SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes.

Pancreatic ß-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in ß-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human ß-cells. Mice with ß-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

Edoxaban Versus Low-Molecular-Weight Heparin in Hospitalized COVID-19 Patients With Atrial Fibrillation.

OBJECTIVE: During the first wave of the SARS-CoV-2 pandemic, management of anticoagulation therapy in hospitalized patients with atrial fibrillation (AF) was simplified to low-molecular-weight heparin (LMWH) followed by oral anticoagulation, mainly owing to the risk of drug-drug interactions. However, not all oral anticoagulants carry the same risk. METHODS: Observational, retrospective, and multicenter study that consecutively included hospitalized patients with AF anticoagulated with LMWH followed by oral anticoagulation or edoxaban concomitantly with empirical COVID-19 therapy. Time-to-event (mortality, total bleeds, and admissions to ICU) curves, using an unadjusted Kaplan-Meier method and Cox regression model adjusted for potential confounders were constructed. RESULTS: A total of 232 patients were included (80.3 ± 7.7 years, 50.0% men, CHA2DS2-VASc 4.1 ± 1.4; HAS-BLED 2.6 ± 1.0). During hospitalization, patients were taking azithromycin (98.7%), hydroxychloroquine (89.7%), and ritonavir/lopinavir (81.5%). The mean length of hospital stay was 14.6 ± 7.2 days, and total follow-up was 31.6 ± 13.4 days; 12.9% of patients required admission to ICU, 18.5% died, and 9.9% had a bleeding complication (34.8% major bleeding). Length of hospital stay was longer in patients taking LMWH (16.0 ± 7.7 vs 13.3 ± 6.5 days; P = .005), but mortality and total bleeds were similar in patients treated with edoxaban and those treated with LMWH followed by oral anticoagulation. CONCLUSIONS: Mortality rates, arterial and venous thromboembolic complications, and bleeds did not significantly differ between AF patients receiving anticoagulation therapy with edoxaban or LMWH followed by oral anticoagulation. However, the duration of hospitalization was significantly lower with edoxaban. Edoxaban had a similar therapeutic profile to LMWH followed by oral anticoagulation and may provide additional benefits.

Increased RSV-A Bronchiolitis Severity in RSV-Infected Children Admitted to a Reference Center in Catalonia (Spain) Between 2014 and 2018.

Between 2014 and 2018, we evaluated the severity of 687 cases of bronchiolitis caused by respiratory syncytial virus (RSV) in Catalonia, Spain. Compared to RSV-B, RSV-A cases required intensive care (adjusted relative risk (aRR) = 1.44, p < 0.01) and respiratory support (aRR = 1.07, p < 0.01) more often; hospital stay was one day longer (p < 0.01). Subgroup identification may aid clinical evaluation and seasonal healthcare planning.

Management of Hospitalized Respiratory Syncytial Virus Bronchiolitis in the Pediatric Ward in Spain: Assessing the Impact of a New Clinical Practice Protocol.

BACKGROUND: Bronchiolitis caused by the respiratory syncytial virus (RSV) is the main reason for hospitalization in infants. Supportive care is the mainstay of treatment, and tests are restricted to a few indications. During 2015, our hospital bronchiolitis protocol (2015 HBP) was updated according to the latest practice guidelines. OBJECTIVE: The objective of this study was to assess implementation of the 2015 HBP and the clinical outcome of children aged ≤ 24 months with RSV bronchiolitis admitted to a pediatric ward. METHODS: We compared the use of treatments and tests, hospital length of stay (LOS), and oxygen requirements before implementation of the 2015 HBP (2014-2015 and 2015-2016 seasons) and after implementation (2016-2017 and 2017-2018 seasons). RESULTS: The study population comprised 251 children (44.90%) in the first period and 308 (55.10%) in the second (median age 99 days, interquartile range 44-233). After implementation of the 2015 HBP, a statistically significant reduction was found in the percentage of patients undergoing the following treatments or diagnostic tests: salbutamol, from 57.77 to 31.17% (p < 0.001); epinephrine, from 61.75 to 1.30% (p < 0.001); 3% hypertonic saline, from 70.12 to 6.82% (p < 0.001); antibiotics, from 33.07 to 23.05% (p = 0.008); and chest X-ray, from 43.82 to 31.17% (p = 0.001). No statistically significant reductions were observed in the use of corticosteroids and blood tests. Hospital LOS and oxygen requirements were similar in each period. CONCLUSIONS: Appropriate implementation of the 2015 HBP in the pediatric ward improves the use of medication and chest X-ray without modifying clinical outcomes. However, further efforts are needed to reduce the use of salbutamol, corticosteroids, and blood tests.

