Serum ARGS-aggrecan in a phase 2 clinical trial targeting osteoarthritis.

OBJECTIVE: To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee-related pain and function. DESIGN: ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post-treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured by magnetic resonance imaging, function and pain by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscores. Associations between cumulative change in ARGS and change in cartilage thickness or WOMAC subscores were evaluated by linear regression. RESULTS: S201086 reduced serum levels of ARGS in a dose-dependent manner throughout the treatment period. Maximal reduction was at 4 weeks with a 58.5% [95% CI 60.8%, 56.2%] reduction of ARGS compared to baseline for 300 mg S201086. Two weeks post-treatment, ARGS concentrations rebounded with a dose-dependent overshoot compared to baseline levels. Cumulative change of ARGS concentration from baseline to week 52 had no effect on change in cartilage thickness (slope -0.8×10-6 [-2.9×10-6, 1.3×10-6]) or change in WOMAC pain and function (slopes -30×10-6 [-64×10-6, 5.2×10-6] and -97×10-6 [-214×10-6, 20×10-6], respectively) at week 52. CONCLUSION: Systemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function.

A deep learning method for predicting knee osteoarthritis radiographic progression from MRI.

BACKGROUND: The identification of patients with knee osteoarthritis (OA) likely to progress rapidly in terms of structure is critical to facilitate the development of disease-modifying drugs. METHODS: Using 9280 knee magnetic resonance (MR) images (3268 patients) from the Osteoarthritis Initiative (OAI) database , we implemented a deep learning method to predict, from MR images and clinical variables including body mass index (BMI), further cartilage degradation measured by joint space narrowing at 12 months. RESULTS: Using COR IW TSE images, our classification model achieved a ROC AUC score of 65%. On a similar task, trained radiologists obtained a ROC AUC score of 58.7% highlighting the difficulty of the classification task. Additional analyses conducted in parallel to predict pain grade evaluated by the WOMAC pain index achieved a ROC AUC score of 72%. Attention maps provided evidence for distinct specific areas as being relevant in those two predictive models, including the medial joint space for JSN progression and the intra-articular space for pain prediction. CONCLUSIONS: This feasibility study demonstrates the interest of deep learning applied to OA, with a potential to support even trained radiologists in the challenging task of identifying patients with a high-risk of disease progression.

Bottlenecks in the Acute Stroke Care System during the COVID-19 Pandemic in Catalonia.

INTRODUCTION: The COVID-19 pandemic resulted in significant healthcare reorganizations, potentially striking standard medical care. We investigated the impact of the COVID-19 pandemic on acute stroke care quality and clinical outcomes to detect healthcare system's bottlenecks from a territorial point of view. METHODS: Crossed-data analysis between a prospective nation-based mandatory registry of acute stroke, Emergency Medical System (EMS) records, and daily incidence of COVID-19 in Catalonia (Spain). We included all stroke code activations during the pandemic (March 15-May 2, 2020) and an immediate prepandemic period (January 26-March 14, 2020). Primary outcomes were stroke code activations and reperfusion therapies in both periods. Secondary outcomes included clinical characteristics, workflow metrics, differences across types of stroke centers, correlation analysis between weekly EMS alerts, COVID-19 cases, and workflow metrics, and impact on mortality and clinical outcome at 90 days. RESULTS: Stroke code activations decreased by 22% and reperfusion therapies dropped by 29% during the pandemic period, with no differences in age, stroke severity, or large vessel occlusion. Calls to EMS were handled 42 min later, and time from onset to hospital arrival increased by 53 min, with significant correlations between weekly COVID-19 cases and more EMS calls (rho = 0.81), less stroke code activations (rho = -0.37), and longer prehospital delays (rho = 0.25). Telestroke centers were afflicted with higher reductions in stroke code activations, reperfusion treatments, referrals to endovascular centers, and increased delays to thrombolytics. The independent odds of death increased (OR 1.6 [1.05-2.4], p 0.03) and good functional outcome decreased (mRS ≤2 at 90 days: OR 0.6 [0.4-0.9], p 0.015) during the pandemic period. CONCLUSION: During the COVID-19 pandemic, Catalonia's stroke system's weakest points were the delay to EMS alert and a decline of stroke code activations, reperfusion treatments, and interhospital transfers, mostly at local centers. Patients suffering an acute stroke during the pandemic period had higher odds of poor functional outcome and death. The complete stroke care system's analysis is crucial to allocate resources appropriately.

