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Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to American College of Medical Genetics/Association for Molecular Pathology criterion PVS1). The exact nature and predictability of splicing effects of unselected rare CSSVs in blood-expressed genes are poorly understood. We identified 168 rare CSSVs in blood-expressed genes in 112 individuals using genome sequencing, and studied their impact on splicing using RNA sequencing (RNA-seq). There was no evidence of a frameshift, nor of reduced expression consistent with nonsense-mediated decay, for 25.6% of CSSVs: 17.9% had wildtype splicing only and normal junction depths, 3.6% resulted in cryptic splice site usage and in-frame insertions or deletions, 3.6% resulted in full exon skipping (in frame), and 0.6% resulted in full intron inclusion (in frame). Blind to these RNA-seq data, we attempted to predict the precise impact of CSSVs by applying in silico tools and the ClinGen Sequence Variant Interpretation Working Group 2018 guidelines for applying PVS1 criterion. The predicted impact on splicing using (1) SpliceAI, (2) MaxEntScan, and (3) AutoPVS1, an automatic classification tool for PVS1 interpretation of null variants that utilizes Ensembl Variant Effect Predictor and MaxEntScan, was concordant with RNA-seq analyses for 65%, 63%, and 61% of CSSVs, respectively. In summary, approximately one in four rare CSSVs did not show evidence for LoF based on analysis of RNA-seq data. Predictions from in silico methods were often discordant with findings from RNA-seq. More caution may be warranted in applying PVS1-level evidence to CSSVs in the absence of functional data.

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12-73%), 33% (6-86%) in cohorts with prior genetic testing, and 33% (9-60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24-100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations.

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function., Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function., Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

El presente trabajo resume la literatura existente relativa a los modelos de ajuste de los precios nominales, centrándose en los modelos de comportamiento óptimo o casi óptimo. El documento abarca tres clases principales de mecanismos: 1) modelos que suponen un coste fijo (menu cost) al ajustar el precio nominal de un producto, 2) modelos en los que la probabilidad de ajuste del precio es una función creciente de las ganancias asociadas con dicho ajuste (generalized hazard function) y 3) modelos que suponen algún tipo de racionalidad acotada que conlleva fricciones en la toma de decisiones. El documento destaca también el papel clave de las rigideces reales en el reforzamiento del impacto de las rigideces nominales. Para concluir, el trabajo evalúa el éxito de estos modelos a la hora de explicar tanto la dinámica de precios en los datos microeconómicos del sector minorista como la dinámica de inflación en los datos macroeconómicos., We review models of nominal price adjustment based on optimizing or near-optimal behavior, including menu cost models, generalized hazard function models and models of frictional decisions. We also discuss the role of real rigidities and assess the models’ success in explaining retail microdata and inflation dynamics.

This paper empirically quantifies the effect on Spain’s public finances of the asset purchase programmes implemented in the euro area between 2015 and 2022. Specifically, it evaluates the impact of the ECB’s Asset Purchase Programme (APP) and Pandemic Emergency Purchase Programme (PEPP) on Spanish public revenue, expenditure, deficit and debt. The results suggest that these programmes have had a significant cumulative downward effect on the level of public debt., Este documento ofrece una cuantificación empírica del efecto sobre las cuentas públicas en España de los programas de compras de activos implementados en el área del euro entre 2015 y 2022. En particular, se evalúa el impacto sobre los ingresos, los gastos, el déficit y la deuda pública de España del Asset Purchase Programme (APP) y el Pandemic Emergency Purchase Programme (PEPP). Los resultados sugieren que ambos programas habrían tenido un significativo efecto acumulado a la baja sobre la ratio de deuda pública.

Este documento ofrece una cuantificación empírica del efecto sobre las cuentas públicas en España de los programas de compras de activos implementados en el área del euro entre 2015 y 2022. En particular, se evalúa el impacto sobre los ingresos, los gastos, el déficit y la deuda pública de España del Asset Purchase Programme (APP) y el Pandemic Emergency Purchase Programme (PEPP). Los resultados sugieren que ambos programas habrían tenido un significativo efecto acumulado a la baja sobre la ratio de deuda pública., This paper empirically quantifies the effect on Spain’s public finances of the asset purchase programmes implemented in the euro area between 2015 and 2022. Specifically, it evaluates the impact of the ECB’s Asset Purchase Programme (APP) and Pandemic Emergency Purchase Programme (PEPP) on Spanish public revenue, expenditure, deficit and debt. The results suggest that these programmes have had a significant cumulative downward effect on the level of public debt.

BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis w

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

01 februari 2023, Item does not contain fulltext, Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Item does not contain fulltext, Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.

As part of the production of written information, patient reader panels provide judgments of their understanding to evaluate the comprehensibility of draft documents. Previous research has suggested i) that there is a limited association, on average, between judgments of understanding and the comprehension demonstrated in tests of understanding and ii) that there is considerable variability between individuals in the direction and magnitude of this association. Unfortunately, while previous research implies, critically, that reader judgments of comprehensibility have limited utility, this research itself is characterized by important limitations that prevent firm conclusions. This thesis comprises three experimental studies. The study design, method of measurement, and the approach to analysis were motivated by a critical review of previous research. The specification of participant, text and question sample sizes was determined by a novel method of prospective study design analysis, evaluating the accuracy and precision in effect estimation. The robustness of effect estimates are established through the series of empirical replications and in analytical sensitivity checks. Across the studies, a weakly positive association between perceived and assessed comprehension was found across individuals, on average. Differences in reading ability and background knowledge did not reliably influence metacomprehension accuracy. Further, metacomprehension judgements were similarly predictive of performance on comprehension questions that targeted more versus less semantically central information. In contrast, metacomprehension judgements targeting specific ideas within texts were more predictive of understanding. The findings of this thesis indicate that metacomprehension judgements are not a gold-standard method of evaluation: judgements show some predictive validity of comprehension outcomes, yet provide little insight into whether critical elements of the documents are suffi

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis., Funding Agencies|Fondazione AIRC per la Ricerca sul Cancro [IG 21558]; Italian Ministry for University and Research (MIUR) [PRIN 20174TB8KW]; FWO [1861419N]; Queen Elisabeth Medical Foundation; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [418081722, 433158657]; CPA grant [PG01217]; NHMRC Principal Research Fellowship [GNT1120615]; BICARE, Australia; King Salman Center for Disability Research [RG-2022-010, RG-2022-011]; MRC [MR/T007087/1]; GOSH Charity [VS0122]; Rosetrees Trust [CF2\100018]; NHMRC Investigator Grant [GNT20081]; Projekt DEAL; NIHR GOSH BRC

Prior works have demonstrated that implicit representations trained only for reconstruction tasks typically generate encodings that are not useful for semantic tasks. In this work, we propose a method that contextualises the encodings of implicit representations, enabling their use in downstream tasks (e.g. semantic segmentation), without requiring access to the original training data or encoding network. Using an implicit representation trained for a reconstruction task alone, our contextualising module takes an encoding trained for reconstruction only and reveals meaningful semantic information that is hidden in the encodings, without compromising the reconstruction performance. With our proposed module, it becomes possible to pre-train implicit representations on larger datasets, improving their reconstruction performance compared to training on only a smaller labelled dataset, whilst maintaining their segmentation performance on the labelled dataset. Importantly, our method allows for future foundation implicit representation models to be fine-tuned on unseen tasks, regardless of encoder or dataset availability.

Rationale: Mucin homeostasis is fundamental to airway health. Upregulation of airway mucus glycoprotein MUC5B is observed in diverse common lung diseases and represents a potential therapeutic target. In mice, Muc5b is required for mucociliary clearance and for controlling inflammation after microbial exposure. The consequences of its loss in humans are unclear. Objectives: The goal of this study was to identify and characterize a family with congenital absence of MUC5B protein. Methods: We performed whole-genome sequencing in an adult proband with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infection. Deep phenotyping over a 12-year period included assessments of pulmonary radioaerosol mucociliary clearance. Genotyping with reverse phenotyping was organized for eight family members. Extensive experiments, including immunofluorescence staining and mass spectrometry for mucins, were performed across accessible sample types. Measurements and Main Results: The proband, and her symptomatic sibling who also had extensive sinus disease with nasal polyps, were homozygous for a novel splicing variant in the MUC5B gene (NM_002458.2: c.1938 + 1G>A). MUC5B was absent from saliva, sputum, and nasal samples. Mucociliary clearance was impaired in the proband, and large numbers of apoptotic macrophages were present in sputum. Three siblings heterozygous for the familial MUC5B variant were asymptomatic but had a shared pattern of mild lung function impairments. Conclusions: Congenital absence of MUC5B defines a new category of genetic respiratory disease. The human phenotype is highly concordant with that of the Muc5b-/- murine model. Further study of individuals with decreased MUC5B production could provide unique mechanistic insights into airway mucus biology.

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BACKGROUND: Outcome measurement in bipolar disorder (BD) traditionally focused on clinical improvement without considering other domains. Improvement trajectories in clinical and social-functional domains are different and can simultaneously appear in one while not in other domains. Measuring personal recovery (PR) has become a priority internationally. This review explored the shift in research investigating operational recovery definitions and underpinning factors of recovery in BD over the past four decades. METHODS: Studies defining recovery domains (other than clinical recovery) in BD were systematically reviewed; operational recovery definitions and factors assessed in association with recovery were thematically categorised and integrated in a narrative synthesis. RESULTS: Thirty-three studies, comprising 3638 participants from 19 countries were included. Identified operational recovery definition themes included i) PR ii) social-functional (SFR), and iii) occupational-residential (ORR) recovery. Examined factors were grouped as demographic, clinical and psychosocial factors. Predominantly demographic factors were linked to ORR and clinical factors to SFR. Depressive symptomatology was the only clinical factor associated with PR. Research investigating psychosocial factors in PR is emerging and has showed that resilience and appraisals of mood seem to be associated with PR. LIMITATIONS: Studies not available in English or examining functioning without defining recovery were excluded. CONCLUSIONS: Earlier operational recovery definitions of ORR and SFR were often arbitrary and inconsistent, and predominantly focused on clinical and demographic underpinning factors. While research attempts to follow the significant policy shifts towards personalised care by measuring what matters to individuals and exploring broader underpinning psychosocial factors, it is still lagging behind.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

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Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical ne

The additional sex combs-like (ASXL) gene family-encoded by ASXL1, ASXL2, and ASXL3-is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina's Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath's epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects

Es difícil cuadrar la reacción asimétrica de las curvas de tipos en el área del euro tras el anuncio del programa de compras de emergencia frente a la pandemia (PEPP, por sus siglas en inglés) del Banco Central Europeo (BCE) con la interpretación ortodoxa de los efectos de las compras de bonos por parte de los bancos centrales, que enfatiza un mecanismo de «extracción de riesgo de duración». Motivados por esta observación, construimos un modelo de curvas de tipos soberanas en una unión monetaria de dos países, uno de los cuales emite bonos sin riesgo de impago, mientras que los bonos del otro pueden sufrir un impago. Obtenemos una solución analítica afín para la estructura temporal de los tipos soberanos, y descomponemos los rendimientos en componentes relacionados con la prima de plazo y con el riesgo de crédito. A continuación, extendemos el modelo básico para endogenizar la probabilidad de impago por parte del país periférico. Debido a la posibilidad de no poder refinanciar la deuda durante una crisis de liquidez, la probabilidad de impago soberano es una función creciente de la oferta de bonos soberanos neta de las tenencias del banco central. Calibramos el modelo para Alemania e Italia, y mostramos que el modelo replica bien la reacción de las curvas de tipos de estos países al anuncio del PEPP. Un mecanismo que llamamos «extracción de riesgo de impago» explica la mayor parte del impacto sobre los tipos italianos. La flexibilidad del diseño del PEPP aumentó de manera material el impacto de las compras., The highly asymmetric reaction of euro area yield curves to the announcement of the ECB’s pandemic emergency purchase programme (PEPP) is hard to reconcile with the standard “duration risk extraction” view of the transmission of central banks’ asset purchase policies. This observation motivates us to build a no-arbitrage model of the term structure of sovereign interest rates in a two-country monetary union, in which one country issues default-free bonds and the other issues defaultable bonds. We derive an affine term structure solution, and we decompose yields into term premium and credit risk components. In an extension, we endogenise the peripheral default probability, showing that the possibility of rollover crises makes it an increasing function of bond supply net of central bank holdings. We calibrate the model to Germany and Italy, showing that it matches well the reaction of these countries’ yield curves to the PEPP announcement. A channel we call “default risk extraction” accounts for most of the impact on Italian yields. The programme’s flexible design substantially enhanced this impact.

