Abstract: Pancreatic adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME), which contributes to treatment resistance. Recent research shows that the microbiome plays a key role in PDAC development, with microbial imbalances (dysbiosis) promoting inflammation, cancer progression, therapy resistance, and treatment side effects. Microbial metabolites can also affect immune cells, especially natural killer (NK) cells, which are vital for tumor surveillance, therapy response and treatment-related side effects. Dysbiosis can affect NK cell function, leading to resistance and side effects. We propose that a combined biomarker approach, integrating microbiome composition and NK cell profiles, can help predict treatment resistance and side effects, enabling more per-sonalized therapies. This review examines how dysbiosis contributes to NK cell dysfunction in PDAC and discusses strategies (e.g., antibiotics, probiotics, vaccines) to modulate the microbiome and enhance NK cell function. Targeting dysbiosis could modulate NK cell activity, improve the effectiveness of PDAC treatments, and reduce side effects. However, further research is needed to develop unified NK cell-microbiome interaction-based biomarkers for more precise and effective patient outcomes.

Abstract: In multiple sclerosis (MS), there is significant evidence indicating that both progression independent of relapse activity (PIRA) and relapse-related worsening events contribute to the accumulation of progressive disability from the onset of the disease and throughout its course. Understanding the compartmentalized pathophysiology in MS would enhance comprehension of disease progression mechanisms, overcoming the traditional distinction in phenotypes. Smoldering MS activity is thought to be maintained by a continuous interaction between the parenchymal chronic processes of neuroinflammation and neurodegeneration and the intrathecal compartment. This review provides a comprehensive and up-to-date overview of the neuropathological and immunological evidence related to the mechanisms underlying PIRA phenomena in MS, with a focus on studies investigating the impact of currently available therapies on these complex mechanisms.

Abstract: Endometriosis afflicts 10% of women in their reproductive years and nearly half of women with infertility and its etiology is not yet clear. Pharmacological therapy is generally based on progestins like progestogen. This drug binds to progesterone receptors with many known side effects. Here we described the case of a 33-year-old woman surgically treated for endometriosis continued with drug therapy based on estradiol valerate and dienogest. Approximately 21 months after treatment, she reported ocular symptoms with vision alteration, diplopia and metamorphopsia related to central serous chorioretinopathy (CSC). After discontinuation of combined progestin-based treatment, CSC fully subsided. Semeiological, clinical and laboratory approaches were adopted; urinary steroids were measured. A slight increase in prolactinemia in the absence of macro-prolactinemia was reported. Steroidal profile appeared without abnormalities, without abnormalities, although a slight alteration of estrogens balance was noted. Considering the pharmacodynamics of dienogest versus selective progesterone receptor modulators, it can be assumed that patients clinical events are related to specific-site-response of steroids that bind the progesterone receptor. Dienogest may have induced the CSC, as a not yet characterized side effect of the drug. Undoubtedly, further specific studies are needed concerning the metabolic and pharmacodynamic aspects that cannot be exhaustively covered here.

Abstract: Gravitational changes have been shown to cause significant abnormalities in various body systems, including the cardiovascular, immune, vestibular, and musculoskeletal systems. While numerous studies have examined the response of the vestibular system to gravitational stimulation, research on functional changes in the peripheral inner ear remains limited. The inner ear comprises two closely related structures: the vestibule and cochlea. These components share similar structures and neural functions, highlighting the importance of investigating changes in auditory nerve cells in response to gravitational alterations. To address this gap, we studied the functional and structural changes in the inner ear following exposure to hypergravity stimuli. Our findings demonstrate changes in Auditory Brainstem Responses (ABRs) in the cochlea. ABR recordings were used to analyze click thresholds, as well as amplitude and latency of tone bursts. The click thresholds at all frequencies increased in the group exposed to hypergravity in the long-term. Additionally, tone burst results revealed significantly reduced amplitudes at high frequencies and delayed latencies in the hypergravity models. Notably, greater hair cell loss was observed in the middle and basal turns of the cochlea, indicating that mid and high-frequency regions are more vulnerable to hypergravity stimulation. Furthermore, nerve damage on the cochlear surface was evident in subjects exposed to 4G stimulation for 4 weeks. These findings suggest that the inner ear and its neural activity can be functionally and structurally affected by prolonged exposure to hypergravity.