Impaired Succinate Response to a Mixed Meal in Obesity and Type 2 Diabetes Is Normalized After Metabolic Surgery.

OBJECTIVE: To explore the meal response of circulating succinate in patients with obesity and type 2 diabetes undergoing bariatric surgery and to examine the role of gastrointestinal glucose sensing in succinate dynamics in healthy subjects. RESEARCH DESIGN AND METHODS: Cohort I comprised 45 patients with morbid obesity and type 2 diabetes (BMI 39.4 ± 1.9 kg/m2) undergoing metabolic surgery. Cohort II was a confirmatory cohort of 13 patients (BMI 39.3 ± 1.4 kg/m2) undergoing gastric bypass surgery. Cohort III comprised 15 healthy subjects (BMI 26.4 ± 0.5 kg/m2). Cohorts I and II completed a 2-h mixed-meal tolerance test (MTT) before the intervention and at 1 year of follow-up, and cohort II also completed a 3-h lipid test (LT). Cohort III underwent a 3-h oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) study. RESULTS: In cohort I, succinate response to MTT at follow-up was greater than before the intervention (P < 0.0001). This response was confirmed in cohort II with a greater increase after 1 year of surgery (P = 0.009). By contrast, LT did not elicit a succinate response. Changes in succinate response were associated with changes in the area under the curve of glucose (r = 0.417, P < 0.0001) and insulin (r = 0.204, P = 0.002). In cohort III, glycemia, per se, stimulated a plasma succinate response (P = 0.0004), but its response was greater in the OGTT (P = 0.02; OGTT versus IIGI). CONCLUSIONS: The meal-related response of circulating succinate in patients with obesity and type 2 diabetes is recovered after metabolic surgery.

Utility of Insulin Resistance in Estimating Cardiovascular Risk in Subjects with Type 1 Diabetes According to the Scores of the Steno Type 1 Risk Engine.

BACKGROUND: We sought to assess the potential of insulin resistance (IR) for estimating cardiovascular disease (CVD) risk in adults with type 1 diabetes (T1DM) according to the scores of the Steno Type 1 Risk Engine (ST1RE). METHODS: A total of 179 adults with T1DM (50.8% men, age 41.2 ± 13.1 years, duration of T1DM 16 (12-23) years) without established CVD were evaluated. IR was assessed by the estimation of insulin sensitivity (eIS) using two validated prediction equations: the estimated insulin sensitivity developed from the Pittsburgh Epidemiology of Diabetes Complications Study (eIS-EDC) and the estimated insulin sensitivity developed from Coronary Artery Calcification in T1DM Study (eIS-CACTI) ST1RE was used to estimate 10-year CVD risk and to classify subjects into three groups according to their risk: low (<10%; n = 105), moderate (10-20%; n = 53), and high (≥20%; n = 21). RESULTS: Both eIS-EDC and eIS-CACTI correlated negatively with ST1RE scores (eIS-EDC: r = -0.636, p < 0.001; eIS-CACTI: r = -0.291, p < 0.001). The C-statistic for predicting moderate/high risk and high risk was 0.816 (95% confidence interval (CI): 0.754-0.878) and 0.843 (95% CI: 0.772-0.913), respectively, for the eIS-EDC equation, and was 0.686 (95% CI: 0.609-0.763) and 0.646 (95% CI: 0.513-0.778), respectively, for the eIS-CACTI equation. The eIS-EDC equation had a significantly higher C-statistic both for moderate-/high-risk (p = 0.001) and high-risk (p = 0.007) subjects. Two cut-off points of eIS-EDC were identified for detecting moderate/high risk (8.52 mg·kg-1·min-1; sensitivity 74% and specificity 76%) and high risk (8.08 mg·kg-1·min-1; sensitivity 65% and specificity 95%) with potential applicability in clinical practice. CONCLUSIONS: eIS negatively correlates with the score of CVD risk in the ST1RE. Two cut-off points of eIS are reported with potential utility in clinical practice for detecting adults with T1DM with the highest CVD risk.

Preoperative Circulating Succinate Levels as a Biomarker for Diabetes Remission After Bariatric Surgery.

