Therapeutic potential of 1,3,4-oxadiazole derivative in EAE-induced optic neuritis.

Targeting focal adhesion kinase (FAK) in non-small cell lung cancer (NSCLC): Molecular mechanisms and combination therapeutic strategies.

The conventional drug discovery pipeline is labour-intensive, time-consuming, and costly, involving target identification, hit discovery, lead optimization, and extensive preclinical and clinical evaluation. To overcome these limitations, artificial intelligence (AI) has emerged as a transformative tool in drug discovery, gaining widespread adoption in the pharmaceutical industry during the 2010s due to advances in computing power, data availability, and deep learning. AI-based approaches, including molecular property prediction, protein structure modelling, natural language processing, and ADME/Tox prediction, have enhanced efficiency, reduced costs, and improved decision-making across multiple stages of drug development. Several AI-guided molecules have progressed into clinical trials, with encouraging early-phase success rates, highlighting the potential of AI to accelerate innovation. However, despite more than a decade of intensive research, no AI-only originated drug has yet achieved full regulatory approval, reflecting persistent challenges consistent with Eroom's law. Key limitations include poor data quality and accessibility, lack of model interpretability, gaps between computational predictions and chemical feasibility, and the inherent complexity of biological systems that limit translational success. Furthermore, AI-driven hypothesis generation does not replace the need for scientific reasoning and experimental validation. Overall, while AI has significantly accelerated early drug discovery stages, it remains a supportive tool rather than a standalone solution, underscoring the continued need for human expertise and experimental research.

Nitrogen-containing heterocycles constitute the core of many approved drugs and clinical candidates, making efficient and predictable C-N bond construction a central objetive in medicinal chemistry. Aliphatic azo compounds, traditionally employed as radical initiators, have recently emerged as versatile programmable nitrogen donors, capable of transferring their nitrogen atoms directly into heterocyclic scaffolds. This review summarizes advances in the reactivity of azoaliphatic derivatives with alkynes, highlighting pathways where nitrogen atoms are retained in the final products and on their implications for drug delivery. Cycloaddition processes provide rapid access to privileged heterocycles such as pyrazoles and pyrroles, scaffolds that are well represented in marketed drugs and support early structure-activity relationship exploration. Complementary radical and carbenoid manifolds enable the formation of hydrazides, atropisomeric frameworks and rarer nitrogen-sulfur motifs, offering increased three-dimensionality and new vectors for tuning potency, selectivity and pharmacokinetic properties. Where available, representative case studies illustrate how these scaffolds have contributed to lead optimization, target selectivity or progression toward clinical evaluation. Beyond reactivity, this review critically evaluates scalability, operational robustness and sustainability to define when azo-alkyne methodologies are realistically applicable in medicinal chemistry workflows. Rather than presenting azo compounds as general-purpose reagents, we frame them as strategic nitrogen donors whose reactivity can be aligned with specific stages of the drug discovery pipeline. When used in this manner, azo-alkyne transformations enable efficient scaffold generation, late-stage diversification and access to underexplored chemical space relevant to modern medicinal chemistry.

A novel multidimensional classification system for bone graft healing assessment in guided bone regeneration.

Longitudinal subcortical volume changes and their correlations with multiple PET and fluid biomarkers in dominantly inherited Alzheimer's disease.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is a central conduit linking cytokine signals to immune and tissue homeostasis. Over the past decade, a rapidly expanding spectrum of STATopathies, monogenic inborn errors of immunity caused by loss or gain-of-function mutations in individual STAT genes, has been recognized. This review integrates emerging evidence highlighting that, while STAT proteins have been extensively characterized in adaptive immunity, innate immune mechanisms remain insufficiently explored in many STATopathies, even though they are central to host defense, inflammation, and immune regulation. Recent studies have delineated cell-specific roles of individual STATs in innate lineages, including monocytes, macrophages, dendritic cells, neutrophils, and natural killer cells. Novel insights reveal how aberrant STAT signaling disrupts interferon responsiveness, pathogen sensing, cytokine feedback, and myeloid cell differentiation. Parallel therapeutic advances, such as JAK inhibitors or cytokine blockade and early gene-correcting are reshaping management of STATopathies. Recognition of innate immune dysregulation as an important driver of STATopathies broadens diagnostic and therapeutic horizons. Integrating innate immune profiling into clinical evaluation may refine prognostication and treatment selection, while mechanistic understanding of STAT control in myeloid lineages paves the way for precision immunomodulation and future curative interventions.

Nailfold video capillaroscopy as a non-invasive biomarker in juvenile dermatomyositis: A longitudinal analysis of microvascular changes and clinical relevance over one year.

To evaluate the cost-effectiveness of opportunistic CT for sarcopenia screening compared with standard-of-care clinical screening methods, using a decision-analytic model based on quality-adjusted life years (QALYs) and healthcare costs. We developed a decision-analytic model simulating a hypothetical cohort of 70-year-old male patients at risk for sarcopenia over a 3-year time horizon from a US healthcare system perspective. The model compared two screening strategies: standard-of-care clinical evaluation per EWGSOP2 guidelines (physical exam + DXA evaluation of lean mass) and opportunistic CT as measures of muscle mass and quality. Model inputs-including screening sensitivities/specificities, costs, utility values, and probabilities of cardiovascular complications-were derived from published literature. Incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB) were calculated, and sensitivity analyses were performed to assess the robustness of findings across variable inputs. Opportunistic CT was the favored strategy, with lower costs ($845 vs. $1,295), comparable effectiveness (0.87 QALYs), and higher net monetary benefit ($86,037 vs. $85,588) relative to the standard-of-care strategy. The standard-of-care strategy's ICER was $47.7 million per QALY, exceeding our willingness-to-pay threshold of $100,000. Probabilistic sensitivity analysis across 100,000 simulations demonstrated that opportunistic CT was favored across all tested willingness-to-pay thresholds up to $200,000. Opportunistic CT is a cost-effective strategy for sarcopenia screening, offering similar effectiveness at a lower cost compared to the standard-of-care approach. By leveraging existing imaging studies, opportunistic CT screening has the potential to enhance early detection and decrease the underdiagnosis of sarcopenia while also reducing the burden of additional DXA scans and clinical visits.

Pumpkin seed oil improves hepatotoxicity in rats through inhibition of CYP2E1 and activation of Nrf2 signaling pathways.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is an autosomal dominant condition that may co-occur with cardiac, renal, and skeletal abnormalities. It affects females causing utero-vaginal agenesis. Radiological assessment tools such as ultrasound and Magnetic Resonance Imaging (MRI) can be utilised for the confirmation of MRKH syndrome and for planning further management. Management of MRKH syndrome includes both non-surgical and surgical approaches, depending on the clinical presentation. The current report presents a case of a 21-year-old female who presented with a complaint of primary amenorrhoea and dyspareunia. Examination of the genitalia revealed normal external urethral meatus, labia majora and minora, and pubic hair development. Speculum examination confirmed the lack of a vaginal canal. Radiological findings were suggestive of uterine agenesis. Genetic analysis showed a 46,XX karyotype, thereby ruling out the chromosomal abnormalities. Based on the above findings and clinical evaluations, a final diagnosis of MRKH syndrome was confirmed. The patient declined surgical interventions at present and was managed non-surgically. In MRKH syndrome patients, counselling is crucial attributed to the associated physical abnormalities, related queries and mental stress.

To estimate the six-month prevalence of dementia with Lewy bodies (DLB) in a Colombian memory clinic using the Lewy Body Composite Risk Score (LBCRS) and interdisciplinary consensus diagnosis, and to describe the scale's clinical performance parameters. We analyzed data from 850 patients evaluated over six months at the Intellectus Memory Clinic in Bogotá, Colombia (HUSI). The LBCRS was applied in addition to a standardized interdisciplinary assessment that included clinical, paraclinical, and neuropsychological evaluations. Final diagnoses were established by consensus based on current international criteria for DLB. LBCRS data were available for 592 participants (69.6%). Of these, 42 (7.1%) screened positive (score ≥3), but only 5 (0.84%) received a consensus diagnosis of probable DLB. Six screened-positive patients were diagnosed with Parkinson's disease dementia (PDD); in three, cognitive symptoms developed within one year of motor onset and could alternatively be classified as DLB, increasing the number of DLB cases to 8. The remaining LBCRS-positive patients were diagnosed with Alzheimer's disease, vascular dementia, mild cognitive impairment, or no cognitive disorder. LBCRS performance in this setting demonstrated a sensitivity of 100%, specificity of 94.2%, positive predictive value of 19%, and negative predictive value of 100%. The low incidence of DLB identified by interdisciplinary assessment, together with the discrepancy between LBCRS screening and final diagnoses, underscores the need for further research on the applicability and predictive value of LBCRS in Latin America.

