A qualitative study trialling the acceptability of new hepatitis C prevention messages for people who inject drugs: symbiotic messages, pleasure and conditional interpretations

Aim: Prevention of hepatitis C (HCV) remains a public health challenge. A new body of work is emerging seeking to explore and exploit "symbiotic goals" of people who inject drugs (PWID). That is, strategies used by PWID to achieve other goals may be doubly useful in facilitating the same behaviours (use of sterile injecting equipment) required to prevent HCV. This project developed and trialled new HCV prevention messages based on the notion of symbiotic messages. Method: New HCV prevention messages were developed in a series of 12 posters after consultation with staff from needle and syringe programs (NSPs) and a drug user organisation. Two posters were displayed each week for a 6-week period within one NSP. NSP staff and clients were invited to focus groups to discuss their responses to the posters. Results: A total of four focus groups were conducted; one group of seven staff members and three groups of clients with a total of 21 participants. Responses to each of the posters were mixed. Staff and clients interpreted messages in literal ways rather than as dependent on context, with staff concerned that not all HCV prevention information was included in any one message; while clients felt that some messages were misleading in relation to the expectations of pleasure. Clients appreciated the efforts to use bright imagery and messages that included acknowledgement of pleasure. Clients were not aware of some harm reduction information contained in the messages (such as "shoot to the heart"), and this generated potential for misunderstanding of the intended message. Clients felt that any message provided by the NSP could be trusted and did not require visible endorsement by health departments. Conclusions: While the logic of symbiotic messages is appealing, it is challenging to produce eye-catching, brief messages that provide sufficient information to cover the breadth of HCV prevention. Incorporation of symbiotic messages in conversations or activities between staff and clients may provide opportunities for these messages to be related to the clients' needs and priorities and for staff to provide HCV prevention information in accord with their professional ethos

Hypertensive disorders of pregnancy and risk of neurodevelopmental disorders in the offspring: a systematic review and meta-analysis protocol

Introduction Hypertensive disorders of pregnancy (HDPs), that is chronic hypertension, gestational hypertension, pre-eclampsia (de novo or superimposed on chronic hypertension) and white coat hypertension, affect approximately 5%–15% of pregnancies. HDP exposure has been linked to an increased risk of autism spectrum disorder, attention deficit/hyperactivity disorder and other neurodevelopmental disorders in children. However, findings are inconsistent, and a clear consensus on the impact of HDPs on the risk of neurodevelopmental disorders is needed. Therefore, we aim to synthesise the published literature on the relationship between HDPs and the risk of neurodevelopmental disorders in the form of a systematic review and meta-analysis. Methods and analysis We will include cohort, case– control and cross-sectional studies in which diagnosis of an HDP was reported, and neurodevelopmental disorders were the outcome of interest based on a preprepared protocol. A systematic search of PubMed, CINAHL, Embase, PsycINFO and Web of Science will be conducted in accordance with a detailed search strategy. Two authors will independently review the titles and abstracts of all studies, perform data extraction using a standardised data collection form and assess study quality using a bias classification tool. Meta-analyses will be performed to calculate overall pooled estimates using the generic inverse variance method. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses. Ethics and dissemination This proposed systematic review and meta-analysis is based on published data, therefore, does not require ethics approval. Findings will be presented at scientific conferences and disseminated through publication in a peer-reviewed journal. Registration CRD42017068258

Occupying wide open spaces? Late Pleistocene hunter–gatherer activities in the Eastern Levant

With a specific focus on eastern Jordan, the Epipalaeolithic Foragers in Azraq Project explores changing hunter-gatherer strategies, behaviours and adaptations to this vast area throughout the Late Pleistocene. In particular, we examine how lifeways here (may have) differed from surrounding areas and what circumstances drew human and animal populations to the region. Integrating multiple material cultural and environmental datasets, we explore some of the strategies of these eastern Jordanian groups that resulted in changes in settlement, subsistence and interaction and, in some areas, the occupation of substantial aggregation sites. Five years of excavation at the aggregation site of Kharaneh IV suggest some very intriguing technological and social on-site activities, as well as adaptations to a dynamic landscape unlike that of today. Here we discuss particular aspects of the Kharaneh IV material record within the context of ongoing palaeoenvironmental reconstructions and place these findings in the wider spatial and temporal narratives of the Azraq Basin

Molecular insight into a new low affinity xylan binding module from the xylanolytic gut symbiont Roseburia intestinalis

Efficient capture of glycans, the prime metabolic resources in the human gut, confers a key competitive advantage for gut microbiota members equipped with extracellular glycoside hydrolases (GHs) to target these substrates. The association of glycans to the bacterial cell surface is typically mediated by carbohydrate binding modules (CBMs). Here, we report the structure of RiCBM86 appended to a GH family 10 xylanase from Roseburia intestinalis. This CBM represents a new family of xylan binding CBMs present in xylanases from abundant and prevalent healthy human gut Clostridiales. RiCBM86 adopts a canonical β-sandwich fold, but shows structural divergence from known CBMs. The structure of RiCBM86 has been determined with a bound xylohexaose, which revealed an open and shallow binding site. RiCBM86 recognizes only a single xylosyl ring with direct hydrogen bonds. This mode of recognition is unprecedented amongst previously reported xylan binding type-B CBMs that display more extensive hydrogen-bonding patterns to their ligands or employ Ca2+ to mediate ligand-binding. The architecture of RiCBM86 is consistent with an atypically low binding affinity (KD about 0.5 mm for xylohexaose) compared to most xylan binding CBMs. Analyses using NMR spectroscopy corroborated the observations from the complex structure and the preference of RiCBM86 to arabinoxylan over glucuronoxylan, consistent with the largely negatively charged surface flanking the binding site. Mutational analysis and affinity electrophoresis established the importance of key binding residues, which are conserved in the family. This study provides novel insight into the structural features that shape low-affinity CBMs that mediate extended bacterial glycan capture in the human gut niche. Databases: Structural data are available in the protein data bank database under the accession number 6SGF. Sequence data are available in the GenBank database under the accession number EEV01588.1. The assignment of the Roseburia intestinalis xylan binding module into the CBM86 new family is available in the CAZy database (http://www.cazy.org/CBM86.html)

Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder with variable expressivity and a predisposition to tumorigenesis, results from disordered expression and/or function of imprinted genes at chromosome 11p15.5. There are no generally agreed clinical diagnostic criteria, with molecular studies commonly performed to confirm diagnosis. In particular, methylation status analysis at two 11p15.5 imprinting control centres (IC1 and IC2) detects up to 80% of BWS cases (though low-level mosaicism may not be detected). In order to evaluate the relationship between the clinical presentation of suspected BWS and IC1/2 methylation abnormalities we reviewed the results of >1,000 referrals for molecular diagnostic testing. RESULTS: Out of 1,091 referrals, 507 (46.5%) had a positive diagnostic test for BWS. The frequency of tumours was 3.4% in those with a molecular diagnosis of BWS. Previously reported genotype-phenotype associations with paternal uniparental disomy, IC1, and IC2 epimutation groups were confirmed and potential novel associations detected. Predictive values of previously described clinical diagnostic criteria were compared and, although there were differences in their sensitivity and specificity, receiver operating characteristic (ROC) analysis demonstrated that these were not optimal in predicting 11p15.5 methylation abnormalities. Using logistic regression, we identified clinical features with the best predictive value for a positive methylation abnormality. Furthermore, we developed a weighted scoring system (sensitivity 75.9%, and specificity 81.8%) to prioritise patients presenting with the most common features of BWS, and ROC analysis demonstrated superior performance (area under the curve 0.85, 95% CI 0.83 to 0.87) compared to previous criteria. CONCLUSIONS: We suggest that this novel tool will facilitate selection of patients with suspected BWS for routine diagnostic testing and so improve the diagnosis of the disorder.We thank Action Medical Research and the Cambridge NIHR Biomedical Research Centre for financial support.This is the final published version. It first appeared at http://www.clinicalepigeneticsjournal.com/content/6/1/11

Germline Mutation in NLRP2 (NALP2) in a Familial Imprinting Disorder (Beckwith-Wiedemann Syndrome)

Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans

Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL.

A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in GAD1 was described as a candidate mutation in a single family diagnosed with autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513). Following the ascertainment of a further branch of the CPSQ1 kindred, we found that the previously reported GAD1 variant did not segregate with the neurological disease phenotype in the recently ascertained branch of the kindred. Following genetic linkage studies to map autozygous regions and whole-exome sequencing, a missense variant (c.527 T > C; p. Leu176Pro, rs773333490) in the HPDL gene was detected and found to segregate with disease status in both branches of the kindred. HPDL encodes a 371-amino acid protein (4-Hydroxyphenylpyruvate Dioxygenase Like) that localizes to mitochondria but whose function is uncertain. Recently, biallelic loss of function variants and missense substitution-causing variants in HPDL were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that HPDL-related neurological disease may mimic spastic cerebral palsy and that GAD1 should not be included in diagnostic gene panels for inherited cerebral palsy.NIH

A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease.

Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5β-reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are