The design of a randomized, placebo-controlled, dose-ranging trial to investigate the efficacy and safety of the ADAMTS-5 inhibitor S201086/GLPG1972 in knee osteoarthritis.

Objective: This study aims to assess the efficacy of the anticatabolic 'a disintegrin and metalloproteinase with thrombospondin motif-5' (ADAMTS-5) inhibitor, S201086/GLPG1972, in slowing cartilage loss in participants with knee osteoarthritis (OA). Design: ROCCELLA (NCT03595618) is a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 trial. We plan to enrol a total of 852 participants with knee OA across 12 countries. Participants will be randomized 1:1:1:1 to receive 75, 150 or 300 â€‹mg S201086/GLPG1972, or placebo orally, once daily for 52 weeks. Eligible participants will be aged 40-75 years and have predominantly medial knee OA with centrally read Kellgren-Lawrence grade 2 or 3, OARSI atlas medial femorotibial joint space narrowing grade 1 or 2, and consistent moderate to severe baseline pain. The primary endpoint will be the change from baseline to week 52 in magnetic resonance imaging-assessed central medial femorotibial compartment cartilage thickness. Secondary endpoints will include other structural outcomes, and patient-reported outcomes, as well as safety and pharmacokinetic assessments. Study sites will be assessed for eligibility based on factors including imaging quality, and images will be centrally read and quality checked. Conclusions: Using strict inclusion criteria and leading imaging techniques with stringent quality controls, the ROCCELLA trial will evaluate the efficacy of S201086/GLPG1972 in slowing cartilage loss in participants with knee OA. The selected eligibility criteria should enrich for participants with OA who experience sufficient cartilage loss to allow detection of a substantial treatment effect.

A simple inclusion criteria combination increases the rate of cartilage loss in patients with knee osteoarthritis.

Objectives: Selection of patients with KL radiographic grade 2 and 3 is widely used in clinical trials, but this approach could have some limitations. The purpose of this study performed on OsteoArthritis Initiative (OAI) data is to assess whether adding OARSI-JSN to KL grading could select a population with increased rate of cartilage loss. Indeed, KL is not compartment-specific and not uniformly graded amongst expert readers. OARSI-JSN is another established, compartment-specific grading scale that specifically captures the joint space narrowing from radiographs. Design: 1019 knee radiographs data from the progression cohort of the OAI public database were used. Cartilage loss measured with magnetic resonance imaging was evaluated using change over 1 year from baseline in cartilage thickness in the central Medial Tibio-Femoral Compartment (cMTFC) in the KL2-3 and KL2-3+JSN1-2 populations. Results: The mean cMTFC cartilage loss over one year was -0.135 â€‹± â€‹0.29 â€‹mm (median â€‹= â€‹-0.095 â€‹mm) in the KL2-3 population and -0.176 â€‹± â€‹0.29 â€‹mm (median â€‹= â€‹-0.140 â€‹mm) in the KL2-3 +JSN1-2 population. Conclusions: OARSI-JSN appears to be an effective inclusion criterion to be considered in combination with the KL grade in future clinical trials testing the structural efficacy of DMOADs in a time window of 1-year as it contributes to identify knees in whom the disease progresses rapidly.

A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms.

INTRODUCTION: S47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors that may emerge as a favorable candidate for the symptomatic treatment of cognitive and depressive disorders in patients suffering from Alzheimer's disease (AD) of mild to moderate severity and with depressive symptoms. METHODS: For this double-blind, placebo-controlled 24-week phase II trial, 520 outpatients aged between 55 and 85 years, with probable AD at mild to moderate stages (a Mini-Mental State Examination score of 24-15 inclusive) and exhibiting depressive symptoms (Cornell Scale for Depression in Dementia [CSDD] ≥ 8) were recruited in twelve countries and randomized to 3 doses of S47445 (5-15-50 mg) or placebo. The primary end point was the change from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score at week 24. Secondary measures included the Disability Assessment for Dementia, Mini-Mental State Examination, ADAS-Cog 13-item, CSDD, Clinical Global Impression of Change (Alzheimer's Disease Cooperative Study-CGIC), Neuropsychiatric Inventory (NPI), and safety criteria. RESULTS: Baseline characteristics were comparable between the 4 groups. After 24 weeks, no statistically significant treatment difference was demonstrated between S47445 (5, 15 or 50 mg/d) and placebo on cognition (ADAS-Cog), function (Disability Assessment for Dementia), or depressive symptoms (CSDD). An improvement on neuropsychiatric symptoms assessed by NPI was evidenced at the lower dose 5 mg/d (Δ -2.55, P = .023, post hoc analysis) compared to placebo. CSDD and total NPI scores improved in all groups including placebo. There were no specific and/or unexpected safety signals observed with any of the S47445 doses. DISCUSSION: S47445 administered for 24 weeks was safe and well tolerated by patients with mild to moderate AD; the compound did not show significant benefits over placebo on cognition, function, or depressive symptoms.

