Ocular involvement in adult and paediatric patients with monogenic autoinflammatory diseases: a Spanish multicentre retrospective study.

OBJECTIVES: Ophthalmologic involvement in monogenic autoinflammatory diseases has been explored mainly in paediatric patients. The aim of this study is to characterise ophthalmologic manifestations, therapeutic management and visual outcomes in a Spanish (UVESAI) cohort of adult/paediatric patients with monogenic autoinflammatory diseases. METHODS: Multicentre and retrospective study of patients with monogenic autoinflammatory diseases and ocular involvement. Eye manifestations, structural complications, treatments used and visual outcomes were analysed, and compared with previous studies. RESULTS: Forty-six patients (44/2 adults/children; 21/25 adult/paediatric-onset) with monogenic autoinflammatory diseases [cryopyrin associated periodic syndromes (n=13/28.3%), mainly Muckle-Wells syndrome (MWS) (n=11/24%); familial Mediterranean fever (FMF) (n=12/26%); TNF receptor-associated periodic syndrome (TRAPS); (n=9/20%); Blau syndrome (n=8/17%); hyperimmunoglobulin D syndrome (HIDS) (n=2/4.3%), deficiency of adenosine deaminase-2 and NLRC4-Autoinflammatory disease] (one each) were included. Conjunctivitis (n=26/56.5%) and uveitis (n=23/50%) were the most frequent ocular manifestations. Twelve (26.1%) patients developed structural complications, being cataracts (n=11/24%) and posterior synechiae (n=10/22%) the most frequent. Conjunctivitis predominated in TRAPS, FMF, MWS and HIDS (mainly in adults), and uveitis, in Blau syndrome. Seven (8%) eyes (all with uveitis) presented with impaired visual acuity. Local and systemic treatment led to good visual outcomes in most patients. Compared with previous studies mainly including paediatric patients, less severe ocular involvement was observed in our adult/paediatric cohort. CONCLUSIONS: Conjunctivitis was the most common ocular manifestation in our TRAPS, FMF, MWS and HIDS patients, and uveitis predominated in Blau syndrome. Severe eye complications and poor visual prognosis were associated with uveitis. Adults with monogenic autoinflammatory diseases seem to exhibit a less severe ophthalmologic presentation than paediatric patients.

Clinical features and health-related quality of life in adult patients with mucopolysaccharidosis IVA: the Spanish experience.

BACKGROUND: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is a progressive and disabling disease characterized by a deficiency of the enzyme N-acetylgalactosamine-6-sulphate sulphatase. Its clinical presentation is very heterogeneous and poorly understood in adults. The aim of this study was to describe the clinical manifestations of MPS IVA in adult patients in Spain and to assess their health-related quality of life (HRQoL). RESULTS: Thirty-three patients from nine reference centres participated in the study. The median age was 32 (interquartile range [IQR]: 20.5-40.5) years. The phenotype was classical in 54.5% of patients, intermediate in 33.3% of patients, and non-classical in 12.1% of patients. The most common clinical manifestation was bone dysplasia, with a median height of 118 (IQR: 106-136) cm. Other frequent clinical manifestations were hearing loss (75.7%), ligamentous laxity (72.7%), odontoid dysplasia (69.7%), limb deformities that required orthopaedic aids (mainly hip dysplasia and genu valgus) (63.6%), and corneal clouding (60.6%). In addition, 36.0% of patients had obstructive sleep apnoea/hypopnoea syndrome and 33.3% needed non-invasive ventilation. Cervical surgery and varisation osteotomy were the most common surgical interventions (36.4% each). Almost 80% of patients had mobility problems and 36.4% used a wheelchair at all times. Furthermore, 87.9% needed help with self-care, 33.3% were fully dependent, and 78.8% had some degree of pain. HRQoL according to the health assessment questionnaire was 1.43 (IQR: 1.03-2.00) in patients with the non-classical phenotype, but 2.5 (IQR: 1.68-3.00) in those with the classical phenotype. Seven patients were initiated on enzyme replacement therapy (ERT), but two of them were lost to follow-up. Lung function improved in four patients and slightly worsened in one patient. The distance achieved in the six-minute walk test increased in the four patients who could perform it. HRQoL was better in patients treated with elosulfase alfa, with a median (IQR) of 1.75 (1.25-2.34) versus 2.25 (1.62-3.00) in patients not treated with ERT. CONCLUSIONS: The study provides real-world data on patients with MPS IVA. Limited mobility, difficulties with self-care, dependence, and pain were common, together with poor HRQoL. The severity and heterogeneity of clinical manifestations require the combined efforts of multidisciplinary teams.

Tocilizumab in refractory Caucasian Takayasu's arteritis: a multicenter study of 54 patients and literature review.

OBJECTIVE: To assess the efficacy and safety of tocilizumab (TCZ) in Caucasian patients with refractory Takayasu's arteritis (TAK) in clinical practice. METHODS: A multicenter study of Caucasian patients with refractory TAK who received TCZ. The outcome variables were remission, glucocorticoid-sparing effect, improvement in imaging techniques, and adverse events. A comparative study between patients who received TCZ as monotherapy (TCZMONO) and combined with conventional disease modifying anti-rheumatic drugs (cDMARDs) (TCZCOMBO) was performed. RESULTS: The study comprised 54 patients (46 women/8 men) with a median [interquartile range (IQR)] age of 42.0 (32.5-50.5) years. TCZ was started after a median (IQR) of 12.0 (3.0-31.5) months since TAK diagnosis. Remission was achieved in 12/54 (22.2%), 19/49 (38.8%), 23/44 (52.3%), and 27/36 (75%) patients at 1, 3, 6, and 12 months, respectively. The prednisone dose was reduced from 30.0 mg/day (12.5-50.0) to 5.0 (0.0-5.6) mg/day at 12 months. An improvement in imaging findings was reported in 28 (73.7%) patients after a median (IQR) of 9.0 (6.0-14.0) months. Twenty-three (42.6%) patients were on TCZMONO and 31 (57.4%) on TCZCOMBO: MTX (n = 28), cyclosporine A (n = 2), azathioprine (n = 1). Patients on TCZCOMBO were younger [38.0 (27.0-46.0) versus 45.0 (38.0-57.0)] years; difference (diff) [95% confidence interval (CI) = -7.0 (-17.9, -0.56] with a trend to longer TAK duration [21.0 (6.0-38.0) versus 6.0 (1.0-23.0)] months; diff 95% CI = 15 (-8.9, 35.5), and higher c-reactive protein [2.4 (0.7-5.6) versus 1.3 (0.3-3.3)] mg/dl; diff 95% CI = 1.1 (-0.26, 2.99). Despite these differences, similar outcomes were observed in both groups (log rank p = 0.862). Relevant adverse events were reported in six (11.1%) patients, but only three developed severe events that required TCZ withdrawal. CONCLUSION: TCZ in monotherapy, or combined with cDMARDs, is effective and safe in patients with refractory TAK of Caucasian origin.

Coexistence of immune-mediated diseases in sarcoidosis. Frequency and clinical significance in 1737 patients.

OBJECTIVE: To analyze whether immune-mediated diseases (IMDs) occurs in sarcoidosis more commonly than expected in the general population, and how concomitant IMDs influence the clinical presentation of the disease. METHODS: We searched for coexisting IMDs in patients included in the SARCOGEAS-cohort, a multicenter nationwide database of consecutive patients diagnosed according to the ATS/ESC/WASOG criteria. Comparisons were made considering the presence or absence of IMD clustering, and odds ratios (OR) and their 95% confidence intervals (CI) were calculated as the ratio of observed cases of every IMD in the sarcoidosis cohort to the observed cases in the general population. RESULTS: Among 1737 patients with sarcoidosis, 283 (16%) patients presented at least one associated IMD. These patients were more commonly female (OR: 1.98, 95% CI: 1.49-2.62) and were diagnosed with sarcoidosis at an older age (49.6 vs. 47.5years, P<0.05). The frequency of IMDs in patients with sarcoidosis was nearly 2-fold higher than the frequency observed in the general population (OR: 1.64, 95% CI: 1.44-1.86). Significant associations were identified in 17 individual IMDs. In comparison with the general population, the IMDs with the strongest strength of association with sarcoidosis (OR>5) were common variable immunodeficiency (CVID) (OR: 431.8), familial Mediterranean fever (OR 33.9), primary biliary cholangitis (OR: 16.57), haemolytic anemia (OR: 12.17), autoimmune hepatitis (OR: 9.01), antiphospholipid syndrome (OR: 8.70), immune thrombocytopenia (OR: 8.43), Sjögren syndrome (OR: 6.98), systemic sclerosis (OR: 5.71), ankylosing spondylitis (OR: 5.49), IgA deficiency (OR: 5.07) and psoriatic arthritis (OR: 5.06). Sex-adjusted ORs were considerably higher than crude ORs for eosinophilic digestive disease in women, and for immune thrombocytopenia, systemic sclerosis and autoimmune hepatitis in men. CONCLUSION: We found coexisting IMDs in 1 out of 6 patients with sarcoidosis. The strongest associations were found for immunodeficiencies and some systemic, rheumatic, hepatic and hematological autoimmune diseases.