Abstract: The study of mitochondrial dysfunction has become increasingly pivotal in elucidating the pathophysiology of various cerebral pathologies, particularly neurodegenerative disorders. Mitochondria are essential for cellular energy metabolism, regulation of reactive oxygen species (ROS), calcium homeostasis, and the execution of apoptotic processes. Disruptions in mitochondrial function, driven by factors such as oxidative stress, excitotoxicity, and altered ion balance, lead to neuronal death and contribute to cognitive impairments in several brain diseases. Mitochondrial dysfunction can arise from genetic mutations, ischemic events, hypoxia, and other environmental factors. This article highlights the critical role of mitochondrial dysfunction in the progression of neurodegenerative diseases and discusses the need for targeted therapeutic strategies to attenuate cellular damage, restore mitochondrial function, and enhance neuroprotection.

Abstract: Background and Objectives: Behçet syndrome (BS) is a multisystemic inflammatory disorder of unknown etiology. Currently, BS is classified as a complex autoinflammatory disorder presenting with a variable vessel vasculitis. Inconsistent, sometimes contrasting immunological findings observed in BS studies and considerable geographic variation in BS’s disease expression are in need of explanation. Significant gene expression and molecular disease mechanisms differences were documented between BS clinical phenotypes. Such differences among patients of the same population brings to mind the case across different populations. This study aimed to compare gene expression profiles of Portuguese and Turkish BS patients. Materials and Methods: Publicly available (GEO repository) transcriptome datasets from Portuguese (GSE17114) and Turkish (GSE209567) BS cohorts were retrieved and analyzed. Differentially expressed genes (DEGs) were identified using p≤0.05 and fold-change (FC) thresholds of ≥1.5 and ≥2. BRB-ArrayTools for class comparisons, Venny 2.1.0 for Venn diagram analyses, Cluster 3.0 and Java Treeview for clustering analyses, and WebGestalt for functional enrichment analyses were used. Results: Substantial differences in DEG profiles were observed between Portuguese and Turkish BS patients. During the class comparison PBvs.TB (PB: Portuguese and TB: Turkish BS patients), 8024 DEGs were documented with an FC≥2. Venn diagram analysis showed no shared genes at the intersection PBvs.PC TBvs.TC (PC: Portuguese and TC: Turkish controls). Both populations demonstrated decreased anti-inflammatory gene expressions, albeit with distinct gene identities. A set of 20 genes including IFI27 successfully clustered PB&TB. No enriched gene ontology terms were shared during functional enrichment analyses. Conclusions: Significant molecular differences exist between Portuguese and Turkish BS patients. In addition to its complex genetic background, BS is a heterogeneous syndrome. Decreased expression of anti-inflammatory genes is common in BS. The identities of these genes are different across populations. Pro-inflammatory genes may further enhance disease severity in BS. A forthcoming era of personalized therapeutics based on molecular profiles may be approaching.

Abstract: Background: The Montreal Cognitive Assessment (MoCA) is widely used to evaluate global cognitive function in older Brazilian adults. However, concerns persist regarding its applicability in non-homogeneous socio-demographic groups. This study scrutinizes the Brazilian version of the MoCA, focusing on its measurement properties in a diverse cohort of patients with Parkinson's disease (PD). Purpose: This study examined the psychometric properties of the Brazilian Portuguese MoCA in a heterogeneous sample of PD patients using item response theory (IRT) methods. Material and Methods: In a multicenter cross-sectional study, 484 PD patients aged 26-90 years (mean ± SD, 59.9 ± 11.1 years), with disease durations ranging from 1 to 35 years (mean ± SD, 8.7 ± 5.4 years), underwent MoCA testing. IRT analyses, including the Graded Response Model, evaluated item parameters, such as difficulty (location) and discrimination. Differential item functioning was analyzed vis-à-vis age and education using multiple indicators multiple causes (MIMIC) modeling. Results: The MoCA exhibited essential unidimensionality and satisfactory model fit. Attention and naming demonstrated high discrimination. Orientation and naming items were less challenging. Multiple domains showed differential item functioning related to age and education, underscoring the necessity of considering background characteristics when interpreting total scores. Conclusion: This study enriches validity evidence for the MoCA in PD by providing a detailed analysis of its measurement properties and sources of score bias. Tailoring test content and norms based on education and establishing computerized scoring algorithms leveraging item parameters may optimize the tool’s reliability and fairness. Refinements to mitigate differential item functioning could enable precise cognitive screening across diverse socio-demographic backgrounds.

