Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features.

Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle magnetic resonance image (MRI), with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterised by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although interindividual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganisation. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients' muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.

Characteristics and clinical outcome in 312 patients with moderate to severe pneumonia due to SARS-COV-2 and hyperinflammation treated with anakinra and corticosteroids: A retrospective cohort study.

OBJECTIVE: To assess the clinical outcome (death and/or Intensive Care Unit (ICU) admission) based on the time from hospital admission to the administration of anakinra and the possible usefulness of a "simplified" SCOPE score to stratify the risk of worse prognosis in our cohort of patients with moderate/severe SARS-CoV-2 pneumonia, both vaccinated and unvaccinated, that received anakinra and corticosteroids. In addition, the clinical, analytical, and imaging characteristics of patients at admission are described. METHODS: Retrospective cohort study of 312 patients admitted to Hospital Clínico San Cecilio in Granada for moderate/severe pneumonia caused by SARS-CoV-2 that received anakinra and corticosteroids between March 2020 and January 2022. Clinical and analytical data were collected as well as the patient outcome at 30 and 60 days after admission. Three treatment groups were established according to the time from hospital admission to administration of anakinra: early (1st-2nd day), intermediate (3rd-5th day), and late (after the 5th day). RESULTS: The median age was 67.4 years (IQR 22-97 years) and 204 (65.4%) were male. The most common comorbidity was hypertension (58%). The median time from the start of symptoms to anakinra administration was 6 days (IQR 5-10) and the SaFi (SaO2/FiO2) was 228 (IQR 71-471). The cure rate was higher in the early-onset anakinra group versus the late-onset group (73% vs 56.6%). The latter had a higher percentage of deaths (27.4%) and a greater number of patients remained hospitalized for a month (16%). On admission, the patients had elevated C-reactive protein (CRP), ferritin, and D-dimer values and decreased total lymphocytes. Analytical improvement was observed at both 72 hours and one month after treatment. 42 (13.5%) required ICU admission, and 23 (7.3%) orotracheal intubation. At 60 days, 221 (70.8%) were discharged, 87 (27.8%) had died and 4 (1.4%) remained hospitalized. The mean dose of anakinra was 1000 mg (100-2600 mg) with differences found between the dose administered and the clinical outcome. There were no differences in the primary outcome based on vaccination. A simplified SCOPE score at the start of anakinra administration was lower in patients with better clinical evolution. CONCLUSIONS: Early treatment with anakinra and corticosteroids was associated with a better outcome regardless of vaccination status. A simplified SCOPE was found to be a good prognostic tool.

Dexametasona frente a metilprednisolona ajustada al peso en pacientes con neumonía moderada-grave por SARS-CoV-2 / Dexamethasone versus weight-adjusted methylprednisolone in patients with moderate-severe SARS-CoV-2 pneumonia

Objetivos: Comparar el desenlace clínico (mortalidad y/o ingreso en UCI) a 30 días de los pacientes ingresados por neumonía moderada-grave por SARS-CoV-2 tratados con dexametasona tras el estudio RECOVERY frente aquellos tratados con metilprednisolona ajustada al peso.MétodosEstudio de cohortes retrospectivo de 65 pacientes con neumonía moderada-grave que recibieron 6 mg/día de dexametasona (grupo DXM) frente a 80 tratados con metilprednisolona ajustada al peso (grupo MTPN).ResultadosFallecieron 21 (32,3%) pacientes del grupo DXM vs. 8 (10%) del grupo MTPN (valor p < 0,001) y 29 (44,6%) del grupo DXM requirieron ingreso en UCI vs. 2 (2,5%) del grupo MTPN (valor p < 0,001). No hubo diferencias basales respecto a características sociodemográficas con un qSOFA medio superior en el grupo MTPN. La razón de riesgo para la mortalidad y el ingreso en UCI ajustada por edad, sexo y PCR al ingreso fue de 2,189 (1,082-4,426; IC 95%) y 10,589 (2,139-48,347; IC 95%) para el grupo DXM, respectivamente, vs. grupo MTPN.ConclusionesLa mortalidad e ingreso en UCI fue menor en pacientes tratados con metilprednisolona ajustada al peso frente a los tratados con dexametasona. (AU)

