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.

Analysis of ASS1 gene in ten unrelated middle eastern families with citrullinemia type 1 identifies rare and novel variants.

BACKGROUND: Citrullinemia type 1 (CTLN1) is a rare autosomal recessive disease caused by argininosuccinate synthetase (ASS) deficiency. Manifestations vary from the acute neonatal or "classic" form to a milder, late-onset, or "unconventional" form. To date, more than 93 variants in the ASS1 gene located on chromosome 9q43.11 (OMIM #215700) are reportedly responsible for CTLN1. Their incidence and distribution vary according to geographic origins and ethnicity, and a correlation, although not clearly delineated, has been established between the genotype and the phenotype of the disease. Though, in the Middle East, national descriptions of CTLN1 are still lacking. METHODS: A total of ten unrelated Middle Eastern families, five Lebanese, two Syrians, and three Iraqis with citrullinemia index cases, were included in this study. Upon informed consent, DNA was extracted from the whole blood of the index patients as well as their parents and siblings. Genetic analysis was carried out by Sanger sequencing of the ASS1 gene. RESULTS: Seven different variants were identified. Two novel variants, c.286C>A (p.(Pro96Thr), RNA not analyzed) in exon 5 and deletion c.685_688+6del(p.(Lys229Glyfs*4), RNA not analyzed) in exon 10, were found in one Lebanese and one Syrian family, respectively, and were correlated with early-onset and severe clinical presentation. Five other known variants: c.535T>C (p.(Trp179Arg), RNA not analyzed) in exon 8, c.787G>A (p.(Val263Met), RNA not analyzed) in exon 12, c.847G>A (p.(Glu283Lys), RNA not analyzed) in exon 13, c.910C>T (p.(Arg304Trp), RNA not analyzed) in exon 13, and c.1168G>A (p.(Gly390Arg), RNA not analyzed) in exon 15, were found in Lebanese, Syrian, and Iraqi families, and were associated with diverse clinical presentations. CONCLUSION: Two novel variants and five known variants were found in a total of ten unrelated Middle Eastern families.

Severe Social Anxiety Among Adolescents During COVID-19 Lockdown.

To study the prevalence of severe social anxiety (SSA) among a group of adolescents during the coronavirus disease of 2019 (COVID-19) pandemic. A total of 178 adolescents attending the private clinics of the authors were screened online for the presence of SSA, by using the self-reporting format of the Liebowitz Social Anxiety Scale for children and adolescents (LSAS-CA). SSA defined as LSAS-CA scores of 80 or more was checked for statistical association with the adolescents' sociodemographic data and knowledge about the COVID-19 infection. The 18% of our participants had SSA, no correlation was found between having SSA and ä acknowledging or fearing the COVID-19 morbidity. Factors associated with SSA included texting, using social media, and playing video games during the lockdown. Mitigating factors include high family socioeconomic status, history of socialization with friends, and the use of WhatsApp as a source of information about COVID-19 infection.

The added value of WES reanalysis in the field of genetic diagnosis: lessons learned from 200 exomes in the Lebanese population.

BACKGROUND: The past few decades have witnessed a tremendous development in the field of genetics. The implementation of next generation sequencing (NGS) technologies revolutionized the field of molecular biology and made the genetic information accessible at a large scale. However, connecting a rare genetic variation to a complex phenotype remains challenging. Indeed, identifying the cause of a genetic disease requires a multidisciplinary approach, starting with the establishment of a clear phenotype with a detailed family history and ending, in some cases, with functional assays that are crucial for the validation of the pathogenicity of a mutation. METHODS: Two hundred Lebanese patients, presenting a wide spectrum of genetic disorders (neurodevelopmental, neuromuscular or metabolic disorders, etc.), sporadic or inherited, dominant or recessive, were referred, over the last three and a half years, to the Medical Genetics Unit (UGM) of Saint Joseph University (USJ). In order to identify the genetic basis of these diseases, Whole Exome Sequencing (WES), followed by a targeted analysis, was performed for each case. In order to improve the genetic diagnostic yield, WES data, generated during the first 2 years of this study, were reanalyzed for all patients who were left undiagnosed at the genetic level. Reanalysis was based on updated bioinformatics tools and novel gene discoveries. RESULTS: Our initial analysis allowed us to identify the specific genetic mutation causing the disease in 49.5% of the cases, in line with other international studies. Repeated WES analysis enabled us to increase the diagnostics yield to 56%. CONCLUSION: The present article reports the detailed results of both analysis and pinpoints the contribution of WES data reanalysis to an efficient genetic diagnosis. Lessons learned from WES reanalysis and interpretation are also shared.

Xanthophylls and eye health of infants and adults.

Lutein and zeaxanthin are the only carotenoids present in the eye. They cannot be synthesized de novo and are specifically concentrated in the macula. They appear to have at least two major functions: to filter out blue light and thus prevent ensuing damages to the eye and to act as antioxidants. Infants are particularly at risk from both blue light and oxidative damage to eye tissues. Lutein is present in human milk but is not currently added to infant formulas. Fortifying formulae with lutein in order to match more closely human milk might help protect the infant's sensitive eyes. In adults, the exact pathogenesis of age-related maculopathy remains unknown. Light damage, inflammation, and the disruption of cellular processes by oxidative stress may play an important role in the degenerative process. Manipulation of intake of xanthophylls has been shown to augment macular pigment, therefore it is thought that carotenoid dietary supplements could prevent, delay, or modify the course of age-related maculopathy. However, definite evidence of the effect of carotenoids, the optimal doses to use, and the supplementation duration are still under investigation.

Chromium in parenteral nutrition: too little or too much?

Although guidelines for routine parenteral supplements of chromium (Cr) were published, there remain major concerns about the infusion of excess Cr. In addition, little information is available on appropriate dosage for intravenous usage. Cr functions as a regulator of insulin action. In humans, the 3 reported cases of Cr deficiency developed peripheral neuropathy, weight loss, and hyperglycemia. Supplementation of Cr to the parenteral nutrition (PN) solution corrected these abnormalities. For parenteral Cr, concerns arise from the high levels found in sera (up to 40-fold higher) and tissues (10- to 100-fold higher) and their effects on kidneys: In 15 children receiving long-term PN, the glomerular filtration rate was lower than that of non-PN controls and was inversely correlated with Cr indices. Furthermore, in a randomized blinded prospective protocol involving 75 newborns, the group receiving the recommended dose of Cr showed higher levels of creatinine that were positively correlated with Cr intake. Of note, Cr contaminants in PN solutions can increase the amount delivered by 10%-100%. A possible method for estimating adequate Cr to be provided IV is to calculate the amount physiologically absorbed in healthy people. This amount is 10 to 100 times less than the daily recommended parenteral Cr in adults. The accumulated scientific data presented here point to a serious need to lower the recommended amount of parenteral Cr.

Effects of a prethickened formula on esophageal pH and gastric emptying of infants with GER.

OBJECTIVE(S): Advantages of prethickened formulas (AR) with regards to esophageal pH and gastric emptying were investigated in this study as compared with a regular formula (R). STUDY DESIGN: Seventy-four healthy infants, <6 months old, with gastroesophageal reflux were enrolled into the study. All infants underwent 24-hour esophageal pH monitoring while receiving R and AR, alternately. Electrogastrography was measured before and after feeding each study formula. Thereafter, the infants were randomly assigned to receive either R or AR for 1 month. Episodes of regurgitation, vomiting, coughing, crying, and bowel movements were recorded on a weekly interval. RESULTS: Reflux index (RI) of AR-fed infants were lower (5.64%) than the R-fed infants (7.77%) showing a significant difference (P<0.01) between the 2 groups, favoring AR. Eighty-seven percent of infants improved their RI while receiving the AR formula. Electrogastrography variables were not significantly different between the 2 study groups. A significant decrease (P<0.01) in the daily episodes of regurgitation and vomiting was observed in the AR-fed infants. No adverse events were reported during the study. CONCLUSIONS: Prethickened infant formula was effective in reducing clinical symptoms of uncomplicated gastroesophageal reflux and reducing RI. Prethickened formulas do not alter gastric emptying time and was very well tolerated.

Estimate of specific energy expenditure of fat-free mass and fat mass in children receiving total parenteral nutrition.

OBJECTIVES: Simple methods for calculation of the energy expenditure may be useful for clinicians involved in the treatment of nutritional disorders in children. The aims of this study were to (1) estimate the specific energy expenditure (SEE) of fat mass (FM) and fat-free mass (FFM) and (2) determine a sensitive predictive indicator of resting energy expenditure (REE). METHODS: The REE of 26 children receiving longterm TPN, was measured by long-term indirect calorimetry. Body composition was estimated from the sum of four skinfold measurements. RESULTS: The following regression equations were derived: (1) REE (kcal/d) = 56.6 x FFM (kg) + 97.9 (r2 = 0.98, p < 0.001); (2) REE (kcal/d) = 45.6 x BW (kg) + 136 (r2 = 0.92, p < 0.001); (3) REE (kcal/d) = 68.9 x FFM (kg) + 3.3 x FM (kg) (r2 = 0.985, p < 0.001). The results obtained allowed the estimate of K1 and K2 with their respective SEE: K1 = 3.3 +/- 18.0 kcal/kg of FM, K2 = 68.9 +/- 3.1 kcal/kg of FFM. CONClUSIONS Anthropometrically measured FFM is an easily determined predictive factor of REE. The above equations may be used to estimate the REE in stable children receiving TPN.

Irritable bowel syndrome and nonspecific diarrhea in infancy and childhood--relationship with juice carbohydrate malabsorption.

Lactose intolerance and malabsorbed carbohydrate present in some fruitjuice may trigger symptoms commonly seen in irritable bowel syndrome. In a two-site study, 28 subjects 9 months to 18 years old (mean 6.9 +/- 5.9 years) with significant intake of apple juice or pear nectar (> 6 oz a day) with the diagnoses of irritable bowel syndrome, functional abdominal pain, or chronic nonspecific diarrhea were recruited. Breath hydrogen tolerance tests utilizing lactose, sucrose, and apple juice in the amount they typically consumed were positive in 32%, 0%, and 50%, respectively. Subjects were asked to refrain from the ingestion ofjuice for 1 month: 13 of the 28 (46%) subjects improved while 15 (54%) showed no change in their symptoms. In fact, none consuming 6 to 12 oz of apple or pear juice daily improved, 27% of those consuming 12 to 16 oz improved, and 91% of those consuming > 16 oz improved (P < 0.02). Subjects were then given comparable amounts of white grape juice for 1 year. The initial symptoms did not recur in any of the subjects who initially responded to the juice-free diet. Of the 15 subjects who did not respond to the juice-free diet, seven became asymptomatic. Overall, 20 subjects (71%) were asymptomatic, and eight (29%) had no change in their symptoms. Some individuals with irritable bowel syndrome have their symptoms based on their malabsorption of carbohydrates present in apple juice and pear nectar and may improve with adequate choices of fruit juice such as changing to white grape juice.

Eletrogastrografia (EGG): atividade miolétrica gástrica em recém-nascidos / Electrogastrography (EGG): gastric myoelectric activity in newborns

Os autores mostram estudo da atividade mioelétrica gástrica realizada por eletrogastrografia em dois grupos de recém-nascidos (RN) saudáveis (pré-termo e a termo) em que se comparou o traçado do EGG entre ambos. Nao foi encontrada diferença significativa na percentagem de ondas lentas entre os dois grupos, assim como nao ocorreu aumento significativo no período pós-prandial, nem na MnDF, DFIC, DPIC. No entanto a amplitude da onda de freqüência dominante no período pós-prandial, quando comparado ao pré-prandial, aumentou 4,2 vezes nos RN a termo e somente 1,2 nos RN pré-termo (p < O,05). Isso demonstra contraçao gástrica mais eficiente nos RN a termo.