Medicine and Pharmacology

Abstract: Fibromyalgia remains inconsistently recognized, particularly with shared-symptom comorbidities across specialties. This paper reconstructs diagnosis as a longitudinal causal task through historical and case-derived analysis, tracing Mayo’s primary–secondary fibrositis distinction, Philip Kahler Hench’s preservation of causal inquiry at Scripps, and subsequent fibromyalgia criteria. Earlier reasoning separated syndrome recognition from determining whether another disease merely coexisted or drove or sustained the amplification state. Later classification improved recognition without resolving that causal question. The framework uses secondary fibromyalgia to describe an amplification state driven or sustained by underlying disease, distinguishing it from self-sustaining primary fibromyalgia and mere comorbid coexistence. Mild fibromyalgia may be missed when limited hypersensitivity, disability, flares, or medication requirements produce fewer diagnostic signals. Proposed severity levels and distinctions among flares, baseline drift, and runaway fibromyalgia organize longitudinal assessment. Fibromyalgia demonstrates why syndrome recognition alone cannot determine the relationship between shared symptoms and coexisting disease. Differential diagnosis must continue across specialties and time, preserving competing causal formulations, symptoms, objective findings, disease activity, treatment exposure and response, and responsibility for revision. The transferable proposition concerns longitudinal diagnostic responsibility rather than shared biology across complex conditions. The framework is offered for prospective evaluation; the index case does not establish prevalence, mechanism, or treatment efficacy.

Abstract: Background: Older adults with chronic obstructive pulmonary disease (COPD) and multiple cardiometabolic disorders may exhibit overlapping inflammatory and vascular abnormalities. Evidence regarding intravenous oxyhydrogen nanobubble (NB-HHO) formulations remains limited. Case presentation: A 78-year-old man with COPD, coronary artery disease, hypertension, type 2 diabetes mellitus, and ankylosing spondylitis received 15 adjunctive NB-HHO infusion sessions between 6 October and 19 November 2025, using the documented stepwise dose-titration protocol. Clinical observations: From baseline to the end of the treatment period, C-reactive protein changed from 5.2 to 2.2 mg/L, blood pressure from 172/97 to 146/71 mmHg, estimated glomerular filtration rate from 80 to 89 mL/min/1.73 m², total cholesterol from 333 to 297 mg/dL, LDL cholesterol from 201 to 170 mg/dL, and COPD Assessment Test score from 23 to 20. The patient also reported less productive cough and greater energy. Conclusion: These temporal changes are descriptive and hypothesis-generating. A single uncontrolled case with concurrent clinical management and incomplete formulation and safety information cannot establish efficacy, causality, or long-term safety.

Abstract: Gout is the most common form of inflammatory arthritis and results from persistent hyperuricemia leading to deposition of monosodium urate crystals within joints and soft tissues. Although conventional urate-lowering therapy remains effective for most patients, suboptimal adherence, delayed dose escalation, intolerance, and refractory disease continue to limit long-term disease control. Contemporary management has shifted toward a treat-to-target (T2T) strategy that aims to achieve and maintain serum urate concentrations below the saturation threshold to promote crystal dissolution and prevent recurrent flares, tophus formation, and structural joint damage. Recent advances have expanded therapeutic options through selective urate transporter inhibitors, next-generation xanthine oxidase inhibitors, engineered uricase formulations, immune tolerance platforms, biologic therapies targeting the IL-1 pathway, and novel NLRP3 inflammasome inhibitors. Emerging evidence also supports the potential urate-lowering and cardiometabolic benefits of sodium–glucose cotransporter-2 inhibitors, while advances in proteomics, metabolomics, and transcriptomics have identified promising biomarkers that may improve diagnosis, disease monitoring, and precision medicine approaches. This narrative review summarizes current evidence on treat-to-target strategies, established urate-lowering therapies, emerging pharmacologic agents, biologic therapies, and novel biomarkers, and highlights future directions that may facilitate individualized management of gout.