Objectives: To compare the 30-day outcome (mortality and/or ICU admission) of patients admitted for moderate-severe SARS-CoV-2 pneumonia treated with dexamethasone after the Recovery study versus those treated with weight-adjusted methylprednisolone.MethodsRetrospective cohort study of 65 patients with moderate-severe pneumonia who received dexamethasone 6 mg/day (DXM group) versus 80 treated with weight-adjusted methylprednisolone (MTPN group).ResultsTwenty-one (32.3%) patients in the DXM group died vs. 8 (10%) in the MTPN group (p-value < 0.001) and 29 (44.6%) in the DXM group required ICU admission vs. 2 (2.5%) of the MTPN group (p-value < 0.001). There were no baseline differences regarding sociodemographic characteristics with a higher mean qSOFA in the MTPN group. The hazard ratio for mortality and ICU admission adjusted for age, sex, and admission CRP was 2.189 (1.082–4.426; 95% CI) and 10.589 (2.139–48.347; 95% CI) for the DXM group, respectively, vs. MTPN group.ConclusionsMortality and admission to the ICU were lower in patients treated with weight-adjusted methylprednisolone compared to those treated with dexamethasone. (AU)

Dexamethasone versus weight-adjusted methylprednisolone in patients with moderate-severe SARS-CoV-2 pneumonia.

Objectives: To compare the 30-day outcome (mortality and/or ICU admission) of patients admitted for moderate-severe SARS-CoV-2 pneumonia treated with dexamethasone after the Recovery study versus those treated with weight-adjusted methylprednisolone. Methods: Retrospective cohort study of 65 patients with moderate-severe pneumonia who received dexamethasone 6 mg/day (DXM group) versus 80 treated with weight-adjusted methylprednisolone (MTPN group). Results: 21 (32.3%) patients in the DXM group died vs 8 (10%) in the MTPN group (p-value < 0.001) and 29 (44.6%) in the DXM group required ICU admission vs 2 (2,5%) of the MTPN group (p-value <0.001). There were no baseline differences regarding sociodemographic characteristics with a higher mean qSOFA in the MTPN group. The hazard ratio for mortality and ICU admission adjusted for age, sex, and admission CRP was 2.189 (1.082-4.426; 95% CI) and 10.589 (2.139-48.347; 95% CI) for the DXM group, respectively, vs. MTPN group. Conclusions: Mortality and admission to the ICU were lower in patients treated with weight-adjusted methylprednisolone compared to those treated with dexamethasone.

Objetivos: Comparar el desenlace clínico (mortalidad y/o ingreso en UCI) a 30 días de los pacientes ingresados por neumonía moderada-grave por SARS-CoV-2 tratados con dexametasona tras el estudio Recovery frente aquellos tratados con metilprednisolona ajustada al peso. Métodos: Estudio de cohortes retrospectivo de 65 pacientes con neumonía moderada-grave que recibieron 6 mg/día de dexametasona (grupo DXM) frente a 80 tratados con metilprednisolona ajustada al peso (grupo MTPN). Resultados: Fallecieron 21 (32,3%) pacientes del grupo DXM vs 8 (10%) del grupo MTPN (p-valor < 0,001) y 29 (44,6%) del grupo DXM requirieron ingreso en UCI vs 2 (2,5%) del grupo MTPN (p-valor < 0,001). No hubo diferencias basales respecto a características sociodemográficas con un qSOFA medio superior en el grupo MTPN. La razón de riesgo para la mortalidad y el ingreso en UCI ajustada por edad, sexo y PCR al ingreso fue de 2,189 (1,082−4,426; IC 95%) y 10,589 (2,139−48,347; IC 95%) para el grupo DXM, respectivamente, vs grupo MTPN. Conclusiones: La mortalidad e ingreso en UCI fue menor en pacientes tratados con metilprednisolona ajustada al peso frente a los tratados con dexametasona.

[Dexamethasone versus weight-adjusted methylprednisolone in patients with moderate-severe SARS-CoV-2 pneumonia]. / Dexametasona frente a metilprednisolona ajustada al peso en pacientes con neumonía moderada-grave por SARS-CoV-2.

