Systematic review of global functioning and quality of life in people with psychotic disorders

Aims People with psychotic disorders face impairments in their global functioning and their quality of life (QoL). The relationship between the two outcomes has not been systematically investigated. Through a systematic review, we aim to explore the presence and extent of associations between global functioning and QoL and establish whether associations depend on the instruments employed.Methods In May 2016, ten electronic databases were searched using a two-phase process to identify articles in which associations between global functioning and QoL were assessed. Basic descriptive data and correlation coefficients between global functioning and QoL instruments were extracted, with the strength of the correlation assessed according to the specifications of Cohen 1988. Results were reported with reference to the Meta-analysis of Observational Studies in Epidemiology guidelines and PRISMA standards. A narrative synthesis was performed due to heterogeneity in methodological approaches.Results Of an initial 15 183 non-duplicate articles identified, 756 were deemed potentially relevant, with 40 studies encompassing 42 articles included. Fourteen instruments for measuring global functioning and 22 instruments for measuring QoL were used. Twenty-nine articles reported linear associations while 19 assessed QoL predictors. Correlations between overall scores varied in strength, primarily dependent on the QoL instrument employed, and whether QoL was objectively or subjectively assessed. Correlations observed for objective QoL measures were consistently larger than those observed for subjective measures, as were correlations for an interviewer than self-assessed QoL. When correlations were assessed by domains of QoL, the highest correlations were found for social domains of QoL, for which most correlations were moderate or higher. Global functioning consistently predicted overall QoL as did depressive and negative symptoms.Conclusions This review is the first to explore the extent of associations between global functioning and QoL in people with psychotic disorders. We consistently found a positive association between global functioning and QoL. The strength of the association was dependent on the QoL instrument employed. QoL domains strongly associated with global functioning were highlighted. The review illustrates the extensive array of instruments used for the assessment of QoL and to a lesser extent global functioning in people with psychotic disorders and provides a framework to understand the different findings reported in the literature. The findings can also inform the future choice of instruments by researchers and/or clinicians. The observed associations reassure that interventions for improving global functioning will have a positive impact on the QoL of people living with a psychotic disorder

Multiannual observations and modelling of seasonal thermal profiles through supraglacial debris in the Central Himalaya

Many glaciers in the Central Himalaya are covered with rock debris that modifies the transfer of heat from the atmosphere to the underlying ice. These debris-covered glaciers are experiencing rapid mass loss at rates that have accelerated during the last two decades. Quantifying recent and future glacier mass change requires understanding the relationship between debris thickness and ablation particularly through the summer monsoon season. We present air, near-surface and debris temperatures measured during three monsoon seasons at five sites on Khumbu Glacier in Nepal, and compare these results to similar measurements from two other debris-covered glaciers in this region. Seasonal debris temperature profiles are approximately linear and consistent between sites for thick (>?0.5?m) and thin (<?0.5?m) debris across thicknesses ranging from 0.26 to 2.0?m. The similarities between these multiannual data imply that they are representative of supraglacial debris layers in the monsoon-influenced Himalaya more generally. We compare three methods to calculate sub-debris ablation, including using our temperature measurements with a thermal diffusion model that incorporates a simplified treatment of debris moisture. Estimated ablation between 3 June and 11 October at around 5000?m above sea level ranged from 0.10?m water equivalent beneath 1.5?m of debris to 0.47?m water equivalent beneath 0.3?m debris. However, these values are small when compared to remotely observed rates of surface lowering, suggesting that mass loss from these debris-covered glaciers is greatly enhanced by supraglacial and englacial processes that locally amplify ablationauthorsversionPeer reviewe

Multiplex ligation-dependent probe amplification (MLPA) analysis is an effective tool for the detection of novel intragenic PLA2G6 mutations: Implications for molecular diagnosis

Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the PLA2G6 gene. Direct gene sequencing detects 85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of PLA2G6 mutations. MLPA should thus be employed to detect CNVs of PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencin

Whole exome sequencing identifies a mutation in thrombomodulin as the genetic cause of a suspected platelet disorder in a family with normal platelet function

Here, we describe a mother and son with a lifelong bleeding tendency and posttraumatic bleeding who were recruited to the UK Genotyping and Phenotyping of Platelets (GAPP) study with a suspected platelet function disorder. However, despite a clinically significant bleeding score, both had normal platelet counts and normal platelet function. The patients’ blood was analyzed by light transmission aggregometry and genotyping by whole exome sequencing, as outlined by the GAPP study. Approximately 25 000 genetic variants were found for each patient as a result of sequencing and were filtered using a specialized bioinformatics pipeline. A heterozygous variant displaying autosomal dominant inheritance (c.1611 C>A) was found in the gene THBD which encodes the glycoprotein thrombomodulin. This sequence change results in a stop codon (p.Cys537Stop) and truncation of the protein and has been previously described in two other families with bleeding events which suggests it may be a recurrent mutation. In summary, this study shows that patients with a suspected platelet disorder but who present with a normal pattern of platelet aggregation should be investigated for defects in nonplatelet genes

Initiation codon mutation in βB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract

PurposeTo identify the molecular basis for autosomal recessively inherited congenital non-syndromic pulverulent cataracts in a consanguineous family with four affected children.MethodsAn autozygosity mapping strategy using high density SNP microarrays and microsatellite markers was employed to detect regions of homozygosity. Subsequently good candidate genes were screened for mutations by direct sequencing.ResultsThe SNP microarray data demonstrated a 24.96 Mb region of homozygosity at 22q11.21-22q13.2 which was confirmed by microsatellite marker analysis. The candidate target region contained the beta-crystallin gene cluster and direct sequencing in affected family members revealed a novel mutation in CRYBB1 (c.2T&gt;A; p.Met1Lys).ConclusionsTo our knowledge this is the first case of an initiation codon mutation in a human crystallin gene, and only the second report of a CRYBB1 mutation associated with autosomal recessive congenital cataracts. In addition, although a number of genetic causes of autosomal dominant pulverulent cataracts have been identified (including CRYBB1) this is the first gene to have been implicated in autosomal recessive nuclear pulverulent cataract

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

Optimised insert design for improved single-molecule imaging and quantification through CRISPR-Cas9 mediated knock-in

© 2019, The Author(s). The use of CRISPR-Cas9 genome editing to introduce endogenously expressed tags has the potential to address a number of the classical limitations of single molecule localisation microscopy. In this work we present the first systematic comparison of inserts introduced through CRISPR-knock in, with the aim of optimising this approach for single molecule imaging. We show that more highly monomeric and codon optimised variants of mEos result in improved expression at the TubA1B locus, despite the use of identical guides, homology templates, and selection strategies. We apply this approach to target the G protein-coupled receptor (GPCR) CXCR4 and show a further insert dependent effect on expression and protein function. Finally, we show that compared to over-expressed CXCR4, endogenously labelled samples allow for accurate single molecule quantification on ligand treatment. This suggests that despite the complications evident in CRISPR mediated labelling, the development of CRISPR-PALM has substantial quantitative benefits

The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity.

Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.This work was supported by the Medical Research Council (U105192732 and U105178805), the European Research Council (309756), the Lister Institute for Preventive Medicine, and the EMBO Young Investigator Program (to D.K.); a Marie-Sklodowska Curie Individual Fellowship from the European Commission (MC-IF-654019) and a Research Fellowship from Corpus Christi College Cambridge (to R.B.D.); and Wellcome Trust (to N.V.M., E.R.M., and A.N.J.M [100963/Z/13/Z]), WellChild (to N.V.M. and E.R.M.), and UCB (to H.L.T., D.M. and E.R.M.).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.cell.2016.07.01