Abstract: Background. Elevated total circulating vitamin B12 is a nonspecific biochemical finding that may reflect supplementation, altered cobalamin-binding proteins, liver or kidney disease, malignancy, or analytical interference. “Idiopathic” elevation should describe a finding that remains unexplained after an appropriate assessment, rather than an established disease entity. Methods. This narrative review integrates verified clinical studies, laboratory investigations, and recent systematic reviews, with targeted updates through October 2026. It distinguishes association from causation and evidence on initially unexplained elevation from evidence in established disease. Findings. In a French cohort, solid cancer developed within five years in 20.8% of patients with persistent vitamin B12 elevation, compared with 6.0% with transient elevation and 3.8% with consistently normal values; the adjusted hazard ratio for persistent elevation was 5.90 (95% confidence interval, 2.79–12.45). These estimates arose from a selected clinical population and are not screening probabilities for the general population. A 2025 mortality meta-analysis included 28 studies, 69,610 participants, and 15,815 deaths, but heterogeneity limited universal prognostic interpretation. Recent laboratory studies also support considering immunoglobulin-associated vitamin B12 in selected cases, while the specificity of polyethylene glycol precipitation remains disputed. Elevated total vitamin B12 does not exclude clinically significant deficiency. Conclusions. Evaluation should verify exposure and measurement, identify common organ-specific causes, and pursue malignancy-directed investigations according to clinical findings and persistence. Follow-up intervals and the intensity of surveillance remain unvalidated. Neither treatment directed solely at lowering vitamin B12 nor indiscriminate cancer imaging is supported by the available evidence.

Abstract: Background and Objectives: Kidney dysfunction has been associated with arterial stiffening, but the relationship may depend on shared cardiometabolic and haemody-namic factors. This study examined the association between estimated glomerular fil-tration rate (eGFR) and local carotid arterial stiffness in adults with a high prevalence of diabetes and hypertension. Materials and Methods: This single-centre cross-sectional study included 135 adults. Local carotid pulse wave velocity derived from the beta stiffness index (PWVβ) was the primary outcome. Secondary outcomes were the beta stiffness index, pressure–strain elastic modulus, arterial compliance, and augmentation index. Multivariable linear regression evaluated associations with eGFR, age, sex, dia-betes, and hypertension. Separate models replaced hypertension status with peripheral or central aortic systolic blood pressure. Results: Mean age was 57.4 ± 7.4 years, and mean eGFR was 83.3 ± 20.0 mL/min/1.73 m². PWVβ differed across the four diabetes–hypertension groups (p < 0.001). In the primary model, based on 117 participants, higher PWVβ was associated with age, diabetes, and hypertension. There was no evidence of an independent association between eGFR and PWVβ (B = −0.003 per mL/min/1.73 m²; 95% confidence interval, −0.014 to 0.009; p = 0.676). eGFR was also not associated with the secondary outcomes. Peripheral and central aortic systolic blood pressure were positively associated with PWVβ in separate adjusted models. Conclusion: In this cardiometabolic risk population, eGFR was not independently associated with local carotid arterial stiffness. Age, diabetes, and blood pressure were associated with higher PWVβ. The findings concern contemporaneous associations and should not be extrapolated to ad-vanced chronic kidney disease or interpreted as excluding a longitudinal relationship between kidney function and vascular stiffness.

