – including the quality of weather and climate forecasts and agronomic advisories, the distribution of that information, the uptake of that information, and actions taken by farmers (See Fig. 1). Our logic model links the provision of information on weather, climate, and agriculture with decision making, and ultimately with improved social and economic outcomes. While such a logic model necessarily simplifies the full context of any climate services program, it also makes project evaluation much more tractable and generalizable across contexts. Furthermore, this simple logic model can serve to deconstruct conventional thinking about climate services by explicitly addressing the social and process dimensions of climate services that are sometimes neglected in project design, implementation, and evaluation. CAMI partner countries are developing climate outlook bulletins to communicate a three-month seasonal forecast. Despite these high quality seasonal forecasts, we note shortcomings regarding the dissemination of that information, its uptake by farmers, or the ability or willingness of farmers to act on that information.

Summary: Memory is formed by synapse-to-nucleus communication that leads to regulation of gene transcription, but the identity and organizational logic of signaling pathways involved in this communication remain unclear. Here we find that the transcription cofactor CRTC1 is a critical determinant of sustained gene transcription and memory strength in the hippocampus. Following associative learning, synaptically localized CRTC1 is translocated to the nucleus and regulates Fgf1b transcription in an activity-dependent manner. After both weak and strong training, the HDAC3-N-CoR corepressor complex leaves the Fgf1b promoter and a complex involving the translocated CRTC1, phosphorylated CREB, and histone acetyltransferase CBP induces transient transcription. Strong training later substitutes KAT5 for CBP, a process that is dependent on CRTC1, but not on CREB phosphorylation. This in turn leads to long-lasting Fgf1b transcription and memory enhancement. Thus, memory strength relies on activity-dependent changes in chromatin and temporal regulation of gene transcription on specific CREB/CRTC1 gene targets. : Uchida et al. link CRTC1 synapse-to-nucleus shuttling in memory. Weak and strong training induce CRTC1 nuclear transport and transient Fgf1b transcription by a complex including CRTC1, CREB, and histone acetyltransferase CBP, whereas strong training alone maintains Fgf1b transcription through CRTC1-dependent substitution of KAT5 for CBP, leading to memory enhancement. Keywords: memory enhancement, long-term potentiation, hippocampus, nuclear transport, epigenetics, FGF1, CRTC1, KAT5/Tip60, HDAC3, CREB