IntroductionMultiple myeloma (MM) is a hematologic malignancy that predominantly affects older adults and poses substantial therapeutic challenges due to the high prevalence of comorbidities and limited treatment tolerability. This study evaluates the cost-effectiveness of four first-line treatment regimens for elderly MM patients, ineligible for autologous stem cell transplantation (ASCT): bortezomib, melphalan, and prednisone (VMP); daratumumab in combination with VMP (D-VMP); lenalidomide and dexamethasone (Rd); and daratumumab combined with Rd (DARA-Rd).MethodsA state-transition Markov model was developed, with transition probabilities parameterized using data derived from the pivotal ALCYONE and MAIA clinical trials. Cost-effectiveness was assessed from the perspective of the Italian National Health Service using a state-transition model comparing VMP, D-VMP, Rd and DARA-Rd over a 5.25-year horizon. Probabilistic sensitivity analyses (PSA) were conducted to account for parameter uncertainty and summarized through cost-effectiveness acceptability curves (CEACs).ResultsRd generated 1.53 QALYs for €60,483, whereas D-VMP generated 1.70 QALYs at €88,331, resulting in an ICER of €160,804/QALY. DARA-Rd and VMP were dominated.ConclusionThe findings indicate that Rd is the strategy with the highest probability of being cost-effective at willingness-to-pay (WTP) thresholds below €250,000 per quality-adjusted life year (QALY) gained. Conversely, for WTP thresholds exceeding €250,000 per QALY gained, D-VMP emerges as the preferred option, offering the most favorable balance between additional costs and health benefits.

Current guidelines are split on the role that imaging has in the clinical assessment of osteoarthritis (OA), yet clinical CT imaging has now revealed how a 3D approach can improve prediction of TH replacement (THR) over 2D measures alone. We applied 2D grading and measurement along with 3D cortical bone mapping to ordinary clinical CT imaging of the pelvis in a cohort of healthy older people, aiming to discover which of these features had clinical utility in predicting THR within 8 yr and which were related to baseline hip pain. Using a nested case-control design in the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study, 74 future THR cases were age and sex-matched with 184 controls from the cohort (age 74 ± 5 yr). Baseline assessment involved a validated hip pain questionnaire and pelvic CT. The following were performance-tested using receiver operating characteristics analysis and clinical utility index: (1) hip pain, (2) Kellgren and Lawrence grade (K&L grade), (3) minimum joint space width, and (4) 3D cortical bone thickness (CTh). The clinical utility index for prediction of future THR from baseline pain was poor at 0.28, with the inclusion of imaging improving this to 0.79 (K&L grade) and 0.82 (3D CTh). Self-reported hip pain at baseline was also a poor-to-marginal predictor of THR (AUC = 0.63), but 3D cortical thickening at the femoral head was predictive of future THR (0.81). Having radiographic OA strongly predicted THR irrespective of hip pain (0.85). Combining hip pain, K&L grade, and 3D CTh gave optimal prediction (0.88). Ascertainment bias may have occurred, if primary care physicians requested their own radiographs of their patients' hips. Imaging features from standard clinical CT identifies patients at high risk of progression to surgery for OA, regardless of baseline pain.

Pompe disease is a rare, progressive lysosomal storage disorder caused by acid α-glucosidase deficiency, leading to glycogen accumulation, proximal muscle weakness, and respiratory decline. Enzyme replacement therapy (ERT) significantly improves survival and stabilizes motor function, but IgE-mediated hypersensitivity reactions (HSRs) can critically compromise treatment, posing a major clinical challenge. Desensitization protocols allow temporary tolerance to ERT, yet breakthrough reactions may occur, necessitating adjunctive strategies such as omalizumab. We report a 40-year-old woman with late-onset Pompe disease who developed severe IgE-mediated HSRs to alglucosidase alfa after years of uneventful therapy. Basophil activation testing (BAT) and serum-specific IgE confirmed an IgE-mediated mechanism. A 15-step, 5-bag desensitization protocol allowed temporary tolerance, but breakthrough reactions required therapy interruption. Upon switching to avalglucosidase alfa, BAT demonstrated IgE cross-reactivity, and a new desensitization protocol was implemented. Initial infusions were complicated by recurrent HSRs. The addition of subcutaneous omalizumab (300 mg monthly), administered two days before ERT, enabled safe reintroduction. Moreover, therapy was resumed gradually, starting at 50

