Background:Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-galactosidase A enzyme deficiency, resulting in multiorgan accumulation of glycosphingolipid. Cardiac accumulation leads to left ventricular hypertrophy, diastolic dysfunction, fibrosis, and sudden cardiac death. Advances in transthoracic echocardiograms (TTEs) have enabled the detection of subclinical atrial and ventricular cardiomyopathy. Until now, studies assessing changes on TTE in FD have been small and cross-sectional. To understand longitudinal changes, our aim was to quantify trends in TTE parameters, linked to relevant physiological and biochemical parameters. Methods:A single-centre retrospective study was conducted of 75 FD patients who received longitudinal follow-up care (53% female, 57% on enzyme replacement therapy) between 2011 and 2023. Results:Longitudinal follow-up care demonstrated increasingly impaired left ventricular global longitudinal strain (GLS), tissue Doppler imaging, and right ventricular systolic function. Atrial changes included increasingly impaired left atrial GLS, greater volumes, and reduced left atrial ejection fraction and fractional area change. A sex-specific increase occurred in indexed left ventricular mass in male patients. Biochemical changes included increases in high-sensitivity Troponin-T and N-terminal-pro-B-type natriuretic peptide levels. A sex-specific increase in the urine protein level and the albumin-creatinine ratio in male patients. Conclusions:TTE and biochemical trends highlight the gradual and insidious nature of FD progression, and stress the importance of considering multiparametric endpoints, including GLS, atrial function, and biomarkers, when assessing outcome in FD.

Familial chylomicronemia syndrome (FCS) is a rare inherited disorder characterized by severe hypertriglyceridemia, posing a heightened risk of acute pancreatitis. Recently, Volanesorsen, an APOC3 antisense oligonucleotide, gained approval for FCS treatment in the UK. Caution is advised during pregnancy due to limited safety data, although animal studies show no toxicity/teratogenicity. Two case scenarios are presented: In the first case, a patient with FCS continued Volanesorsen injections without having thrombocytopenia during an unplanned pregnancy until third trimester, maintaining triglyceride control. Upon discovering the pregnancy at 38 weeks, Volanesorsen was ceased, and a low-fat diet reinstated. Despite a heightened risk of pancreatitis, no episodes of pancreatitis occurred during the pregnancy. In the second case, stopping Volanesorsen before conception led to elevated triglycerides, and an episode of acute pancreatitis at 22 weeks, despite strict very low-fat diet and fibrate therapy from 14 weeks. At 23 weeks, Volanesorsen was reintroduced concurrently with regular therapeutic plasma exchange. No further episodes of pancreatitis occurred. In both case, fetal health was maintained throughout pregnancy, fetal scans revealed no anomalies, and planned C-sections delivered healthy babies without congenital issues. Both babies are well and developing normally at 24 and 19 months.

Background and aims: The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies.Methods: Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks.Results: Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (-10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%-55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (-17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%-38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 x 109/L.Conclusions: This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure.

The emergence of novel A(H1N1)pdm2009 virus threatened to lead to frequent severe manifestations.To describe the clinical, virological, and biological characteristics of the disease and identify the factors associated with severe presentations.This prospective multicenter study recruited consecutive hospitalized patients with confirmed A(H1N1)pdm2009 disease. Clinical, virological and biological assessments were carried out at inclusion and 30 days post-inclusion. Disease manifestations were assessed by an adjudication committee using pre-identified definitions of complications and severity scores.The study analyzed from November 30th, 2009 to February 8th, 2010, 40 hospitalized patients, 21 children and 19 adults. Eighteen (45%) were considered to have severe presentations. Except age, main characteristics in children and adults did not differ. The majority (18/21) of children and all adults had a respiratory presentation; extra-respiratory manifestations tended to be more frequent in children (12 vs. 6, P = 0.10). Two children against 5 adults presented acute respiratory distress syndrome (ARDS, P = 0.23), but more children suffered respiratory failure (7 vs. 1, P = 0.046) without ARDS. At day 30, one death had occurred in each group. The main factor associated with non-severe presentation was an early (<48 h) implementation of oseltamivir treatment (P = 0.038).Although the study failed to achieve its main objective, due mainly to the difficulty of carrying a study of this nature in the midst of a pandemic, it allowed the description of a panel of unusual and complicated forms and confirmed the added value of early oseltamivir treatment in limiting severity in hospitalized children and adults.