Genotype-phenotype correlation of 17 cases of Pompe disease in Spanish patients and identification of 4 novel GAA variants.

BACKGROUND: Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid α-glucosidase gene (GAA) that produces defects in the lysosomal acid α-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype-phenotype correlation. METHODS: A total of 2637 samples of patients who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing. RESULTS: Fourteen different variants from 17 diagnosed patients were identified, seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7-64) and a 2-day-old boy with IOPD, four genetic variants had not been described in the literature previously, including a homozygous variant. In all of them α-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients. CONCLUSIONS: This study report four new genetic variants that contribute to the pathogenic variants spectrum of the GAA gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T>G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC pathogenic variant in homozygosity is associated with early disease and a worse prognosis.

Accuracy diagnosis improvement of Fabry disease from dried blood spots: Enzyme activity, lyso-Gb3 accumulation and GLA gene sequencing.

The purpose of this study was to examine the applicability of the use of samples in dried blood spot (DBS) for the definitive diagnosis of Fabry disease (FD) in males and females and to compare the diagnostic role of α-galactosidase A activity (α-Gal A), levels of lyso-Gb3 and sequencing of the GLA gene in screening patients with suspected FD. Measurement of α-Gal A activity in suspected FD patients in DBS was made followed by lyso-Gb3 determination and GLA gene sequencing. Of the 2381 subjects analyzed, FD was confirmed in 24 patients. Thirteen different variants were considered like pathogenic, five of which had not been previously described (c.143A > G; c.455A > C; c.487G > T; c.554delA; c.1045_1046insA). None of the patients with normal enzyme activity had FD confirmation. The DBS measurement of α-Gal A was more sensitive than lyso-Gb3 levels in both men and women. Definitive diagnosis of FD from a single DBS is possible, allowing samples to be easily sent from anywhere to the reference laboratory.

Genotype/phenotype relationship in Gaucher disease patients. Novel mutation in glucocerebrosidase gene.

Objectives Gaucher disease (GD) is the most common inherited lysosomal storage disease, caused by mutations in acid ß-glucosidase (GBA) gene. This study aimed to identify mutations in Andalusia patients with GD and their genotype-phenotype correlation. Methods Descriptive observational study. University Hospital Virgen del Rocio patients diagnosed from GD from 1999 to 2019 were included. Demographic and clinical data, ß-glucocerebrosidase activity, variants pathogenic in GBA gene and biomarkers for monitoring treatment were collected from digital medical record. Results Twenty-six patients with aged between 1 day and 52 years were studied. A total of six mutations described as pathogenic and one mutation not described above [c.937T>C (p.Tyr313His)] were identified in the GBA gene, four patients were homozygotes and 22 compound heterozygotes. Twenty-four patients were diagnosed in non-neuropathic form (type 1) and two cases presented neurological involvement (type 2 or 3). The most common variant was c.1226A>G (p.Asn409Ser), which was detected in 24 patients, followed by c.1448T>C (p.Leu483Pro) variant, identified in 13 patients. The c.1448T>C (p.Leu483Pro) mutation has been presented in the most severe phenotypes with neurological involvement associated with type 2 and 3 GD, while c.1226A>G (p.Asn409Ser) mutation has not been associated with neurological alterations. Splenomegaly and bone disease were the most frequent clinical manifestations, and thrombocytopenia was the most common hematological disorder. Conclusions The c.1226A>G (p.Asn409Ser) and c.1448T>C (p.Leu483Pro) mutations were the most common. The c.937T>C (p.Tyr313His) was identified as a novel mutation. The c.1448T>C (p.Leu483Pro) mutation was associated with neurological alterations and c.1226A>G (p.Asn409Ser) mutation has not been associated it.

