Incident use of hydroxychloroquine for the treatment of rheumatoid arthritis and systemic lupus erythematosus during the COVID-19 pandemic.

OBJECTIVE: We studied whether the use of hydroxychloroquine (HCQ) for COVID-19 resulted in supply shortages for patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used US claims data (IQVIA PHARMETRICS® Plus for Academics [PHARMETRICS]) and hospital electronic records from Spain (IMASIS) to estimate monthly rates of HCQ use between January 2019 and March 2022, in the general population, and in RA and SLE patients. Methotrexate (MTX) was use was estimated as a control. RESULTS: Over 13.5 million individuals (13,311,811 PHARMETRICS, 207,646 IMASIS) were included in the general population cohort. RA and SLE cohorts enrolled 135,259 and 39,295 patients respectively, in PHARMETRICS. Incidence of MTX and HCQ were stable before March 2020. On March 2020, the incidence of HCQ increased by 9- and 67-fold in PHARMETRICS and IMASIS respectively, to decrease in May 2020. Usage rates of HCQ went back to pre-pandemic trends in Spain, but remained high in the US, mimicking waves of COVID-19. No significant changes in HCQ use were noted among patients with RA and SLE. MTX use rates decreased during HCQ approval period for COVID-19 treatment. CONCLUSIONS: Use of HCQ increased dramatically in the general population in both Spain and the US during March and April 2020. While Spain returned to pre-pandemic rates after the first wave, use of HCQ remained high and followed waves of COVID-19 in the US. However, we found no evidence of general shortages in the use of HCQ for both RA and SLE in the US. This article is protected by copyright. All rights reserved.

The leaf idioblastome of the medicinal plant Catharanthus roseus is associated with stress resistance and alkaloid metabolism.

Catharanthus roseus leaves produce a range of monoterpenoid indole alkaloids (MIAs) that include low levels of the anticancer drugs vinblastine and vincristine. The MIA pathway displays a complex architecture spanning different subcellular and cell type localizations, and is under complex regulation. As a result, the development of strategies to increase the levels of the anticancer MIAs has remained elusive. The pathway involves mesophyll specialized idioblasts where the late unsolved biosynthetic steps are thought to occur. Here, protoplasts of C. roseus leaf idioblasts were isolated by fluorescence-activated cell sorting, and their differential alkaloid and transcriptomic profiles were characterized. This involved the assembly of an improved C. roseus transcriptome from short- and long-read data, IDIO+. It was observed that C. roseus mesophyll idioblasts possess a distinctive transcriptomic profile associated with protection against biotic and abiotic stresses, and indicative that this cell type is a carbon sink, in contrast to surrounding mesophyll cells. Moreover, it is shown that idioblasts are a hotspot of alkaloid accumulation, suggesting that their transcriptome may hold the key to the in-depth understanding of the MIA pathway and the success of strategies leading to higher levels of the anticancer drugs.

Comparison of the Permeability of Potential Ballast Rocks from Northern Rio de Janeiro State under Different Fouling Rates after Sodium Sulfate Attack.

This paper aimed to analyze the reduction in the ballast layer permeability simulated in a laboratory in saturated conditions by the presence of rock dust as a contaminant of three types of rocks explored in different deposits in the northern region of the state of Rio de Janeiro, Brazil, through laboratory testing relating the physical properties of rock particles before and after sodium sulfate attack. Sodium sulfate attack is justified by the proximity of some sections of the planned EF-118 Vitória-Rio railway line to the coast and of the sulfated water table to the ballast bed, which could degrade the material used and compromise the railway track. Granulometry and permeability tests were performed to compare ballast samples with fouling rates of 0, 10, 20, and 40% rock dust by volume. A constant head permeameter was used to analyze hydraulic conductivity and establish correlations between the petrography and mercury intrusion porosimetry of the rocks, namely two types of metagranite (Mg1 and Mg3) and a gneisse (Gn2). Rocks, such as Mg1 and Mg3, with a larger composition of minerals susceptible to weathering according to petrography analyses, tend to be more sensitive to weathering tests. This, in conjunction with the climate in the region studied, with average annual temperature and rainfall of 27 °C and 1200 mm, could compromise track safety and user comfort. Additionally, the Mg1 and Mg3 samples showed greater percentage variation in wear after the Micro-Deval test, which could damage the ballast due to the considerable changeability of the material. The mass loss caused by abrasion due to the passage of rail vehicles was assessed by the Micro-Deval test, with Mg3 (intact rock) declining from 8.50 ± 1.5 to 11.04 ± 0.5% after chemical attack. However, Gn2, which exhibited the greatest mass loss among the samples, showed no significant variation in average wear, and its mineralogical characteristics remained almost unchanged after 60 sodium sulfate cycles. These aspects, combined with its satisfactory hydraulic conductivity rate, indicate that Gn2 is suitable for use as railway ballast in the EF-118 railway line.

Sensitive Zika biomarker detection assisted by quantum dot-modified electrochemical immunosensing platform.

We report the development of a new nanostructured electrochemical immunosensing platform for the detection of the Zika virus envelope protein (EP-ZIKV). For this, quantum dots (QDs) were explored in combination with screen-printed carbon electrodes (SPCEs) functionalized with a conductor polymeric film, formed from 2-(1H-pyrrol-1-yl)ethanamine (Pyam), and anti-EP DIII ZIKV antibodies. Carboxylated CdTe QDs were synthesized, characterized by optical and structural techniques, and covalently immobilized onto the SPCE/PPyam surface. Then, anti-EP ZIKV antibodies were also covalently conjugated to QDs. All stages of platform assembly were evaluated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The detection of EP-ZIKV was performed by differential pulse voltammetry (DPV). Results indicated that QDs were efficiently immobilized, and did not show oxidation, under the conditions evaluated, for at least 7 months. Anti-EP ZIKV antibodies were effectively immobilized on the PPyam/QDs surface, even after 2 months of electrode storage. The platform enabled the detection of EP-ZIKV with high sensitivity using minimal sample volumes (LOD = 0.1 ng mL-1 and LOQ = 0.4 ng mL-1). The platform was also able to detect EP-ZIKV in spiked serum samples. Moreover, the platform showed specificity, not detecting the EP-DENV 3 nor a mixture of four DENV serotypes antigens. Thus, the proposed combination favored the development of a sensitive immunosensing platform, promising for the detection of Zika in the viremic phase, which also holds potential for transposition to other arboviruses.

Liver fat accumulation more than fibrosis causes early liver dynamic dysfunction in patients with non-alcoholic fatty liver disease.

INTRODUCTION: In Non-Alcoholic Fatty Liver Disease (NAFLD), events driving early hepatic dysfunction with respect to specific metabolic pathways are still poorly known. METHODS: We enrolled 84 subjects with obesity and/or type 2 diabetes (T2D). FibroScan® served to assess NAFLD by controlled attenuation parameter (CAP), and fibrosis by liver stiffness (LS). Patients with LS above 7 kPa were excluded. APRI and FIB-4 were used as additional serum biomarkers of fibrosis. The stable-isotope dynamic breath test was used to assess the hepatic efficiency of portal extraction (as DOB15) and microsomal metabolization (as cPDR30) of orally-administered (13C)-methacetin. RESULTS: NAFLD occurred in 45%, 65.9%, and 91.3% of normal weight, overweight, and obese subjects, respectively. Biomarkers of liver fibrosis were comparable across subgroups, and LS was higher in obese, than in normal weight subjects. DOB15 was 23.2 ± 1.5‰ in normal weight subjects, tended to decrease in overweight (19.9 ± 1.0‰) and decreased significantly in obese subjects (16.9 ± 1.3, P = 0.008 vs. normal weight). Subjects with NAFLD had lower DOB15 (18.7 ± 0.9 vs. 22.1 ± 1.2, P = 0.03) but higher LS (4.7 ± 0.1 vs. 4.0 ± 0.2 kPa, P = 0.0003) than subjects without NAFLD, irrespective of fibrosis. DOB15 (but not cPDR30) decreased with increasing degree of NAFLD (R = -0.26; P = 0.01) and LS (R = -0.23, P = 0.03). Patients with T2D showed increased rate of NAFLD than those without T2D but similar LS, DOB15 and cPDR30. CONCLUSIONS: Overweight, obesity and liver fat accumulation manifest with deranged portal extraction efficiency of methacetin into the steatotic hepatocyte. This functional alteration occurs early, and irrespective of significant fibrosis and presence of T2D.

Fibrosis nonalcoholic steatohepatitis index validation and applicability considering glycaemic severity and T2D duration.

Nonalcoholic fatty liver disease (NAFLD) diagnosis without using invasive methods is extremely challenging, highlighting the need for simple indexes for this end. Recently, the fibrotic nonalcoholic steatohepatitis index (FNI) was developed and proposed as an affordable non-invasive score calculated with aspartate aminotransferase, high-density lipoprotein cholesterol and haemoglobin A1c. Herein, and given the link between NAFLD and diabetes, we aimed at validating FNI in a population with type 2 diabetes (T2D), also considering diabetes duration and glycaemic severity. The performance of FNI was higher than FIB-4 (AUROC = 0.89 vs 0.67, respectively). Additionally, using 0.1 as the rule-out cut-off of FNI, the sensitivity was 0.99 and the positive predictive value was 0.19. Both duration of diabetes and A1c did not impact FNI performance. In sum, FNI is a valuable score for predicting fibrotic nonalcoholic steatohepatitis not only for primary care units but also for diabetes specialized care.

Interpersonal Relationships in Diabetes: Views and Experience of People with Diabetes, Informal Carers, and Healthcare Professionals in Portugal.