Neuropsychiatric Symptoms and Risk of Progression to Alzheimer's Disease Among Mild Cognitive Impairment Subjects.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in mild cognitive impairment (MCI), but we do not know much about their role in progression to dementia. OBJECTIVE: To investigate NPS and the risk of progression to probable Alzheimer's disease dementia (AD) among subjects with MCI. METHODS: 96 MCI participants were followed for 4 years. Progression to probable AD was defined by the change of CDR total score from 0.5 to ≥1, reviewed by an expert consensus panel. NPS were determined using the Neuropsychiatric Inventory (NPI) 12-items. This study analyzed prognostic value of each NPI item and 5 sub-syndromes of NPS (apathy, psychosis, affective, hyperactivity, and vegetative) for prediction of progression to probable AD. A Cox proportional hazard model was used; hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with time dependent variable to compare the incidence of progression considering presence/absence of any NPS or sub-syndromes throughout the study. RESULTS: The presence of symptoms "agitation/aggression", "delusions", and "aberrant motor behavior" significantly increased the risk of probable AD (HR = 3.9; 95% CI = 1.9-8.2; HR = 13.9; 95% CI = 4.1-48.9; HR = 4.3; 95% CI = 1.7-10.3, respectively). The presence of sub-syndromes "psychosis" and "hyperactivity" were also predictors of progression (HR = 14.0; 95% CI = 4.4-44.5; HR = 2.0; 95% CI = 1.1-3.7, respectively). These results did not change after adjusting by potential confounders. CONCLUSION: Presence of delusions, agitation/aggression, and aberrant motor behavior is predictor of progression to probable AD.

Cardiovascular risk factors and disease among non-European immigrants living in Catalonia.

OBJECTIVE: To describe the prevalence and incidence of cardiovascular risk factors, established cardiovascular disease (CVD) and cardiovascular medication use, among immigrant individuals of diverse national origins living in Catalonia (Spain), a region receiving large groups of immigrants from all around the world, and with universal access to healthcare. METHODS: We conducted a population-based analysis including >6 million adult individuals living in Catalonia, using the local administrative healthcare databases. Immigrants were classified in 6 World Bank geographic areas: Latin America/Caribbean, North Africa/Middle East, sub-Saharan Africa, East Asia and South Asia. Prevalence calculations were set as of 31 December 2017. RESULTS: Immigrant groups were younger than the local population; despite this, the prevalence of CVD risk factors and of established CVD was very high in some immigrant subgroups compared with local individuals. South Asians had the highest prevalence of diabetes, and of hyperlipidemia among adults aged <55 years; hypertension was highly prevalent among sub-Saharan Africans, and obesity was most common among women of African and South Asian ancestry. In this context, South Asians had the highest prevalence of coronary heart disease across all groups, and of heart failure among women. Heart failure was also highly prevalent in African women. CONCLUSIONS: The high prevalence of risk factors and established CVD among South Asians and sub-Saharan Africans stresses the need for tailored, aggressive health promotion interventions. These are likely to be beneficial in Catalonia, and in countries receiving similar migratory fluxes, as well as in their countries of origin.

Health policies for the reduction of obstetric interventions in singleton full-term births in Catalonia.