OBJECTIVES: To compare the 30-day outcome (mortality and/or ICU admission) of patients admitted for moderate-severe SARS-CoV-2 pneumonia treated with dexamethasone after the Recovery study versus those treated with weight-adjusted methylprednisolone. METHODS: Retrospective cohort study of 65 patients with moderate-severe pneumonia who received dexamethasone 6 mg/day (DXM group) versus 80 treated with weight-adjusted methylprednisolone (MTPN group). RESULTS: Twenty-one (32.3%) patients in the DXM group died vs. 8 (10%) in the MTPN group (p-value < 0.001) and 29 (44.6%) in the DXM group required ICU admission vs. 2 (2.5%) of the MTPN group (p-value < 0.001). There were no baseline differences regarding sociodemographic characteristics with a higher mean qSOFA in the MTPN group. The hazard ratio for mortality and ICU admission adjusted for age, sex, and admission CRP was 2.189 (1.082-4.426; 95% CI) and 10.589 (2.139-48.347; 95% CI) for the DXM group, respectively, vs. MTPN group. CONCLUSIONS: Mortality and admission to the ICU were lower in patients treated with weight-adjusted methylprednisolone compared to those treated with dexamethasone.

Validation of dynamic risk stratification and impact of BRAF in risk assessment of thyroid cancer, a nation-wide multicenter study.

Introduction: The dynamic risk stratification (DRS) is a relatively new system in thyroid cancer that considers the response to primary treatment to improve the initial risk of recurrence. We wanted to validate DRS system in a nationwide multicenter study and explore if the incorporation of BRAFV600E into DRS helps to better categorize and predict outcomes. Materials and methods: Retrospective study of 685 patients from seven centers between 1991 and 2016, with a mean age of 48 years and a median follow-up time of 45 months (range 23-77). The overall BRAFV600E prevalence was 53.4%. We classified patients into four categories based on DRS ('excellent', 'indeterminate', 'biochemical incomplete', and 'structural incomplete' response). Cox regression was used to calculate adjusted hazard ratios (AHR) and proportions of variance explained (PVEs). Results: We found 21.6% recurrences and 2.3% cancer-related deaths. The proportion of patients that developed recurrence in excellent, indeterminate, biochemical incomplete and structural incomplete response to therapy was 1.8%, 54%, 91.7% and 96.2% respectively. Considering the outcome at the end of the follow up, patients showed no evidence of disease (NED) in 98.2, 52, 33.3 and 25.6% respectively. Patients in the structural incomplete category were the only who died (17.7%). Because they have similar outcomes in terms of NED and survival, we integrated the indeterminate and biochemical incomplete response into one unique category creating the 3-tiered DRS system. The PVEs of the AJCC/TNM staging, ATA risk classification, 4-tiered DRS, and 3-tiered DRS to predict recurrence at five years were 21%, 25%, 57% and 59% respectively. BRAFV600E was significantly associated with biochemical incomplete response (71.1 vs 28.9%) (HR 2.43; 95% CI, 1.21 to 5.23; p=0.016), but not with structural incomplete response or distant metastases. BRAF status slightly changes the AHR values of the DRS categories but is not useful for different risk grouping. Conclusions: This is the first multicenter study to validate the 4-tiered DRS system. Our results also show that the 3-tiered DRS system, by integrating indeterminate and biochemical incomplete response into one unique category, may simplify response to therapy keeping the system accurate. BRAF status does not provide any additional benefit to DRS.

[Not Available]. / Análisis del perfil de los pacientes ancianos diabéticos y hospitalizados que participaron en el estudio VIDA.

Introduction: Malnutrition is a problem of high significance in hospitalized patients and it has an impact in patient stay and risk of infections. Diabetic patients represent an important percentage of hospitalized population. VIDA study aims to determine the prevalence of malnutrition in elderly diabetic patients admitted to Spanish hospitals. Aim: The aim of this study is to describe the population of VIDA study including biochemical and anthropometric parameters on admission. Methods: Cross sectional, multicentre study of 1098 diabetic patients above 65 years of age. 35 medical centers were included. Results: Mean age was 78 SD 7.1 years. The most common diagnosis at admission was respiratory tract infection. The duration of diabetes disease was above ten years in 51.2% and 33.09% was under insulin treatment. At admission, 21.22% was malnourished and 39.07% was at risk of malnutrition. The prevalence of malnutrition was higher in women (p < 0.0002). Discussion: VIDA study is the first Spanish multicentre study describing nutritional status of a large sample of elderly inpatients with diabetes mellitus. 21.22% of the 1,098 patients were malnourished. This result depends on age and sex, and can increase mortality rate.

