Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids

Treatment of common bile duct disorders such as biliary atresia or ischaemic strictures is limited to liver transplantation or hepatojejunostomy due to the lack of suitable tissue for surgical reconstruction. Here, we report a novel method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree and we explore the potential of bioengineered biliary tissue consisting of these extrahepatic cholangiocyte organoids (ECOs) and biodegradable scaffolds for transplantation and biliary reconstruction in vivo. ECOs closely correlate with primary cholangiocytes in terms of transcriptomic profile and functional properties (ALP, GGT). Following transplantation in immunocompromised mice ECOs self-organize into tubular structures expressing biliary markers (CK7). When seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary marker expression (CK7) and function (ALP, GGT). This bioengineered tissue can reconstruct the wall of the biliary tree (gallbladder) and rescue and extrahepatic biliary injury mouse model following transplantation. Furthermore, it can be fashioned into bioengineered ducts and replace the native common bile duct of immunocompromised mice, with no evidence of cholestasis or lumen occlusion up to one month after reconstruction. In conclusion, ECOs can successfully reconstruct the biliary tree following transplantation, providing proof-of-principle for organ regeneration using human primary cells expanded in vitro

Anxiety and Depression in Adults with Autism Spectrum Disorder: A Systematic Review and Meta-analysis

Adults with autism spectrum disorder (ASD) are thought to be at disproportionate risk of developing mental health comorbidities, with anxiety and depression being considered most prominent amongst these. Yet, no systematic review has been carried out to date to examine rates of both anxiety and depression focusing specifically on adults with ASD. This systematic review and meta-analysis examined the rates of anxiety and depression in adults with ASD and the impact of factors such as assessment methods and presence of comorbid intellectual disability (ID) diagnosis on estimated prevalence rates. Electronic database searches for studies published between January 2000 and September 2017 identified a total of 35 studies, including 30 studies measuring anxiety (n = 26 070; mean age = 30.9, s.d. = 6.2 years) and 29 studies measuring depression (n = 26 117; mean age = 31.1, s.d. = 6.8 years). The pooled estimation of current and lifetime prevalence for adults with ASD were 27% and 42% for any anxiety disorder, and 23% and 37% for depressive disorder. Further analyses revealed that the use of questionnaire measures and the presence of ID may significantly influence estimates of prevalence. The current literature suffers from a high degree of heterogeneity in study method and an overreliance on clinical samples. These results highlight the importance of community-based studies and the identification and inclusion of well-characterized samples to reduce heterogeneity and bias in estimates of prevalence for comorbidity in adults with ASD and other populations with complex psychiatric presentations

Advance care planning in patients with advanced cancer: A 6-country, cluster-randomised clinical trial

Background Advance care planning (ACP) supports individuals to define, discuss, and record goals and preferences for future medical treatment and care. Despite being internationally recommended, randomised clinical trials of ACP in patients with advanced cancer are scarce. Methods and findings To test the implementation of ACP in patients with advanced cancer, we conducted a cluster-randomised trial in 23 hospitals across Belgium, Denmark, Italy, Netherlands, Slovenia, and United Kingdom in 2015–2018. Patients with advanced lung (stage III/IV) or colorectal (stage IV) cancer, WHO performance status 0–3, and at least 3 months life expectancy were eligible. The ACTION Respecting Choices ACP intervention as offered to patients in the intervention arm included scripted ACP conversations between patients, family members, and certified facilitators; standardised leaflets; and standardised advance directives. Control patients received care as usual. Main outcome measures were quality of life (operationalised as European Organisation for Research and Treatment of Cancer [EORTC] emotional functioning) and symptoms. Secondary outcomes were coping, patient satisfaction, shared decision-making, patient involvement in decision-making, inclusion of advance directives (ADs) in hospital files, and use of hospital care. In all, 1,117 patients were included (442 intervention; 675 control), and 809 (72%) completed the 12-week questionnaire. Patients’ age ranged from 18 to 91 years, with a mean of 66; 39% were female. The mean number of ACP conversations per patient was 1.3. Fidelity was 86%. Sixteen percent of patients found ACP conversations distressing. Mean change in patients’ quality of life did not differ between intervention and control groups (T-score −1.8 versus −0.8, p = 0.59), nor did changes in symptoms, coping, patient satisfaction, and shared decision-making. Specialist palliative care (37% versus 27%, p = 0.002) and AD inclusion in hospital files (10% versus 3%, p < 0.001) were more likely in the intervention group. A key limitation of the study is that recruitment rates were lower in intervention than in control hospitals. Conclusions Our results show that quality of life effects were not different between patients who had ACP conversations and those who received usual care. The increased use of specialist palliative care and AD inclusion in hospital files of intervention patients is meaningful and requires further study. Our findings suggest that alternative approaches to support patient-centred end-of-life care in this population are needed

STRP Screening Sets for the human genome at 5 cM density

BACKGROUND: Short tandem repeat polymorphisms (STRPs) are powerful tools for gene mapping and other applications. A STRP genome scan of 10 cM is usually adequate for mapping single gene disorders. However mapping studies involving genetically complex disorders and especially association (linkage disequilibrium) often require higher STRP density. RESULTS: We report the development of two separate 10 cM human STRP Screening Sets (Sets 12 and 52) which span all chromosomes. When combined, the two Sets contain a total of 782 STRPs, with average STRP spacing of 4.8 cM, average heterozygosity of 0.72, and total sex-average coverage of 3535 cM. The current Sets are comprised almost entirely of STRPs based on tri- and tetranucleotide repeats. We also report correction of primer sequences for many STRPs used in previous Screening Sets. Detailed information for the new Screening Sets is available from our web site: . CONCLUSION: Our new human STRP Screening Sets will improve the quality and cost effectiveness of genotyping for gene mapping and other applications

Tourette disorder spectrum maps to chromosome 14q31.1 in an Italian kindred

Tourette syndrome (TS) is a frequent neuropsychiatric disorder of unknown etiology. A number of chromosomal regions have been nominated as TS loci in linkage studies, but confirmation has met with limited success and causative mutations have not yet been definitely identified. Furthermore, TS, chronic tics, and obsessive–compulsive disorder (OCD) occur at increased frequencies among TS relatives, supporting the view that these phenotypes represent parts of the same genetically determined spectrum. We ascertained a four-generation Italian kindred segregating TS, chronic multiple motor tics (CMT), and OCD, and we performed a ten-centimorgan (cM) genome-wide linkage scan in order to map the underlying genetic defect. Suggestive linkage to chromosome 14q31.1 (multipoint LOD = 2.4) was detected by affected-only analysis under an autosomal dominant model and a narrower phenotype definition (only the subjects with TS and CMT were considered as affected). The linkage peak increased and it approached genome-wide significance (LOD = 3.29) when a broader phenotype definition was adopted (subjects with TS, CMT, and OCD considered as affected). Haplotype analysis defined a ∼2.3 cM critical region, shared by all the relatives with TS, CMT, or OCD. In conclusion, we provide strong evidence for linkage of TS spectrum to chromosome 14q31.1. Suggestive linkage to an overlapping region of chromosome 14q was reported in a recent scan of TS sibling pairs. This region might therefore contain an important gene for TS, and it should be prioritized for further study

Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer.

The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures and a signature of localized hypermutation called kataegis. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B, has been associated with modestly increased risk of breast cancer. Here we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A-APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this increase in activity occurs remains unknown.We would like to thank the Wellcome Trust for support (grant reference 098051). SN-Z is a Wellcome-Beit Prize Fellow and is supported through a Wellcome Trust Intermediate Fellowship (grant reference WT100183MA). PJC is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). NB is an EHA fellow and is supported by a Lady Tata Memorial Trust award. The H.L. Holmes Award from the National Research Council Canada and an EMBO Fellowship supports AS

The contribution of X-linked coding variation to severe developmental disorders

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders