Search Results (48,471)

(1) Background: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease associated with immune dysregulation. The TYRO3, AXL, and MER (TAM) signaling pathway, comprising AXL receptor tyrosine kinase (AXL), MER tyrosine kinase (MERTK), growth arrest-specific 6 (GAS6), and Protein S, is a key regulator of immune homeostasis. This study investigated these receptor–ligand components in patients with AS. (2) Methods: A total of 45 patients with AS and 44 healthy controls were enrolled. Serum GAS6 and Protein S levels were measured by ELISA, and AXL and MERTK expression levels were analyzed by RT-qPCR. Clinical and inflammatory parameters were also evaluated. (3) Results: ESR, CRP, and IL-6 levels were significantly higher, whereas Protein S levels were significantly lower in patients with AS than in controls. No significant differences were observed in GAS6, AXL, or MERTK expression levels, although lower expression trends were detected in patients. Logistic regression analysis identified CRP, IL-6, Protein S, and AXL expression as variables independently associated with AS. ROC analysis demonstrated significant discriminatory performance for AXL expression. (4) Conclusions: Alterations in the TAM signaling pathway, particularly reduced Protein S levels and altered AXL expression, may contribute to immune dysregulation and persistent inflammation in AS. Full article

Organophosphate pesticides (OPPs) are widely used in agriculture and are associated with metabolic dysregulation and cognitive impairment. Emerging evidence links OPP exposure to insulin resistance and diabetes mellitus, a condition known to negatively impact brain function. Prior investigations in our laboratory identified significant dysregulation of arachidonic acid (AA) metabolites associated with the endocannabinoid system in both diabetic patients and those with chronic OPP exposure, with a marked reduction in serum AA levels in the OPP-exposed cohort. This study investigates the impact of OPP exposure and pre-diabetes on the hippocampal proteome and whether AA supplementation can mitigate the resulting neuronal proteomic alterations. Using a controlled rat model, high-resolution LC-MS/MS-based proteomics identified differentially expressed proteins across experimental groups. Both OPP exposure and pre-diabetes were associated with increased cognitive impairment and were associated with overlapping disruptions in pathways related to insulin resistance, mitochondrial function, synaptic plasticity, and neuronal development. AA supplementation mitigated cognitive decline and stabilized synaptic and metabolic proteins; however, residual pathway dysregulation highlights the complexity of these stressors. Our results reveal novel molecular intersections between environmental and metabolic drivers of cognitive impairment, establishing a rationale for further research into inexpensive, protective dietary interventions. Full article

Background/Objectives: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder marked by developmental delay, intellectual disability, and progressive movement abnormalities. Variants in RYR1 can cause congenital myopathies, but data on the co-occurrence of variants in populations are limited. The aim of this study was to characterize the clinical and genetic basis of the neurometabolic and neuromuscular abnormalities and to investigate the potential interaction between the identified variants. Methods: Patients with complex, previously undiagnosed clinical presentations underwent neurological evaluation, including brain magnetic resonance imaging, electromyography, biochemical testing, and whole-exome sequencing (WES). Identified variants were analyzed in silico and confirmed by Sanger sequencing in the patient and her parents. Three cases were reviewed, and one of these patients exhibited developmental delay, hypotonia, intellectual disability, and progressive motor dysfunction. Biochemical tests revealed markedly elevated urinary 2-hydroxyglutaric acid levels, consistent with L2HGA. Results: WES identified a homozygous likely pathogenic variant in L2HGDH (c.589_590insGGC, p.Q197insG), confirming the molecular diagnosis of L2HGA. In addition, a heterozygous missense variant in RYR1 (c.7268T>A, p.M2423K), classified as a variant of uncertain significance, was detected and was inherited from her mildly affected father. The L2HGDH variant explains the neurometabolic phenotype of the patient, whereas the RYR1 variant remains of uncertain significance, and its clinical contribution cannot be clearly established. Conclusions: To our knowledge, this case illustrates the co-occurrence of a likely pathogenic L2HGDH variant and a heterozygous RYR1 variant of uncertain significance. The findings expand the mutational spectrum of L2HGA and underscore the value of comprehensive genomic testing in complex neurometabolic and neuromuscular disorders. Full article

Background/Objectives: Iatrogenic nerve injury is a significant challenge in urologic surgery, with radical prostatectomy posing a high risk due to complex pelvic neural anatomy. Despite advances in robotic-assisted and nerve-sparing techniques, postoperative urinary incontinence and erectile dysfunction remain prevalent, adversely affecting patients’ quality of life and imposing substantial healthcare costs. Methods: A narrative review was conducted using PubMed, MEDLINE, and the Cochrane Library (searches through February 2026) for studies on radical prostatectomy epidemiology, mechanisms of nerve injury, functional outcomes, and economic burden. Emerging intraoperative fluorescence imaging technologies, surgical strategies to mitigate iatrogenic nerve injuries, and the financial costs of post-prostatectomy complications were assessed. Results: Robotic-assisted radical prostatectomy now accounts for >80% of procedures in the United States, and has been associated in observational studies with improved early recovery of erectile function compared with open and laparoscopic approaches. However, the lack of real-time nerve visualization remains a limiting factor. Recent milestones (January 2026) include the Food and Drug Administration Investigational New Drug clearance for the nerve-specific fluorophore LGW16-03 (NerveTrace), which enables real-time identification of sub-millimeter nerve branches, and the 510(k) premarket clearance of Dendrite imaging (November 2025). Conclusions: Enhanced intraoperative nerve discrimination via molecularly targeted imaging has the potential to reduce iatrogenic complications and improve long-term functional and economic outcomes in prostate cancer surgery, although these benefits have yet to be demonstrated in prospective clinical and health-economic studies. Full article

Background and Objectives: Microscopic colitis (MC) encompasses two chronic inflammatory disorders of the large intestine: collagenous colitis (CC) and lymphocytic colitis (LC). Both conditions are characterised by chronic watery diarrhoea and substantially impaired quality of life. Diagnosis relies on colonoscopy with multiple biopsies, and no reliable non-invasive biomarker currently exists. This exploratory study aimed to investigate circulating fatty acid-binding protein 2 (FABP2), interleukin-10 (IL-10), and lipopolysaccharides (LPSs) as potential biomarkers for MC and to compare their profiles with those in ulcerative colitis (UC). Materials and Methods: Plasma samples were obtained from 45 patients with active CC, 16 patients with active LC, 52 healthy controls, 43 patients with active UC, and 43 patients with inactive UC. Concentrations of FABP2, IL-10, and LPS were measured by enzyme-linked immunosorbent assay (ELISA). Results: Plasma FABP2 concentrations differed significantly across groups (Kruskal–Wallis p = 0.008). CC patients exhibited the highest levels (median 1719.0 pg/mL, IQR 1364.0–2240.0) compared with active UC (median 1272.0 pg/mL, IQR 861.7–1727.5; p = 0.005) and inactive UC (median 1334.0 pg/mL, IQR 854.2–1702.0; p = 0.001), but did not differ significantly from controls (median 1364.5 pg/mL, IQR 982.6–2160.5; p = 0.076) or LC (median 1421.5 pg/mL, IQR 1207.0–2002.2; p = 0.171). IL-10 concentrations also differed across groups (Kruskal–Wallis p = 0.029 after removal of one extreme outlier in active UC). Active UC patients had significantly lower levels (median 2.6 pg/mL, IQR 1.4–4.6) than CC (median 4.0 pg/mL, IQR 3.0–7.2; p = 0.009) and controls (median 4.8 pg/mL, IQR 2.6–7.4; p = 0.005). LPS concentrations showed no overall differences across groups (Kruskal–Wallis p = 0.55), although CC patients had numerically higher levels (median 73.7 pg/mL, IQR 45.6–104.9) compared with controls (median 56.4 pg/mL, IQR 33.7–87.1; p = 0.124). No significant differences were observed between LC and other groups for any biomarker. Conclusions: In this exploratory study, plasma FABP2 and IL-10 showed limited diagnostic accuracy in differentiating CC from UC but failed to distinguish MC from healthy controls. LPS levels were not significantly different among study groups. None of the biomarkers reliably separated LC from other groups, possibly reflecting the small LC sample size. These preliminary findings suggest subtle differences in circulating biomarker profiles between CC and UC that warrant validation in larger cohorts. Full article