Lesiones vasculares en paciente diagnosticada de arteritis de Takayasu y elevación masiva de lipoproteína(a). ¿Afectación residual o arterioesclerosis prematura? / Vascular lesions in patient with Takayasu arteritis and massive elevated lipoprotein(a) levels. Residual involvement or premature aterosclerosis?

La lipoproteína (a) [Lp(a)] es una lipoproteína definida por presentar una apolipoproteína específica, la apoA, unida a la apoB-100 por diversos tipos de enlaces químicos, entre ellos un puente disulfuro. A pesar de que su mecanismo aterogénico no es completamente conocido, está demostrada su importancia en el desarrollo de ateroesclerosis prematura, mostrando múltiples estudios su papel como factor de riesgo cardiovascular asociado a enfermedad coronaria e ictus. Presentamos el caso de una paciente con diagnóstico de arteritis de Takayasu en la que se detectó una elevación masiva de Lp(a), y abordamos las implicaciones diagnósticas y terapéuticas que tuvo este hallazgo

Lipoprotein (a) [Lp(a)] is a lipoprotein defined by presenting a specific apolipoprotein, ApoA, linked to the ApoB-100 by different types of chemical bonds, including a disulfide bridge. Despite their atherogenic mechanism is not fully understood, its importance has been demonstrated in the development of premature aterosclerosis. Multiple studies have shown its role as a cardiovascular risk factor associated with heart disease and stroke. We report the case of a patient with a diagnosis of Takayasu arteritis in which a massive elevation of Lp(a) was detected. We emphasize its diagnostic and therapeutic implications

Vascular lesions in patient with Takayasu arteritis and massive elevated lipoprotein(a) levels. Residual involvement or premature aterosclerosis? / Lesiones vasculares en paciente diagnosticada de arteritis de Takayasu y elevación masiva de lipoproteína(a). ¿Afectación residual o arterioesclerosis prematura?

Lipoprotein (a) [Lp(a)] is a lipoprotein defined by presenting a specific apolipoprotein, ApoA, linked to the ApoB-100 by different types of chemical bonds, including a disulfide bridge. Despite their atherogenic mechanism is not fully understood, its importance has been demonstrated in the development of premature aterosclerosis. Multiple studies have shown its role as a cardiovascular risk factor associated with heart disease and stroke. We report the case of a patient with a diagnosis of Takayasu arteritis in which a massive elevation of Lp(a) was detected. We emphasize its diagnostic and therapeutic implications.

Delayed diagnosis of late-onset Pompe disease in patients with myopathies of unknown origin and/or hyperCKemia.

Pompe disease is a rare metabolic myopathy whose diagnosis is sometimes delayed despite being essential for improving clinical outcomes. We aimed to investigate the prevalence of late-onset Pompe disease among patients with a myopathy of unknown etiology, including polymyositis, or with idiopathic rise of creatine kinase (CK) levels, in a department of internal medicine. A cohort study was conducted in 241 subjects: 140 patients with myopathies of unknown origin or increased CK levels, 30 with polymyositis and 71 who constituted the control group of other myopathies. Acid α-glucosidase (GAA) activity was tested in dried blood spots. If a positive result was obtained, GAA activity in isolated lymphocytes and/or genetic testing was performed as a confirmatory diagnosis. Out of the 140 investigated patients, 2 patients with myopathies of unknown origin were confirmed to be positive for Pompe disease. Thus, late-onset Pompe disease should be considered among adult patients with myopathy of unknown origin.

Porfiria variegata y fibrilación auricular: ataque agudo inducido por propafenona / Variegate porphyria and atrial fibrillation: acute attack induced by propafenone

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Abnormal levels of antioxidant defenses in a large sample of patients with hypertensive disorders of pregnancy.