BACKGROUND: Outcome measurement in bipolar disorder (BD) traditionally focused on clinical improvement without considering other domains. Improvement trajectories in clinical and social-functional domains are different and can simultaneously appear in one while not in other domains. Measuring personal recovery (PR) has become a priority internationally. This review explored the shift in research investigating operational recovery definitions and underpinning factors of recovery in BD over the past four decades. METHODS: Studies defining recovery domains (other than clinical recovery) in BD were systematically reviewed; operational recovery definitions and factors assessed in association with recovery were thematically categorised and integrated in a narrative synthesis. RESULTS: Thirty-three studies, comprising 3638 participants from 19 countries were included. Identified operational recovery definition themes included i) PR ii) social-functional (SFR), and iii) occupational-residential (ORR) recovery. Examined factors were grouped as demographic, clinical and psychosocial factors. Predominantly demographic factors were linked to ORR and clinical factors to SFR. Depressive symptomatology was the only clinical factor associated with PR. Research investigating psychosocial factors in PR is emerging and has showed that resilience and appraisals of mood seem to be associated with PR. LIMITATIONS: Studies not available in English or examining functioning without defining recovery were excluded. CONCLUSIONS: Earlier operational recovery definitions of ORR and SFR were often arbitrary and inconsistent, and predominantly focused on clinical and demographic underpinning factors. While research attempts to follow the significant policy shifts towards personalised care by measuring what matters to individuals and exploring broader underpinning psychosocial factors, it is still lagging behind.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects

We present ApproxConv, a novel method for compressing the layers of a convolutional neural network. Reframing conventional discrete convolution as continuous convolution of parametrised functions over space, we use functional approximations to capture the essential structures of CNN filters with fewer parameters than conventional operations. Our method is able to reduce the size of trained CNN layers requiring only a small amount of fine-tuning. We show that our method is able to compress existing deep network models by half whilst losing only 1.86% accuracy. Further, we demonstrate that our method is compatible with other compression methods like quantisation allowing for further reductions in model size., Comment: BMVC 2022

Rationale: Mucin homeostasis is fundamental to airway health. Upregulation of airway mucus glycoprotein MUC5B is observed in diverse common lung diseases and represents a potential therapeutic target. In mice, Muc5b is required for mucociliary clearance and for controlling inflammation after microbial exposure. The consequences of its loss in humans are unclear. Objectives: The goal of this study was to identify and characterize a family with congenital absence of MUC5B protein. Methods: We performed whole-genome sequencing in an adult proband with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infection. Deep phenotyping over a 12-year period included assessments of pulmonary radioaerosol mucociliary clearance. Genotyping with reverse phenotyping was organized for eight family members. Extensive experiments, including immunofluorescence staining and mass spectrometry for mucins, were performed across accessible sample types. Measurements and Main Results: The proband, and her symptomatic sibling who also had extensive sinus disease with nasal polyps, were homozygous for a novel splicing variant in the MUC5B gene (NM_002458.2: c.1938 + 1G>A). MUC5B was absent from saliva, sputum, and nasal samples. Mucociliary clearance was impaired in the proband, and large numbers of apoptotic macrophages were present in sputum. Three siblings heterozygous for the familial MUC5B variant were asymptomatic but had a shared pattern of mild lung function impairments. Conclusions: Congenital absence of MUC5B defines a new category of genetic respiratory disease. The human phenotype is highly concordant with that of the Muc5b-/- murine model. Further study of individuals with decreased MUC5B production could provide unique mechanistic insights into airway mucus biology.