Abstract: This study investigates the relationship between SARS-CoV-2 RT-PCR cycle threshold (Ct) values and key COVID-19 transmission and outcome metrics across five years of the pandemic in Jalisco, Mexico. Utilizing a comprehensive time-series analysis, we evaluated weekly median Ct values as proxies for viral load and their temporal associations with positivity rates, reproduction numbers (Rt), hospitalizations, and mortality. Cross-correlation and lagged regression analyses revealed significant lead-lag relationships, with declining Ct values consistently preceding surges in positivity rates and hospitalizations, particularly during the early pandemic phases. Granger causality tests and vector autoregressive modeling confirmed the predictive value of Ct values, highlighting their potential as early warning indicators. Demographic stratification showed lower Ct values in older adults and males, indicative of higher viral loads in these subgroups. The study further observed a weakening association in later pandemic stages, likely due to vaccination campaigns, natural immunity, and diagnostic shifts. These findings underscore the utility of Ct values as scalable tools for public health surveillance, offering actionable insights for resource allocation and outbreak mitigation. Integrating Ct monitoring into surveillance systems could enhance preparedness for respiratory viral pandemics and improve epidemiological modeling frameworks.

Abstract: Background/Objectives: To overcome the disadvantages of the methods in the literature, such as the reliance on manual measurements requiring a lot of time and effort and the difficulty of routine clinical application due to large sample sizes, we aimed to automatically estimate tooth age from panoramic radiographs using artificial intelligence (AI) algorithms. Methods: Two Dimensional Deep Convolutional Neural Network (2D-DCNN) and One Dimensional Deep Convolutional Neural Network (1D-DCNN) techniques were used to extract features from panoramic radiographs and patient records. To perform age estimation using feature information, Genetic algorithm (GA) and Random Forest algorithm (RF) are modified and combined and defined as Modified Genetic-Random Forest Algorithm (MG-RF). The performance of the system used in our study was analyzed based on the MSE, MAE, RMSE and R2 value calculated during the implementation of the code. Results: As a result of the applied algorithms, the MSE value was 0.00027, MAE value was 0.0079, RMSE was 0.0888 and R2 score was 0.999. Conclusions: The findings of our study indicate that the AI-based system employed therein is an effective tool for age detection. Consequently, we propose that this technology could be utilized in forensic sciences in the future.

Abstract:

Background/Objectives: B. bigemina is a highly pathogenic and widely distributed tick-borne disease parasite responsible for bovine babesiosis. The development of effective and safe therapies is urgently needed for global disease control. The aim of this study was to compare the effects of endochin-like quinolone (ELQ316), buparvaquone (BPQ), imidocarb (ID), and the combinations of ID + ELQ-316 and BPQ + ELQ-316, on in vitro survival of B. bigemina. Methods: Parasites at a starting parasitemia level of 2%, were incubated with each single drug and combination of drugs, ranging from 25 to 1200 nM of concentration over four consecutive days. The inhibitory concentration 50% (IC50%) and 99% (IC99%) were estimated. Parasitemia levels were evaluated daily using microscopic examination. Data were statistically compared using the non-parametrical KruskallWallis test. Results: All drugs tested significantly inhibited (p<0.05) the growth of B. bigemina at 2% parasitemia. The combination of ID + ELQ-316 exhibited lower mean IC50% (9.2); confidence interval 95% (8.7 – 9.9) than ID (IC50%: 61.5; confidence interval 95%: 59.54 - 63.46), ELQ-316 (IC50%: 48.10; confidence interval 95%: 42.76 – 58.83), BPQ (IC50%: 44.66; confidence interval 95%: 43.56 – 45.81), and BPQ + ELQ-316 (IC50%: 27.59; confidence interval: N/A). Parasites were no longer viable in cultures treated with the BPQ + ELQ-316 combination, as well as with BPQ alone at a concentration of 1200 nM, on days 2 and 3 of treatment, respectively.; Conclusions: BPQ and ID increase the babesiacidal effect of ELQ-316. The efficacy of these combinations deserves to be evaluated in vivo, which could lead to a promising and safer treatment option against B. bigemina.