Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Hipercolesterolemia familiar: serie de 36 casos con fenotipo de hipercolesterolemia familiar homocigótica / Familial hypercholesterolaemia: A study of 36 cases with a phenotype of homozygous familiar hypercholesterolaemia

Resumen Introducción: La hipercolesterolemia familiar homocigótica (HFHo) se caracteriza por niveles muy elevados de cLDL y por enfermedad aterosclerótica temprana. Aunque la frecuencia es baja (1/300.000), las complicaciones son muy severas y pueden ser evitadas. Encontrar y tratar esta población de manera temprana podría reducir la mortalidad. Se describen 36 casos en Colombia, en donde se calcula que haya entre 160 y 200 casos. Resultados: Un total de 36 pacientes con fenotipo sugestivo de HFHo fueron identificados y tratados en un período de observación de cuatro años. La media de edad fue 27 años (24 mujeres). 34 pacientes tuvieron un puntaje según la Red de Clínicas de Lípidos de Holanda (RCLH) mayor de 8 (diagnóstico definitivo) y los restantes 2 tenían puntaje equivalente a diagnóstico probable. Un cuarto de los casos procedían de la costa norte colombiana. En las pruebas genéticas, 14 fueron homocigóticos verdaderos para mutación del gen que codifica para el receptor de LDL (LDLR), 12 heterocigóticos compuestos, 2 heterocigóticos dobles y uno autosómico recesivo (LDLRAP1); 5 pacientes fueron heterocigóticos simples (LDLR) y 2 pacientes no autorizaron la prueba. En los homocigóticos verdaderos, la variante más frecuente encontrada fue la c.11G>A. 14 pacientes cursaron con enfermedad coronaria, 9 con estenosis carotídea, 8 con estenosis aórtica y 2 tuvieron ataques cerebrovasculares (ACV). 34 pacientes recibían estatinas (24 rosuvastatina), 30 recibían ezetimibe, 2 recibían evolocumab y 20 recibían lomitapide (dosis promedio 12,7mg). Ninguno recibió aféresis de cLDL. Los medicamentos, en general, fueron bien tolerados y la reducción promedio de cLDL con la terapia fue de 533,7mg/dl a 245,1mg/dl (54%). Conclusiones: Todos los pacientes recibieron tratamiento hipolipemiante y se encontraron alteraciones genéticas diagnósticas en todos aquellos que autorizaron el examen. Los niveles elevados de cLDL conllevan tanto riesgo que el tratamiento debe establecerse aún sin conocer el diagnóstico genético.

Abstract Background: Homozygous familial hypercholesterolemia (HoFH) is characterized for very high levels of cLDL and early cardiovascular disease. Although incidence is low (1/300 000), complications are very severe and can be avoided. Finding and treating this population promptly could reduce mortality. We describe 36 cases in Colombia, where 160 to 200 cases are expected. Results: 36 patients with phenotype of HoHF were identified and treated in a follow-up of 4 years. The mean age was 27 years (24 women). 34 of them had at least 8 points in the FH Dutch Lipid Clinic Criteria (definitive diagnosis) and two had probable diagnosis. A quarter of the cases came from the Colombian North Coast. In molecular tests, 14 were true homozygous for LDLR, 12 were compound heterozygous for LDLR, 2 double heterozygous and one was autosomal recessive; 5 were heterozygous and 2 patients did not authorized genetic test. In true homozygous subjects, the most frequent variant was c.11G>A. 14 patients had coronary disease, 9 carotid stenosis, 8 aortic stenosis and 2 had stroke. 34 patients were on statins (25 rosuvastatin), 30 were receiving ezetimibe, 2 were receiving a PSCK9 inhibitor (evolocumab) and 20 were on lomitapide with mean doses of 12.7mg. None received lipoprotein apheresis. Medications were very well tolerated. Changes in cLDL after therapy was from 533.7 mg/dL to 245 mg/dL, (54%). Conclusions: Treatment was started in all patients. We found genetic mutations in all patients with genetic tests. The high levels of cLDL mean such a high risk that treatment must be started promptly, even without a genetic test.

Correlación entre características físicas neonatales y maternas con el recuento total de células nucleadas y de células cd34+ por microlitro en sangre de cordón umbilical / Correlation between neonatal and maternal physical characteristics with total nucleated cell count and cell count per microliter cd34+ in cord blood / Correlação entre características físicas neonatais e maternas com a contagem total de células nucleadas e células cd34 + por microlitro no sangue do cordão umbilical

Introducción: La sangre de cordón umbilical (SCU) ha sido reconocida como una fuente de células madre hematopoyéticas. Múltiples estudios han sido realizados con el propósito de determinar variables maternas y neonatales que afecten el volumen, el recuento total de células nucleadas y de células CD34+. El presente estudio correlaciona variables maternas y neonatales con el recuento total de células nucleadas y de CD34+ medidas en μL (microlitro). Materiales y Métodos: Estudio correlacional en el que se analizaron 50 muestras de sangre de cordón umbilical de gestantes atendidas en dos IPS, una de Bogotá y otra de Ubaté, (Cundinamarca), durante un período de 7 meses del año 2013. La selección de estas muestras fue basada en un muestreo no probabilístico. Se calculó el coeficiente de correlación de Pearson con su respectiva significancia estadística entre las variables cuantitativas de la madre y del neonato, y el volumen, el recuento de células CD34+ y el recuento total de células nucleadas por μL. Resultados: Se encontró correlación positiva entre la longitud del cordón y el recuento total de células nucleadas. Así mismo entre el volumen inicial de la muestra y el recuento total de células nucleadas y el recuento de células CD34+ en μL y en mL (mililitro). Discusión: Múltiples estudios se han desarrollado entorno a la búsqueda de variables maternas y neonatales que afectan la calidad de la muestra. En Colombia no se habían descrito las correlaciones encontradas en el presente estudio. Es por ello, que el desarrollo de nuevos estudios con diseños analíticos será enriquecedor.

Background: The cord blood has been recognized as a source of hematopoietic stem. Multiple studies have been conducted in order to determine maternal and neonatal variables that affect the volume, total nucleated cell count and CD34+ cells. This study correlated maternal and neonatal variables with the total nucleated cell count and CD34+ cells measured by μL. Materials and methods: Correlational study in which 50 samples of umbilical cord blood were analyzed of pregnant women at two health institutions, one at Bogotá and the other one at Ubaté, Cundinamarca, for a period of seven months of 2013. The selection of these samples was based on a non-probability sample. The Pearson correlation coefficient was calculated with their respective statistical significance between quantitative variables of mother and newborn, and the volume, the count of CD34+ cells and the total nucleated cell count measured by μL. Results: Positive correlation between the length of the umbilical cord and the total nucleated cell count was found. Similarly, correlation between total nucleated cell count with the initial volume and count of CD34+ cells in μL and mL was found. Discussion: Several studies have been conducted around to look maternal and neonatal variables that affect the sample quality, however, the Colombian literature has not described the correlation found in this study, so it requires the development of new research with designs of analytical studies to establish associations between the variables described.

Introdução: O sangue do cordão umbilical (SCU) tem sido reconhecido como uma fonte de células-tronco hematopoiéticas. Vários estudos têm sido realizados com a finalidade de determinar as variáveis maternas e neonatais que afetam o volume e a contagem total de células nucleadas e células CD34+. O presente estudo correlaciona as variáveis maternas e neonatais com a contagem total das células nucleadas e células CD34+ medidas em μL (microlitro). Materiais e métodos: Estudo correlacional no que 50 amostras de sangue do cordão umbilical de mulheres grávidas atendidas em dois IPs foram analisadas, uma em Bogota e outra em Ubaté (Cundinamarca), durante um período de 7 meses do ano 2013. A seleção destas amostras foi baseada em uma amostragem não probabilística. O coeficiente de correlação de Pearson foi calculado com a respectiva significância estatística entre variáveis quantitativas da mãe e do recém-nascido, assim como o volume, a contagem de células CD34 + e contagem total de células nucleadas por μL. Resultados: Correlação positiva foi encontrada entre o comprimento do cordão e a contagem total de células nucleadas. Também entre o volume da amostra inicial e contagem total de células nucleadas e contagem de células CD34+ em μL e em mL (mililitro). Discussão: Vários estudos têm sido desenvolvidos em torno da busca de variáveis maternas e neonatais que afetam a qualidade da amostra. Na Colômbia não tinham sido descritas as correlações encontradas no presente estudo. É por esta razão que será gratificante o desenvolvimento de novos estudos com desenhos analíticos.

Intestinal absorption rate in children after small intestinal transplantation.