Abstract: Renal abnormalities are increasingly recognized in transfusion-dependent β-thalassemia, but evidence on intrarenal Doppler indices remains limited. This single-center case–control study compared the resistive index (RI) and pulsatility index (PI) in 44 patients aged 7–57 years and 30 apparently healthy controls aged 7–45 years. Three interlobar arterial measurements from each kidney were averaged for each participant. Group differences were evaluated using Welch’s t-test, and receiver operating characteristic analysis assessed discrimination between thalassemia and control status. Mean RI was higher in patients than controls (0.6789 ± 0.0500 versus 0.5943 ± 0.0440; mean difference, 0.0846; 95% confidence interval, 0.0626–0.1066). Mean PI was also higher (1.1655 ± 0.1824 versus 0.9197 ± 0.1290; mean difference, 0.2458; 95% confidence interval, 0.1736–0.3180). Both differences were significant (p < 0.001), with Hedges’ g values of 1.76 and 1.49, respectively. Areas under the curve were 0.895 for RI and 0.865 for PI. These findings indicate altered intrarenal hemodynamics in transfusion-dependent β-thalassemia. Without an independent kidney-injury reference standard or adjustment for potential confounders, they do not establish either index as a diagnostic marker of kidney injury.

Abstract: Background and Objectives: Variation in RANK/RANKL/OPG signaling may contribute to rheumatoid arthritis (RA) heterogeneity. We examined whether recorded TNFRSF11A exon 5–flanking variant carrier status was associated with six-month clinical outcomes in treatment-naïve RA. Materials and Methods: This prospective cohort included 57 patients: 10 carriers and 47 non-carriers. The primary outcome was six-month DAS28-CRP. Welch tests, Fisher’s exact tests, effect sizes, 95% confidence intervals, and exploratory baseline-adjusted models were used; missing outcomes were not imputed. Results: Carriers had lower six-month DAS28-CRP than non-carriers (2.53 ± 0.98 [n=10] vs 2.85 ± 0.99 [n=37]) and lower CRP (6.58 ± 6.96 vs 7.59 ± 9.29 mg/L). DAS28-CRP < 2.6 occurred in 60.0% of carriers and 35.1% of non-carriers (OR, 2.769; 95% CI, 0.660–11.618). High activity, recorded deformity, and biologic initiation were 10.0% vs 35.1%, 10.0% vs 29.8%, and 20.0% vs 36.1%, respectively. The composite score was 3.60 ± 1.08 vs 2.83 ± 1.07 (d=0.720; p=0.064). The adjusted DAS28-CRP coefficient was −0.165 (95% CI, −0.850 to 0.520; p=0.629). Conclusions: The carrier pattern suggests a more favorable short-term RA profile, but remains hypothesis-generating and requires prospective validation.

Abstract: Background: Maxillary sinus fungus ball (MSFB) is a non-invasive form of fungal rhinosinusitis characterized by an accumulation of fungal material within the sinus lumen without tissue invasion. Clinical manifestations are often non-specific, whereas computed tomography (CT) may provide important diagnostic clues. Methods: We describe five patients with clinical and radiological findings suggestive of MSFB who underwent endoscopic sinus surgery. Clinical manifestations, nasal endoscopic findings, CT features, histopathological and/or mycological results, and surgical management were reviewed. Results: The patients ranged from 29 to 66 years of age. All lesions were unilateral and involved the maxillary sinus. Purulent nasal discharge and headache were the predominant symptoms. CT demonstrated maxillary sinus opacification or mucosal thickening associated with intralesional calcifications in all patients. All patients underwent endoscopic maxillary sinus surgery. Fungal culture was negative in three patients and positive for filamentous fungi in one patient; histopathological examination in the remaining patient showed inflammatory tissue. Conclusions: MSFB should be considered in persistent unilateral maxillary sinus disease, particularly when CT demonstrates intralesional hyperattenuation or calcification. Negative fungal culture does not exclude MSFB. Diagnosis should integrate clinical, endoscopic, radiological, intraoperative, histopathological, and mycological findings. Endoscopic sinus surgery remains the treatment of choice for symptomatic disease.

Abstract: Suspected immune thrombotic thrombocytopenic purpura (iTTP) creates a dual emergency: treatment must begin before ADAMTS13 confirmation, while lethal mimics must be investigated concurrently. A 44-year-old woman presented with fever, severe thrombocytopenia, progressive limb weakness, and multifocal cerebral infarctions. Although the schistocyte proportion was <1% and her PLASMIC score was 5, iTTP could not be safely excluded. ADAMTS13 activity was sampled before treatment, and plasma exchange plus corticosteroids was started. Blood cultures grew methicillin-susceptible Staphylococcus aureus. Despite three negative transthoracic echocardiograms, transesophageal echocardiography demonstrated a 10-mm mitral vegetation, establishing infective endocarditis (IE). Pretreatment ADAMTS13 activity was 35%, allowing TTP-directed therapy to be withdrawn. IE can produce thrombocytopenia, microangiopathic hemolysis, TMA-like presentations, and occasionally marked ADAMTS13 reduction; conversely, schistocytes may be initially inapparent in true iTTP. Thus, neither a low schistocyte count nor an intermediate prediction score should end diagnostic reasoning. When iTTP and IE remain plausible, pretreatment ADAMTS13 sampling, risk-adapted empiric TTP therapy, blood cultures, antimicrobial treatment, and definitive cardiac imaging should proceed in parallel.

Abstract: Objectives: Sjögren’s disease (SjD) and Hashimoto’s thyroiditis (HT) are closely associated autoimmune diseases. This study compared elastographic changes in the major salivary and thyroid glands of patients with SjD and HT. Methods: This cross-sectional study included 30 SjD and 31 HT patients. Ultrasonography and Shear Wave Elastography (SWE) were performed to evaluate the parotid, submandibular, and thyroid glands. Salivary gland structural changes were assessed using OMERACT scores, while thyroids were evaluated for heterogeneity and pseudonodular appearance. Results: Thyroid parenchymal heterogeneity was more frequent in HT patients, though 43% of SjD patients also exhibited HT-like thyroid features. In contrast, no HT patients showed SjD-like salivary gland changes (OMERACT score ≥3). Elastographic measurements of thyroid and salivary glands did not differ significantly between groups, even after age adjustment via ANCOVA. Furthermore, clinical disease activity (ESSDAI) did not correlate with elastographic findings in SjD. However, SjD patients with severe structural changes (OMERACT score ≥4) had significantly higher elastography indices exclusively in the left parotid gland (p=0.004). Conclusion: SjD is associated with thyroiditis-like changes in the thyroid, but HT lacks structural salivary gland involvement. Elastographic findings of these glands are similar in both diseases. Generally, ultrasonographically detected salivary gland parenchymal changes in SjD do not significantly affect glandular elasticity.

Abstract: Background and Objectives: Metabolic perturbations frequently occur during the acute phase of critical illness and may disrupt lipid homeostasis. Acute respiratory distress syndrome (ARDS) is a severe condition that contributes to multiple organ failure and is associated with high morbidity and mortality in critically ill patients with sepsis. This study aimed to evaluate the association between conventional plasma lipid parameters and clinical outcomes in critically ill sepsis patients. Materials and Methods: We conducted a prospective observational cohort study of critically ill sepsis patients in Taiwan between October 2020 and July 2025. Conventional plasma lipid parameters and clinical variables were measured at intensive care unit (ICU) admission. Clinical outcomes were compared between patients stratified by plasma HDL-C levels. Results: A total of 285 critically ill patients with sepsis were included. The overall all-cause hospital mortality rate was 37.9%. Patients with ARDS had significantly higher C-reactive protein (CRP) and interleukin-6 (IL-6) levels, higher risk of organ failure (i.e., APACHE II and SOFA scores), and lower plasma HDL-C levels (all p < 0.05). Non-survivors exhibited significantly greater organ failure severity and lower HDL-C levels compared with survivors (all p < 0.05). Patients with low HDL-C (≤ 22.5 mg/dL; n = 162, 56.8%) had significantly higher CRP and IL-6, greater organ failure severity, and increased 28-, 60-, 90-day, and hospital mortality, compared with those with high HDL-C (> 22.5 mg/dL; n = 123, 43.2%) (all p < 0.05). In multivariable logistic regression analyses, lower HDL-C were independently associated with hospital mortality. Conclusions: Plasma HDL-C levels at ICU admission are independently associated with hospital mortality in critically ill patients with sepsis. HDL-C may serve as a simple, accessible, and useful for early risk stratification in critically ill patients with sepsis.

Abstract: Background/Objectives: Metabolic syndrome (MetS) is a common cardiometabolic condition characterized by clustering of metabolic risk factors. Early identification in routine clinical practice remains challenging. This study aimed to explore the performance of artificial intelligence (AI)–based models for the prediction of MetS using routinely available clinical and laboratory parameters, with a particular focus on serum uric acid. Methods: This retrospective study was conducted using a publicly available dataset including 640 individuals (320 MetS-positive and 320 MetS-negative). MetS was defined according to modified National Cholesterol Education Program Adult Treatment Panel III criteria. Machine learning models were developed using combinations of age, sex, body mass index, uric acid, and albumin. Logistic regression, support vector machines, decision trees, k-nearest neighbors, and random forest algorithms were evaluated. Model performance was assessed using accuracy, area under the receiver operating characteristic curve (AUC), precision, recall, and F1-score. Internal validation was performed using 5-fold cross-validation. Results: Individuals with MetS had significantly higher uric acid levels compared to those without MetS (6.02 ± 1.57 vs. 2.84 ± 0.35 mg/dL, p < 0.001), while albumin levels were similar. The evaluated models demonstrated high classification performance within the study dataset, with accuracy values up to 0.99 and AUC values up to 0.99. Models using a limited number of variables, particularly body mass index, age, and uric acid, showed consistent performance. Models based on uric acid and albumin achieved accuracy values around 0.98, while single-variable models using uric acid alone achieved accuracy of 0.97. Conclusions: AI-based models using a limited set of routinely available clinical and laboratory parameters demonstrated the potential to classify MetS. Serum uric acid consistently emerged as one of the most discriminative variables, supporting its potential role as a clinically informative and accessible biomarker in MetS classification.

Abstract: Orofacial myofunctional therapy (OMT) addresses functional impairments involving tongue and lip function, swallowing, and breathing behaviors. Mobile health (mHealth) platforms may facilitate structured delivery and monitoring of home-based exercises, but evidence regarding feasibility in clinical practice remains limited. This study evaluated the feasibility of a smartphone-based OMT platform by examining pre- to post-intervention changes in functional measures and adherence. A retrospective observational analysis was conducted using 15 de-identified clinical records from a single clinical database. Eligible records included documented platform use, baseline and post-intervention measurements, symptoms of at least six months’ duration, and participation in the 16-week intervention. Measures included lip pressure, tongue pressure, swallowing performance, peak nasal inspiratory flow (PNIF), forward head posture, and incentive spirometry. Paired t-tests or Wilcoxon signed-rank tests were used as appropriate. Significant pre- to post-intervention changes were observed in forward head posture, PNIF, incentive spirometry, lip pressure, tongue pressure, and swallowing performance. Adherence was high, with 14 of 15 participants (93%) completing the 16-week program. No adverse events were reported. This retrospective analysis provides preliminary feasibility data for smartphone-delivered OMT. Findings are exploratory and do not establish efficacy, causality, diagnostic validity, or effectiveness for specific medical conditions. Prospective controlled studies using standardized outcome measures are warranted.

Abstract: Background. Modulation of the gut-liver axis with non-viable microbial components is a promising approach to correct metabolic disorders. The aim of the study was to evaluate the short-term efficacy and safety of the postbiotic lysate Lactobacillus rhamnosus DV-NRRL B-68023 on non-invasive measures of hepatic steatosis, trans-aminase activity, and anthropometric parameters in patients with MASLD. Methods. In a randomized, double-blind, placebo-controlled trial (NCT06352697), 52 patients were assigned 1:1 to receive the postbiotic Del-Immune V® Extra (100 mg twice daily; n=26) or placebo (n=26) for 3 months followed by a 3-month follow-up without treatment. The primary endpoints were FLI, HSI, and TyG. Additionally, lipid profile, ALT, AST and GGT activities, inflammatory markers and body composition indices were assessed. Results. In the ITT analysis, FLI decreased significantly more in the postbiotic group compared to placebo (p=0.049). HSI decreased in both groups without a significant difference between them (p=0.737), and a downward trend was observed for TyG. In the PP analysis (n=24 in each group), postbiotics were associated with a significant de-crease in waist circumference (p=0.003) and a trend towards a decrease in visceral fat (p=0.079). ALT activity decreased by 17.5% (p=0.011), AST by 10.4% (p=0.007), but gradually returned to baseline values after treatment discontinuation. Lipid profile and inflammation indices did not change significantly. All adverse events were mild and self-limiting. Conclusions. Three months of postbiotic L. rhamnosus lysate DV-NRRL B-68023 ad-ministration was well tolerated and improved noninvasive measures of steatosis and abdominal obesity in patients with MASLD. The effect on transaminases was transient. Postbiotics may be considered as an additional noninvasive approach to the treatment of MASLD in combination with lifestyle changes.

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disorder shaped by inter-organ crosstalk: dynamic, bidirectional communication through which the liver and endocrine organs, gut, adipose tissue, brain, kidney, skeletal muscle, and bone exchange signals to coordinate metabolism, immunity, and tissue homeostasis. Across these axes, neural circuits, hormones, cytokines, adipokines, hepatokines, myokines, osteokines, bile acids, microbial metabolites, lipids, extracellular vesicles, and microRNAs integrate nutrient handling, insulin action, immunity, mitochondrial function, and tissue remodeling. Perturbation of these networks converts physiological homeostasis into self-reinforcing loops of substrate overflow, endocrine dysregulation, dysbiosis, inflammation, and fibrogenesis, while hepatic dysfunction propagates renal, neurocognitive, cardiometabolic, and musculoskeletal complications. This framework helps explain why individuals with comparable steatosis show divergent trajectories of metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, extrahepatic disease, and treatment response. It also highlights tractable points of intervention, including restoration of adipose buffering, modulation of gut microbial and bile-acid signaling, correction of endocrine drivers, preservation of muscle and bone, and integrated cardio–kidney–liver risk reduction across different disease stages and clinical phenotypes. We argue that precision hepatology should move beyond isolated assessment of liver fat and fibrosis towards multidimensional phenotyping of dominant crosstalk mechanisms. Longitudinal multi-omic studies and trials incorporating outcomes across organs are now required to distinguish causal signals from disease correlates, define clinically actionable endotypes, and test whether targeting one node can restore durable metabolic and functional resilience throughout the interconnected MASLD network, while improving patient-centered outcomes across the disease course.

Abstract: Background/Objectives: Diabetic foot syndrome (DFS) is a serious complication of diabetes that poses a high risk of morbidity/mortality. The management of these patients requires a multidisciplinary team approach, as these patients are “complex” and “fragile”. Despite this, the rate of re-amputation remains high. This study aims to evaluate the degree of multidimensional complexity in patients with DFS using specific tools and to determine if it is an additional risk factor for amputation. Methods: The study was conducted on a cohort of 115 patients referred to a Tertiary Center of University Hospital of Modena from January to December 2021. The study used 12 variables to assess patients, including age, sex, caregiver presence, BARTHEL INDEX, LAWTON-BRODY SCALE, Mini Mental State Examination, Cumulative Illness Rating Scale (CIRS), SINBAD system, Malnutrition Universal Screening Tool and Italian National Association of Social Workers Tool. All patients were taken care of by the Multidisciplinary Team in order to standardize care according to the updated guidelines. Patients were classified based on amputation and revascularization status. Statistical analyses were performed using R software version 4.1.1. Results: The analysis showed that a greater clinical complexity and more severe ulcer had a greater risk of amputation (respectively OR 3.13, p 0.035 and OR 1.53, p 0.015). The study confirms the predictive value of tools such as CIRS and SINBAD in amputation risk stratification for patients with DFS. Conclusions: Although limitations, due to a small sample size, the use of multidisciplinary approach and multidimensional evaluation tools can identify “unconventional” risk factors that, if modified, could delay and/or reduce the risk of amputation. Further studies are needed to investigate the role of caregiving in the prevention of amputation in patients with DFS.

Abstract: Many people take more than one medicine at a time — a spoon of cough syrup, a fever tablet, a cold-and-flu sachet — often on the same afternoon, and sometimes with a drink of alcohol. This is casually called a “medicine cocktail.” This article explains, in plain school-textbook language, why such combinations can be harmful. It corrects a common misunderstanding: dangerous combinations usually do not arise because two drugs meet in a glass and brew a brand-new poison. Far more often the harm comes from duplicated active ingredients, additive effects, or the way the body chemically transforms a drug once it is swallowed. We examine what makes any molecule “poisonous,” the small number of cases where a genuinely toxic new molecule is formed, and — in an expanded central section — why alcohol is the single most dangerous thing to mix with everyday medicines. Every worked example ends with a short, simple “what to avoid” box written for school students. All chemical changes are given as balanced equations.

Abstract: Increasingly sophisticated genetic panels have disproportionately increased the identification rate of novel gene variants in Mendelian conditions. In Fabry disease (FD), this phenomenon is particularly relevant because the pathogenicity of individual gene variants has an impact on treatment proposal. In fact, FD is characterized by a phenotypical heterogeneity depending on patients' biological sex and the underlying GLA mutation. This represents the main reason why integrating genetic data with phenotypic expression is challenging, and defining the pathogenic role of novel variants remains complex. The early discrimination between pathogenic and non-pathogenic GLA variants is crucial to enable timely initiation of treatments such as Enzyme Replacement Therapy (ERT), which has been shown to significantly slow down the progression of the disease. In fact, the most severe cases of FD have a significantly compromised quality of life up to reduced life expectancy, especially with regard to cardiac and renal complications. In recent years, some GLA variants have been reclassified following investigation and clinical observations by multidisciplinary working groups that have made it possible to better define if they are pathogenic or not. Regardless of the clinical scenario leading to the identification of a novel GLA variant (i.e., family screening, neonatal screening, clinical profile suggestive of FD, incidental finding), any genetic finding becomes relevant when it is complemented by laboratory, clinical and instrumental investigations that require a concerted effort among the many health care professionals involved in the diagnostic process. The present work summarizes the outcomes of a series of expert meetings with the aim to provide some shared and practical indications for managing the genetic report of a novel GLA variant so to promptly start the most suitable diagnostic journey and assess corresponding phenotype and clinical characterization.