Virtual reality (VR) has shown promising potential for upper-extremity rehabilitation; however, its successful integration into clinical practice depends not only on therapeutic effectiveness but also on the acceptance of the technology by patients and healthcare professionals alike. Despite growing international research in this area, there is limited evidence on clinical attitudes toward VR rehabilitation in Thailand and other middle-income settings. This study investigates Thai patients’ and clinicians’ perceptions of VR for upper-extremity rehabilitation through two complementary studies focusing on perceived usability and usefulness. The first study evaluated the perceived usability of a VR rehabilitation game using the System Usability Scale (SUS) among 40 first-time VR users divided into younger and senior groups. The younger group reported a higher average SUS score (64.6) than the senior group (55.4). While both groups generally perceived VR rehabilitation positively, senior participants expressed greater concern regarding system complexity, consistency, and the need for technical assistance. Nevertheless, the findings indicate that VR remained an acceptable rehabilitation approach even among elderly first-time users in a population with relatively lower technological readiness. The second study explored clinicians’ perceptions of utilizing VR-generated movement data to support rehabilitation decision-making. Five rehabilitation professionals evaluated the potential usefulness of VR data visualizations for diagnosis and treatment monitoring. Clinicians generally perceived VR data as valuable, particularly for tracking rehabilitation progress rather than diagnostic decision-making. Feedback from interviews also highlighted practical considerations for future implementation, including the importance of normative data, simplified visualization formats, and the feasibility of clinical workflows. By combining patient usability perspectives with clinicians’ evaluations of clinical usefulness, this research provides a broader understanding of the factors influencing VR adoption for upper-extremity rehabilitation in Thailand. The findings contribute contextual evidence from an underrepresented healthcare environment and offer insights relevant to the future deployment of VR-assisted rehabilitation systems in similar socio-economic settings. Full article

Background: Dislocations and fracture-dislocations of the lower cervical spine represent complex injuries with a high risk of neurological damage. Especially in the presence of a confirmed traumatic disc lesion, an anterior surgical approach is described as favoured in the literature. However, studies show that with sufficient reduction technique, even in the presence of a confirmed disc protrusion, posterior stabilization can be considered a safe therapeutic option. The aim of this study is to analyze anterior and posterior treatment of dislocations and fracture-dislocations of the subaxial cervical spine with regard to neurological and radiological outcomes. Methods: In our monocentric cohort study, we investigated the immediate postoperative radiological and neurological outcome depending on the chosen surgical approach and the presence of a disc protrusion. Patients treated at our centre between January 2005 and June 2025 were included. Patients with preoperative complete spinal cord injury were excluded. Neurological status was assessed using the ASIA score preoperatively at admission and postoperatively at discharge or prior to staged surgery. Results: A total of 92 patients were included in the study. Most patients showed an ASIA score C (33.7%). A total of 49 patients (53.3%) were operated anteriorly and 42 patients (45.6%) posteriorly. One patient was primarily stabilized bilaterally. Nine patients initially treated anteriorly had to be secondarily stabilized additionally from posterior. In both groups, neurological deterioration occurred in one case. All other patients remained stable on the ASIA score or improved by at least one point on the scale. Conclusions: The findings provide evidence in favour of a personalized, pathology-oriented approach to lower cervical spine fracture-dislocations rather than selecting the surgical approach based solely on the presence of traumatic disc protrusion. Further prospective studies are needed to validate these observations. Full article

Sustainable innovation constitutes the cornerstone of firms’ long-term competitive edge, yet the underlying mechanisms via which patient capital facilitates corporate sustainable innovation remain understudied. Based on a sample of Chinese A-share listed firms spanning 2013 to 2024, this study operationalizes patient capital through two proxies: relational debt and stable institutional ownership. We systematically investigate the impact of patient capital on sustainable innovation, alongside the mediating pathway of internal control quality and the moderating role of climate policy uncertainty. The empirical outcomes indicate that both forms of patient capital exert a significant positive effect on sustainable innovation, with internal control quality serving as a partial mediator in this relationship. Additionally, climate policy uncertainty reinforces the promotional influence of patient capital on sustainable innovation. We further stratify heterogeneity analyses into two dimensions: firm-inherent heterogeneity and external environmental heterogeneity. From the perspective of endogenous firm attributes, the innovation-stimulating effect of patient capital differs markedly across enterprises with distinct ownership types, life-cycle stages, and total asset sizes. Externally, the observed positive impact varies considerably conditional on industrial factor intensity and the regional marketization degree of the firm’s location. These findings expand the existing literature concerning long-term capital and sustainable innovation, and yield actionable implications for corporate management, institutional investors, and policymakers. Full article

Despite significant improvement in long-term survival with the advent of immunotherapy, a substantial proportion of lung cancer patients develop primary and acquired resistance. Among emerging strategies to overcome this challenge, cancer vaccines represent a promising approach, especially for non-small-cell lung cancer (NSCLC). A variety of vaccine platforms have been investigated, including nucleic acid-based vaccines, peptide vaccines, dendritic cell vaccines, and viral vector-based approaches. To date, cancer vaccines have not demonstrated consistent survival benefit in large randomized trials, and their clinical application remains limited. Challenges include high production costs, complexity in manufacturing, and issues related to drug stability and scalability. However, several ongoing early-phase trials show promising signals for several platforms, as new tools and technology become available to optimize neoantigen selection, vaccine production, efficacy, and safety. In this review, we summarize the current evidence of vaccines in NSCLC treatment across different stages and therapeutic settings. Full article

Neurolymphomatosis (NL), a rare manifestation of non-Hodgkin’s lymphoma affecting the peripheral nervous system, remains a diagnostic challenge. This study aimed to define an optimal diagnostic approach for timely and effective identification of NL. We analyzed 559 NL cases from 231 articles published from 1951 to 2022, examining how patient outcomes correlated with various diagnostic modalities, including magnetic resonance imaging (MRI), computed tomography (CT), [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET), electromyography-nerve conduction studies (EMG-NCS), ultrasound, and tissue biopsy when used individually or in combination. Separate analyses were performed in a mutually exclusive fashion to minimize confounding effects from multiple modalities. The results of this investigation revealed that patients with biopsies had a longer time interval from first treatment to progression (Kruskal–Wallis p < 0.0001), survival from diagnosis (overall survival) (p < 0.0001), and survival from symptom onset (p < 0.0001), but not symptom onset to diagnosis (p = 0.2134). Pairwise comparisons of biopsy plus 2, 3, or 4 diagnostic modalities revealed a positive trend for the combination of biopsy + PET + MRI + EMG-NCS. A majority of patients without biopsy had secondary NL. In this non-biopsied population, no diagnostic modality had a significant correlation with outcome. The data collectively indicate that histological confirmation of NL from biopsy was associated with a positive patient outcome. Management of NL patients requires timely testing using PET, MRI, and EMG-NCS to quickly identify a site for image-guided nerve biopsy. Full article

Objective: Patellofemoral pain syndrome (PFPS) is one of the most common causes of anterior knee pain and is associated with biomechanical, muscular, and functional impairments affecting the extensor mechanism of the knee. Quadriceps muscle dysfunction, altered tendon morphology, and impaired lower extremity biomechanics have been suggested to contribute to patellofemoral joint instability and pain development. The aim of this study was to evaluate the muscle and tendon thicknesses of the extensor mechanism using ultrasonography in individuals with PFPS and to investigate the relationship of these measurements with knee pain, knee function, and physical performance, with particular emphasis on the combined assessment of muscle morphology, tendon morphology, and functional performance parameters. Methods: This cross-sectional study was conducted between 5 November 2019 and 15 December 2019, including 80 individuals aged 18–45 years who presented with anterior knee pain and were clinically diagnosed with patellofemoral pain syndrome (PFPS). Demographic characteristics of the participants were collected. Pain severity was assessed using the Visual Analog Scale (VAS), and functional status was evaluated with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Physical performance was assessed using the 6 m walk test and the five-repetition sit-to-stand test. Ultrasonographic examination was used to measure rectus femoris muscle thickness, vastus intermedius muscle thickness, quadriceps tendon thickness, and patellar tendon thickness using a high-frequency linear probe in a standardized supine position with the knee relaxed and the lower extremity muscles at rest. Results: The mean age of the participants was 32.11 ± 7.08 years, and the mean body mass index (BMI) was 25.05 ± 4.11 kg/m². Of the participants, 42 (52.5%) were male and 38 (47.5%) were female; 46 (57.5%) were smokers and 34 (42.5%) were non-smokers. Ultrasonographic measurements showed that rectus femoris muscle thickness was 1.98 ± 0.45 cm, vastus intermedius muscle thickness was 1.75 ± 0.53 cm, quadriceps tendon thickness was 0.54 ± 0.12 cm, and patellar tendon thickness was 0.35 ± 0.08 cm. Rectus femoris, vastus intermedius, and quadriceps tendon thicknesses were significantly higher in males compared to females (p = 0.001). Individuals with BMI > 25 had greater rectus femoris (p = 0.023) and vastus intermedius (p = 0.001) muscle thicknesses. A negative correlation was found between rectus femoris muscle thickness and WOMAC total (r = −0.227, p = 0.042) and WOMAC pain scores (r = −0.233, p = 0.028). Additionally, a significant relationship was observed between quadriceps tendon thickness and the five-repetition sit-to-stand test (r = −0.247, p = 0.044). Conclusions: In patients with PFPS, quadriceps muscle and tendon thicknesses were found to be associated with certain demographic and clinical parameters. Ultrasonographic evaluation of muscle and tendon structures may be a useful, non-invasive, dynamic, and radiation-free method for better understanding the clinical characteristics of PFPS and its relationship with physical performance. Ultrasonographic assessment may also provide complementary information for rehabilitation planning and functional evaluation in individuals with PFPS, although these findings should be interpreted cautiously because of the cross-sectional design and weak correlations observed. Full article

