Clinical trials for genetic diseases in Latin America.

Latin American geneticists have been contributing to the scientific development of Human and Medical Genetics fields since the early 1950s. In the last decades, as Medical Genetics is moving toward a new era of innovative therapies for previously untreatable conditions, the participation of Latin America in clinical trials is also increasing. This review discusses the particularities regarding funding, regulatory, and ethical aspects of conducting clinical trials for genetic diseases in Latin America, with an especial focus on Brazil, the largest country with the highest number of studies. Although there are still several barriers to overcome, the recent development of orphan drug legislation and policies for rare diseases in many Latin American countries indicates a growing opportunity for the participation of the region in international efforts for the development of new therapies for genetic diseases.

Association Between Implementing Comprehensive Learning Collaborative Strategies in a Statewide Collaborative and Changes in Hospital Safety Culture.

Importance: Hospital safety culture remains a critical consideration when seeking to reduce medical errors and improve quality of care. Little is known regarding whether participation in a comprehensive, multicomponent, statewide quality collaborative is associated with changes in hospital safety culture. Objective: To examine whether implementation of a comprehensive, multicomponent, statewide surgical quality improvement collaborative is associated with changes in hospital safety culture. Design, Setting, and Participants: In this survey study, the Safety Attitudes Questionnaire, a 56-item validated survey covering 6 culture domains (teamwork, safety, operating room safety, working conditions, perceptions of management, and employee engagement), was administered to a random sample of physicians, nurses, operating room staff, administrators, and leaders across Illinois hospitals to assess hospital safety culture prior to launching a new statewide quality collaborative in 2015 and then again in 2017. The final analysis included 1024 respondents from 36 diverse hospitals, including major academic, community, and rural centers, enrolled in ISQIC (Illinois Surgical Quality Improvement Collaborative). Exposures: Participation in a comprehensive, multicomponent statewide surgical quality improvement collaborative. Key components included enrollment in a common standardized data registry, formal quality and process improvement training, participation in collaborative-wide quality improvement projects, funding support for local projects, and guidance provided by surgeon mentors and process improvement coaches. Main Outcomes and Measures: Perception of hospital safety culture. Results: The overall survey response rate was 43.0% (580 of 1350 surveys) in 2015 and 39.0% (444 of 1138 surveys) in 2017 from 36 hospitals. Improvement occurred in all the overall domains, with significant improvement in teamwork climate (change, 3.9%; P = .03) and safety climate (change, 3.2%; P = .02). The largest improvements occurred in individual measures within domains, including physician-nurse collaboration (change, 7.2%; P = .004), reporting of concerns (change, 4.7%; P = .009), and reduction in communication breakdowns (change, 8.4%; P = .005). Hospitals with the lowest baseline safety culture experienced the largest improvements following collaborative implementation (change range, 11.1%-14.9% per domain; P < .05 for all). Although several hospitals experienced improvement in safety culture in 1 domain, most hospitals experienced improvement across several domains. Conclusions and Relevance: This survey study found that hospital enrollment in a statewide quality improvement collaborative was associated with overall improvement in safety culture after implementing multiple learning collaborative strategies. Hospitals with the poorest baseline culture reported the greatest improvement following implementation of the collaborative.

Clinical research challenges in rare genetic diseases in Brazil.

Rare diseases are defined as conditions with a prevalence of no more than 6.5 per 10,000 people. Although each rare disease individually affects a small number of people, collectively, the 6,000 to 8,000 rare conditions (80% of them with genetic cause) affect around 8% of the world's population. Research about the natural history and underlying pathophysiological mechanisms of rare diseases, as well as clinical trials with new drugs, are important and necessary to develop new strategies for the treatment of these conditions. This report describes the experience of a clinical research group working with rare diseases in a reference center for lysosomal diseases in Brazil (Medical Genetics Service, Hospital de Clínicas de Porto Alegre). The activities of this research group enabled its participation in several international multicenter clinical research protocols related to the natural history or therapy development for rare genetic diseases. This participation has allowed the development of personal skills and institutional facilities for clinical research. The clinical research developed in our center has raised the quality of the medical assistance provided to non-clinical research patients in addition to enabling early access to new therapies to many patients with orphan conditions.

Cyclic pamidronate treatment for osteogenesis imperfecta: Report from a Brazilian reference center.