AIM: To explore the effect of hospital's characteristics in the proportion of obstetric interventions (OI) performed in singleton fullterm births (SFTB) in Catalonia (2010-2014), while incentives were employed to reduce C-sections. METHODS: Data about SFTB assisted at 42 public hospitals were extracted from the dataset of hospital discharges. Hospitals were classified according to the level of complexity, the volume of births attended, and the adoption of a non-medicalized delivery (NMD) strategy. The annual average change in the percentage for OI was calculated based on Poisson regression models. RESULTS: The rate of OI (35% of all SFTB) including C-sections (20.6%) remained stable through the period. Hospitals attending less complex cases had a lower average of OI, while hospitals attending lower volumes had the highest average. Higher levels of complexity increased the use of C-sections (+4% yearly) and forceps (+16%). The adoption of the NMD strategy decreased the rate of C-sections. CONCLUSIONS: The proportion of OI, including C-sections, remained stable in spite of public incentives to reduce them. The adoption of the NMD strategy could help in decreasing the rate of OI. To reduce the OI rate, new strategies should be launched as the development of low-risk pregnancies units, alignment of incentives and hospital payment, increased value of incentives and encouragement of a cultural shift towards non-medicalized births.

Incident Cerebral Microbleeds Detected by Susceptibility Weight-Imaging Help to Identify Patients with Mild Cognitive Impairment Progressing to Alzheimer's Disease.

BACKGROUND: The relationship between cerebral microbleeds (CMB) and Alzheimer's disease (AD) has not yet been clearly determined, particularly with susceptibility weight-imaging (SWI). OBJECTIVE: To evaluate the SWI sequence using 3T MRI for the detection of CMB, and its ability to differentiate elderly control subjects (CS), stable mild cognitive impairment patients (MCI-s), MCI patients progressing to AD (MCI-p), and AD patients. METHODS: It was a prospective, monocentric, observational study that took place in Toulouse, France. Participants were 65 years and older, enrolled in three groups: CS, MCI, and AD. Based on the longitudinal analysis of cognitive decline, MCI subjects were retrospectively classified as MCI-s or MCI-p. Each patient had a 4-year follow-up with MRI at baseline (MRI#1) and during the fourth year (MRI#3). CMB were counted on native SWI images juxtaposed to minIP reformatted images. RESULTS: 150 patients were enrolled: 48 CS, 25 MCI-s, 18 MCI-p, 59 AD. At MRI#1 and at MRI#3, there was no significant difference in the prevalence of CMB between groups (p = 0.75 and p = 0.87). In the MCI-p + AD group, significantly more subjects had≥4 incident CMB compared to the CS + MCI-s group (p = 0.016). In the MCI-p + AD group, the prevalence of patients with >4 CMB was significantly higher at MRI#3 than at MRI#1 (p = 0.008). CONCLUSION: Using SWI, AD and MCI-p patients had developed significantly more new CMB than CS and MCI-s patients during the follow-up. Incident CMB might be suggested as a potential imaging marker of AD progression.

A critical review of the birth plan use in Catalonia.

INTRODUCTION: The birth plan allows the woman to express her expectations and needs with regards to the childbearing continuum but its use has been debated in the clinical context and in published literature. The birth plan was first introduced in the Spanish Health Service in 2008 through the Strategy for the Care in Normal Childbirth. In Catalonia, the Normal Childbirth Care Programme has promoted the use of birth plans in hospitals participating in this Programme. OBJECTIVE: This works describes and analyses the birth plans produced by the participating hospitals in order to gather knowledge about the options available to women. METHOD: Qualitative study in which the content of birth plans is systematically and quantitatively described in order to evaluate options available to women. The final sample includes all the birth plans provided by 30 Catalonian public hospitals. Following an initial assessment, it was decided to devise a grading scale which allowed to code and assign a value to each of the items contained in the birth plans. RESULTS: Three different types of birth plan are identified: a) those which present a list of items with no (or very little) associated explanations, b) list of items with some explanations and c) plans without items which only explain normal working practices in the hospital and/or protocols.

Increased Aß42-α7-like nicotinic acetylcholine receptor complex level in lymphocytes is associated with apolipoprotein E4-driven Alzheimer's disease pathogenesis.