OBJECTIVE: To determine the potential use of baseline circulating succinate to predict type 2 diabetes remission after bariatric surgery. RESEARCH DESIGN AND METHODS: Forty-five obese patients with diabetes were randomly assigned to Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or laparoscopic greater curvature plication. Anthropometric parameters were evaluated, and a complete biochemical analysis including circulating serum succinate concentrations was performed at baseline and 1 year after surgery. The results were externally validated in a second cohort including 88 obese patients with diabetes assigned to RYGB or SG based on clinical criteria. RESULTS: Succinate baseline concentrations were an independent predictor of diabetes remission after bariatric surgery. Patients achieving remission after 1 year had lower levels of baseline succinate (47.8 [37.6-64.6] µmol/L vs. 64.1 [52.5-82.9] µmol/L; P = 0.018). Moreover, succinate concentrations were significantly decreased 1 year after surgery (58.9 [46.4-82.4] µmol/L vs. 46.0 [35.8-65.3] µmol/L, P = 0.005). In multivariate analysis, the best logistic regression model showed that baseline succinate (odds ratio [OR] 11.3, P = 0.031) and the type of surgery (OR 26.4, P = 0.010) were independently associated with remission. The C-statistic for this model was 0.899 (95% CI 0.809-0.989) in the derivation cohort, which significantly improved the prediction of remission compared with current available scores, and 0.729 (95% CI 0.612-0.846) in the validation cohort. Interestingly, patients had a different response to the type of surgery according to baseline succinate, with significant differences in remission rates. CONCLUSIONS: Circulating succinate is reduced after bariatric surgery. Baseline succinate levels have predictive value for diabetes remission independently of previously described presurgical factors and improve upon the current available scores to predict remission.

Anthracycline-induced cardiotoxicity in diffuse large B-cell lymphoma: NT-proBNP and cardiovascular score for risk stratification.

OBJECTIVE: To evaluate the role of N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and a cardiovascular (CV) risk score named FRESCO for predicting anthracycline-induced cardiotoxicity (AIC) in diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 130 consecutive DLBCL patients treated in first-line with anthracycline-containing immunochemotherapy. Competitive risk between NT-proBNP, FRESCO, and time to AIC was considered. RESULTS: Cumulative incidence of AIC was 12.2% and 17.5% at 1 and 5 years, respectively. Median time to development cardiotoxicity was 6.4 months, with half of the cases showing heart failure and the other half silent AIC. Both NT-proBNP levels and FRESCO score were independently associated with higher risk of AIC (P = 0.001 and P = 0.03, respectively). Patients with NT-proBNP ≥600 pg/mL or those with FRESCO ≥4.5% had 3.97 or 2.54 times higher risk of AIC than those with lower values (P = 0.001 and P = 0.048, respectively). According to the previous cutoffs, three groups of patients with a significantly different risk of AIC could be identified (P < 0.0001). CONCLUSIONS: Doxorubicin-containing chemotherapy is associated with increased risk of silent and overt AIC. Baseline NT-proBNP levels and FRESCO CV risk score are accurate predictors of AIC and can identify groups of patients at different risk, in which personalized cardiologic evaluation should be offered.

Accuracy of new recommendations for adrenal incidentalomas in the evaluation of excessive cortisol secretion and follow-up.

OBJECTIVE: To evaluate whether the 2016 European Society of Endocrinology (ESE) recommendations for the management of adrenal incidentalomas accurately classifies those patients who do not require further follow-up. DESIGN AND METHODS: Single centre retrospective study. From 2010 to 2015, 130 patients with adrenal incidentaloma were evaluated and followed-up. Clinical, analytical and radiological data were recorded and the presence of comorbidities was assessed. Patients were grouped as nonfunctional or subclinical Cushing syndrome according to American guidelines; and nonfunctional, possible autonomous cortisol secretion and autonomous cortisol secretion, according to ESE guidelines. RESULTS: Based on American guidelines, 94% of patients had nonfunctional adrenal incidentalomas and 6% had subclinical Cushing syndrome. Based on ESE guidelines, patients were classified into nonfunctional (54%), possible autonomous cortisol secretion (40%) and autonomous cortisol secretion (6%) groups. No differences were observed in demographic characteristics and comorbidities between groups in either classification. Following ESE guidelines, no patient in the nonfunctional group was reclassified into the possible autonomous or autonomous cortisol secretion groups during follow-up, but one patient in the possible autonomous cortisol secretion group was reclassified into the autonomous cortisol secretion group. Also, 30 patients included in the groups of possible autonomous or autonomous cortisol secretion experienced progression of a comorbidity associated with cortisol excess, with diabetes mellitus as the most frequent comorbidity observed. CONCLUSION: Although adrenal incidentalomas with an excess of cortisol secretion were more frequently diagnosed with the new ESE recommendations, patients who did not require longer follow-up after first evaluation were accurately classified.