Treatment of moderate and severe forms of osteogenesis imperfecta (OI) with cyclic pamidronate at the Reference Center for OI Treatment in Southern Brazil was studied. A retrospective cohort study was conducted from 2002 to 2012. Data were obtained during inpatient (drug infusion) and outpatient care. Clinical data, including the presence of blue sclerae, dentinogenesis imperfecta, history and site of the fractures, biochemical data, including calcium, phosphorus, and alkaline phosphatase levels, were systematically collected. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry (DXA). Forty-five patients (26 females) were included in the study, and the age of the patients at the time of diagnosis ranged from 1 to 144 months, with a median age (p25-p75) of 38 (5-96) months. Most cases presented OI-4 (51.1%), and the median age of the patients at the start of treatment was 3.3 years (25-75 percentiles: 0.5 - 8.7 years). Twenty-four patients (54.5%) had some adverse events or intercurrences during treatment, and the treatment compliance mean was 92.3% (± 10.7). The treatment with intravenous pamidronate has shown to be safe, well-tolerated, and effective in regard to the improvement of BMD and the reduction of the number of fractures in children and adolescents with OI.

Health-related quality of life of children and adolescents with osteogenesis imperfecta: a cross-sectional study using PedsQL™.

BACKGROUND: Osteogenesis imperfecta (OI) is a disorder of bone formation leading to low mineral density and fractures. Children and adolescents with OI require periodic medical follow up, corrective surgery, drug therapy and physical therapy, as well as specific daily care practices. In addition, they have an increased incidence of fractures, which require immobilization and cause severe discomfort and short-term disability. This study evaluated the health-related quality of life of children and adolescents with OI in two reference centers for OI treatment in southern Brazil. METHODS: In this prospective cross-sectional study, the Pediatric Quality of Life Inventory (PedsQLTM) was applied in two university-affiliated reference centers for OI treatment in southern Brazil. Children and adolescents aged ≥ 5 years with clinical diagnoses of OI were included. Clinical data and socioeconomic status was evaluated. RESULTS: The sample consisted of 52 children and adolescents with OI (aged 5-17 years); 26 (50%) participants with type I OI, 13 (25%) type IV, 12 (23.1 %) type III, and 1 (1.9%) type V OI. Physical and social functioning domains differed significantly according to clinical presentation of OI with lowest scores in the severe type (OI type III). Pain seems to be the variable that is most associated with impact on the PedsQL domains. CONCLUSIONS: Overall, this study revealed differences in physical functioning and social functioning in relation to OI clinical presentation. These results reinforcing the importance of the clinical management of these patients with the aim of functional improvement and importance of pain control.

Difference between Methods for Estimation of Basal Metabolic Rate and Body Composition in Pediatric Patients with Osteogenesis Imperfecta.

BACKGROUND/AIMS: Osteogenesis Imperfecta (OI) is a bone disease characterized by bone fragility, deformities, and multiple fractures. The aim of this study was to compare the different methods of measuring the basal metabolic rate (BMR) and body composition (BC) in pediatric patients with OI. METHODS: This cross-sectional study included 52 individuals with a median age of 9 (5.25-12.7) years. BMR was calculated by bioelectrical impedance analyses (BIA), predictive values according to age from the World Health Organization (WHO), a kcal/cm formula, and indirect calorimetry (IC). BC was assessed using the anthropometric calculation of percentage body fat (%BF) and lean mass (kg), BIA, and dual-energy X-ray absorptiometry (DEXA). Agreement among the methods was assessed using the Bland-Altman technique. RESULTS: IC estimates of BMR were greater than BIA and lower than values obtained using the WHO and kcal/cm methods. Better agreement was observed using the WHO values for mild forms of OI and the kcal/cm formula for moderate-to-severe forms. For BC, DEXA estimates of %BF were higher and the lean mass was lower than the values obtained using BIA and anthropometry. Neither method agreed with the DEXA method results. CONCLUSIONS: Significant differences exist among the various methods used for measuring BMR and BC with regard to phenotypic differences between OI types.

CLINICAL FEATURES AND PATTERN OF FRACTURES AT THE TIME OF DIAGNOSIS OF OSTEOGENESIS IMPERFECTA IN CHILDREN. / CARACTERÍSTICAS CLÍNICAS E PADRÃO DE FRATURAS NO MOMENTO DO DIAGNÓSTICO DE OSTEOGÊNESE IMPERFEITA EM CRIANÇAS.