Gaucher disease (GD) is a lysosomal disease caused by mutations in the GBA1 gene, leading to glucosylceramide and glucosylsphingosine accumulation. GBA1 mutations are also the most common genetic risk factor for Parkinson’s disease (PD). Increased expression of glycoprotein non-metastatic melanoma protein B (gpNMB), a potential biomarker of inflammation and neurodegeneration, has been reported in PD, GD and other LSDs. Plasma concentrations of gpNMB are correlated with the accumulation of bioactive lipid substrates in several chronic inflammatory diseases and gpNMB stimulates lipogenesis in white adipocytes. To explore its potential significance in GD we measured plasma gpNMB in patients with Gaucher Disease type 1 (GD1), Gaucher Disease Type 3 (GD3), GD1-PD, PD and GBA heterozygous PD and in different clinicopathological subtypes. The study enrolled participants the GAUCHERITE Cohort in the UK (172 GD1 and 20 GD3 patients) and the Biopark Cohort (72 IPD patients) in Sweden. Plasma concentrations of gpNMB were significantly higher in patients with Gaucher disease (mean: 200.9; range: 9.8-1643 ng/ml) compared with healthy controls (mean: 35.1; range.: 10.1- 125 ng/ml), including those receiving enzyme replacement therapy (ERT). Notably, gpNMB concentrations remained elevated in GD1 patients who had received ERT for more than 5 years. The biomarker was particularly elevated in patients who had been splenectomized, those with known pulmonary or liver disease, and those with monoclonal gammopathy, despite enzyme therapy. No statistical difference was found in plasma gpNMB concentrations between treated patients with GD1 and GD3. On average, there was no difference in plasma gpNMB concentrations between Gaucher patients with or without Pakinsonism. As expected however plasma gpNMB concentrations among patients with Parkinsonism were higher in those with type 1 Gaucher disease than either GBA1 heterozygotes or those with idiopathic PD (p=0.0001). Our findings indicate that the association of plasma gpNMB with liver cirrhosis, gammopathy and pulmonary disease in Gaucher disease warrants further investigation. Additionally, plasma gpNMB may serve as a supportive biomarker in the evaluation and clinical monitoring of residual disease activity. However, plasma gpNMB neither differentiated between the neuronopathic subtypes of Gaucher disease nor idiopathic Parkinson’s disease.

Background/Objectives: Gaucher disease (GD) is a lysosomal disorder caused by a deficiency of β-glucosidase. Disease-modifying therapies (DMTs) include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Glucosylsphingosine (lyso-Gb1) is a biomarker with high sensitivity and specificity in GD. Methods: In GD patients attending a specialist centre, we evaluated dried blood spot lyso-Gb1 levels (normal values ≤ 6.8 ng/mL) by treatment status, sex, GD type and genotype, ERT dose, DMT type and duration, spleen status, and association with other GD biomarkers. Results: A total of 111 patients were screened; 100 (54M:46F; 93 GD1 and 7 GD3; median age 45.2 years, IQR 34.2–57.2; 7 naive and 93 patients on DMTs for a median of 10.4 years, IQR 5.7–21.2) had at least one lyso-Gb1 measurement. Median lyso-Gb1 values were higher in naïve (195, IQR 48.6–388) patients than treated patients (47.1, IQR 23.1–89.7), p = 0.015; higher in those treated ≥ 15 years (62.9, IQR 36.6–103) than in those treated < 15 years (35.1, IQR 20.3–73.9), p = 0.006; and higher in splenectomised (83.4, IQR 34.7–224.5) patients than non-splenectomised patients (40.7, IQR 21.4–77.1), p = 0.044. ERT dose > 60 U/kg had high median lyso-Gb1 values (87.3, IQR 19.7–126), reflecting greater disease burden, and this high dose was only used in patients with GD3. Lyso-Gb1 correlated with chitotriosidase (r = 0.495; p < 0.001) and haemoglobin (r = −0.231; p = 0.022). In a subset of 50 patients with paired values, lyso-Gb1 decreased from baseline (median −1.7 ng/mL, IQR −24.5–14.8). Conclusions: Whilst there was a modest decrease in lyso-Gb1 over time on DMTs, the values remained significantly above the normal range, which may be driven by underlying mechanisms such as inflammation.