INTRODUCTION: The increasing burden of diabetes poses a great challenge to healthcare systems and economy worldwide. Although modern therapeutic strategies for diabetes are widely available, most patients still fail to achieve optimal clinical targets and well-being. The primary objective of this study was to assess and explore potential drivers and successful management of diabetes among people with diabetes, family members and healthcare professionals in Portugal, by applying the protocol of the multinational study "Diabetes, Attitudes, Wishes and Needs (DAWN2)". MATERIAL AND METHODS: A total of 767 adults, including 417 people with diabetes, 123 family members and 227 healthcare professionals, participated in the study. Surveys assessed health-related quality of life, self-management, attitudes/beliefs, social support and priorities for improvement areas in diabetes care. RESULTS: Diabetes has a negative impact on the physical health and emotional well-being of patients in Portugal and is also a psychological burden for family members. Earlier diagnosis and treatment of diabetes were mentioned as a major area of improvement. Healthcare professionals indicated the need for diabetes self-management education. CONCLUSION: We have used for the first time in Portugal the DAWN2 protocol to address the wishes, needs, and attitudes of Portuguese diabetes patients, their relatives, and healthcare professionals regarding the disease.

Introdução: Os encargos crescentes com a diabetes representam um desafio para os sistemas de saúde e economia a nível mundial. Apesar de terapias modernas para a diabetes disponíveis, a maioria das pessoas continua privada de cuidados e bem-estar adequados. O objetivo primário deste estudo foi avaliar e explorar os fatores relevantes para o controlo ativo e eficaz da diabetes para as pessoas com diabetes, familiares e profissionais de saúde em Portugal, aplicando o protocolo do estudo multinacional "Diabetes, Attitudes, Wishes and Needs (DAWN2)". Material e Métodos: Participaram no estudo 767 adultos (417 pessoas com diabetes, 123 familiares e 227 profissionais de saúde). Foram avaliados a qualidade de vida associada à saúde, autogestão, atitudes/crenças, apoio social e prioridades em áreas de melhoria no tratamento da diabetes. Resultados: A diabetes tem um impacto negativo na saúde física e no bem-estar emocional das pessoas em Portugal, sendo também uma carga psicológica para os seus familiares. O diagnóstico e tratamento precoces da diabetes foram indicados como a principal área de melhoria. Profissionais de saúde indicaram a necessidade de educação para a autogestão da diabetes. Conclusão: Pela primeira vez em Portugal usámos o protocolo DAWN2 para ir ao encontro dos desejos, necessidades e atitudes dos doentes Portugueses com diabetes, os seus familiares e profissionais de saúde relativamente à doença.

Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion.

AIMS/HYPOTHESIS: Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven. METHODS: We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet. RESULTS: In individuals with normoglycaemia, DPP4 single-nucleotide variants governed glycaemic excursions (rs4664446, p=1.63x10-7) and C-peptide release responses (rs2300757, p=6.86x10-5) upon OGTT. Association with blood glucose levels was stronger at 30 min OGTT, but a higher association with the genetic control of insulin secretion was detected in later phases of the post-OGTT response, suggesting that the DPP4 gene directly senses glucose challenges. Accordingly, in mice fed a normal chow diet but not a high-fat diet, we found that, under OGTT, expression of Dpp4 is strongly downregulated at 30 min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals, indicating that post-OGTT control by DPP4 is abrogated in prediabetes. Furthermore, Dpp4 KO mice provided concordant evidence that Dpp4 modulates post-OGTT C-peptide release in normoglycaemic but not dysmetabolic states. CONCLUSIONS/INTERPRETATION: These results showed the DPP4 gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in DPP4 control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes.

Increased Intake of Both Caffeine and Non-Caffeine Coffee Components Is Associated with Reduced NAFLD Severity in Subjects with Type 2 Diabetes.

Coffee may protect against non-alcoholic fatty liver disease (NAFLD), but the roles of the caffeine and non-caffeine components are unclear. Coffee intake by 156 overweight subjects (87% with Type-2-Diabetes, T2D) was assessed via a questionnaire, with 98 subjects (all T2D) also providing a 24 h urine sample for quantification of coffee metabolites by LC-MS/MS. NAFLD was characterized by the fatty liver index (FLI) and by Fibroscan® assessment of fibrosis. No associations were found between self-reported coffee intake and NAFLD parameters; however, total urine caffeine metabolites, defined as Σcaffeine (caffeine + paraxanthine + theophylline), and adjusted for fat-free body mass, were significantly higher for subjects with no liver fibrosis than for those with fibrosis. Total non-caffeine metabolites, defined as Σncm (trigonelline + caffeic acid + p-coumaric acid), showed a significant negative association with the FLI. Multiple regression analyses for overweight/obese T2D subjects (n = 89) showed that both Σcaffeine and Σncm were negatively associated with the FLI, after adjusting for age, sex, HbA1c, ethanol intake and glomerular filtration rate. The theophylline fraction of Σcaffeine was significantly increased with both fibrosis and the FLI, possibly reflecting elevated CYP2E1 activity-a hallmark of NAFLD worsening. Thus, for overweight/obese T2D patients, higher intake of both caffeine and non-caffeine coffee components is associated with less severe NAFLD. Caffeine metabolites represent novel markers of NAFLD progression.

