Global health for rare diseases through primary care.

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges.

A new algorithm DEtectS critical Congenital Heart Disease at different altitudes: ANDES-CHD study.

BACKGROUND: Neonatal pulse oximetry screening (POS) algorithms for critical congenital heart disease (CCHD) have contributed towards decreasing neonatal mortality but cannot be applied at high altitudes. New POS algorithms at high altitudes are needed. METHODS: This observational, prospective study included newborns born at different altitudes from 0 to 4380 meters above the sea level in Peru. Healthy newborns underwent neonatal preductal and postductal oximetry, echocardiography and telephonic follow-up up to 12 months of age. Newborns with CCHD underwent preductal and postductal oximetry at the time of telemedicine evaluation while located at the high-altitude hospital where they were born, and their diagnoses were confirmed with echocardiography locally or after arriving to the referral center. Two new algorithms were designed using clinically accepted neonatal oximetry cutoffs or the 5th and 10th percentiles for preductal and postductal oximetry values. RESULTS: A total of 502 healthy newborns and 15 newborns with CCHD were enrolled. Echocardiography and telephonic follow-up were completed in 227 (45%) and 330 healthy newborns (65%), respectively. The algorithm based on clinically accepted cutoffs had a sensitivity of 92%, specificity of 73% and false positive rate of 27% The algorithm based on the 5th and 10th percentiles had a sensitivity of 80%, specificity of 88% and false positive rate of 12%. CONCLUSIONS: Two algorithms that detect CCHD at different altitudes had adequate performance but high false positive rates.

[The SYNTAX Revascularization Index and major cardiovascular events in patients with multivessel coronary artery disease in the Instituto Nacional de Cardiología Ignacio Chávez - Mexico]. / Índice de revascularización SYNTAX y eventos cardiovasculares mayores en pacientes con enfermedad coronaria multiarterial en el Instituto Nacional de Cardiología Ignacio Chávez - México.

Objective: To evaluate the degree of incomplete revascularization in patients with multiarterial coronary artery disease who underwent percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) using the Syntax revascularization index (SRI) and its relationship to major cardiovascular events during follow-up. Materials and Methods: Observational, retrospective study with 4-year follow-up of patients with multiarterial coronary artery disease who underwent surgical or percutaneous coronary revascularization, in whom the baseline Syntax score (SSb) and the residual Syntax score (SSr) were calculated. The Syntax Revascularization Index (SRI) was determined with the following formula: SRI = (1- [SSr/SSb]) x 100, and major cardiovascular events at 4-year follow-up were compared. Results: Two hundred patients (100 in each group) were evaluated. Mean SSr in group 1 was 83.2%, and in group 2, 79.0% (p=0.88). Mean complete revascularization was 41% in the first group and 35% in the second. A cutoff point of ≤90% of IRS had the best accuracy for predicting major cardiovascular events (area under the curve of 0.60; 95% CI: 0.49-0.71, p<0.05). In multivariate analysis IRS was an independent predictor of major cardiovascular events (HR 2.6; 95%CI: 1.32-3.22, p= 0.043). Conclusions: The Syntax Revascularization Index may be useful for measuring the degree of revascularization in patients with multiarterial coronary artery disease treated percutaneously or surgically. An SRI ³90% may be an acceptable target for revascularization.

[Copy number variation and parental consanguinity elevated in newborns of high altitude with major congenital anomalies in Perú]. / Variantes en el número de copias y consanguinidad parental en neonatos de altura con anomalías congénitas en Perú.

Introduction: Congenital abnormalities could be caused by copy number variation or homozygous variants inherited of parental consanguineous. Purpose. Objetive: To show copy number variants and regions of homozygosity in neonates with malformative syndrome or one congenital anomaly major associated to facial dysmorphia or hypotonia. Methodology: Performed chromosomal microarray analysis (CGH/SNP) to 60 neonates with congenital anomalies born in Hospital Antonio Lorena and Hospital Regional Cusco. Results: 70% of the newborns had an abnormal test (n=42); 48,3% (n=29) patients had with regions of homozygosity above to 0,5% (endogamy coefficient up to 1/64). Pathogenic or likely pathogenic copy number variations with or without region of homozygosity were present in 14,2% (n=6) newborns with congenital abnormalities. We founded five patients with uncertain pathogenic copy number variations that have not been described previously and might correlate with phenotype. Conclusion: We founded a similar frequency of CNV in newborns with congenital abnormalities compared to previous reports. Nonetheless, parental consanguinity was increased compared to other countries of South America. This is the first report in Peru that showed to CMA as a useful diagnostic method in patients with congenital abnormalities and is pioneer in relation to other countries in Latinoamerica.