Inborn errors of immunity (IEI) entail a diverse group of disorders resulting from hereditary or de novo mutations in single genes, leading to immune dysregulation. This study explores the clinical utility of next-generation sequencing (NGS) techniques in diagnosing monogenic immune defects. Eight patients attending the immunodeficiency clinic and with unclassified antibody deficiency were included in the analysis. Clinical records, immune characteristics, and family histories were reviewed, and a target gene panel (TGP) sequencing was performed to identify pathogenic variants. TGPs identified seven variants in TNFRSF13B (TACI), CARMIL2, STAT1, STAT3, and ORAI1 genes. These findings provided definitive diagnoses and proper prognostic assessment. Patients exhibited a wide range of clinical manifestations, including recurrent infections, autoimmune cytopenias, and organ-specific complications. The genetic diversity observed highlights the importance of genetic testing in diagnosing IEIs and tailoring treatments. This study underscores the role of TGPs in diagnosing IEIs, revealing significant genetic heterogeneity and phenotypic variability. They offer a precise tool for identifying underlying genetic defects, facilitating personalized medicine approaches, and eventually improving patient outcomes. The findings emphasize the need for comprehensive genetic testing to uncover novel pathogenic variants, enhancing our understanding of immune system dysfunction. NGS is a critical tool for the management of IEI, enabling precise diagnosis and personalized treatment strategies. Despite resource limitations, the progressive affordability is likely to expand its clinical utility, ultimately improving patient care and advancing the field of immunology. In the meantime, accurate phenotypic assessment is essential for resource optimization and case prioritization.

Hypereosinophilic syndrome (HES) encompasses a heterogeneous and complex group of different subtypes within the wider group of hypereosinophilic disorders. Despite increasing research interest, several unmet needs in terms of disease identification, pathobiology, phenotyping, and personalized treatment remain to be addressed. Also, the prospective burden of non-malignant HES and, more in general, HE disorders is currently unknown. On a practical note, shortening the diagnostic delay and the time to an appropriate treatment approach probably represents the most urgent issue, even in light of the great impact of HES on the quality of life of affected patients. The present document represents the first action that the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC) has finalized within a wider project aiming to establish a collaborative national network on HES (InHES—Italian Network on HES) for patients and physicians. The first step of the project could not but focus on defining a common language as well as sharing with all of the medical community an update on the most recent advances in the field. In fact, the existing literature has been carefully reviewed in order to critically integrate the different views on the topic and derive practical recommendations on disease identification and treatment approaches.