Epidermolysis bullosa (EB) is a group of genetic diseases characterized by skin fragility. Although therapeutic options aim to accelerate wound-healing, improvement is needed; therefore, birch bark and propolis were investigated due to their beneficial biological properties. A representative ethanolic extract was analyzed by reversed-phase high-performance liquid chromatography with diode array detection (RP-HPLC-DAD) for chemical profiling of the raw materials. A hydrophobic natural deep eutectic solvent (HNaDES) for birch bark extraction, as well as a hydrogel and a bigel enriched with propolis and birch bark extract, were prepared and characterized by Fourier transform infrared (FT-IR) spectroscopy. Cytotoxicity and wound-healing potential were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch assays in six human keratinocyte cell lines: two from healthy individuals, two from recessive dystrophic ΕΒ patients (RDEB), and two from laminin-332-deficient junctional EB patients (JEB). RP-HPLC-DAD revealed the presence of phenolic compounds (e.g., chrysin, pinocembrin, pinobanksin) and pentacyclic triterpenes (e.g., betulin and betulinic acid), characteristic of propolis and birch bark, respectively. FT-IR confirmed HNaDES formation and indicated physical interactions within the gels. All systems exhibited no cytotoxicity at 1 μg/mL and increased cell vitality. Moreover, in keratinocytes derived from JEB patients, hydrogel improved wound- healing significantly at 24 h, whereas bigel showed significant improvement at 8 h. The developed systems could be promising topical treatments. Full article

Background: Neuroendocrine tumors—are relatively rare but increasingly diagnosed malignancies originating from diffuse neuroendocrine cells, most commonly affecting the gastroenteropancreatic system. Due to their long asymptomatic development and low incidence, pose a diagnostic and therapeutic challenge for physicians. Recently, the role of nuclear medicine has been growing not only in the diagnostic stage but also in treatment. Systemic radionuclide therapy using somatostatin analogs labelled with the radioisotope lutetium-177 is becoming increasingly common in patients with advanced-stage disease. Currently, most patients receive a standard activity of therapeutic radiopharmaceuticals. Recent clinical studies provide increasing evidence of a close relationship between the absorbed radiation dose in pathological lesions and the therapeutic effect of radioisotope therapy. Internal dosimetry is used to measure the doses of ionising radiation absorbed by the patient after administration of the radiopharmaceutical. The lack of individual internal dosimetry prior to therapy means that only a small fraction of patients receive optimal doses of radioactivity, which is markedly different from external beam radiotherapy planning. Methods: A narrative literature review was conducted using the PubMed/MEDLINE and Embase databases, focusing primarily on publications from the last years. The search strategy included combinations of keywords related to peptide receptor radionuclide therapy and dosimetry, such as “Lutetium-177”, “neuroendocrine tumors”, “dosimetry”, “PRRT”, “systemic radionuclide therapy” and “artificial intelligence”. Particular emphasis was placed on recent prospective clinical studies, multicenter investigations, systematic reviews and consensus documents published by major nuclear medicine societies, including the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). Seminal earlier publications considered essential for understanding the development of dosimetry concepts and clinical implementation were also included. Results: This study confirms the existence of a clinically significant dose-response relationship in ¹⁷⁷Lu-PRRT. Higher absorbed doses to tumour lesions are associated with longer progression-free survival. The lack of individualized internal dosimetry prior to therapy means that only a small proportion of patients receive optimal radiation doses. Simplified dosimetric approaches with a reduced number of imaging time points, together with emerging artificial intelligence–based tools, appear promising for reducing the complexity of the dosimetry process. Conclusions: The aim of this study was to analyse the current literature on the role of internal dosimetry in the treatment of neuroendocrine tumors using the radioisotope lutetium-177. Available data support the clinical relevance of individualized dosimetry and highlight its potential to optimize both therapeutic efficacy and treatment safety. Full article