Estimar los costes médicos directos en los pacientes con artritis reumatoide (AR) y los factores predictores en los pacientes tratados con fármacos biológicos y sin biológicos.Se realizó un estudio transversal en una muestra incluyendo pacientes de toda la geografía nacional. Se obtuvieron datos sociodemográficos y de tratamiento. Se registró la utilización de recursos para los 2 años de estudio y se hizo imputación de costes. Se realizaron análisis de correlación en todos los pacientes con AR y en los tratados con y sin biológicos, para estimar las diferencias entre los grupos. Los predictores de costes se analizaron mediante modelos de regresión lineal.Se incluyeron 1.095 pacientes con AR, el 26% hombres, con una edad media de 62 ± 14 años. La media de los costes médicos directos por paciente fue de 24.291 ± 45.382 €. Excluyendo los fármacos biológicos, el coste medio por paciente fue de 3.742 ± 3.711 €. Después de ajustar, los factores predictores de costes médicos directos para todos los pacientes con AR fueron los fármacos biológicos (p = 0,00), la comorbilidad (p = 0,00) y la edad del paciente (p = 0,01). En el grupo sin biológicos, los predictores fueron la comorbilidad (p = 0,00) y la edad del paciente (p = 0,01). En el grupo con biológicos los predictores fueron el sexo del paciente (p = 0,03) y la actividad de la enfermedad (p = 0,02).Los datos muestran un notable impacto económico de la AR. Es importante identificar y estimar los factores asociados a mayor coste para desarrollar estrategias de reducción de costes y aumentar la calidad de la atención.To analyze the resource utilization in rheumatoid arthritis (RA) patients and predictive factors in and patients treated with biological drugs and biologic-naïve.A cross-sectional study was performed in a sample including all regions and hospitals throughout the country. Sociodemographic data, disease activity parameters and treatment data were obtained. Resource utilization for two years of study was recorded and we made costs imputation. Correlation analyzes were performed on all RA patients and those treated with biological and biological naïve, to estimate the differences in resource utilization. Factors associated with increased resources utilization (costs) attending to treatment was analyzed by linear regression models.We included 1,095 RA patients, 26% male, mean age of 62 ± 14 years. Mean of direct medical costs per patient was €24,291 ± €45,382. Excluding biological drugs, the average cost per patient was €3,742 ± €3,711. After adjustment, factors associated with direct medical costs for all RA patients were biologic drugs (P = .02) and disease activity (P = .004). In the biologic-naïve group, the predictor of direct medical costs was comorbidity (P < .001). In the biologic treatment group predictors were follow-up length of the disease (P = .04), age (P = .02) and disease activity (P = .007).Our data show a remarkable economic impact of RA. It is important to identify and estimate the economic impact of the disease, compare data from other geographic samples and to develop improvement strategies to reduce these costs and increase the quality of care.

Introduction Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiovascular manifestations. Angina is common in FD due to multiple mechanisms, including thickening of fibrocellular intima, narrowing of myocardial capillaries due to sphingolipid inclusion bodies, and demand-supply mis-match in hypertrophy. With improved care, patients are surviving to an age when atherosclerotic disease may contribute to morbidity and mortality. Aims and Methods In a contemporary cohort of FD, the aims of this study are: 1.To examine risk factor profile and control of classical risk factors for atherosclerosis 2.To determine frequency of coronary calcification and obstructive coronary artery disease (CAD)We therefore conducted a retrospective analysis of 47 patients with genotypically confirmed FD established on ERT to assess for conventional risk factors for CAD and prevalence of CAD. Results Demographic characteristics for the cohort are illustrated in Table 1. The average age was 52.4 years (47% female). In total, 13/47 (28%) patients had stage 3–5 CKD and 14/47 (30%) with stage 2 CKD. 32/47 (68%) were on anti-hypertensive medication, 18/47 (38%) were on a statin, and 12/47 (26%) had a total Cholesterol > 5 mmol/L. Within our cohort, 25/47 (53%) patients had a formal assessment of their coronary arteries (see Table 2). 12/47 (26%) underwent an invasive coronary angiogram (ICA) and 13/47 (28%) underwent a computed tomography coronary angiogram (CTCA). Of those who underwent an ICA, 7/12 (58%) had no flow-limiting CAD with the remaining 5 having significant CAD, defined as >50% coronary artery stenosis and/or revascularisation (3/12 required coronary artery bypass grafting (CABG) and 2/12 required percutaneous coronary intervention (PCI)). Although none of the patients studied by CTCA had flow-limiting or significant CAD, 7/13 (54%) had either mild or moderate coronary calcification. 9/13 (69%) had no coronary calcium. Five patients underwent a Technetium-99 m single photon emission computed tomography scan with CT attenuation, 3 of which were normal and 2 which demonstrated fixed perfusion defects in a non-ischaemic pattern in patients without known coronary artery disease (see Figure 1). Conclusions There is high frequency of conventional risk factors in adults with FD It is likely these contribute to accelerated atherosclerosis via a conventional pathophysiological process. This emphasises the clinical importance of control of conventional risk factors. References 1. Roy A, Umar H, Ochoa-Ferraro A, Warfield A, Lewis N, Geberhiwot T, et al. Atherosclerosis in Fabry Disease-A Contemporary Review. J Clin Med. 2021;10(19). Conflict of Interest NONE

Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population.

Background Cerebral venous thrombosis (CVT) is an important cause of stroke particularly in younger patients and potentially fatal if diagnosis is delayed. The presentation of symptoms is highly variable and consequently the diagnosis and underlying cause is often delayed or overlooked. Homocystinuria, a rare autosomal recessive disorder is an identified risk factor for CVT. Purpose A timely diagnosis and treatment of the underlying cause of CVT could result in improved outcome and prevent further events. This case series describes the clinical course of six adults presented with unprovoked CVT, in whom the diagnosis of underlying homocystinuria was delayed with adverse consequences. We aim to highlight the importance of recognising homocystinuria as an underlying cause of CVT and offer a practical approach to the diagnosis and management. Methods This is a retrospective case series of a cohort of 30 consecutive patients seen in a UK tertiary referral centre. Result Six out of 30 patients presented with CVT prior to homocystinuria diagnosis. The mean and range of age at the time of the first CVT episode was 22.6 (range 11–31) years. The mean ±SD age at diagnosis of homocystinuria as the underlying cause was 26 ± 4.2 years. The time between first CVT and diagnosis of homocystinuria ranged from 1.6 to 11 years resulting in a delay to introduction of effective treatment and, in some cases, a further large vessels thrombotic event. Conclusion Physician awareness of homocystinuria as an underlying cause for an unprovoked CVT will facilitate timely introduction of effective treatment to prevent a further event.

Background and Purpose The respiratory manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been extensively documented. There is emerging evidence that coronavirus disease 2019 (COVID-19) has number of other presenting features which might not be related to the severity of the respiratory disease. We have previously described a case of hypoactive delirium as the first manifestation of COVID-19 without profound lung disease. Here we present five cases of elderly patients, without a prior history of dementia and had no overt COVID-19-related pneumonia, who presented with the acute onset of delirium as the primary manifestation of COVID-19. Methods This retrospective, single-center study performed a health informatics search to produce a list of patients who were admitted with acute confusion and tested positive for the SARS-CoV-2 virus between March 1 and June 30, 2020. The electronic medical admission notes were screened for all patients with confusion who tested positive for SARS-CoV-2. Patients with a history of dementia and a high risk of delirium were excluded, such as severe COVID-19-related pneumonia or any other infection, malignancy, drugs, or severe illness of any kind. Results During the first wave of the COVID-19 pandemic our hospital experienced just over 3,000 SARS-CoV-2 positive patients, and 45 of them had documented confusion upon admission. Secondary causes for their acute confusion were excluded. Five patients were identified as having delirium as the initial presentation of COVID-19-related illness without significant COVID-19-related pneumonitis. None of them had overt chest symptoms or a previous history of confusion, and the 3 patients who underwent head CT scans had normal findings. Conclusions This case series illustrates the importance of recognizing acute confusion as the first manifestation of COVID-19 in susceptible individuals.

Podocytes are highly differentiated visceral cells, and several related specific proteins, such as podocalyxin and podocin are potential tools for the evaluation of podocyturia. However, precise quantitation of podocyturia-related proteins is complex and often unreliable.A reversed-phase ultra-performance liquid chromatography coupled to tandem mass spectrometry method was developed and validated to quantify podocalyxin and podocin levels in urine supernatant by using specific cleavable peptides and standards. Urine samples from women with normotensive or hypertensive pregnancies, gestational diabetes and preeclampsia, as well as treated and untreated Fabry patients, and gender-matched controls were investigated.The multiplex analysis shows that podocalyxin levels were higher than podocin levels in patients, the former being particularly higher in pregnant women. Women with preeclampsia had abnormal urine levels of both proteins with a higher sensitivity for podocalyxin. Slightly increased levels of podocin were also observed in Fabry males, while both proteins were increased in untreated Fabry females. Correlations were established between podocalyxin and podocin levels and clinical parameters associated with Fabry disease and preeclampsia.This methodology makes possible the precise, simultaneous and reliable analysis of podocalyxin and podocin levels, and offers a valuable tool for the evaluation of podocyturia.