Background Fabry disease is a rare inherited disorder resulting from deficient α-galactosidase A enzyme activity. Common disease manifestations are sweating abnormalities, neuropathic pain, gastrointestinal symptoms and fatigue. Challenges are faced by health care professionals in evaluating symptom burden in the current clinical setting, and the demand for alternative methods for monitoring disease-specific symptoms has seen an acceleration in recent years. Smartphone technologies offer the potential for continuity of care and surveillance. As a part of a quality improvement project, a disease specific app was developed in collaboration with a software company (Health Touch Ltd) and made available for patient use in May 2018. The Fabry mobile app records five categories: pain, gastrointestinal symptoms, sweating, activity levels, medications. Fabry disease patients with gastrointestinal and pain symptoms attending the Lysosomal Storage Disorders Unit of the Royal Free London NHS Foundation Trust were reviewed to assess eligibility and invited to download the app for recording their symptoms (activity, sweating, pain and gastrointestinal) and medications. Patient-generated data were transmitted to a secure website for clinicians to review. Results One-hundred and thirty-nine symptomatic Fabry disease patients who had a smartphone (iPhone or android) were invited to download the app. Sixty-seven patients (26 males and 41 females; median age, 49 years [range, 20–81]) downloaded and tracked the Fabry App at least once. The median frequency of use per patient was 6 (range, 1–629). Pain in the hands and abdominal pain were significantly higher ( p = 0.009 and p = 0.007, respectively) in patients with classic phenotype compared with patients with non-classic phenotypes. Conclusions We demonstrated the feasibility and acceptability of a smartphone app to facilitate the remote assessment and monitoring of Fabry disease symptom burden on a daily/weekly basis, as an alternative to the current standard of care that requires patients to recall their symptoms during 6 to 12 monthly annual clinic visits. Patients who were more likely to use the app had greater disease burden. This innovation has the potential to assess disease progression, early therapeutic intervention, thereby decreasing the burden of morbidity and mortality among Fabry patients, and to record long-term effects of Fabry-specific therapies.

BACKGROUND:There is limited information on the α-galactosidase A (α-Gal-A) in vivo response in Fabry patients receiving migalastat. In this single centre study, we evaluated changes from baseline in α-Gal A activity, lyso-Gb3 and other assessments in patients on migalastat. RESULTS:79 patients were recruited (48 M:31F; median duration receiving migalastat 3.8 years [range = 0.4-14.9 years]). N215S was the commonest genotype in males (67 %) and females (29 %). Leukocyte α-Gal-A showed a positive change from baseline in males (n = 4; median = 20.05); females (n = 8; median = 26). Of these, 3 males and 1 female had N215S (median = 16.7), while 7 females and 1 male had other genotypes (median = 26). No significant changes observed in plasma α-Gal-A. Cross-sectional analysis of post-baseline data confirmed leukocyte α-Gal-A enhancement in males (n = 47; median = 20); females (n = 30; median = 72); N215S (n = 41; median = 29) and other genotypes (n = 36; median = 36.5). Plasma and dried blood spot (DBS) lyso-Gb3 correlated at baseline and post-baseline (r = 0.77 and r = 0.96; p=<0.0001). CONCLUSIONS:In the 12 patients with paired data, there was a median enzyme enhancement of 17.4 (relative change = 2.54) and 33 (relative change = 0.87) in males and in females, respectively. The cross-sectional post-baseline data in 47 patients corroborated leukocyte α-Gal-A enhancement on migalastat. Plasma and DBS lyso-Gb3 correlated well supporting DBS utility for disease monitoring.

Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.

Background/Objectives: Patients with Gaucher disease have a high risk of bone disease, with osteonecrosis representing the most debilitating complication. The pathogenesis of osteonecrosis has not been fully elucidated yet, and there is an unmet need for predictive biomarkers of bone complications. We aimed to assess the utility of angiogenesis and bone turnover biomarkers as predictors of osteonecrosis in Gaucher disease. Methods: Angiogenesis and bone turnover biomarkers were measured in 146 Gaucher disease patients (70M:76F, median age 49.5 [IQR 36.7 to 61]) with/without osteonecrosis enrolled in the UK-based registry GAUCHERITE [enrolment 2015–2017]. Receiver-operating characteristic curve analysis was used to compare the osteonecrosis predictive value of angiogenesis and bone turnover biomarkers and determine the optimal cut-off values for each biomarker. Results: Sixty-two patients had osteonecrosis before study enrolment, 11 had osteonecrosis during follow-up, and 73 remained osteonecrosis-free. Patients with osteonecrosis showed increased osteopontin and matrix metalloproteinase (MMP)-2 levels and decreased MMP-9 and vascular endothelial growth factor (VEGF)-C compared with those free from osteonecrosis. MMP-9 predicted future osteonecrosis with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC] 0.84 [95% CI 0.84–0.99]; sensitivity/specificity 82%/75%; cutoff value ≤ 72,420 pg/mL) than osteopontin, MMP-2 and VEGF-C when taken alone. The combination of MMP-9 and VEGF-C further increased the discriminating accuracy. Conclusions: The osteopontin–MMPs–VEGF axis is dysregulated in Gaucher disease patients with osteonecrosis. The combination of MMP-9 and VEGF-C circulating levels may serve to identify Gaucher disease patients at risk of osteonecrosis.