Quality of the record of drug-related problems in a database for voluntary adverse event reporting / Calidad del registro de problemas relacionados con los medicamentos en una base de datos de notificación voluntaria de eventos adversos

Objective: To determine the number and type of errors found in the record of drug-related problems in the SINEA database, an electronic system for voluntary reporting of adverse events in healthcare, in order to quantify the differences between the raw and refined databases, suggest improvements, and determine the need for refining said databases. Methods: A Pharmacist reviewed the database and refined the adverse events reported from January to August, 2014, considering the ‘describe_what_happened’ field as the gold standard. There was a comparison of the rates of medication errors, both potential and real, adverse reactions, impact on the patient, impact on healthcare, and medications more frequently involved in the raw and refined databases. Agreement was calculated through Cohen’s Kappa Coefficient. Results: 364 adverse events were reported: 66.7% were medication errors, 2.7% adverse reactions to the medication (2 were wrongly classified as both, showing a total percentage >100%) and 31% were other events. After refinement, the percentages were 69.5%, 5.8% and 24.7%, respectively (κ=0.85; CI95% [0.80-0.90]). Before refinement, 73.6% of medication errors were considered potential vs. 82.3% after refinement (κ=0.65; CI95% [0.54-0.76]). The medication most frequently involved was trastuzumab (20.9%). The ‘molecule’ field was blank in 133 entries. A mean of 1.8±1.9 errors per entry were detected. Conclusions: Although agreement is good, the refinement process cannot be avoided, as it provides valuable information to improve pharmacotherapy. Data quality could be improved by reducing the number of type-in text fields, using drop-down lists, and by increasing the training of the reporters (AU)

Objetivo: Determinar el número y tipo de errores en los registros de problemas relacionados con los medicamentos encontrados en la base de datos de SINEA, sistema electrónico de notificación voluntaria de eventos adversos de la asistencia sanitaria, para cuantificar las diferencias entre las bases de datos bruta y refinada, proponer mejoras y establecer la necesidad de depuración. Métodos: Un farmacéutico revisó la base de datos y depuró los eventos adversos notificados de enero a agosto de 2014, considerando el campo ‘describa_lo_que_pasó’ como gold standard. Se compararon los porcentajes de errores de medicación, tanto potenciales como reales, reacciones adversas, efecto en el paciente, impacto en la asistencia y medicamentos implicados más frecuentemente en las bases de datos bruta y depurada. Se calculó la concordancia con el coeficiente kappa (κ) de Cohen. Resultados: Se notificaron 364 eventos adversos, 66,7% errores de medicación, 2,7% reacciones adversas al medicamento (2 clasificados erróneamente en ambas clases arrojando un porcentaje total>100%) y 31% de otros eventos. Tras la depuración, los porcentajes respectivamente fueron 69,5%, 5,8% y 24,7% (κ=0,85; CI95% [0,80-0,90]). Antes de la depuración, el 73,6% de los errores de medicación se consideraron potenciales versus 82,3% tras la depuración (κ=0,65; CI95% [0,54-0,76]). El medicamento implicado más frecuentemente fue trastuzumab (20,9%). El campo ‘principio_activo’ estaba vacío en 133 registros. Se detectó una media de 1,8±1,9 errores por registro. Conclusiones: Aunque la concordancia es buena, no puede evitarse la depuración, que proporciona información valiosa para mejorar la farmacoterapia. Reducir los campos de texto libre, utilizar listas desplegables y aumentar la formación de los notificadores podría incrementar la calidad de los datos (AU)

Quality of the record of drug-related problems in a database for voluntary adverse event reporting.