Ensino da segurança do paciente na graduação em enfermagem no estado da Bahia / Enseñanza sobre la seguridad del paciente en el pregrado en enfermería en el estado de Bahia-Brasil / Teaching patient safety in undergraduate nursing in the state of Bahia

RESUMO Objetivo: identificar o tema segurança do paciente nos componentes curriculares de cursos de graduação em enfermagem no estado da Bahia. Método: pesquisa quantitativa, descritiva, exploratória de base documental desenvolvida em fevereiro de 2019, com dados extraídos da Matriz Curricular, Projeto Pedagógico e Ementa, disponíveis nos websites de instituições de ensino superior com situação ativa no sistema e-MEC. Resultados: das 75 instituições cadastradas, nove eram públicas, e 66 privadas. O tema segurança do paciente não foi encontrado em nenhum website de universidades públicas e apenas em 8,06% das privadas. O contato inicial com a temática dava-se no 3º semestre, a carga horária média das disciplinas que abordavam o tema variava de 30 a 306 horas e o componente curricular era obrigatório para estas disciplinas. Apenas 1,71% dos websites das instituições públicas apresentavam todos os documentos pesquisados, enquanto as privadas apresentaram 33,33%, a matriz curricular foi o documento mais disponibilizado. Conclusão: a inserção do tema segurança do paciente nos componentes curriculares mostrou-se insuficiente, apontando necessidade de revisão dos processos formativos e inclusão de abordagem interdisciplinar e transdisciplinar, tendo em vista a complexidade do cuidado em saúde e a importância do desenvolvimento de competências específicas com foco na segurança do paciente.

RESUMEN Objetivo: identificar el tema seguridad del paciente en los componentes curriculares de cursos de pregrado en enfermería en el estado de Bahia-Brasil. Método: investigación cuantitativa, descriptiva, exploratoria de base documental desarrollada en febrero de 2019, con datos extraídos de la Matriz Curricular, Proyecto Pedagógico y Directrices, disponibles en los sitios electrónicos de instituciones de enseñanza superior con situación activa en el sistema e-MEC. Resultados: de las 75 instituciones registradas, nueve eran públicas y 66 privadas. El tema de la seguridad del paciente no se encontró en ningún website de universidades públicas y solo en el 8,06% de las privadas. El contacto inicial con la temática se trabajaba en el 3º semestre, el promedio de la carga horaria de las asignaturas que trataban el tema variaba de 30 a 306 horas y el componente curricular era obligatorio para estas asignaturas. Solo el 1,71% de los sitios electrónicos de las instituciones públicas presentaba todos los documentos investigados, mientras que los privados presentaron el 33,33%, la matriz curricular fue el documento más disponible. Conclusión: la inserción del tema seguridad del paciente en los componentes curriculares se mostró insuficiente, señalando necesidad de revisión de los procesos formativos e inclusión de abordaje interdisciplinario y transdisciplinario, teniendo en cuenta la complejidad del cuidado de la salud y la importancia del desarrollo de competencias específicas centradas en la seguridad del paciente.

ABSTRACT Objective: to identify the theme of patient safety in the curricular components of undergraduate nursing courses in the state of Bahia. Method: quantitative, descriptive, exploratory research of documentary basis developed in February 2019, with data extracted from the Curricular Matrix, Pedagogical Project and Menu, available on the websites of higher education institutions with active situation in the e-MEC system. Results: of the 75 registered institutions, nine were public, and 66 were private. The theme of patient safety was not found in any website of public universities and only in 8.06% of private universities. The initial contact with the theme took place in the 3rd semester, the average workload of the subjects that addressed the theme ranged from 30 to 306 hours and the curricular component was mandatory for these disciplines. Only 1.71% of the websites of public institutions had all the documents surveyed, while the private ones presented 33.33%, the curriculum matrix was the most available document. Conclusion: the insertion of the patient safety theme in the curricular components proved insufficient, pointing out the need for review of training processes and inclusion of an interdisciplinary and transdisciplinary approach, in view of the complexity of health care and the importance of developing specific competencies focused on patient safety.

Quartzite Mining Waste: Diagnosis of ASR Alkali-Silica Reaction in Mortars and Portland Cement Concrete.

The main objective was to determine the deleterious potential of quartzite mining tailings subjected to different ASR alkali-silica reaction tests. The studies included petrographic analysis, chemical analysis of cements, expansion tests in mortar bars and concrete prisms, and microstructural analysis. Petrographic analysis of quartzites indicated high percentages of deformed quartz (95%), and were classified as potentially reactive. Two types of HES high early strength cement with alkaline equivalents of 0.749% and 0.61%, respectively, were selected. Of the 8 samples analyzed by the accelerated method in mortars, only 2 quartzite samples and 1 diabasium sample indicated potentially reactive behavior. The accelerated and long-term methods in concrete prisms proved to be effective and were consistent with the deleterious potential of the samples. All analyzed samples were diagnosed with the ASR gel. In the microstructural analysis, in addition to the ASR products, other expansive products of late ettringite were detected. Reaction mitigation methods are proposed so that quartzite waste can be used as an alternative aggregate in concrete, and thus contribute to the reduction of mine tailings and, consequently, reduce the negative environmental impact from mining.

Perfil da Cultura de Segurança do Paciente em um Hospital Público / Patient safety culture profile in a public hospital / Perfil de la cultura de seguridad del paciente en un hospital público

Objetivo: Avaliar o perfil da cultura de segurança do paciente de um hospital público de Salvador-Bahia na visão de enfermeiras líderes. Metodologia: Estudo exploratório descritivo, transversal do tipo survey interseccional de abordagem quantitativa. Utilizou-se o questionário "Pesquisa sobre Segurança do Paciente em Hospitais" da Agency for Healthcare Research and Quality.Resultados: 80,9% são coordenadoras de enfermagem. A dimensão de área forte foi "Expectativas e ações do supervisor/chefia para promoção da segurança do paciente" apresentando 80,9% de respostas positivas. As dimensões de áreas com potencial para a melhoria da segurança foram "Apoio da gestão hospitalar para a segurança do paciente", "Trabalho em equipe na unidade" e "Aprendizado organizacional/melhoria contínua". As demais dimensões foram consideradas de áreas frágeis (66%). 34% das enfermeiras líderes não realizaram nenhuma notificação de evento adverso, no período de 12 meses. 59% das participantes avaliaram a segurança do paciente como regular. Discussão: Os resultados não devem ser interpretados isoladamente, requerem visão de conjunto com outras características do hospital e o contexto sócio, político e econômico do país. Conclusão: O perfil da cultura de segurança foi classificado como frágil, no entanto, a cultura de segurança do paciente está sendo construída de maneira efetiva na instituição. (AU)

Objective: Evaluate the profile of patient safety culture in a public hospital in Salvador-Bahia from the perspective of leaders nurses. Methods: Descriptive, exploratory and cross-sectional study of the intersectional survey type with a quantitative approach. The questionnaire "Research on Patient Safety in Hospitals" from the Agency for Healthcare Research and Quality was used. Results: 80,9% are nursing coordinators. The dimension of strong area was "Expectations and actions of the supervisor/manager to promote patient safety" with 80,9% positive responses. The dimensions of areas with potential for improving safety were "Hospital management support for patient safety", "Teamwork in the unit" and "Organizational learning/continuous improvement". The other dimensions were considered to be fragile areas (66%). 36.4% of the leader nurses did not report any adverse events during the 12-month period. 60.9% of participants rated patient safety as regular. Discussion: Results should not be interpreted in isolation, they require an overview of the hospital's other characteristics and the country's social, political and economic context. Conclusion: The safety culture profile was classified as fragile, however, the patient safety culture is being built effectively in institution. (AU)

Objetivo: Avaliar el perfil de la cultura de seguridad del paciente de un hospital público de Salvador-Bahia en la visión de las enfermeras líderes. Métodos: Estudio exploratorio descriptivo, transversal del tipo survey interseccional de abordaje cuantitativa. Se Utilizó el cuestionario "Búsqueda sobre Seguridad del Paciente en Hospitales" de la Agency for Healthcare Research and Quality. Resultados: 80,9% son enfermeras coordinadoras. La dimensión de área fuerte fue "Expectativas y acciones del supervisor/jefe para la promoción de la seguridad del paciente" presentándose 80,9% de respuestas positivas. Las dimensiones de áreas con potencial para la mejoría de la seguridad fueron "Apoyo de la gestión hospitalar para la seguridad del paciente", "Trabajo en equipo de la unidad" y "Aprendizaje organizacional/mejoría contínua". Las demás dimensiones fueron consideradas de áreas frágiles (66%). 36,4% de las enfermeras líderes no realizaron ninguna notificación de evento adverso, en el período de 12 meses. 60,9% de las participantes avaliaron la seguidad del paciente como regular. Discusión: Los resultados no deben ser interpretados separadamente, requieren de visión en conjunto con otras características del hospital y del contexto sócio - político y económico del país. Conclusión: El perfil de la cultura de seguridad fue clasificado como frágil, no entanto, la cultura de seguridad del paciente está siendo construida de manera efectiva en la institución. (AU)

Nationwide questionnaire data of 229 Williams-Beuren syndrome patients using WhatsApp tool.