Immunoglobulin (Ig) replacement therapy (IgRT) consists of the administration of low-dose human polyclonal Igs for the treatment of primary and secondary hypogammaglobulinemia that are associated with recurrent infections and immune dysfunction. IgRT restores physiological antibody levels and induces an immunomodulatory effect by strengthening immune effector cells, thus reducing infections. Here, we describe the pharmacology of different Ig formulations with a particular focus on their mechanism of action as low-dose IgRT, including the direct anti-microbial effect and the immunomodulatory function. In addition, we describe the use of therapeutic Igs for the management of multiple myeloma (MM), a hematologic malignancy characterized by severe secondary hypogammaglobulinemia associated with poor patient outcome. In MM settings, IgRT prevents life-threatening and recurrent infections showing promising results regarding patient survival and quality of life. Nevertheless, the clinical benefits of IgRT are still controversial. A deeper understanding of the immune-mediated effects of low-dose IgRT will provide the basis for novel combined therapeutic options and personalized therapy in MM and other conditions characterized by hypogammaglobulinemia.

Background Work organization and psychosocial factors influencing sleep patterns may be significant risk factors for developing obesity and metabolic syndrome (MetS). However, the impact on the health of working patterns in the fishing sector is not well characterized. The aim of the study is to determine the prevalence of MetS and its components in fishermen and to analyze occupational-specific risk factors contributing to metabolic alterations. Methods One hundred forty-three male fishermen from Apulia (Southern Italy) and 93 male university workers age-matched and from the same geographical area were included in this cross-sectional study. A questionnaire was administered to investigate socio-demographic variables, work activity, health status, and dietary habits. All subjects underwent clinical evaluation and blood sampling to depict their metabolic profile. Results A higher body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (p < 0.001) were observed in fishermen than in university workers. No significant difference between the two groups was observed in the prevalence of MetS (15.4% fishermen vs 16.1% university workers) and its relevant diagnostic criteria, except abdominal obesity (42.7% fishermen vs 29.0% university workers, p = 0.021). The Castelli risk index, the monocyte/c-HDL ratio, and the Sokolow index were significantly greater in fishermen (p < 0.001). In the fishermen group, the total number of sleeping hours on working days was negatively correlated with WC (r = -0.17; p = 0.04), low-density lipoprotein cholesterol (c-LDL) (r = -0.21; p = 0.02), and the homeostasis model assessment (HOMA) index (r = -0.19; p = 0.02). Conclusion The higher prevalence of obesity and the imbalance of the metabolic profile observed in fishermen could be related to occupational factors, including the specific working pattern that influences their sleeping hours and sleeping-waking rhythms.

Background This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature. Methods/results We combined classic plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, 6 months after bariatric surgery, revealed the loss of the abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurred via the establishment of novel gene expression landscapes. NETosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. Conclusions We showed that the morbidly obese and lipodystrophy groups, despite some differences, shared a common cardiometabolic syndrome signature. We also showed that this could be used to discriminate, amongst the normal population, those individuals with a higher likelihood of presenting with the disease, even when not displaying the classic features.

Background Patients with Gaucher disease (GD) have a high risk of fragility fractures. Routine evaluation of bone involvement in these patients includes radiography and repeated dual-energy x-ray absorptiometry (DXA). However, osteonecrosis and bone fracture may affect the accuracy of DXA. Purpose To assess the utility of DXA and radiographic femoral cortical thickness measurements as predictors of fragility fracture in patients with GD with long-term follow-up (up to 30 years). Materials and Methods Patients with GD age 16 years and older with a detailed medical history, at least one bone image (DXA and/or radiographs), and minimum 2 years follow-up were retrospectively identified using three merged UK-based registries (Gaucherite study, enrollment 2015-2017; Clinical Bone Registry, enrollment 2003-2006; and Mortality Registry, enrollment 1993-2019). Cortical thickness index (CTI) and canal-to-calcar ratio (CCR) were measured by two independent observers, and inter- and intraobserver reliability was calculated. The fracture-predictive value of DXA, CTI, CCR, and cutoff values were calculated using receiver operating characteristic curves. Statistical differences were assessed using univariable and multivariable analysis. Results Bone imaging in 247 patients (123 men, 124 women; baseline median age, 39 years; IQR, 27-50 years) was reviewed. The median follow-up period was 11 years (IQR, 7-19 years; range, 2-30 years). Thirty-five patients had fractures before or at first bone imaging, 23 patients had fractures after first bone imaging, and 189 patients remained fracture-free. Inter- and intraobserver reproducibility for CTI/CCR measurements was substantial (range, 0.96-0.98). In the 212 patients with no baseline fracture, CTI (cutoff, ≤0.50) predicted future fractures with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI: 0.84, 0.99; sensitivity, 92%; specificity, 96%) than DXA T-score at total hip (AUC, 0.78; 95% CI: 0.51, 0.91; sensitivity, 64%; specificity, 93%), femoral neck (AUC, 0.73; 95% CI: 0.50, 0.86; sensitivity, 64%; specificity, 73%), lumbar spine (AUC, 0.69; 95% CI: 0.49, 0.82; sensitivity, 57%; specificity, 63%), and forearm (AUC, 0.78; 95% CI: 0.59, 0.89; sensitivity, 70%; specificity, 70%). Conclusion Radiographic cortical thickness index of 0.50 or less was a reliable independent predictor of fracture risk in Gaucher disease. Clinical trial registration no. NCT03240653 © RSNA, 2022 Supplemental material is available for this article.

Several studies highlighted the importance of platelets in the tumor microenvironment due to their ability to interact with other cell types such as leukocytes, endothelial, stromal and cancer cells. Platelets can influence tumor development and metastasis formation through several processes consisting of the secretion of growth factors and cytokines and/or via direct interaction with cancer cells and endothelium. Patients with visceral obesity (VO) are susceptible to pro-thrombotic and pro-inflammatory states and to development of cancer, especially colon cancer. These findings provide us with the impetus to analyze the role of platelets isolated from VO patients in tumor growth and progression with the aim to explore a possible link between platelet activation, obesity and colon cancer. Here, using xenograft colon cancer models, we prove that platelets from patients with visceral obesity are able to strongly promote colon cancer growth. Then, sequencing platelet miRNome, we identify miR-19a as the highest expressed miRNA in obese subjects and prove that miR-19a is induced in colon cancer. Last, administration of miR-19a per se in the xenograft colon cancer model is able to promote colon cancer growth. We thus elect platelets with their specific miRNA abundance as important factors in the tumor promoting microenvironment of patients with visceral obesity.

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated "omics" approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (vs. controls). Compared with healthy subjects, MetS patients showed higher free fatty acids, diglycerides, phosphatidylcholines, and triglycerides, particularly those enriched in products of de novo lipogenesis. On the other hand, the "lysophosphatidylcholines to phosphatidylcholines" and "cholesteryl ester to free cholesterol" ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated "omics" approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.