BACKGROUND: Small bowel transplantation has now become a recognized treatment of irreversible, permanent, and subtotal intestinal failure. OBJECTIVE: The aim of this study was to assess intestinal absorption at the time of weaning from parenteral nutrition in a series of children after intestinal transplantation. DESIGN: Twenty-four children (age range: 14-115 mo) received intestinal transplantation, together with the liver in 6 children and the colon in 16 children. Parenteral nutrition was slowly tapered while increasing enteral tube feeding. The absorption rate was measured from a 3-d stool balance analysis performed a few days after the child had weaned from parenteral nutrition to exclusive enteral tube feeding. Results were analyzed according to the resting energy expenditure (REE; Schofield formula). RESULTS: All children were weaned from parenteral nutrition between 31 and 85 d posttransplantation. Median intakes were as follows: energy, 107 kcal · kg(-1) · d(-1) (range: 79-168 kcal · kg(-1) · d(-1)); lipids, 39 kcal · kg(-1) · d(-1) (range: 20-70 kcal · kg(-1) · d(-1)); and nitrogen, 17 kcal · kg(-1) · d(-1) (range: 11-27 kcal · kg(-1) · d(-1)). Median daily stool output was 998 mL/d (range: 220-2025 mL/d). Median absorption rates were 88% (range: 75-96%) for energy, 82% (range: 55-98%) for lipids, and 77% (range: 61-88%) for nitrogen. The ratios for ingested energy to REE and absorbed energy to REE were 2.2 (range: 1.6-3.6) and 1.8 (range: 1.3-3.3), respectively. CONCLUSION: These data indicate a suboptimal intestinal graft absorption capacity with fat malabsorption, which necessitates energy intakes of at least twice the REE.

Pediatric ulcerative colitis associated with autoimmune diseases: a distinct form of inflammatory bowel disease?

BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) is multifactorial, with some patients presenting additional autoimmune symptoms. Inflammatory colitis associated with autoimmune (AI) liver disease appears to have clinical features different from those of "classical" ulcerative colitis (CUC). The aim of this study was to describe these features, in order to differentiate a subgroup of colitis associated with autoimmunity (CAI) from CUC. METHODS: Twenty-eight consecutive children with inflammatory colitis associated with primary sclerosing cholangitis (PSC), celiac disease, or AI hepatitis were compared with a matched control group of 27 children with isolated UC. Clinical course, histology, as well as inflammatory profile in the colonic mucosa based on real-time polymerase chain reaction (PCR) were analyzed. RESULTS: In CAI the main digestive symptoms at disease onset were abdominal pain (12/28) and bloody strings in the stool (12/28), along with a high prevalence of autoimmune diseases in relatives, as compared with bloody diarrhea in the CUC group (26/27). At diagnosis, pancolitis was seen in 18/28 CAI patients compared with 8/27 in UC. In CAI, the pathological findings were different from CUC: 1) major lesions predominantly located in the right colon; 2) pseudo-villous appearance of the mucosa, and strong infiltration with eosinophils; 3) mild glandular lesions; and 4) differing inflammatory infiltrate with reduced FOXP3, interleukin (IL)-2, and thymic stromal lymphopoietin (TSLP) levels. Evolution in CAI was less aggressive, requiring less corticosteroids/immunomodulators. CONCLUSIONS: Precise clinical, histological, and molecular analyses reveal marked differences between patients with CUC and those with associated AI phenomena, supporting the hypothesis of a distinct AI presentation of IBD.

Escenario Sociocultural Camba

Caracteristicas del area de estudio,(oriente Boliviano) area urbana, educacion, escuela curriculo, area rural, educacion, escuela, curriculo, interculturalidad y lengua, conclusiones, recomendaciones

Carcinoma mamario medular y mucinoso correlación histopatológica-mamográfica / Mammary carcinoma to medular and mucinoso mamográfica-histopatológica correlation

Analiza que el cáncer es una de las causas más importantes de mortalidad en el Ecuador y produce más de 5.700 muertes por año. En la área oncológica de la mujer, el cáncer de mama es la 3era causa de muerte, después del Ca. de cervix. La incidencia del cáncer de mama se ha elevado estadísticamente en los últimos años, probablemente, debido al incremento del screning mamográfico. El presente estudio establece la correlación histopatológica con las características mamográficas de las lesiones, en 26 mujeres portadoras de Ca. mamario de tipo medular y mucinoso, al tiempo que analiza su incidencia y determina la edad de detección, tamaño, localización y el estadío al momento del diagnóstico...