BACKGROUND: Williams-Beuren syndrome is a multisystemic disorder caused by a microdeletion of the 7q11.23 region. Although familial cases with autosomal dominant inheritance have been reported, the vast majority are sporadic. OBJECTIVE: To investigate the main complaints and clinical findings of patients with Williams-Beuren syndrome. METHODS: A total of 757 parents of patients registered in the Brazilian Association of Williams-Beuren Syndrome (ABSW) received a questionnaire via WhatsApp from March to July 2017. RESULTS: In total, 229 parents answered the survey. Age of diagnosis ranged from 2 days to 34 years (median: 3 years). The main clinical findings reported by the parents were abdominal colic (83.3%), failure to thrive (71.5%), feeding difficulty in the first year (68.9%), otitis (56.6%), urinary tract infections (31.9%), precocious puberty (27.1%) and scoliosis (15.9%). Cardiac defects were present in 66% of patients, and the most frequent defect was supravalvular aortic stenosis (36%). Arterial hypertension was reported in 23%. Hypercalcemia was reported in 10.5% of patients, mainly during the first year of life. Hyperacusis and hypersociability were common complaints (both present in 89%). Other behavioral and neuropsychiatric symptoms reported by the parents included attention deficit (89%), anger crises (83%), excessive fear (66%), depression (64%), anxiety (67%) and hypersexuality (33%). The most common complaints were hypersensitivity to sounds, talkative personality, emotional dependence and learning difficulties. In 98.3%, the parents denied family history. CONCLUSIONS: Williams-Beuren syndrome requires close follow-up with different medical specialties due to their variable clinical comorbidities, including language and school learning difficulties, behavioral and psychiatric problems.

Nationwide questionnaire data of 229 Williams-Beuren syndrome patients using WhatsApp tool / Resultados de um questionário nacional de 229 pacientes com síndrome de Williams-Beuren obtidos por WhatsApp

ABSTRACT Background: Williams-Beuren syndrome is a multisystemic disorder caused by a microdeletion of the 7q11.23 region. Although familial cases with autosomal dominant inheritance have been reported, the vast majority are sporadic. Objective: To investigate the main complaints and clinical findings of patients with Williams-Beuren syndrome. Methods: A total of 757 parents of patients registered in the Brazilian Association of Williams-Beuren Syndrome (ABSW) received a questionnaire via WhatsApp from March to July 2017. Results: In total, 229 parents answered the survey. Age of diagnosis ranged from 2 days to 34 years (median: 3 years). The main clinical findings reported by the parents were abdominal colic (83.3%), failure to thrive (71.5%), feeding difficulty in the first year (68.9%), otitis (56.6%), urinary tract infections (31.9%), precocious puberty (27.1%) and scoliosis (15.9%). Cardiac defects were present in 66% of patients, and the most frequent defect was supravalvular aortic stenosis (36%). Arterial hypertension was reported in 23%. Hypercalcemia was reported in 10.5% of patients, mainly during the first year of life. Hyperacusis and hypersociability were common complaints (both present in 89%). Other behavioral and neuropsychiatric symptoms reported by the parents included attention deficit (89%), anger crises (83%), excessive fear (66%), depression (64%), anxiety (67%) and hypersexuality (33%). The most common complaints were hypersensitivity to sounds, talkative personality, emotional dependence and learning difficulties. In 98.3%, the parents denied family history. Conclusions: Williams-Beuren syndrome requires close follow-up with different medical specialties due to their variable clinical comorbidities, including language and school learning difficulties, behavioral and psychiatric problems.

RESUMO Antecedentes: A síndrome de Williams-Beauren é doença de acometimento multisistêmico causado pela microdeleção da região 7q11.23. Apesar de haver casos familiares com herança autossômica dominante, a grande maioria dos casos é esporádica. Objetivo: Investigar as principais queixas e achados clínicos da síndrome. Métodos: 757 pais de pacientes inscritos na Associação Brasileira de Síndrome de Williams-Beuren (ABSW) receberam um questionário pelo WhatsApp, entre março e julho de 2017. Resultados: 229 pais de pacientes responderam à pesquisa. A idade de diagnóstico variou de 2 dias até 34 anos (mediana: 3 anos). Os principais achados reportados pelos pais: cólicas abdominais (83,3%), deficiência ponderoestatural (71,5%), dificuldade de alimentação no primeiro ano (68,9%), otite (56,6%), infecções do trato urinário (31,9%), puberdade precoce (27,1%) e escoliose (15,9%). Cardiopatias estavam presentes em 66%, sendo que a mais frequente era a estenose pulmonar supravalvar (36%). Hipertensão arterial foi reportada em 23%. Hipercalcemia foi reportada em 10,5%, principalmente no primeiro ano de vida. Hiperacusia e hiperssociabilidade foram achados comuns (89%). Os principais achados comportamentais e psiquiátricos reportados pelos pais foram: déficit de atenção (89%), crises de raiva (83%), medo excessivo (66%), depressão (64%), ansiedade (67%) e hiperssexualidade (33%). As queixas principais referidas foram hipersensibilidade a sons, personalidade excessivamente amigável, dependência emocional e dificuldades escolares. Em 98,3% dos casos os pais negaram história familial. Conclusões: A síndrome de Williams-Beuren é requer um seguimento e manejo estritos, com diferentes especialidades médicas devido às comorbidades clínicas variadas, que incluem dificuldades de linguagem e aprendizagem escolar, além de dificuldades comportamentais e psiquiátricas.