Introducción: Las variantes en el número de copias son un tipo de cambios en el genoma provocan anomalías congénitas. Objetivo: Determinar las variantes en el número de copias y el grado de consanguinidad parental en neonatos con síndromes malformativos o una anomalía congénita mayor asociado a dismorfia facial o hipotonía. Materiales y métodos: Se realizó el análisis cromosómico por micromatrices a 60 neonatos con anomalías congénitas evaluados en los Hospitales Antonio Lorena y Regional de Cusco. Resultados: Del total de pacientes estudiados, el 70% tuvo un resultado anómalo; de los cuales en el 14,2% de los recién nacidos se encontraron variantes en el número de copias patogénicas o probablemente patogénicas asociadas o no a regiones de homocigosidad que tuvieron relación con las anomalías congénitas descritas. En el 48,3% de los recién se encontró regiones de homocigosidad mayores a 0,5% (coeficiente de endogamia superior a 1/64). Por otro lado, encontramos cinco variantes en el número de copias de patogenicidad desconocida que no se han descrito anteriormente y podrían estar relacionadas con el fenotipo. Conclusión: Nuestra tasa de detección de las variantes en el número de copias está en relación con los reportes internacionales previos. Sin embargo, el porcentaje de neonatos con consanguinidad parental se encuentra por encima de lo reportado previamente, siendo superior a otras regiones de Sudamerica. Este es el primer reporte en el Perú, y es pionero en Latinoamérica al utilizar el análisis cromosómico por micromatrices en esta cohorte específica de pacientes.

Do research participants share genomic screening results with family members?

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network-3 (eMERGE-3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE-3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first-degree relatives. Across the sites, 279 participants completed a 1-month and/or 6-month post-results survey. By 6 months, only 34% of the 156 respondents shared their results with all first-degree relatives and 4% did not share with any. Over a third (39%) first-degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first-degree relatives compared with 11% of participants who received their results from a non-genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.

Allelic and genotypic frequencies of NAT2, CYP2E1, and AADAC genes in a cohort of Peruvian tuberculosis patients.

BACKGROUND: We determined the frequency of genetic polymorphisms in three anti-TB drug metabolic proteins previously reported: N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), and arylacetamide deacetylase (AADAC) within a Peruvian population in a cohort of TB patients. METHODS: We genotyped SNPs rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2; rs3813867 and rs2031920 for CYP2E1; and rs1803155 for AADAC in 395 participants completed their antituberculosis treatment. RESULTS: Seventy-four percent of the participants are carriers of slow metabolizer genotypes: NAT2*5, NAT2*6, and NAT2*7, which increase the sensitivity of INH at low doses and increase the risk of drug-induced liver injuries. Sixty-four percent are homozygous for the wild-type CYP2E1*1A allele, which could increase the risk of hepatotoxicity. However, 16% had a NAT2 fast metabolizer phenotype which could increase the risk of acquiring resistance to INH, thereby increasing the risk of multidrug-resistant (MDR) or treatment failure. The frequency of rs1803155 (AADAC*2 allele) was higher (99.9%) in Peruvians than in European American, African American, Japanese, and Korean populations. CONCLUSIONS: This high prevalence of slow metabolizers for isoniazid in the Peruvian population should be further studied and considered to help individualize drug regimens, especially in countries with a great genetic diversity like Peru. These data will help the Peruvian National Tuberculosis Control Program develop new strategies for therapies.

Considering Proximal Urea Cycle Disorders in Expanded Newborn Screening.

Proximal urea cycle disorders (PUCDs) have adverse outcomes such as intellectual disability and death, which may benefit from newborn screening (NBS) through early detection and prevention with early treatment. Ornithine transcarbamylase deficiency (OTCD) and carbamoyl phosphate synthetase 1 deficiency (CPS1D) are screened in six and eight states in the United States. We analyzed current evidence to see if it supports inclusion of PUCDs in the NBS panels based upon prevention potential, medical, diagnostic, treatment, and public health rationales. A literature review was performed in PubMed using MESH terms for OTCD, CPS1D, and NAGSD. A systematic review was performed in the hallmark of NBS inclusion criteria. We reviewed 31 articles. Molecular and biochemical diagnosis is available to provide diagnostic evidence. Untreated PUCDs have a significant burden with considerable developmental delay and mortality that may improve with early treatment. Tandem mass spectrometry can be used for NBS for PUCDs; however, citrulline and glutamine alone are not specific. Medical treatments currently available for PUCDs meet existing medical, diagnostic, treatment, and public health rationales. Improvement in NBS algorithms to increase sensitivity and specificity will allow earlier diagnosis and treatment to potentially improve disability and mortality rates.

Beliefs and Values About Gene Therapy and In-Utero Gene Editing in Patients with Hemophilia and Their Relatives.