Increased levels of oxidative stress have been demonstrated in Preeclampsia in previous studies, but this finding has not been established in other hypertensive disorders in pregnancy (HDP). We measured different markers of lipid peroxidation and antioxidant defenses by spectrophotometry or enzymoimmunoanalysis in 339 pregnant women: 85 with gestational hypertension (GH), 88 chronic hypertension (CH), 104 Preeclampsia and 62 healthy pregnant control women (PCW). Lower activity of superoxide dismutase and higher levels of catalase were found in GH, CH and preeclampsia compared with PCW (964.4±116.5, 970.0±120.4, 971.2±137.5 and 1063.4±133.7 U g(-1) Hb, P<0.001; and 313.0±71.7, 292.2±45.3, 297.1±47.2, 215.5±26.2 U mg(-1) Hb, P<0.0001; respectively). Regarding the glutathione REDOX cycle, we found the following in GH, CH and preeclampsia compared with PCW: a decrease in its reduced form (2.6±0.6, 2.7±0.8, 2.7±0.9, 3.3±1.3 µmol l(-1), P<0.003), a parallel increase in the oxidized form (185.6±68.9, 194.7±75.0, 184.3±78.3, 85.1±27.5 µmol l(-1), P<0.0001) and an increment in glutathione peroxidase (85.9±22.0, 86.4±20.9, 82.1±23.5 and 77.2±19.7 U g(-1) Hb, P<0.04) and glutathione reductase (6384.3±1261.9, 6724.6±1154.1, 6287.9±1399.9 and 6044.4±1208.4 mU g(-1) Hb, P<0.01, respectively). Nitrites/nitrates were higher in patients with preeclampsia than in PCW (31.50±15.08, 26.80±8.39 µmol l(-1), P<0.002). Although malondialdehyde and oxidized-LDL levels were similar among groups, free fatty acids were increased in every HDP (GH 514.6±194.6, CH 501.3±197.4, preeclampsia 555.2±230.1 µmol l(-1)) compared with PCW (351.4±146.1 µmol l(-1)), P<0.0001. Our results show an oxidation/reduction imbalance with an increase in oxidative stress coupled with a decreased capacity of antioxidant systems, not only in preeclampsia but also in every HDP.

[Overload felt by the figure of the main caregiver in a cohort of patients with multiple pathologies]. / Sobrecarga sentida por la figura del cuidador principal en una cohorte de pacientes pluripatológicos.

OBJECTIVE: To determine the profile of the main caregiver (MC) and the factors associated with her/his care burden, in a multi-centre cohort of patients with multiple pathologies (PMP). DESIGN: Multi-centre cross-sectional study. SETTING: Four health districts in the Virgen del Rocío University Hospitals Health Area, Seville, Spain. PARTICIPANTS: The PMP cohort was created by checking all the patients who satisfied the health department criteria for PMP (2002): patients suffering from chronic diseases in 2 or more of the 7 clinical categories defined. MAIN MEASUREMENTS: The profile of PMP caregiver was determined for all patients. The caregiver strain index (CSI) was determined by the index of care stress (ICS). Predictive factors were analysed by the Student t, ANOVA, and Pearson's tests. Multivariate analysis was performed by a forward stepwise linear regression model. RESULTS: The interview was attended by 461 (69%) out of 662 eligible PMP. Of these, 293 (63.6%) had an MC whose mean age was 62 (15) years; 80% of them were women. First-degree relatives made up 88% of caregivers, with spouses 49.7% of them (n=146). In 41.5%, the CSI was >7 points (mean CSI was 5.35 [3.5]). This was higher in those caring for PMP with neurological illnesses (7 [3.2 vs 4.5 [3.3]; P=.0001). The CSI was compared directly with the medical vulnerability of the PMP (R=0.37; P=.001), cognitive deterioration on the Pfeiffer scale (PS) (R=0.4; P=.0001), and inversely with functional status on Barthel's scale (BS) (R=-0.67; P=.0001). Patient's age (P=.03), his/her medical vulnerability (P=.016) and functional (P< .0001) and cognitive (P=.019) deterioration were independently associated with the CSI. CONCLUSIONS: The profile of the MC of the PMP cohort corresponded mainly to first-degree female relatives around sixty years old. The burden of care was high in more than a third of them. Predictive factors were age, medical vulnerability, and the functional and cognitive deterioration of the PMP.