Abstract: Background: Acute myeloid leukemia (AML) remains a treatment challenge due to the systemic toxicity of conventional chemotherapy. Venetoclax, a selective BCL-2 inhibitor, shows promise in the treatment of AML; however, its clinical efficacy is limited due to inadequate pharmacokinetic properties. PEG-PLGA-based polymeric nanoparticles provide a biocompatible platform for improving drug stability, controlling release behavior, and potentially enhancing intracellular drug availability. Methods: The physicochemical properties of VEN-PEG-PLGA nanoparticles were evaluated by dynamic light scattering (DLS), scanning electron microscopy (SEM), drug loading analysis, and in vitro drug release. Antileukemic activity was assessed in THP-1 cells using the CCK-8 cytotoxicity assay, propidium iodide (PI)-based cell cycle analysis, Annexin V-FITC/PI apoptosis assay, and Western blot analysis of Bcl-2, cleaved caspase-3, cleaved caspase-9, ERK1/2, phospho-ERK1/2 (p-ERK1/2), NF-κB, and phospho-NF-κB (p-NF-κB). Results: VEN-PEG-PLGA nanoparticles exhibited a mean particle size of 186 ± 4 nm with a polydispersity index of 0.195 ± 0.005, 89% loading efficiency, and 6.26% loading capacity. The nanoparticles demonstrated a pH-responsive drug release profile, reaching approximately 72–74% cumulative release at pH 7.4 and 88–89% at pH 5.5 after 96 h. In THP-1 cells, both free venetoclax and VEN-PEG-PLGA na-noparticles exhibited concentration-dependent cytotoxicity, although free venetoclax showed greater cytotoxicity, with EC₅₀ values of 5.59 × 10⁻⁷ M and 1.35 × 10⁻⁶ M, respectively. Cell cycle analysis demonstrated an increase in the G0/G1 cell population from 49.30% in the control group to 61.04% following treatment with VEN-PEG-PLGA nanoparticles, accompanied by a reduction in the G2/M phase. Annexin V-FITC/PI analysis showed that VEN-PEG-PLGA nanoparticles in-creased the proportion of late apoptotic cells to 36.99%, compared with 22.13% following free venetoclax treatment. Western blot analysis demonstrated reduced Bcl-2, ERK1/2, phos-pho-ERK1/2, and phospho-NF-κB expression, together with increased cleaved caspase-3 and cleaved caspase-9 expression in both treatment groups, with these changes being more pronounced in the VEN-PEG-PLGA nanoparticle-treated group. Conclusions: Venetoclax-loaded PEG-PLGA nanoparticles modulated apoptosis-related responses, cell cycle progression, and BCL-2/ERK1/2/NF-κB-associated signaling pathways in THP-1 cells. These findings provide preliminary in vitro evidence supporting further preclinical evaluation of VEN-PEG-PLGA na-noparticles in AML models.

Abstract: Background/Objectives The accurate estimation of glomerular filtration rate (GFR) is essential for assessing trends in the prevalence (CKD), yet standard serum creatinine (SCr)-based estimates (eGFR_SCr) are limited by individual variations in muscle mass. While demographic surrogates like age and sex are typically used to account for these variations, they often lead to eGFR misclassification in individuals. This study investi-gated whether normalizing SCr to Dual-energy X-ray absorptiometry (DEXA)-derived Lean Mass Index (LMI) improves the association with cardiometabolic risk. Methods We analyzed data from 11,143 adults (mean age 46.0 ± 17.2 years) in the Austrian LEAD (Lung, hEart, sociAl, boDy) cohort. Individual SCr concentrations were normalized to sex- and age-specific LMI reference values to calculate LMI-adjusted eGFR (eGFR_LMISCr). The strength of associations between eGFR_SCr and eGFR_LMISCr with cardiometabolic risk factors (dyslipidemia, hypertension, pre-diabetes/diabetes, and metabolic syndrome) was compared using age- and sex-adjusted logistic regression with bootstrap resampling. Results While eGFR_SCr and eGFR_LMISCr were highly correlated (R2 = 0.897), LMI adjust-ment led to significant reclassification between CKD stages G1, G2, and G3a. eGFR_LMISCr demonstrated significantly stronger associations with dyslipidemia, arterial hyperten-sion, pre-diabetes/diabetes, and metabolic syndrome compared to standard eGFR_SCr. Longitudinal analysis showed that LMI adjustment stabilizes eGFR change estimates, particularly in younger men. Conclusion Adjusting serum creatinine for LMI signifi-cantly enhances the epidemiological utility of GFR estimation. GFR_LMISCr improves car-diometabolic risk stratification, potentially offering a valuable method to "salvage" the utility and comparability of eGFR_SCr in historic cohorts in early-stage filtration impair-ment in settings where DEXA but not Cystatin C is available.