OBJECTIVE: To characterize the fracture pattern and the clinical history at the time of diagnosis of osteogenesis imperfecta. METHODS: In this retrospective study, all patients with osteogenesis imperfecta, of both genders, aged 0-18 years, who were treated between 2002 and 2014 were included. Medical records were assessed to collect clinical data, including the presence of blue sclerae, dentinogenesis imperfecta, positive familial history of osteogenesis imperfecta, and the site of the fractures. In addition, radiographic findings at the time of the diagnosis were reviewed. RESULTS: Seventy-six patients (42 females) were included in the study. Individuals' age ranged from 0 to 114 months, with a median (interquartile range) age of 38 (6-96) months. Blue sclerae were present in 93.4% of patients, dentinogenesis imperfecta was observed in 27.6% of patients, and wormian bones in 29.4% of them. The number of fractures at diagnosis ranged from 0 to 17, with a median of 3 (2-8) fractures. Forty (57%) patients had fractures of the upper and lower extremities, and 9 patients also had spinal fractures. The diagnosis was performed at birth in 85.7% of patients with type 3, and 39.3% of those with type 4/5 of the disorder. CONCLUSIONS: Osteogenesis imperfecta is a genetic disorder with distinctive clinical features such as bone fragility, recurrent fractures, blue sclerae, and dentinogenesis imperfecta. It is important to know how to identify these characteristics in order to facilitate the diagnosis, optimize the treatment, and differentiate osteogenesis imperfecta from other disorders that also can lead to fractures.

OBJETIVO: Caracterizar o padrão de fraturas e a história clínica no momento do diagnóstico de osteogênese imperfeita. MÉTODOS: Neste estudo retrospectivo, foram incluídos todos os pacientes com osteogênese imperfeita de ambos os sexos, com idades entre 0 e 18 anos, que realizaram tratamento entre 2002 e 2014. Os prontuários médicos foram revisados para coleta de dados clínicos, incluindo presença de escleras azuladas, dentinogênese imperfeita, história familiar positiva para a doença e locais das fraturas, além de achados radiográficos no momento do diagnóstico. RESULTADOS: Foram incluídos no estudo 76 pacientes (42 do sexo feminino), com idade, no momento do diagnóstico, entre 0 e 114 meses [mediana (p25-p75) de idade de 38 (6-96) meses]. Escleras azuladas estavam presentes em 93,4% dos pacientes, dentinogênese imperfeita foi observada em 27,6% e ossos wormianos em 29,4%. O número de fraturas ao diagnóstico variou entre 0 e 17, com uma mediana de 3 (2-8) fraturas. Em 40 (57%) pacientes, as fraturas eram de membros superiores e inferiores no momento do diagnóstico e, em 9 pacientes também havia fratura vertebral. O diagnóstico foi realizado ao nascimento em 85,7% dos pacientes com o tipo 3 e em 39,3% daqueles com tipo 4/5 da doença. CONCLUSÕES: Osteogênese imperfeita é uma doença genética com características clínicas distintas, tais como fragilidade óssea, fraturas recorrentes, escleras azuladas e dentinogênese imperfeita. É importante saber identificar essas características, facilitando o diagnóstico, otimizando o tratamento e diferenciando de outras doenças que também podem causar fraturas.

Características clínicas e padrão de fraturas no momento do diagnóstico de osteogênese imperfeita em crianças / Clinical features and pattern of fractures at the time of diagnosis of osteogenesis imperfecta in children

RESUMO Objetivo: Caracterizar o padrão de fraturas e a história clínica no momento do diagnóstico de osteogênese imperfeita. Métodos: Neste estudo retrospectivo, foram incluídos todos os pacientes com osteogênese imperfeita de ambos os sexos, com idades entre 0 e 18 anos, que realizaram tratamento entre 2002 e 2014. Os prontuários médicos foram revisados para coleta de dados clínicos, incluindo presença de escleras azuladas, dentinogênese imperfeita, história familiar positiva para a doença e locais das fraturas, além de achados radiográficos no momento do diagnóstico. Resultados: Foram incluídos no estudo 76 pacientes (42 do sexo feminino), com idade, no momento do diagnóstico, entre 0 e 114 meses [mediana (p25-p75) de idade de 38 (6-96) meses]. Escleras azuladas estavam presentes em 93,4% dos pacientes, dentinogênese imperfeita foi observada em 27,6% e ossos wormianos em 29,4%. O número de fraturas ao diagnóstico variou entre 0 e 17, com uma mediana de 3 (2-8) fraturas. Em 40 (57%) pacientes, as fraturas eram de membros superiores e inferiores no momento do diagnóstico e, em 9 pacientes também havia fratura vertebral. O diagnóstico foi realizado ao nascimento em 85,7% dos pacientes com o tipo 3 e em 39,3% daqueles com tipo 4/5 da doença. Conclusões: Osteogênese imperfeita é uma doença genética com características clínicas distintas, tais como fragilidade óssea, fraturas recorrentes, escleras azuladas e dentinogênese imperfeita. É importante saber identificar essas características, facilitando o diagnóstico, otimizando o tratamento e diferenciando de outras doenças que também podem causar fraturas.