Introducción: la malnutrición es un problema de primer orden en el paciente hospitalizado que prolonga la estancia hospitalaria y la tasa de infecciones. El paciente diabético representa un porcentaje importante de la población hospitalizada. El estudio VIDA tiene como objetivo analizar el estado nutricional de pacientes ancianos con diabetes hospitalizados en España. Objetivo: describir la población del estudio VIDA, incluyendo datos del perfil bioquímico y antropométrico en el momento del ingreso. Métodos: estudio multicéntrico, transversal, observacional llevado a cabo en 1098 pacientes mayores de 65 años. Se incluyeron 35 hospitales españoles. Resultados: la edad media de los pacientes ingresados fue 78 ± 7,1 años. El motivo de ingreso más frecuente fueron las infecciones respiratorias (32,4%). El 51,2% estaban diagnosticados de diabetes desde hacía más de 10 años. Un 33,09% recibía tratamiento con insulina. Un 39,07% presentaba riesgo de malnutrición y un 21,22% estaba mal nutrido en el momento del ingreso. Se encontró mayor prevalencia de malnutrición en el grupo de mujeres (p < 0,0002). Conclusiones: el estudio VIDA es el primero que analiza el estado nutricional de una cohorte de pacientes ancianos diabéticos en España. Enlos resultados de este proyecto se concluye que un 21,2% de la muestra presenta malnutrición. Esta condición es edad y sexo dependiente, y puede empeorar la tasa de mortalidad.

Análisis del perfil de los pacientes ancianos diabéticos y hospitalizados que participaron en el estudio VIDA / Analysis of elderly patients with diabetes participating in VIDA study on admission

Introducción: la malnutrición es un problema de primer orden en el paciente hospitalizado que prolonga la estancia hospitalaria y la tasa de infecciones. El paciente diabético representa un porcentaje importante de la población hospitalizada. El estudio VIDA tiene como objetivo analizar el estado nutricional de pacientes ancianos con diabetes hospitalizados en España. Objetivo: describir la población del estudio VIDA, incluyendo datos del perfil bioquímico y antropométrico en el momento del ingreso. Métodos: estudio multicéntrico, transversal, observacional llevado a cabo en 1098 pacientes mayores de 65 años. Se incluyeron 35 hospitales españoles. Resultados: la edad media de los pacientes ingresados fue 78 ± 7,1 años. El motivo de ingreso más frecuente fueron las infecciones respiratorias (32,4%). El 51,2% estaban diagnosticados de diabetes desde hacía más de 10 años. Un 33,09% recibía tratamiento con insulina. Un 39,07% presentaba riesgo de malnutrición y un 21,22% estaba mal nutrido en el momento del ingreso. Se encontró mayor prevalencia de malnutrición en el grupo de mujeres (p < 0,0002) Conclusiones: el estudio VIDA es el primero que analiza el estado nutricional de una cohorte de pacientes ancianos diabéticos en España. En los resultados de este proyecto se concluye que un 21,2% de la muestra presenta malnutrición. Esta condición es edad y sexo dependiente, y puede empeorar la tasa de mortalidad (AU)

Introduction: Malnutrition is a problem of high significance in hospitalized patients and it has an impact in patient stay and risk of infections. Diabetic patients represent an important percentage of hospitalized population. VIDA study aims to determine the prevalence of malnutrition in elderly diabetic patients admitted to Spanish hospitals. Aim: The aim of this study is to describe the population of VIDA study including biochemical and anthropometric parameters on admission. Methods: Cross sectional, multicentre study of 1098 diabetic patients above 65 years of age. 35 medical centers were included. Results: Mean age was 78 SD 7.1 years. The most common diagnosis at admission was respiratory tract infection. The duration of diabetes disease was above ten years in 51.2% and 33.09% was under insulin treatment. At admission, 21.22% was malnourished and 39.07% was at risk of malnutrition. The prevalence of malnutrition was higher in women (p < 0.0002). Discussion: VIDA study is the first Spanish multicentre study describing nutritional status of a large sample of elderly inpatients with diabetes mellitus. 21.22% of the 1,098 patients were malnourished. This result depends on age and sex, and can increase mortality rate (AU)

Hepatitis aguda por citomegalovirus como causa de trombosis portal y mesentérica / Portal and mesenteric vein thrombosis secondary tocytomega- lovirus hepatitis

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