This article uses microanalysis of a video case example of embodied cognition and language appropriation in a child with congenital deafblindness and multiple disability. The creative and generative nature of the child’s expressions are highlighted in this analysis in an exploration of the dialogical concept of recycling (Linell, 2010), in particular recycling with difference (Anward, 2004; 2014).  The central notion of simulation in cognition is challenged here by highlighting the status of the child’s expressions as re-workings rather than representations or copies of the original interaction. The account of the micro-analysis of alignment in the case is linked to the cognitive-linguistic perspective of dialogic syntax with its key notions of parallelism, resonance and engagement.  https://doi.org/10.21827/jdbsc.5.32572

Introduction: Aortitis refers to abnormal inflammation of the aorta, most commonly caused by giant cell arteritis (GCA). Herein, we present a 57-year-old female with aortitis and arterial-embolic strokes secondary to GCA.Case Report: Our patient presented to the emergency department following an episode of transient, monocular, painless vision loss. Computed tomography angiogram head and neck demonstrated phase II aortitis, and magnetic resonance imaging revealed evidence of arterial-embolic strokes.Conclusion: Cerebrovascular accident is a rare complication of large-vessel vasculitis and can occur due to multiple underlying etiologies including intracranial vasculitis, aortic branch proximal occlusion, or arterial-embolic stroke.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

The control of merchandise inventories is a fundamental part for commercial economic growth; With the appropriate records of income, expenses and returns of the products, there is knowledge of the stocks in the warehouse, a useful andnecessary tool for the correct decision-making; without tight inventory control, businesses are disadvantaged and doomed. The objective of this study was to develop an inventory control systemthat guarantees the correct decision-making process in small and medium-sized companies in the city of Babahoyo. The methodology was made up of qualitative and quantitative modalities. The types of research were bibliographic, explanatory, descriptive andcorrelational; methods used: analytical-synthetic, inductive and deductive; interview and survey techniques; the tools or instruments applied were questionnaire, computer, printer, existing technology; The results served the management for the applicationof a registry and inventory control system, use of the Kardex to control the entry and exit of goods and know the whole process for the correct management decision-making., El control de los inventarios de mercaderías es parte fundamental para el crecimiento económico comercial; con los registros apropiados de ingresos, egresos y devoluciones de los productos se tiene conocimiento de las existencias que hay en la bodega, herramienta útil y necesaria para la acertada tomade decisiones;sin un estricto control deinventarios las empresasestánen desventaja y destinadasal fracaso. El objetivo del presenteestudiofueelaborar un sistema de control de inventario que garanticela acertadatoma de decisiones gerenciales en las pequeñas y medianas empresas de la ciudad de Babahoyo.La metodología estuvo conformada por las modalidades cualitativa y cuantitativa.Los tipos de investigación fueron bibliográfica, explicativa, descriptivaycorrelacional; métodos utilizados: analítico-sintético, inductivo y deductivo; técnicas entrevista y encuestas; las herramientas o instrumentos aplicados fueron cuestionario de preguntas, computadora, impresora, tecnología existente;los resultados sirvieron a la gerencia para la aplicación de un sistema de registro y control de inventarios,utilización de losKardex para el control de entradas y salidas de mercaderías y conocer todo el proceso para la correcta toma de decisiones gerenciales.

Plasmacytoid dendritic cells (pDCs) are potent producers of type I IFN (IFN-I) during viral infection and respond to IFN-I in a positive feedback loop that promotes their function. IFN-I shapes dendritic cell responses during helminth infection, impacting their ability to support Th2 responses. However, the role of pDCs in type 2 inflammation is unclear. Previous studies have shown that pDCs are dispensable for hepatic or splenic Th2 responses during the early stages of murine infection with the trematode Schistosoma mansoni at the onset of parasite egg laying. However, during S. mansoni infection, an ongoing Th2 response against mature parasite eggs is required to protect the liver and intestine from acute damage and how pDCs participate in immune responses to eggs and adult worms in various tissues beyond acute infection remains unclear. We now show that pDCs are required for optimal Th2 cytokine production in response to S. mansoni eggs in the intestinal-draining mesenteric lymph nodes throughout infection and for egg-specific IFN-g at later time points of infection. Further, pDC depletion at chronic stages of infection led to increased hepatic and splenic pathology as well as abrogated Th2 cell cytokine production and activation in the liver. In vitro, mesenteric lymph node pDCs

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and al

Background: Research into bipolar disorder (BD) has primarily focused upon clinical recovery (CR), i.e. symptom reduction, and overlooked personally meaningful recovery outcomes emphasized by service users. Personal recovery (PR) has been a major focus in the formulation of mental health policies and guidelines, and yet, research into factors influencing PR in BD is in its infancy. Methods: This study compared psychological associates of concurrent PR and CR, and determined psychological factors in PR prospectively at 6 months. Results: 107 participants completed baseline assessments, of whom 84% completed follow-up at 6 months. Controlling for potential confounders, multiple linear and ordinal regression models showed that some psychological factors underpinned both CR and PR at baseline: worse PR and CR outcomes were associated with higher negative self-dispositional appraisals and dysfunctional attitudes. Better PR, but worse CR ([hypo]mania related) were associated with higher adaptive coping. Additionally, better PR (but not CR) was associated with higher concurrent risk taking at baseline and predicted at follow-up by higher levels of baseline rumination. Better CR ([hypo]mania related), but not PR, was associated with lower impulsivity, but higher BAS processes. Limitations: Psychological and clinical factors were not measured at follow up and may have changed over time. Participants were a convenience sample. Conclusions: Understanding psychological factors driving recovery in BD is essential for refining the conceptual framework of PR, and informing psychological models and related interventions for BD. The identified differences in psychological factors highlight the importance of more individualised, PR focused therapeutic approaches.

Introduction: Aortitis refers to abnormal inflammation of the aorta, most commonly caused by giant cell arteritis (GCA). Herein, we present a 57-year-old female with aortitis and arterial-embolic strokes secondary to GCA.Case Report: Our patient presented to the emergency department following an episode of transient, monocular, painless vision loss. Computed tomography angiogram head and neck demonstrated phase II aortitis, and magnetic resonance imaging revealed evidence of arterial-embolic strokes.Conclusion: Cerebrovascular accident is a rare complication of large-vessel vasculitis and can occur due to multiple underlying etiologies including intracranial vasculitis, aortic branch proximal occlusion, or arterial-embolic stroke.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Plasmacytoid dendritic cells (pDCs) are potent producers of type I IFN (IFN-I) during viral infection and respond to IFN-I in a positive feedback loop that promotes their function. IFN-I shapes dendritic cell responses during helminth infection, impacting their ability to support Th2 responses. However, the role of pDCs in type 2 inflammation is unclear. Previous studies have shown that pDCs are dispensable for hepatic or splenic Th2 responses during the early stages of murine infection with the trematode Schistosoma mansoni at the onset of parasite egg laying. However, during S. mansoni infection, an ongoing Th2 response against mature parasite eggs is required to protect the liver and intestine from acute damage and how pDCs participate in immune responses to eggs and adult worms in various tissues beyond acute infection remains unclear. We now show that pDCs are required for optimal Th2 cytokine production in response to S. mansoni eggs in the intestinal-draining mesenteric lymph nodes throughout infection and for egg-specific IFN-g at later time points of infection. Further, pDC depletion at chronic stages of infection led to increased hepatic and splenic pathology as well as abrogated Th2 cell cytokine production and activation in the liver. In vitro, mesenteric lymph node pDCs

Background: Research into bipolar disorder (BD) has primarily focused upon clinical recovery (CR), i.e. symptom reduction, and overlooked personally meaningful recovery outcomes emphasized by service users. Personal recovery (PR) has been a major focus in the formulation of mental health policies and guidelines, and yet, research into factors influencing PR in BD is in its infancy. Methods: This study compared psychological associates of concurrent PR and CR, and determined psychological factors in PR prospectively at 6 months. Results: 107 participants completed baseline assessments, of whom 84% completed follow-up at 6 months. Controlling for potential confounders, multiple linear and ordinal regression models showed that some psychological factors underpinned both CR and PR at baseline: worse PR and CR outcomes were associated with higher negative self-dispositional appraisals and dysfunctional attitudes. Better PR, but worse CR ([hypo]mania related) were associated with higher adaptive coping. Additionally, better PR (but not CR) was associated with higher concurrent risk taking at baseline and predicted at follow-up by higher levels of baseline rumination. Better CR ([hypo]mania related), but not PR, was associated with lower impulsivity, but higher BAS processes. Limitations: Psychological and clinical factors were not measured at follow up and may have changed over time. Participants were a convenience sample. Conclusions: Understanding psychological factors driving recovery in BD is essential for refining the conceptual framework of PR, and informing psychological models and related interventions for BD. The identified differences in psychological factors highlight the importance of more individualised, PR focused therapeutic approaches.

We are provided with stroke audit data containing patient baseline measures and 5-year follow-up data for patients admitted to two Liverpool based hospitals with acute stroke between January and June 1996. Motivated by this data, we overview previous research on risk factors for survival post-stroke, and review methods for survival analysis and handling missing data. Multiple imputation accounts for the additional uncertainty when handling missing data, however following analysis of multiple imputed data, assessment of model fit is complicated. We derive and justify formal and visual assessment techniques for the proportional hazards assumption of a Cox regression model fitted to multiply imputed data. Multiple imputation using chained equations is a flexible approach for handling missing data, however misspecification of imputation model form can lead to biased and restricted analyses. There is minimal research on handling nonproportional hazards within an imputation framework. We derive suitable imputation model forms to incorporate survival outcomes appropriately in the presence of non-proportional hazards, and ensure approximate compatibility with the analysis model. On correcting analyses to account for non-proportional hazards, model fit is rarely re-assessed in practice, with standard techniques inappropriate for nonstandard models. We develop formal and visual assessment techniques of the proportional hazards assumption for a survival model with a time-split, extending the work of Grambsch and Therneau (1994) and Winnett and Sasieni (2001). Finally, we illustrate the methodological developments achieved within this thesis through application to the stroke audit data. Our analyses identify important risk factors for time to death following stroke, aiding in identification of stroke patients most at risk of death, both in the acute phase and long-term.

The control of merchandise inventories is a fundamental part for commercial economic growth; With the appropriate records of income, expenses and returns of the products, there is knowledge of the stocks in the warehouse, a useful andnecessary tool for the correct decision-making; without tight inventory control, businesses are disadvantaged and doomed. The objective of this study was to develop an inventory control systemthat guarantees the correct decision-making process in small and medium-sized companies in the city of Babahoyo. The methodology was made up of qualitative and quantitative modalities. The types of research were bibliographic, explanatory, descriptive andcorrelational; methods used: analytical-synthetic, inductive and deductive; interview and survey techniques; the tools or instruments applied were questionnaire, computer, printer, existing technology; The results served the management for the applicationof a registry and inventory control system, use of the Kardex to control the entry and exit of goods and know the whole process for the correct management decision-making., El control de los inventarios de mercaderías es parte fundamental para el crecimiento económico comercial; con los registros apropiados de ingresos, egresos y devoluciones de los productos se tiene conocimiento de las existencias que hay en la bodega, herramienta útil y necesaria para la acertada tomade decisiones;sin un estricto control deinventarios las empresasestánen desventaja y destinadasal fracaso. El objetivo del presenteestudiofueelaborar un sistema de control de inventario que garanticela acertadatoma de decisiones gerenciales en las pequeñas y medianas empresas de la ciudad de Babahoyo.La metodología estuvo conformada por las modalidades cualitativa y cuantitativa.Los tipos de investigación fueron bibliográfica, explicativa, descriptivaycorrelacional; métodos utilizados: analítico-sintético, inductivo y deductivo; técnicas entrevista y encuestas; las herramientas o instrumentos aplicados fueron cuestionario de preguntas, computadora, impresora, tecnología existente;los resultados sirvieron a la gerencia para la aplicación de un sistema de registro y control de inventarios,utilización de losKardex para el control de entradas y salidas de mercaderías y conocer todo el proceso para la correcta toma de decisiones gerenciales.