BACKGROUND: The apolipoprotein E ε4 (APOE4) genotype is a prominent late-onset Alzheimer's disease (AD) risk factor. ApoE4 disrupts memory function in rodents and may contribute to both plaque and tangle formation. METHODS: Coimmunoprecipitation and Western blot detection were used to determine: 1) the effects of select fragments from the apoE low-density lipoprotein (LDL) binding domain and recombinant apoE subtypes on amyloid beta (Aß)42-α7 nicotinic acetylcholine receptor (α7nAChR) interaction and tau phosphorylation in rodent brain synaptosomes; and 2) the level of Aß42-α7nAChR complexes in matched controls and patients with mild cognitive impairment (MCI) and dementia due to AD with known APOE genotypes. RESULTS: In an ex vivo study using rodent synaptosomes, apoE141-148 of the apoE promotes Aß42-α7nAChR association and Aß42-induced α7nAChR-dependent tau phosphorylation. In a single-blind study, we examined lymphocytes isolated from control subjects, patients with MCI and dementia due to AD with known APOE genotypes, sampled at two time points (1 year apart). APOE ε4 genotype was closely correlated with heightened Aß42-α7nAChR complex levels and with blunted exogenous Aß42 effects in lymphocytes derived from AD and MCI due to AD cases. Similarly, plasma from APOE ε4 carriers enhanced the Aß42-induced Aß42-α7nAChR association in rat cortical synaptosomes. The progression of cognitive decline in APOE ε4 carriers correlated with higher levels of Aß42-α7nAChR complexes in lymphocytes and greater enhancement by their plasma of Aß42-induced Aß42-α7nAChR association in rat cortical synaptosomes. CONCLUSIONS: Our data suggest that increased lymphocyte Aß42-α7nAChR-like complexes may indicate the presence of AD pathology especially in APOE ε4 carriers. We show that apoE, especially apoE4, promotes Aß42-α7nAChR interaction and Aß42-induced α7nAChR-dependent tau phosphorylation via its apoE141-148 domain. These apoE-mediated effects may contribute to the APOE ε4-driven neurodysfunction and AD pathologies.

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. METHODS: In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. RESULTS: In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. CONCLUSION: This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis.

Estenosis hipertrófica pilórica del adulto / Hypertrophic pyloric stenosis in adults

No disponible

Risk factors for methicillin-resistant Staphylococcus aureus colonisation or infection in intensive care units and their reliability for predicting MRSA on ICU admission.

Predicting methicillin-resistant Staphylococcus aureus (MRSA) in intensive care units (ICUs) avoids inappropriate antimicrobial empirical treatment and enhances infection control. We describe risk factors for colonisation/infection related to MRSA (MRSA-C/I) in critically ill patients once in the ICU and on ICU admission, and search for an easy-to-use predictive model for MRSA colonisation/infection on ICU admission. This multicentre cohort study included 69,894 patients admitted consecutively (stay>24h) in April-June in the five-year period 2006-2010 from 147 Spanish ICUs participating in the National Surveillance Study of Nosocomial Infections in ICUs (ENVIN-HELICS). Data from all patients included were used to identify risk factors for MRSA-C/I during ICU stays, from admission to discharge, using uni- and multivariable analysis (Poisson regression) to check that the sample to be used to develop the predictive models was representative of standard critical care population. To identify risk factors for MRSA-C/I on ICU admission and to develop prediction models, multivariable logistic regression analysis were then performed only on those admitted in 2010 (n=16950, 2/3 for analysis and 1/3 for subsequent validation). We found that, in the period 2006-2010, 1046 patients were MRSA-C/I. Independent risk factors for MRSA-C/I in ICU were: age>65, trauma or medical patient, high APACHE-II score, admitted from a long-term care facility, urinary catheter, previous antibiotic treatment and skin-soft tissue or post-surgical superficial skin infections. Colonisation with several different MDRs significantly increased the risk of MRSA-C/I. Risk factors on ICU admission were: male gender, trauma critical patient, urgent surgery, admitted from other ICUs, hospital ward or long-term facility, immunosuppression and skin-soft tissue infection. Although the best model to identify carriers of MRSA had a good discrimination (AUC-ROC, 0.77; 95% CI, 0.72-0.82), sensitivity was 67% and specificity 76.5%. Including more complex variables did not improve prediction capability. Our conclusion is that clinical-demographic risk factors for colonisation/infection related to MRSA should not be used to accurately identify patients who would benefit from empirical anti-MRSA treatment or from specific preventive measures. Independent risk factors for MRSA colonisation/infection during ICU stay and on ICU admission are described. The latter should be considered in future studies for MRSA prediction.

Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia.

BACKGROUND: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. OBJECTIVE: We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG. METHODS: We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions. RESULTS: We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis. CONCLUSIONS: Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype.