Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment guidelines. These consensus recommendations are intended to provide guidance for the treatment and monitoring of patients with Fabry disease receiving migalastat. Methods: A modified Delphi process was conducted to determine consensus on treatment decisions and monitoring of patients with Fabry disease receiving migalastat. The multidisciplinary panel comprised 14 expert physicians across nine specialties and two patients with Fabry disease. Two rounds of Delphi surveys were completed and recommendations on the use of biomarkers, multidisciplinary monitoring, and treatment decisions were generated based on statements that reached consensus. Results: The expert panel reached consensus agreement on 49 of 54 statements, including 16 that reached consensus in round 1. Statements that reached consensus agreement are summarized in recommendations for migalastat treatment and monitoring, including baseline and follow-up assessments and frequency. All patients with Fabry disease and an amenable mutation may initiate migalastat treatment if they have evidence of Fabry-related symptoms and/or organ involvement. Treatment decisions should include holistic assessment of the patient, considering clinical symptoms and organ involvement as well as patient-reported outcomes and patient preference. The reliability of α-Gal A and globotriaosylsphingosine as pharmacodynamic response biomarkers remains unclear. Conclusion: These recommendations build on previously published guidelines to highlight the importance of holistic, multidisciplinary monitoring for patients with Fabry disease receiving migalastat, in addition to shared decision-making regarding treatments and monitoring throughout the patient journey. (Figure presented.)

Galactic Rotation Parameters from Data on Open Star Clusters

Currently available data on the field of velocities Vr, Vl, Vb for open star clusters are used to perform a kinematic analysis of various samples that differ by heliocentric distance, age, and membership in individual structures (the Orion, Carina--Sagittarius, and Perseus arms). Based on 375 clusters located within 5 kpc of the Sun with ages up to 1 Gyr, we have determined the Galactic rotation parameters Wo =-26.0+-0.3 km/s/kpc, W'o = 4.18+-0.17 km/s/kpc^2, W''o=-0.45+-0.06 km/s/kpc^3, the system contraction parameter K = -2.4+-0.1 km/s/kpc, and the parameters of the kinematic center Ro =7.4+-0.3 kpc and lo = 0+-1 degrees. The Galactocentric distance Ro in the model used has been found to depend significantly on the sample age. Thus, for example, it is 9.5+-0.7 kpc and 5.6+-0.3 kpc for the samples of young (50 Myr) clusters, respectively. Our study of the kinematics of young open star clusters in various spiral arms has shown that the kinematic parameters are similar to the parameters obtained from the entire sample for the Carina-Sagittarius and Perseus arms and differ significantly from them for the Orion arm. The contraction effect is shown to be typical of star clusters with various ages. It is most pronounced for clusters with a mean age of 100 Myr, with the contraction velocity being Kr = -4.3+-1.0 km/s.Comment: 14 pages, 4 figures, 2 table

Using serum metabolomics analysis to predict sub-clinical atherosclerosis in patients with SLE

Background: Patients with systemic lupus erythematosus (SLE) have an increased risk of developing cardiovascular disease (CVD) and 30-40% have sub-clinical atherosclerosis on vascular ultrasound scanning. Standard measurements of serum lipids in clinical practice do not predict CVD risk in patients with SLE. We hypothesise that more detailed analysis of lipoprotein taxonomy could identify better predictors of CVD risk in SLE. / Methods: Eighty patients with SLE and no history of CVD underwent carotid and femoral ultrasound scans; 30 had atherosclerosis plaques (SLE-P) and 50 had no plaques (SLE-NP). Serum samples obtained at the time of the scan were analysed using a lipoprotein-focused metabolomics platform assessing 228 metabolites by nuclear magnetic resonance spectroscopy. Data was analysed using logistic regression and five binary classification models with 10-fold cross validation; decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions. / Results: Univariate logistic regression identified four metabolites associated with the presence of sub-clinical plaque; three subclasses of very low density lipoprotein (VLDL) (percentage of free cholesterol in medium and large VLDL particles and percentage of phospholipids in chylomicrons and extremely large VLDL particles) and Leucine. Together with age, these metabolites were also within the top features identified by the lasso logistic regression (with and without interactions) and random forest machine learning models. Logistic regression with interactions differentiated between SLE-P and SLE-NP with greatest accuracy (0.800). Notably, percentage of free cholesterol in large VLDL particles and age were identified by all models as being important to differentiate between SLE-P and SLE-NP patients. / Conclusion: Serum metabolites are a promising biomarker for prediction of sub-clinical atherosclerosis development in SLE patients and could provide novel insight into mechanisms of early atherosclerosis development

Trencafiles dels llibres antics

L'estil de les trencafiles recopilades és de caràcter típicament mediterrani, estil arrelat a Itàlia , al sud de França i a l'Espanya mediterrània. Els seus trets característics són la simplicitat i el caràcter funcional més que ornamental. Les variacions existents en tot el fons son poc vistoses en general, però, no obstant això, a través dels petits detalls de construcció podem seguir l'evolució que han sofert fins els nostres dies

Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have an increased risk of developing cardiovascular disease. Standard serum lipid measurements in clinical practice do not predict cardiovascular disease risk in patients with SLE. More detailed analysis of lipoprotein taxonomy could identify better predictors of cardiovascular disease risk in SLE. Approach and Results: Eighty women with SLE and no history of cardiovascular disease underwent carotid and femoral ultrasound scans; 30 had atherosclerosis plaques (patients with SLE with subclinical plaque) and 50 had no plaques (patients with SLE with no subclinical plaque). Serum samples obtained at the time of the scan were analyzed using a lipoprotein-focused metabolomics platform assessing 228 metabolites by nuclear magnetic resonance spectroscopy. Data were analyzed using logistic regression and 5 binary classification models with 10-fold cross validation. Patients with SLE had global changes in complex lipoprotein profiles compared with healthy controls despite having clinical serum lipid levels within normal ranges. In the SLE cohort, univariate logistic regression identified 4 metabolites associated with subclinical plaque; 3 subclasses of VLDL (very low-density lipoprotein; free cholesterol in medium and large VLDL particles and phospholipids in chylomicrons and extremely large VLDL particles) and leucine. Together with age, these metabolites were also within the top features identified by the lasso logistic regression (with and without interactions) and random forest machine learning models. Logistic regression with interactions differentiated between patients with SLE with subclinical plaque and patients with SLE with no subclinical plaque groups with the greatest accuracy (0.800). Notably, free cholesterol in large VLDL particles and age differentiated between patients with SLE with subclinical plaque and patients with SLE with no subclinical plaque in all models. CONCLUSIONS: Serum metabolites are promising biomarkers to uncover and predict multimetabolic phenotypes of subclinical atherosclerosis in SLE

Azithromycin to Prevent Pertussis in Household Contacts, Catalonia and Navarre, Spain, 2012-2013

We retrospectively assessed the effectiveness of azithromycin in preventing transmission of pertussis to a patient's household contacts. We also considered the duration between symptom onset in the primary patient and azithromycin administration. We categorized contacts into 4 groups: those treated within 21 days after illness onset in the primary patient. We studied 476 primary index patients and their 1,975 household contacts, of whom 4.5% were later identified as having pertussis. When contacts started chemoprophylaxis within 14 days after primary patient's symptom onset was less effective. We recommend that contacts of persons with pertussis begin chemoprophylaxis within <14 days after primary patient's symptom onset

Cadmium accumulation and interactions with zinc, copper, and manganese, analysed by ICP-MS in a long-term Caco-2 TC7 cell model

The influence of long-term exposure to cadmium (Cd) on essential minerals was investigated using a Caco-2 TC7 cells and a multi-analytical tool: microwave digestion and inductively coupled plasma mass spectrometry. Intracellular levels, effects on cadmium accumulation, distribution, and reference concentration ranges of the following elements were determined: Na, Mg, Ca, Cr, Fe, Mn, Co, Ni, Cu, Zn, Mo, and Cd. Results showed that Caco-2 TC7 cells incubated long-term with cadmium concentrations ranging from 0 to 10 lmol Cd/l for 5 weeks exhibited a significant increase in cadmium accumulation. Furthermore, this accumulation was more marked in cells exposed long-term to cadmium compared with controls, and that this exposure resulted in a significant accumulation of copper and zinc but not of the other elements measured. Interactions of Cd with three elements: zinc, copper, and manganese were particularly studied. Exposed to 30 lmol/l of the element, manganese showed the highest inhibition and copper the lowest on cadmium intracellular accumulation but Zn, Cu, and Mn behave differently in terms of their mutual competition with Cd. Indeed, increasing cadmium in the culture medium resulted in a gradual and significant increase in the accumulation of zinc. There was a significant decrease in manganese from 5 lmol Cd/l exposure, and no variation was observed with copper. Abbreviation: AAS – Atomic absorption spectrometry; CRM– Certified reference material; PBS – Phosphate buffered saline without calcium and magnesium; DMEM – Dubelcco’s modified Eagle’s medium

Chronic kidney disease as cardiovascular risk factor in routine clinical practice: a position statement by the Council of the European Renal Association

The European Society of Cardiology 2021 guideline on cardiovascular (CV) disease (CVD) prevention in clinical practice has major implications for both CV risk screening and kidney health of interest to primary care physicians, cardiologists, nephrol-ogists, and other professionals involved in CVD prevention. The proposed CVD prevention strategies require as first step the categorization of individuals into those with established atherosclerotic CVD, diabetes, familiar hypercholesterolaemia, or chronic kidney disease (CKD), i.e. conditions that are already associated with a moderate to very-high CVD risk. This places CKD, defined as decreased kidney function or increased albuminuria as a starting step for CVD risk assessment. Thus, for adequate CVD risk assessment, patients with diabetes, familiar hypercholesterolaemia, or CKD should be identified by an initial laboratory assessment that requires not only serum to assess glucose, cholesterol, and creatinine to estimate the glomerular filtration rate, but also urine to assess albuminuria. The addition of albuminuria as an entry-level step in CVD risk assessment should change clinical practice as it differs from the current healthcare situation in which albuminuria is only assessed in persons already considered to be at high risk of CVD. A diagnosis of moderate of severe CKD requires a specific set of interventions to prevent CVD. Further research should address the optimal method for CV risk assessment that includes CKD assessment in the general population, i.e. whether this should remain opportunistic screening or whether systematic screening

Kinematic Peculiarities of Gould Belt Stars

We analyzed the space velocities of Gould Belt stars younger than 125 Myr located at heliocentric distances <650 pc. We determined the rotation and expansion parameters of the Gould Belt by assuming the existence of a single kinematic center whose direction was found to be the following: $l_\circ=128^\circ$ and $R_\circ=150$ pc. The linear velocities reach their maximum at a distance of $\approx300$ pc from the center and are -6 km s$^{-1}$ for the rotation (whose direction coincides with the Galactic rotation) and +4 km s$^{-1}$ for the expansion. The stellar rotation model used here is shown to give a more faithful description of the observed velocity field than the linear model based on the Oort constants $A_G$ and $B_G$. We present evidence that the young clusters $\beta$ Pic, Tuc/HorA, and TWA belong to the Gould Belt structure.Comment: 17 pages, 5 figure