Loss of postprandial insulin clearance control by Insulin-degrading enzyme drives dysmetabolism traits.

Systemic insulin availability is determined by a balance between beta-cell secretion capacity and insulin clearance (IC). Insulin-degrading enzyme (IDE) is involved in the intracellular mechanisms underlying IC. The liver is a major player in IC control yet the role of hepatic IDE in glucose and lipid homeostasis remains unexplored. We hypothesized that IDE governs postprandial IC and hepatic IDE dysfunction amplifies dysmetabolic responses and prediabetes traits such as hepatic steatosis. In a European/Portuguese population-based cohort, IDE SNPs were strongly associated with postprandial IC in normoglycemic men but to a considerably lesser extent in women or in subjects with prediabetes. Liver-specific knockout-mice (LS-IDE KO) under normal chow diet (NCD), showed reduced postprandial IC with glucose intolerance and under high fat diet (HFD) were more susceptible to hepatic steatosis than control mice. This suggests that regulation of IC by IDE contributes to liver metabolic resilience. In agreement, LS-IDE KO hepatocytes revealed reduction of Glut2 expression levels with consequent impairment of glucose uptake and upregulation of CD36, a major hepatic free fatty acid transporter. Together these findings provide strong evidence that dysfunctional IC due to abnormal IDE regulation directly impairs postprandial hepatic glucose disposal and increases susceptibility to dysmetabolic conditions in the setting of Western diet/lifestyle.

Impact of blinded retrospective continuous glucose monitoring on clinical decision making and glycemic control in persons with type 2 diabetes on insulin therapy.

BACKGROUND AND AIMS: Blinded retrospective continuous glucose monitoring (rCGM) provides detailed information about real-life glycaemic profile. In persons with type 2 diabetes without adequate glycaemic control, the structured introduction of rCGM may be beneficial to sustain improvements in diabetes management. METHODS AND RESULTS: 102 individuals with insulin-treated type 2 diabetes, age less than 66 years old and HbA1c >7.5%, were recruited. Participants performed a 7-day blinded rCGM (iPro2) every four months for one year. Biochemical, anthropometric, and rCGM data was collected. Participants' and healthcare professionals' perceptions were assessed. 90 participants completed the protocol. HbA1c was 9.1 ± 0.1% one year prior to enrolment and 9.4 ± 0.1% at enrolment (p < 0.01). With the rCGM-based intervention, a decrease in HbA1c was achieved at 4 months (8.4 ± 0.1%, p < 0.0001), and 12 months (8.1 ± 0.1%, p < 0.0001). A significant increase in time-in-range was observed (50.8 ± 2.4 at baseline vs 61.5 ± 2.2% at 12 months, for 70-180 mg/dL, p < 0.001), with no difference in exposure time to hypoglycaemia. After 12 months, there was an increase in self-reported diabetes treatment satisfaction (p < 0.05). CONCLUSION: In persons with type 2 diabetes and poor metabolic control, specific data from blinded rCGM informed therapeutic changes and referral to targeted education consultations on nutrition and insulin administration technique. Therapeutic changes were made more frequently and targeted to changes in medication dose, timing, and/or type, as well as to lifestyle. Together, these brought significant improvements in clinical outcomes, effective shared decision-making, and satisfaction with treatment. REGISTRATION NUMBER: NCT04141111.

Effects of Meal Fructose/Glucose Composition on Postprandial Glucose Appearance and Hepatic Glycogen Synthesis in Healthy Subjects.

Dietary fructose overshadows glucose in promoting metabolic complications. Intestinal fructose metabolism (IFM) protects against these effects in rodents, by favoring gluconeogenesis, but the extent of IFM in humans is not known. We therefore aimed to infer the extent of IFM by comparing the contribution of dietary fructose to systemic glucose and hepatic glycogen appearance postprandially. Twelve fasting healthy subjects ingested two protein meals in random order, one supplemented with 50 g 5/95 fructose/glucose (LF) and the other with 50 g 55/45 fructose/glucose (HF). Sources of postprandial plasma glucose appearance and hepatic glycogen synthesis were determined with deuterated water. Plasma glucose excursions, as well as pre- and post-meal insulin, c-peptide, and triglyceride levels were nearly identical for both meals. The total gluconeogenic contribution to plasma glucose appearance was significantly higher for HF versus LF (65 ± 2% vs. 34 ± 3%, p < 0.001). For HF, Krebs cycle anaplerosis accounted for two-thirds of total gluconeogenesis (43 ± 2%) with one-third from Triose-P sources (22 ± 1%). With LF, three-quarters of the total gluconeogenic contribution originated via Krebs cycle anaplerosis (26 ± 2%) with one-quarter from Triose-P sources (9 ± 2%). HF and LF gave similar direct and indirect pathway contributions to hepatic glycogen synthesis. Increasing the fructose/glucose ratio had significant effects on glucose appearance sources but no effects on hepatic glycogen synthesis sources, consistent with extensive IFM. The majority of fructose carbons were converted to glucose via the Krebs cycle.

Association between area- and individual-level socio-economic factors with glycated haemoglobin-Evidence from a Portuguese population-based study.

AIMS: This study aims to estimate the associations between area-level deprivation and individual-level socio-economic factors, as well as their interaction, with glycated haemoglobin (HbA1c ) levels. METHODS: We conducted a gamma multilevel regression analysis using individual-level data from the Portuguese National Health Examination Survey and a deprivation index built through factor analysis, at municipality level, with census variables. RESULTS: Living in a municipality with high material deprivation and having a low level of education were independently associated with an increase of 2.3% (95% confidence interval [CI] 0.6, 4.0) and of 1.6% (95% CI 0.6, 2.7) in the mean levels of HbA1c , respectively. The interaction between area material deprivation and individual-level education was not associated with the levels of HbA1c (0.5%, 95% CI -1.3, 2.3). CONCLUSIONS: Our findings support the collective resources model that argues that people in less deprived areas have better health because there are more collective resources. The results suggest that to reduce socio-economic inequalities associated with the levels of HbA1c and, consequently, with diabetes, will require attention to the area material deprivation and individual-level education. Upstream social determinants of health are thus highlighted.

Development of an Interactive Lifestyle Programme for Adolescents at Risk of Developing Type 2 Diabetes: PRE-STARt.

BACKGROUND: Type 2 diabetes (T2D) is increasing in young people. Reporting on the processes used when developing prevention interventions is needed. We present the development of a family-based interactive lifestyle intervention for adolescents with risk factors for T2D in the future. METHOD: A multidisciplinary team in the UK site led the intervention development process with sites in Portugal, Greece, Germany and Spain. Potential programme topics and underpinning theory were gathered from literature and stakeholders. A theoretical framework based on self-efficacy theory and the COM-B (capability, opportunity, motivation, behaviour) model was developed. Sessions and supporting resources were developed and refined via two iterative cycles of session and resource piloting, feedback, reflection and refinement. Decision on delivery and content were made by stakeholders (young people, teachers, parents, paediatricians) and all sites. Materials were translated to local languages. Site-specific adaptations to the language, content and supporting resources were made. RESULTS: The "PRE-STARt" programme is eight 90-min interactive sessions with supporting curriculum and resources. Iterative development work provided valuable feedback on programme content and delivery. CONCLUSION: Reporting on the intervention development process, which includes stakeholder input, could yield a flexible approach for use in this emerging 'at risk' groups and their families.

Impact of combined training with different exercise intensities on inflammatory and lipid markers in type 2 diabetes: a secondary analysis from a 1-year randomized controlled trial.

BACKGROUND: Exercise is a well-accepted strategy to improve lipid and inflammatory profile in individuals with type 2 diabetes (T2DM). However, the exercise intensity having the most benefits on lipids and inflammatory markers in patients with T2DM remains unclear. We aimed to analyse the impact of a 1-year combined high-intensity interval training (HIIT) with resistance training (RT), and a moderate continuous training (MCT) with RT on inflammatory and lipid profile in individuals with T2DM. METHODS: Individuals with T2DM (n = 80, aged 59 years) performed a 1-year randomized controlled trial and were randomized into three groups (control, n = 27; HIIT with RT, n = 25; MCT with RT, n = 28). Exercise sessions were supervised with a frequency of 3 days per week. Inflammatory and lipid profiles were measured at baseline and at 1-year follow-up. Changes in inflammatory and lipid markers were assessed using generalized estimating equations. RESULTS: After adjusting for sex, age and baseline moderate-to-vigorous physical activity (MVPA), we observed a time-by-group interaction for Interleukin-6 (IL-6) in both the MCT with RT (ß = - 0.70, p = 0.034) and HIIT with RT (ß = - 0.62, p = 0.049) groups, whereas, only the HIIT with RT group improved total cholesterol (ß = - 0.03, p = 0.045) and LDL-C (ß = - 0.03, p = 0.034), when compared to control. No effect was observed for C-reactive protein (CRP), cortisol, tumour necrosis factor-α (TNF-α), soluble form of the haptoglobin-hemoglobin receptor CD163 (sCD163), triglycerides and HDL-C in both groups (p > 0.05). CONCLUSIONS: Favorable adaptations on IL-6 were observed in both the HIIT and MCT combined with RT groups following a long-term 1-year exercise intervention in individuals with T2DM. However, only the HIIT with RT prevented further derangement of total cholesterol and LDL-C, when compared to the control group. Therefore, in order to encourage exercise participation and improve inflammatory profile, either exercise protocols may be prescribed, however, HIIT with RT may have further benefits on the lipid profile. Trial registration Clinicaltrials.gov ID: NCT03144505.