Background/Objectives: Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite advances in treatment, outcomes for advanced CRC remain unsatisfactory due to uncontrolled proliferation, metastasis, and recurrence. This study investigated the anti-cancer effects of KMU-11342, an indolin-2-one-based multi-protein kinase inhibitor with previously reported anti-inflammatory properties, in human colorectal cancer models. Methods: The anti-cancer effects of KMU-11342 were evaluated in colorectal cancer cells and further investigated in three-dimensional (3D) spheroid and patient-derived organoid models. Cell proliferation, migration, apoptosis, and cell cycle progression were assessed. Kinase activity profiling and molecular docking analyses were performed to identify potential targets and characterize the underlying signaling pathways. Results: KMU-11342 significantly inhibited the proliferation and migration of CRC cells. It reduced CRC cell density by 58.9% and 83.3% at 0.5 and 1 μM, respectively. These effects were accompanied by G2/M cell cycle arrest and apoptotic cell death. In 3D models, spheroid formation was markedly reduced and stemness-related characteristics were diminished. Patient-derived CRC organoids also showed decreased viability, exhibiting 38.6% and 77.4% reductions at 1 and 2 μM, respectively. These effects were observed in a dose-dependent manner in both two-dimensional (2D) and 3D colorectal cancer models. Kinase activity profiling and molecular docking analyses identified glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase 1 (CDK1) as potential mediators of the anti-cancer effects of KMU-11342 through the p53/nuclear factor kappa B (NF-κB) and FoxO1 signaling axes, respectively. Conclusions: KMU-11342 exhibits potent anti-tumor activity against CRC through suppressing proliferation, migration, and stemness in both 2D and 3D models, including patient-derived organoids. Its effects may be mediated, at least in part, through modulation of GSK3β and CDK1 via the p53/NF-κB and FoxO1 signaling pathways. Full article

Background/Objectives: Semaglutide and tirzepatide demonstrate substantial efficacy in obesity treatment, yet individual responses vary markedly. The incretin system—comprising glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)—is frequently dysregulated in obesity, but whether fasting incretin levels predict differential pharmacological responses remains unexplored. We investigated whether combinatorial fasting GLP-1/GIP tertile profiles predict the initial weight-loss response to semaglutide versus tirzepatide in patients with severe obesity. Methods: This prospective, parallel-group, open-label pilot study enrolled 90 treatment-naïve patients with BMI > 40 kg/m² (mean 42.5 ± 3.5 kg/m²) at the University of Catania, Italy. Fasting serum GLP-1 (0.8–50 pg/mL) and GIP (1–16 ng/mL) were measured by chemiluminescence immunoassay and distributed into tertiles, generating nine combinatorial profiles (P1–P9; n = 10 per profile). Within each profile, five patients were randomly assigned to semaglutide (escalated to 2.4 mg/week) or tirzepatide (escalated to 15 mg/week). Primary outcome was pharmacological response category at six months: low (<5% body weight reduction), intermediate (5–15%), or optimal (>15%). Results: Baseline characteristics were balanced across profiles (age 48 ± 8 years, BMI 42.5 ± 3.5 kg/m², waist circumference 134 ± 12 cm, HOMA-IR 8.5 ± 3.0; all p > 0.05). Tirzepatide achieved optimal response in profiles with low GIP tertile regardless of GLP-1 level (P1, P6, P8), while semaglutide achieved optimal response when GLP-1 was low and GIP was intermediate-to-high (P4, P5). Both drugs showed low response in the high GLP-1/high GIP profile (P3). Mean weight loss in optimal-response groups was 18.2 ± 2.1% for tirzepatide and 16.8 ± 1.9% for semaglutide. Waist circumference reductions paralleled weight loss patterns. HOMA-IR decreased significantly in all optimal-response groups (mean reduction 4.2 ± 1.1 units). Conclusions: In this hypothesis-generating pilot study, fasting GLP-1/GIP combinatorial profiling, obtained from a single fasting blood sample, was associated with differential pharmacological responses to semaglutide and tirzepatide in severe obesity. Low GIP levels were tentatively associated with optimal tirzepatide response; low GLP-1 with intermediate-to-high GIP was tentatively associated with optimal semaglutide response. These preliminary findings provide proof-of-concept for incretin-guided personalised obesity pharmacotherapy but require confirmation in larger, adequately powered randomised trials before any clinical recommendations can be made. The inability to discriminate incretin secretory deficiency from receptor resistance using fasting measurements alone, the absence of a placebo control, and the six-month follow-up (shorter than the 12–18 months at which maximal efficacy is typically observed) remain critical limitations. Full article