Sobrecarga sentida por la figura del cuidador principal en una cohorte de pacientes pluripatológicos / Overload felt by the figure of the main caregiver in a cohort of patients with multiple pathologies

Objetivo. Conocer el perfil del cuidador principal (CP) y los factores relacionados con la sobrecarga sentida, en una cohorte multicéntrica de pacientes pluripatológicos (PP). Diseño. Estudio transversal, multicéntrico. Emplazamiento. Cuatro zonas básicas de salud del área sanitaria de los Hospitales Universitarios Virgen del Rocío, Sevilla. Participantes. La cohorte de PP se generó prospectivamente mediante el censado de todos los pacientes que cumplían los criterios de PP de la Consejería de Salud (2002): aquellos que tienen enfermedades crónicas de dos o más de las 7 categorías clínicas definidas. Mediciones principales. El perfil del cuidador se determinó a todos los PP. El cansancio del CP se determinó mediante el índice de esfuerzo del cuidador (IEC). Los factores predictores se analizaron mediante los tests de la t de Student, ANOVA y Pearson. Posteriormente se realizó una regresión lineal multivariable paso a paso hacia delante. Resultados. Accedieron a la entrevista 461 (69% de los 662 elegibles) PP; 293 (63,6%) pacientes tenían CP, que en el 88% eran familiares de primer grado (146 [49,7%] de ellos, el cónyuge), de 62 ± 15 años de edad, y el 80%, mujeres. El IEC fue > 7 puntos en el 41,5% y en general fue 5,35 ± 3,5, mayor en los que cuidaban de PP con enfermedades neurológicas (7 ± 3,2 frente a 4,5 ± 3,3; p < 0,0001). El IEC se correlacionó directamente con la vulnerabilidad clínica del PP (R = 0,37; p < 0,001), con el deterioro cognitivo por escala de Pfeiffer (R = 0,4; p < 0,0001), e inversamente con la situación funcional por índice de Barthel (R = ­0,67; p < 0,0001). La edad del paciente (p = 0,03), su vulnerabilidad clínica (p = 0,016) y el deterioro funcional (p < 0,0001) y cognitivo (p = 0,019) predijeron de forma independiente el IEC. Conclusiones. El perfil del CP de los PP se correspondió con mujeres familiares en primer grado de unos 60 años. Más de la tercera parte estaban sobrecargadas; los factores predictores fueron la edad, la vulnerabilidad clínica y el deterioro funcional y cognitivo del PP

Objective. To determine the profile of the main caregiver (MC) and the factors associated with her/his care burden, in a multi-centre cohort of patients with multiple pathologies (PMP). Design. Multi-centre cross-sectional study. Setting. Four health districts in the Virgen del Rocío University Hospitals Health Area, Seville, Spain. Participants. The PMP cohort was created by checking all the patients who satisfied the health department criteria for PMP (2002): patients suffering from chronic diseases in 2 or more of the 7 clinical categories defined. Main measurements. The profile of PMP caregiver was determined for all patients. The caregiver strain index (CSI) was determined by the index of care stress (ICS). Predictive factors were analysed by the Student t, ANOVA, and Pearson's tests. Multivariate analysis was performed by a forward stepwise linear regression model. Results. The interview was attended by 461 (69%) out of 662 eligible PMP. Of these, 293 (63.6%) had an MC whose mean age was 62 (15) years; 80% of them were women. First-degree relatives made up 88% of caregivers, with spouses 49.7% of them (n=146). In 41.5%, the CSI was >7 points (mean CSI was 5.35 [3.5]). This was higher in those caring for PMP with neurological illnesses (7 [3.2 vs 4.5 [3.3]; P=.0001). The CSI was compared directly with the medical vulnerability of the PMP (R=0.37; P=.001), cognitive deterioration on the Pfeiffer scale (PS) (R=0.4; P=.0001), and inversely with functional status on Barthel's scale (BS) (R=­0.67; P=.0001). Patient's age (P=.03), his/her medical vulnerability (P=.016) and functional (P<.0001) and cognitive (P=.019) deterioration were independently associated with the CSI. Conclusions. The profile of the MC of the PMP cohort corresponded mainly to first-degree female relatives around sixty years old. The burden of care was high in more than a third of them. Predictive factors were age, medical vulnerability, and the functional and cognitive deterioration of the PMP

Réplica. Aclaraciones acerca de las voluntades anticipadas / Reply. Clarification of wills in advance

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