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Canonical babbling (CB) is commonly defined as present when at least 15% of all syllables produced are canonical, in other words a canonical babbling ratio (CBR) ≥0.15. However, there is limited knowledge about inter-rater reliability in classification of CB status based on CBR and inter-rater differences in assessment of CBR. We investigated inter-rater reliability of experienced Speech Language Therapists (SLTs) on: classification of CB status based on CBR ≥ 0.15, CBRs and the total number of syllables per infant used to calculate CBR.Each infant (n = 484) was video-recorded at a clinical site in play interaction with their parent as part of the randomised controlled trial Timing of Primary Surgery for Cleft Palate. Each recording was subsequently assessed by three independent SLTs, from a pool of 29 SLTs. They assessed the recordings in real time.The three assessing SLTs agreed in classification of CB status in 423 (87.4%) infants, with higher complete agreement for canonical (91%; 326/358) than non-canonical (77%; 97/126). The average difference in CBR and total number of syllables identified between the SLT assessments of each infant was 0.12 and 95, respectively.This study provided new evidence that one trained SLT can reliably classify CB status (CBR ≥ 0.15) in real time when there is clear distinction between the observed CBR and the boundary (0.15); however, when the observed CBR approaches the boundary multiple SLT assessments are beneficial. Thus, we recommend to include assessment of inter-rater reliability, if the purpose is to compare CBR and total syllable count across infants or studies.Trial registration number here: www.clinicaltrials.gov, identifier NCT00993551.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship., Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS., Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 ( p < 0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p < 0.001)., Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment., Impact and Implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency., Competing Interests: Antonia Felzen [MD/PhD scholarship University of Groningen], Daan B.E. van Wessel [MD/PhD scholarship University of Groningen], Emmanuel M. Gonzales [Consultant for CTRS, Vivet Therapeutics, Mirum Pharmaceuticals and Albireo], Richard J. Thompson [Consultant for Shire, Albireo, Mirum Pharmaceuticals, Horizon Pharmaceuticals, Sana Biotechnology, GenerationBio, Retrophin and Qing Bile Therapeutics], Irena Jankowska [Nothing to disclose], Benjamin L. Shneider [Nothing to disclose], Etienne Sokal [Founder, board director and Chairman of the Scientific & Medical advisor board of Promethera Biosciences; consultant Johnson&Johnson], Tassos Grammatikopoulos [Consultant for Albireo], Agustina Kadaristiana [Nothing to disclose], Emmanuel Jacquemin [Consultant for CTRS and Vivet Therapeutics], Anne Spraul [Nothing to disclose], Patryk Lipiński [Nothing to disclose], Piotr Czubkowski [Nothing to disclose], Nathalie Rock [Nothing to disclose], Mohammad Shagrani [Nothing to disclose], Dieter Broering [Nothing to disclose], Emanuele Nicastro [Nothing to disclose] Deirdre Kelly [Consultant for Albireo], Gabriela Nebbia [Nothing to disclose], Henrik Arnell [Consultant for Albireo and Mirum Pharmaceuticals], Bjorn Fischler [Attended one advisory board meeting with Albireo in 2016], Jan Hulscher [Nothing to disclose], Daniele Serranti [Nothing to disclose], Cigdem Arikan [Nothing to disclose], Esra Polat [Nothing to disclose], Dominique Debray [Consultant for Alexion and Orphalan pharmaceuticals], Florence Lacaille [Nothing to disclose], Cristina Goncalves [Nothing to disclose], Loreto Hierro [Nothing to disclose], Gema Munoz Bartolo [Nothing to disclose], Yael Mozer- Glassberg [Nothing to disclose], Amer Azaz [Nothing to disclose], Jernej Brecelj [Nothing to disclose], Antal Dezsofi [Nothing to disclose], Pier Luigi Calvo [Nothing to disclose], Enke Grabhorn [Nothing to disclose], Ekkehard Sturm [Nothing to disclose] Wendy van der Woerd [Nothing to disclose], Binita Kamath [Consultant for Mirum Pharmaceuticals, Shire and DCI], Jian-She Wang [Nothing to disclose], Liting Li [Nothing to disclose], Özlem Durmaz [Nothing to disclose], Nanda Kerkar [Nothing to disclose], Marianne Hørby Jørgensen [Nothing to disclose], Ryan Fischer [Consultant for Albireo and Mirum Pharmaceuticals], Carolina Jimenez-Rivera [Nothing to disclose], Seema Alam [Nothing to disclose], Mara Cananzi [Attended one advisory board meeting with Albireo, Mirum Pharmaceuticals and Nestlè; consultant for CTRS], Noemie Laverdure [Consultant for Abbvie], Cristina Targa Ferreira [Nothing to disclose], Felipe Ordoñez Guerrero [Nothing to disclose], Heng Wang [Nothing to disclose], Valerie Sency [Nothing to disclose], Kyungmo Kim [Nothing to disclose], Huey-Ling Chen [Nothing to disclose], Elisa de Carvalho [Nothing to disclose], Alexandre Fabre [Nothing to disclose], Jesus Quintero Bernabeu [Nothing to disclose], Aglaia Zellos [Nothing to disclose], Estella M. Alonso [Nothing to disclose], Ronald J. Sokol [Consultant for Albireo and Mirum Pharmaceuticals], Frederick J. Suchy [Nothing to disclose], Kathleen M. Loomes [Consultant for Albireo, Mirum and Travere Therapeutics], Patrick J. McKiernan [Consultant for Albireo], Philip Rosenthal [Grant/Research Support by Gilead, AbbVie, Merck, Albireo, Mirum Pharmaceuticals, Arrowhead and Travere; consultant for Gilead, AbbVie, Audentes, Dicerna, Albireo, Mirum Pharmaceuticals, Travere, Takeda, Encoded, BioMarin, MedinCell and Ambys], Yumirle Turmelle [Nothing to disclose], Simon Horslen [Grant/Research support from Mirum Pharmaceuticals], Kathleen Schwarz [Grant support from Gilead, Albireo and the Global Alagille Syndrome Alliance; consultant for Mirum Pharmaceuticals, Up to Date and Sarepta], Jorge A. Bezerra [Grant support from Gilead and Albireo], Kasper Wang [Nothing to disclose], Bettina Hansen [Unrestricted grant support from Cymabay, Intercept, Calliditas, Mirum Pharmaceuticals and Albireo; consultant for Mirum Pharmaceuticals, Albireo AB, Chemomab, Calliditas, Intercept, Cyma Bay,], Henkjan J. Verkade [Consultant for Danone/Nutricia Research, Ausnutria BV, Albireo AB, Mirum Parmaceuticals, Intercept and Vivet]. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

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., (© The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date., Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category., Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001)., Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS., Lay Summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease., Competing Interests: Conflicts of interest Daan B.E. van Wessel: [nothing to disclose], Richard J. Thompson [consultancy for Shire, Albireo, Mirum, Horizon Pharmaceuticals, Sana Biotechnology, GenerationBio, Retrophin and Qing Bile Therapeutics], Emmanuel M. Gonzales [Consultant for CTRS and Mirum Pharmaceuticals], Irena Jankowska [nothing to disclose], Tassos Grammatikopoulos [nothing to disclose], Agustina Kadaristiana [nothing to disclose], Patryk Lipiński [nothing to disclose], Piotr Czubkowski [nothing to disclose], Nathalie Rock [nothing to disclose] Emmanuel Jacquemin [nothing to disclose], Anne Spraul [nothing to disclose], Etienne M. Sokal [founder and CSMO of Promethera Biosciences], Mohammad Shagrani [nothing to disclose], Dieter Broering [nothing to disclose], Talal Algoufi [nothing to disclose], Nejat Mazhar [nothing to disclose], Emanuele Nicastro [nothing to disclose] Deirdre Kelly [Consultant for Albireo], Gabriela Nebbia [nothing to disclose], Henrik Arnell [consultant for Albireo and Mirum Pharmaceuticals], Björn Fischler [has attended one advisory board meeting with Albireo in 2016], Jan Hulscher [nothing to disclose], Daniele Serranti [nothing to disclose], Cigdem Arikan [nothing to disclose], Esra Polat [nothing to disclose], Dominique Debray [consultant for Alexion pharmaceuticals], Florence Lacaille [nothing to disclose], Cristina Goncalves [nothing to disclose], Loreto Hierro [nothing to disclose], Gema Muñoz Bartolo [nothing to disclose], Yael Mozer-Glassberg [nothing to disclose], Amer Azaz [nothing to disclose], Jernej Brecelj [nothing to disclose], Antal Dezsőfi [nothing to disclose], Pier Luigi Calvo [nothing to disclose], Enke Grabhorn [nothing to disclose], Ekkehard Sturm [nothing to disclose] Wendy van der Woerd [nothing to disclose], Binita Kamath [consultant for Mirum Pharmaceuticals, Shire and DCI], Jian-She Wang [nothing to disclose], Liting Li [nothing to disclose], Özlem Durmaz [nothing to disclose], Zerrin Onal [nothing to disclose], Ton Bunt [nothing to disclose], Bettina Hansen [consultant for Mirum Pharmaceuticals, Albireo AB, Chemomab, Calliditas, Intercept, Cyma Bay, unrestricted grants from Cyma bay, Intercept, Mirum and Albireo], Henkjan J. Verkade [Consultant for Danone/Nutricia Research, Ausnutria BV, Albireo AB, GMP+Orphan, Mirum Pharmaceuticals, Intercept and Vivet]. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. All rights reserved.)

Purpose This analysis of the FIRST trial in patients with newly diagnosed multiple myeloma (MM) ineligible for stem-cell transplantation examined updated outcomes and impact of patient age. Patients and Methods Patients with untreated symptomatic MM were randomly assigned at a one-to-one-to-one ratio to lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks), stratified by age (≤ 75 v > 75 years), disease stage (International Staging System stage I/II v III), and country. The primary end point was progression-free survival. Rd continuous and MPT were primary comparators. Results Between August 21, 2008, and March 7, 2011, 1,623 patients were enrolled (Rd continuous, n = 535; Rd18, n = 541; MPT, n = 547), including 567 (35%) age older than 75 years. Higher rates of advanced-stage disease and renal impairment were observed in patients older than 75 versus 75 years of age or younger. Rd continuous reduced the risk of progression or death compared with MPT by 31% (hazard ratio [HR], 0.69; 95% CI, 0.59 to 0.80; P < .001) overall, 36% (HR, 0.64; 95% CI, 0.53 to 0.77; P < .001) in patients age 75 years or younger, and 20% (HR, 0.80; 95% CI, 0.62 to 1.03; P = .084) in those age older than 75 years. Median overall survival was longer with Rd continuous than with MPT, including a 14-month difference in patients age older than 75 years. Progression-free survival with Rd18 was similar to that with MPT, and overall survival with Rd18 was marginally inferior to that with Rd continuous. Rates of grade 3 to 4 treatment-emergent adverse events were similar for Rd continuous-treated patients age 75 years or older and those age older than 75 years; however, older patients had more frequent lenalidomide dose reductions. Conclusion Results support Rd continuous treatment as a new standard of care for stem-cell transplantation-ineligible patients with newly diagnosed MM of all ages.