ABSTRACT Objective: To characterize the fracture pattern and the clinical history at the time of diagnosis of osteogenesis imperfecta. Methods: In this retrospective study, all patients with osteogenesis imperfecta, of both genders, aged 0-18 years, who were treated between 2002 and 2014 were included. Medical records were assessed to collect clinical data, including the presence of blue sclerae, dentinogenesis imperfecta, positive familial history of osteogenesis imperfecta, and the site of the fractures. In addition, radiographic findings at the time of the diagnosis were reviewed. Results: Seventy-six patients (42 females) were included in the study. Individuals' age ranged from 0 to 114 months, with a median (interquartile range) age of 38 (6-96) months. Blue sclerae were present in 93.4% of patients, dentinogenesis imperfecta was observed in 27.6% of patients, and wormian bones in 29.4% of them. The number of fractures at diagnosis ranged from 0 to 17, with a median of 3 (2-8) fractures. Forty (57%) patients had fractures of the upper and lower extremities, and 9 patients also had spinal fractures. The diagnosis was performed at birth in 85.7% of patients with type 3, and 39.3% of those with type 4/5 of the disorder. Conclusions: Osteogenesis imperfecta is a genetic disorder with distinctive clinical features such as bone fragility, recurrent fractures, blue sclerae, and dentinogenesis imperfecta. It is important to know how to identify these characteristics in order to facilitate the diagnosis, optimize the treatment, and differentiate osteogenesis imperfecta from other disorders that also can lead to fractures.

Study of the Determinants of Vitamin D Status in Pediatric Patients With Osteogenesis Imperfecta.

OBJECTIVE: Vitamin D is essential to the development and maintenance of the skeleton, especially for children with bone disorders such as osteogenesis imperfecta (OI). We evaluated serum 25-hydroxyvitamin D (25-OHD) levels to assess the relationship between determinants of vitamin D status in pediatric patients with OI. METHODS: This cross-sectional study evaluated sex, age, weight, height, body mass index, OI type, sunscreen use, season of assessment, sun exposure, vitamin D and calcium supplementation, bisphosphonate treatment, bone mineral density (BMD), milk and soda consumption, mobility, and time of sedentary activity. Levels of serum 25-OHD, calcium, parathyroid hormone (PTH), phosphorus, and alkaline phosphatase (ALP) were analyzed. Serum levels of 25-OHD were classified according to sufficient (>30 ng/ml or 75 nmol/L), insufficient (20-30 ng/ml or 50-75 nmol/L), moderately deficient (20-10 ng/ml or 50-25 nmol/L), and severely deficient (<10 ng/ml or 25 nmol/L). RESULTS: Fifty-two patients were included and 46 (88.4%) were classified as having insufficient or deficient 25-OHD. An inverse correlation between serum 25-OHD and time of sedentary activity (r = -0.597, p < 0.001) and a positive correlation with height (r = 0.521, p = 0.046) and whole body BMD (r = 0.586, p = 0.022) were observed. A significant difference between the number of glasses of milk consumed (p = 0.010) was observed. CONCLUSION: To optimize bone health, patients with OI need to be educated regarding habits that can improve serum 25-OHD levels, such as a reduction in periods of inactivity, the importance of sun exposure, and increasing consumption of milk and fortified dairy products.

Anthropometry, nutritional status, and dietary intake in pediatric patients with osteogenesis imperfecta.

OBJECTIVE: The aim of the present study was to assess anthropometric measurements, nutritional status, dietary intake, and body fat percentage of pediatric patients with osteogenesis imperfecta (OI). METHOD: A cross-sectional study evaluated 63 OI patients from 0 to 19 years of age. We analyzed anthropometric measurements, mobility, bisphosphonate treatment, body fat percentage (by dual-energy x-ray absorptiometry [DEXA] and sum of skinfold thickness), nutritional status, and dietary intake (using World Health Organization [WHO] and dietary reference intake recommendations for macronutrients and calcium intake, respectively). Participants' energy requirements were calculated using both kilocalorie per centimeter measurements and WHO methods. RESULTS: Patients with different types of OI had different anthropometric measurements (p < 0.05), where OI type III had severely limited stature and poor mobility. Nutritional status was correlated with measurements of arm circumference and body fat. We also found a strong correlation between the 2 methods used to calculate percentage of body fat (r = 0.803). OI type III had a higher percentage of energy intake. We observed that 75% of subjects had a calcium intake below 95% of recommended daily value and there was an inverse correlation between age and calcium intake. CONCLUSIONS: This study showed that stature was compromised mainly in OI type III. Skinfold thickness and arm circumference correlated to nutritional status and also to body fat calculated by DEXA. Daily calcium intake was below the recommended levels in pediatric patients with OI. These findings are important for the management of OI subjects.

Estado nutricional e fatores de risco para desnutrição no atendimento nutricional pediátrico da admissão hospitalar / Nutritional status and risk factors for malnutrition in pediatric nutritional care at hospital admission

Introdução: Desnutrição calórico-proteica em crianças menores de cinco anos é um dos maiores problemas de saúde pública nos países em desenvolvimento. Resulta da interação entre fatores como pobreza, infecções e baixa ingestão calórica e proteica. A avaliação do estado nutricional (EN) na admissão hospitalar é fundamental para estabelecer métodos para a recuperação e/ou manutenção do EN durante a internação e identificar os fatores de risco (FR) para desnutrição. Objetivo: O objetivo deste estudo foi classificar o EN de crianças e adolescentes e seus FR para desnutrição na admissão hospitalar. Métodos: Estudo transversal realizado com 387 indivíduos de 0 a 14 anos admitidos em unidades de internação pediátrica. Na avaliação antropométrica, mensurou-se peso e estatura. Os FR para desnutrição incluíam: antropometria, jejum >2 dias, alimentação enteral ou parenteral, disfagia, perda ponderal, vômitos ou diarreia nas últimas 24 horas, febre acima de 37,5º C e risco relacionado ao diagnóstico. O EN foi classificado segundo os critérios da Organização Mundial da Saúde, 2006. Resultados: Na classificação do EN (N=363) utilizamos escore Z (N=327; 85%) e índice de massa corporal (IMC; N=36; 9%), e 23 foram avaliados através de protocolos específicos. Encontramos 48% eutróficos, 27% desnutridos, 15% em risco nutricional, 6% com sobrepeso e 4% obesos. Em relação aos FR para desnutrição, 271 (70%) indivíduos apresentavam até 2 FR; 114 (29,5%) de 3 a 5 (p<0,001) e 2 (0,5%) 6 ou mais. Conclusão: A prevalência de desnutrição e de seus fatores de risco na admissão hospitalar encontrada em crianças e adolescentes foi bastante expressiva. Esse achado é muito relevante, já que a identificação do EN permite uma intervenção nutricional adequada com a prevenção de desfechos clínicos desfavoráveis.

Background: Protein-calorie malnutrition in children under five years is a major public health problem in developing countries. Results from the interaction between factors such as poverty, infections and low energy intake and protein. The assessment of the status (NS) at hospital admission is essential to establish methods for the recovery and/or maintenance of NS during hospitalization and to identify risk factors (RF) to malnutrition. Aim: The aim of this study was to classify the NS of the children and adolescents and their RF for malnutrition at admission. Methods: Cross sectional prospective study with 387 individuals 0 to 14 years admitted to hospital pediatric units. Anthropometric evaluation, measured in weight and height. Risk factors for malnutrition included: anthropometry, fasting > 2 days, enteral or parenteral feeding, dysphagia, weight loss, vomiting or diarrhea in the last 24 hours, fever over 37.5 C and the risk of the diagnosis. NS was classified according to criteria of the World Health Organization, 2006. Results: To classify the NS (N=363) Z score (N=327, 84.5%) and body mass index (BMI, N=36, 9.3%) were used, and 23 were assessed using specific protocols. We found 48% normal weight, 27% malnourished, 15% at nutritional risk, 6% overweight and 4% obese. About RF for malnutrition, 271 (70%) subjects had up to 2 RF, 114 (29.5%) from 3 to 5 (p <0.001) and 2 (0.5%) 6 or more. Conclusion: The prevalence of malnutrition and its risk factors found in children and adolescents at hospitalar admission was very high. This finding is relevant, since the identification of NS allows an appropriate nutritional intervention, preventing unfavourable clinical outcomes.