OBJECTIVE: To determine the number and type of errors found in the record of drug-related problems in the SINEA database, an electronic system for voluntary reporting of adverse events in healthcare, in order to quantify the differences between the raw and refined databases, suggest improvements, and determine the need for refining said databases. METHODS: A Pharmacist reviewed the database and refined the adverse events reported from January to August, 2014, considering the "describe_what_happened" field as the gold standard. There was a comparison of the rates of medication errors, both potential and real, adverse reactions, impact on the patient, impact on healthcare, and medications more frequently involved in the raw and refined databases. Agreement was calculated through Cohen's Kappa Coefficient. RESULTS: 364 adverse events were reported: 66.7% were medication errors, 2.7% adverse reactions to the medication (2 were wrongly classified as both, showing a total percentage >100%) and 31% were other events. After refinement, the percentages were 69.5%, 5.8% and 24.7%, respectively (κ=0.85; CI95% [0.80-0.90]). Before refinement, 73.6% of medication errors were considered potential vs. 82.3% after refinement (κ=0.65; CI95% [0.54- 0.76]). The medication most frequently involved was trastuzumab (20.9%). The  "molecule" field was blank in 133 entries. A mean of 1.8±1.9 errors per entry were detected. CONCLUSIONS: Although agreement is good, the refinement process cannot be avoided, as it provides valuable information to improve pharmacotherapy. Data quality could be improved by reducing the number of type-in text fields, using drop-down lists, and by increasing the training of the reporters.

Objetivo: Determinar el número y tipo de errores en los registros de problemas relacionados con los medicamentos encontrados en la base de datos de SINEA, sistema electrónico de notificación voluntaria de eventos adversos de la asistencia sanitaria, para cuantificar las diferencias entre las bases de datos bruta y refinada, proponer mejoras y establecer la necesidad de depuración.Método: Un farmacéutico revisó la base de datos y depuró los eventos adversos notificados de enero a agosto de 2014, considerando el campo "describa_lo_que_pasó" como gold standard. Se compararon los porcentajes de errores de medicación, tanto potenciales como reales, reacciones adversas, efecto en el paciente, impacto en la asistencia y medicamentos implicados más frecuentemente en las bases de datos bruta y depurada. Se calculó la concordancia con el coeficiente kappa (κ) de Cohen.Resultados: Se notificaron 364 eventos adversos, 66,7% errores de medicación, 2,7% reacciones adversas al medicamento (2 clasificados erróneamente en ambas clases arrojando un porcentaje total>100%) y 31% de otros eventos. Tras la depuración, los porcentajes respectivamente fueron 69,5%, 5,8% y 24,7% (κ=0,85; CI95% [0,80-0,90]). Antes de la depuración, el 73,6% de los errores de medicación se consideraron potenciales versus 82,3% tras la depuración (κ=0,65; CI95% [0,54-0,76]). El medicamento implicado más frecuentemente fue trastuzumab (20,9%). El campo "principio_activo" estaba vacío en 133 registros. Se detectó una media de 1,8±1,9 errores por registro.Conclusiones: Aunque la concordancia es buena, no puede evitarse la depuración, que proporciona información valiosa para mejorar la farmacoterapia. Reducir los campos de texto libre, utilizar listas desplegables y aumentar la formación de los notificadores podría incrementar la calidad de los datos.

Rediscovering TNAP in the Brain: A Major Role in Regulating the Function and Development of the Cerebral Cortex.

The presence of alkaline phosphatase (AP) activity in the neural tissue has been described decades ago. However, only recent studies clarified the isotype, regional distribution and subcellular localization of the AP expressed in the cerebral cortex of diverse mammalian species including the human. In the primate brain the discovery that the bone AP isotype (TNAP) is expressed provided the opportunity of a deeper understanding of the role of this enzyme in neuronal functions based on the knowledge acquired by studying the role of the enzyme in hypophosphatasia, mostly in bone mineralization. TNAP exhibits widespread substrate specificity and, in the brain, it is potentially involved in the regulation of molecules which play fundamental roles in signal transmission and development. In light of these observations, the localization of TNAP in the human cerebral cortex is of high significance when considering that epilepsy is often diagnosed in hypophosphatasia. Here we overview our results on the identification of TNAP in the primate cerebral cortex: TNAP exhibits a noticeably high activity in the synapses and nodes of Ranvier, is specifically present in layer 4 of the sensory cortices and additionally in layer 5 of prefrontal, temporal and other associational areas in human. Our studies also indicate that bone AP activity depends on the level of sensory input and that its developmental time-course exhibits characteristic regional differences. The relevance of our findings regarding human cortical physiology and brain disorders are discussed.