Continuous viral evolution is likely to cause a loss of performance or failure of existing diagnostic assays. Here, we delineate the adaptation and validation of an operational laboratory developed (LDT) multiplex RT-qPCR for simultaneous detection of SARS-CoV-2, influenza A/B (FluA/B) and respiratory syncytial virus (RSV) on a high-throughput, fully automated platform. Furthermore, we explore the integration of an alternative SARS-CoV-2 target to enhance assay robustness METHODS: An adaption of the operational assay (PMID:38820916) was performed and a novel SARS-CoV-2 target (macrodomain, Mac1) was implemented. Analytical performance of the adapted assay was evaluated using digital-PCR based standards or international reference material and clinical performance was assessed on clinical samples with a CE-IVD comparator assay. Analytical sensitivity (lower limit of detection (LoD)) was 70.9 IU/ml for SARS-CoV-2, and 112-474, 919 and 1720 cp/ml for influenza A, influenza B and RSV, respectively, with linear ranges of 26.3-36.4 ct (SARS-CoV-2), 26.8-37.7 ct (FluA), 28.5-37.9 (FluB) and 25.6-38.2 (RSV). Clinical performance evaluation confirmed improved performance (e.g. FluA/B detection -1.6/-4.81 ct) and comparable performance to the CE-IVD assay (excellent correlation of the SARS-CoV-2 assays, more effective detection of influenza B). Overall, positive/negative agreement was 100 %/93 % (SARS-CoV-2), and 100 %/100 % (FluA/B, RSV). The adapted LDT assay as a focused syndromic assay provides reliable detection of major respiratory viruses on a high-throughput platform. The strategic targeting of conserved genomic regions ensures diagnostic resilience, while automated integration facilitates scalable laboratory operations. This approach facilitates robust pathogen surveillance and expedites clinical decision-making during periods of co-circulation and epidemic surge.

Advances in coagulation peptides: Exploring diverse functions from hemostasis to disease treatment.

Tongue lesions are often quite difficult to diagnose. This is especially true in older adults and those with weakened immune systems because such lesions can be even more difficult and can even seem to be premalignant and/or infectious lesions. They can be caused by immune and/or nutritional dysregulation, as well as by more systemic illnesses. This report describes a 71-year-old female with Chronic Lymphocytic Leukaemia (CLL) and autoimmune arthritis who presented with a persistent, painful ulcerative lesion on the mid-dorsal surface of the tongue. The lesion had been present for six months and was associated with occasional spontaneous bleeding. Comprehensive clinical, haematologic, and radiologic evaluation ruled out fungal infection and malignancy. Histopathology revealed epithelial atrophy with subepithelial inflammatory infiltrate, consistent with a benign chronic inflammatory process. Also, remarkable was the family background of this patient, as her mother suffered an undiagnosed condition for many years and her brother had a fissured tongue, or a tongue with deep grooves, but had no symptoms of any disease, which could point to a possible hereditary condition in that family. The patient was diagnosed and managed conservatively with a mouthwash with benzydamine, mucopain, and vitamin A and multivitamin supplements, which improved the ulcer by 90% in the eight weeks and complete symptom resolution on follow-up at 12 weeks. This case underscores the importance of a systematic, multidisciplinary approach in evaluating chronic tongue lesions in immunocompromised individuals. Early recognition of benign inflammatory patterns can prevent unnecessary invasive investigations and patient anxiety. The co-existence of autoimmune and haematologic disorders, along with familial occurrence, further highlights the multifactorial nature of such lesions and their relevance in oral medicine practice.

Recently, great attention has been given to understanding the new pathogenetic mechanisms underlying aortic stenosis (AS). The study aims to understand the role of mature adipocytes in AS and their association with histologic, clinical, and echocardiographic data, an area previously overlooked in AS research. We enrolled 25 patients (15 women and 10 men) with severe AS undergoing elective aortic valve replacement. Each patient underwent clinical and transthoracic echocardiographic evaluations before surgery. We obtained AS valves and left ventricular (LV) septal biopsies to assess the presence of adipocytes within the valve using perilipin 1 (PLIN1) immunohistochemistry, and we also examined other histological characteristics of the ventricular biopsies. Adipocytes were detected in 76% of the aortic stenotic valve samples, often grouped adjacent to calcified areas. Patients with higher values of PLIN1 valvular adipocytes were generally older (p = 0.06) and had lower BMI values (p = 0.06). Moreover, the group with a higher presence of PLIN1(+) valvular adipocytes had significantly decreased mean gradient values and reduced M1 macrophage infiltration in ventricular biopsies. In a binary regression analysis, only mean gradient was significantly associated with the presence of PLIN1(+) adipocytes in the valve, regardless of age, BMI and ventricular M1 macrophage levels. These preliminary findings suggest that valvular adipocytes could be related to the progression of AS, but more investigation is necessary.

Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disorder. The UnitedStates Food and Drug Administration recommends using clinical outcome assessments (COAs) to measure concepts that matter to patients in clinical trials and to document the content validity of the COAs using conceptual models of patient experience. This study aimed to explore and document the patient experience of signs, symptoms, and health-related quality of life impacts of relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) to inform future COA validation research. We conducted a targeted literature review (TLR) and qualitative semi-structured interviews of patients with RRMS and PPMS in the United States of America (USA). Publications and interview transcripts were analyzed, synthesized, and inductively categorized to develop a conceptual model of patient experiences of RRMS and PPMS. Ten publications were reviewed as part of the TLR, and 16 participants (RRMS, n = 7; PPMS, n = 9) were interviewed. Most participants reported fatigue, muscle weakness, difficulty walking, sleep disturbance, and bladder issues. Many participants experienced negative emotional, physical, and social impacts due to the disease. Most participants also described needing to rest and plan/avoid activities, as well as requiring support from their family to manage their symptoms. This study highlights the multidimensional burden of living with RRMS and PPMS. A provisional conceptual model was developed, harmonizing the TLR and interview findings. This conceptual model may be used to promote a better understanding of the patient experience of RRMS and PPMS and to evaluate the content validity of COAs during the development of new drug treatments.

Burn wound infections pose a major challenge in both critical care and surgical settings, owing to the complex interplay of host immune dysfunction, altered pharmacokinetics, surgical wound dynamics, and the high prevalence of multidrug-resistant (MDR) organisms. This review summarizes current evidence on diagnosis, antimicrobial therapy, and multidisciplinary management of burn wound infections, highlighting common pitfalls and strategies to mitigate them. Burn patients display a distinct microbiological profile that evolves over time: Gram-positive cocci initially predominate, whereas nonfermenting Gram-negative bacilli such as Pseudomonas aeruginosa and Acinetobacter baumannii become increasingly prevalent during hospitalization. Differentiating colonization from infection remains a major diagnostic challenge. Although tissue biopsy is the gold standard for confirming wound infection, it is not uniformly implemented across centers. Therefore, a comprehensive clinical and microbiological evaluation involving infectious disease specialists, intensivists, and surgeons is essential for accurate interpretation of wound status. Antimicrobial stewardship interventions, including pharmacokinetic/pharmacodynamic optimization, therapeutic drug monitoring, carbapenem-sparing regimens, shorter antibiotic courses, and avoidance of redundant combination therapies, are key components of burn infection management. New agents, such as β-lactam/β-lactamase inhibitor combinations and novel tetracyclines, show promise against MDR nonfermenting Gram-negative pathogens. A structured, multidisciplinary team offers the most effective framework for improving outcomes in burn wound infections. Optimizing diagnostics, individualizing antimicrobial therapy, and aligning surgical timing with infection control measures are fundamental pillars. Future research should focus on prospective validation of integrated care pathways and on evaluating the real-world effectiveness of novel antimicrobial agents in burn-injured patients.

Non-union of the patella is relatively rare, occurring in 2.4-12.5% of cases, yet it frequently requires surgical treatment due to discomfort and functional impairment. The proximal fracture fragment is usually displaced by the quadriceps, resulting in a gap that hinders recovery. Managing non-union in comminuted patella fractures is extremely challenging due to the presence of numerous tiny pieces and difficulties in attaining stable fixation. The present case series presents an innovative cerclage wiring procedure, referred to as the “Wire Mesh Technique,” employed for patients with comminuted patellar fractures and non-union. The present case series included three male patients aged 35, 42, and 66 years, each exhibiting non-union of comminuted patella fractures subsequent to trauma. All patients experienced difficulty bearing weight and extending the affected knee, characterised by extensor lag and limited range of motion. Radiographic assessments confirmed non-union of the patella in every case. After clinical and radiographic evaluation, the wire mesh procedure was utilised to address insufficient healing and the complex arrangement of fragments. Postoperative rehabilitation included early in-bed mobilisation and quadriceps exercises starting on day zero, walkerassisted non-weight bearing on day two, and gradual range of motion exercises initiated on day ten. Full weight-bearing began at two months. Postoperative imaging showed optimal implant placement and medullary healing. Patients successfully regained weight-bearing capacity and experienced enhanced knee flexibility and motion. This approach reduces circular tension and improves stability, facilitating rapid mobilisation and positive outcomes in complicated patellar fracture non-unions.

Quasi-steady-state CEST for rapid and quantitative lesion detection in multiple sclerosis at 3T.