AIM: Hemophilia is an inherited disease for which current treatment is noncurative. While gene therapy and gene editing are being researched, we do not know how the hemophilia community perceives them. Herein, we explore the beliefs and values regarding these new therapies in patients with hemophilia and their relatives. METHODS: This qualitative study used phone-based semi-structured interviews on 21 adult English-speaking patients with hemophilia A or B and their parents across the United States during March to July 2019. The study was advertised through different chapters of the Hemophilia Foundation. The interview guide included questions about participants' prior experience with hemophilia, and included two case scenarios about the use of gene therapy and in utero gene editing, after which participants were asked about their opinions, beliefs, and values on each scenario. We used a grounded theory approach and identified the main themes using an inductive process. RESULTS: We interviewed 21 participants-12 patients and 9 mothers. Most of them had or were related to a patient with severe disease. The main themes discussed were related to efficacy, safety and financial concerns and insurance coverage for both gene therapy and in utero gene editing. Patients and their parents had expected outcomes in terms of durability of therapy and impact on emotional health and lifestyle changes in the long term. Gene therapy was more accepted among patients with severe and uncontrolled disease. In-utero gene editing was not completely accepted because of safety and ethical issues. CONCLUSION: Patients with severe hemophilia perceive gene therapy as a potential cure, while gene editing was more controversial. Patients still have questions that remain to be answered regarding safety and efficacy that should be assessed with long-term follow up studies.

Variantes en el número de copias en trastornos del neurodesarrollo, síndrome malformativo y talla baja en Perú / Copy number variation in development disorders, malformative syndrome and short stature in Peru

RESUMEN Objetivo : determinar las variantes en el número de copias y regiones de homocigosidad mediante el análisis cromosómico por micromatrices, en niños con diagnóstico de trastorno del neurodesarrollo: retraso del desarrollo psicomotor (RDPM), discapacidad intelectual (DI) y trastorno del espectro autista (TEA), así como pacientes con síndrome malformativo (SM) y talla baja idiopática (TBI). Materiales y métodos : se evaluaron a 367 niños peruanos diagnosticados clínicamente con DI, RDPM, TEA, TBI y SM a quienes se les realizó el análisis cromosómico por micromatrices (CMA 750K CGH+SNP) en sangre periférica, entre los años 2016-2018. Resultados : las edades fluctuaron entre los 4,8 meses y los 18 años, con una media de 5,6 años. Los diagnósticos más frecuentes fueron RDPM (48%) y DI (30%). Se reportaron resultados anormales (variantes patogénicas, probablemente patogénicas, disomías uniparentales y regiones de homocigosidad superiores a 2,56%) en el 50,3% de los pacientes. Los resultados anormales se observaron en el 53,3% de los casos con diagnóstico de DI y el 47,9% de RDPM; mientras que en el resto de los casos con TBI sindrómica, SM y TEA tuvieron resultados anormales en el 52,4%, 52% y 20% respectivamente. Por otro lado, encontramos hasta un 6,2% de los padres eran consanguíneos no declarados. Conclusiones : la tasa de detección de las variantes en el número de copias (CNVs) encontrada en nuestro estudio fue superior a la reportada en estudios internacionales independientemente del diagnóstico clínico. Además, se pudo encontrar una mayor frecuencia de consanguinidad no declarada con relación a estudios anteriores.

ABSTRACT Objective: To establish the ratios of the copy number variations and regions of homozygosity through chromosomal microarray analysis (CMA) in children with neurodevelopmental disorders: development delay (DD), intellectual disability (ID), and/or autistic spectrum disorder (ASD), malformative syndrome (MS) and idiopathic short stature (ISS). Materials and Methods: We evaluated 367 Peruvian children diagnosed clinically with ID, DD, ASD, ISS and MS to whom performed chromosomal microarray analysis in peripheral blood (750K CGH + SNP), between the years 2016-2018. Results: Patients' age fluctuated between 4.8 months and 18 years old, with an average of 5.6 years old. The most frequent diagnoses were development delay (48%) and intellectual disability (30%). Abnormal results (pathogenic variants, likely pathogenic variants, uniparental disomies and loss of heterozygosity> 2.5%) were reported in 50.3%. The 53.28% of the cases with a diagnosis of intellectual disability and 47.92% of development delay showed abnormal results; while the children with short stature syndromic, malformative syndrome, and autistic disorders spectrum disorders showed abnormal results in 52.38%, 52% and 20% respectively. Additionally, we found that 6.25% of parents were non-declared consanguinity. Conclusions: Abnormal results found in our study was a higher ratio than other international reports regardless of the clinical diagnosis. Furthermore, we show a most rate of non-declared consanguinity in relation with previous reports.

Análisis bibliométrico de la producción científica sobre las agendas nacionales de investigación en el Perú 2011-2014 / Bibliometric analysis of scientific production on research national agenda in Peru 2011-2014

Objetivo. Analizar la producción científica enmarcada en las Agendas Nacionales de Investigación de Perú, periodo 2011-2014. Diseño. Estudio bibliométrico en las bases de datos SCOPUS, LILACS y LIPECS. Lugar. Instituto Nacional de Salud, Lima, Perú. Unidad de análisis. Artículo original que tenía al menos un investigador con filiación a una institución peruana o cuya población de estudio o parte de ella procedía de Perú y enmarcados en algún tema de las Agendas Nacionales de Investigación. Principales medidas de resultados. Indicadores bibliométricos de producción. Resultados. De las 882 publicaciones recuperadas, 215 (24,4%) ingresaron al análisis. Las Agendas Nacionales de Investigación con mayor producción científica fueron sobre tuberculosis e ITS­ VIH/sida con 78 y 59 artículos. El idioma más frecuente de publicación fue el inglés (69,8%). Los artículos fueron publicados en 90 revistas científicas. Las instituciones peruanas con mayor cantidad de firmas en artículos originales fueron la Universidad Peruana Cayetano Heredia (49,3%), seguido por el Ministerio de Salud (19,5%) e Instituto Nacional de Salud (14,4%). Los Institutos Nacionales de Salud de los Estados Unidos participaron en el financiamiento del 50,7% de los artículos analizados. Las instituciones peruanas que más investigaciones han financiado fueron el Instituto Nacional de Salud (4,2%) y el MINSA (2,8%). Conclusiones. La producción científica peruana enmarcada en las seis Agendas Nacionales de Investigación del periodo 2011-2014 es limitada, a predominio de la investigación en tuberculosis y ITS-VIH/sida, y estuvo financiada principalmente por instituciones internacionales.

Objectives. To analyze the scientific production framed in the National Research Agenda 2011-2014. Design. Bibliometric research using SCOPUS, LILACS and LIPECS databases. Setting National Health Institute, Lima, Peru. Unit of analysis. Original article with at least one researcher with a Peruvian institution affiliation or whose study population or part of it, ca me from Peru and framed on any issue of national research agendas. Main outcome measures. Bibliometric indicators of production. Results. Out of the 882 publications retrieved, 215 (24.4%) were admitted to the analysis. The national research agendas with more scientific production were tuberculosis and STO-HIV/AIDS that included 78 and 59 articles respectively. The most common language of publication was English (69.8%). The articles were published in 90 scientific journals. Peruvian institutions with the highest number of signatures were the Universidad Peruana Cayetano Heredia (49.3%), followed by the Ministry of Health (19.5%) and the Nationallnstitute of Health (14.4%). The National Institutes of Health (USA) participated in the financing of 50.7% of the articles analyzed. Peruvian institutions that funded more research were the Nationallnstitute of Health (4.2%) and the Ministry of Health (2.8%). Conclusions. Peruvian scientific production framed in the six national research agendas in the period 2011-2014 is limited and focused on tuberculosis and STI-HIV I AIDS research; funding was primarily by international institutions.

Genetic association meta-analysis: a new classification to assess ethnicity using the association of MCP-1 -2518 polymorphism and tuberculosis susceptibility as a model.

BACKGROUND: In meta-analyses of genetic association studies, ancestry and ethnicity are not accurately investigated. Ethnicity is usually classified using conventional race/ethnic categories or continental groupings even though they could introduce bias increasing heterogeneity between and within studies; thus decreasing the external validity of the results. In this study, we performed a meta-analysis using a novel ethnic classification system to test the association between MCP-1 -2518 polymorphism and pulmonary tuberculosis. Our new classification considers genetic distance, migration and linguistic origins, which will increase homogeneity within ethnic groups. METHODS: We included thirteen studies from three continents (Asia, Africa and Latin America) and considered seven ethnic groups (West Africa, South Africa, Saharan Africa, East Asia, South Asia, Persia and Latin America). RESULTS: The results were compared to the continental group classification. We found a significant association between MCP-1 -2518 polymorphism and TB susceptibility only in the East Asian and Latin American groups (OR 3.47, P = 0.08; OR 2.73, P = 0.02). This association is not observed in other ethnic groups that are usually considered in the Asian group, such as India and Persia, or in the African group. CONCLUSIONS: There is an association between MCP-1 -2518 polymorphism and TB susceptibility only in the East Asian and Latin American groups. We suggest the use of our new ethnic classification in future meta-analysis of genetic association studies when ancestry markers are not available. This new classification increases homogeneity for certain ethnic groups compared to the continental classification. We recommend considering previous data about migration, linguistics and genetic distance when classifying ethnicity in further studies.