Validation of the Persistent Complex Bereavement Disorder (PCBD) Checklist: A Developmentally Informed Assessment Tool for Bereaved Youth

The inclusion of Persistent Complex Bereavement Disorder (PCBD) in the DSMâ 5 appendix signifies a call for research regarding the distinguishing features and clinical utility of proposed PCBD criteria. Rigorously constructed tools for assessing PCBD are lacking, especially for youth. This study evaluated the validity and clinical utility of the PCBD Checklist, a 39â item measure designed to assess PCBD criteria in youth aged 8 to18 years. Test construction procedures involved: (a) reviewing the literature regarding developmental manifestations of proposed criteria, (b) creating a developmentally informed item pool, (c) surveying an expert panel to evaluate the clarity and developmental appropriateness of candidate items, (d) conducting focus groups to evaluate the comprehensibility and acceptability of items, and (e) evaluating psychometric properties in 367 bereaved youth (Mage = 13.49, 55.0% female). The panel, clinicians, and youth provided favorable content validity and comprehensibility ratings for candidate items. As hypothesized, youth who met full PCBD criteria, Criterion B (e.g., preoccupation with the deceased and/or circumstances of the death), or Criterion C (e.g., reactive distress and/or social/identity disruption) reported higher posttraumatic stress and depressive symptoms than youth who did not meet these criteria, ηp2 = .07â .16. Youth who met Criterion C reported greater functional impairment than youth who did not, ηp2 = .08â .12. Youth who qualified for the â traumatic bereavement specifierâ reported more frequent posttraumatic stress symptoms than youth who did not, ηp2 = .04. Findings support the convergent, discriminant, and discriminantâ groups validity, developmental appropriateness, and clinical utility of the PCBD Checklist.ResumenValidación de Lista de verificación del Trastorno por Duelo Complejo Persistente (TDCP): Un informe del desarrollo de herramientas de medición para duelo en jóvenesLISTA DE CHEQUEO DE TRASTORNO DE DUELO COMPLEJO PERSISTENTELa inclusión del trastorno de duelo complejo persistente (TDCP en su sigla en español; PCBD en sus siglas en inglés) en el apéndice del DSMâ 5 significa un llamado para investigar en relación a las características distintivas y la utilidad clínica de los criterios propuestos para el TDCP. Se carece de herramientas rigurosamente construidas para evaluar TDCP, especialmente para jóvenes. Este estudio evalúa la validez y utilidad clínica de la lista de verificación de TPCP, una medida con 39 ítems diseñada para medir el criterio de TDCP en jóvenes de edades entre 8 a 18 años. El procedimiento de construcción del test involucró: (a) revisión de la literatura relacionada con manifestaciones desarrolladas del criterio propuesto; (b) creación de un pool de ítems informados para el desarrollo; (c) encuesta a un panel experto para evaluar la claridad y desarrollo apropiado de los ítems; (d) conducir grupos focales para evaluar la compresibilidad y aceptabilidad de los ítems; y (e) evaluación de propiedades psicométricas en 367 jóvenes en proceso de duelo (M edad = 13.49, 55.0% femenino). El panel, los clínicos y los jóvenes en proceso de duelo proveyeron una validez de contenido favorable y rangos de comprensibilidad para los ítems candidatos. Como se hipotetizó, los jóvenes que cumplieron el criterio completo de TDCP, criterio B (ej., preocupación por el fallecido y/o las circunstancias de la muerte) o el criterio C (ej., estrés reactivo y/o perturbación social/identidad) reportaron alto estrés postraumático y síntomas depresivos que los jóvenes que no cumplen este criterio, ηp2 = .07 a .16. Los jóvenes que no cumplieron el criterio C reportaron mayor deterioro funcional que los jóvenes que no lo cumplieron ηp2 = .08 a .12. Los jóvenes que calificaron para el â duelo traumático especificoâ reportaron mayor frecuencia de síntomas de estrés postraumático que jóvenes que no calificaron ηp2 = .04. 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Recurrent Tissue-Specific Mtdna Mutations are Common in Humans

Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in two additional individuals. These recurrent mutations all occur within or in very close proximity to sites that regulate mtDNA replication, strongly implying that these variations alter the replication dynamics of the mutated mtDNA genome. These recurrent variants are all independent of each other and do not occur in the mtDNA coding regions. The most parsimonious explanation of the data is that these frequently repeated mutations experience tissue-specific positive selection, probably through replication advantage

Sexual expression and cognitive function: gender-divergent associations in older adults

Prior research demonstrates a positive association between sexual activity and cognitive function in later life. However, the relationship between the type of sexual activity and cognitive function in older adulthood remains unclear. This study explores the associations between the frequency of engaging in different types of sexual activities (intercourse, masturbation, and kissing/petting/fondling) and cognitive function in older women and men. Using data from Wave 6 of the English Longitudinal Study of Ageing (ELSA), 1915 women and 2195 men (age range 50-89 years; n = 4110) reporting any type of sexual activity over the past 12 months, were included in the study. Multiple regression controlling for age, education, satisfaction with sex life, cohabiting, wealth, general health, physical activity, depression and loneliness, was used to explore the associations between the frequency of engagement in intercourse, masturbation and kissing/petting/fondling, and two measures of cognitive function; word recall and number sequencing. For women, masturbation was linked to better word recall (p = .008), whilst for men, kissing/petting/fondling was associated with better number sequencing (p = .035). In women (p = .016) and men (p = .018), dissatisfaction with sex life was associated with better number sequencing. The results point to gendered links between sexual activity and cognitive function. These gender-related divergences may reflect differences in biological/neurological mechanisms, or in cognitive lifestyle factors that could influence cognitive reserve in later life. This novel study underscores the need to delineate the underlying mechanisms of the association between sex and cognition in men and women

Low dose Btk inhibitors selectively block platelet activation by CLEC-2

Inhibitors of the tyrosine kinase Btk have been proposed as novel antiplatelet agents. In this study we show that low concentrations of the Btk inhibitor ibrutinib block CLEC-2-mediated activation and tyrosine phosphorylation including Syk and PLCγ2 in human platelets. Activation is also blocked in patients with X-linked agammaglobulinaemia (XLA) caused by a deficiency or absence of Btk. In contrast, the response to GPVI is delayed in the presence of low concentrations of ibrutinib or in patients with XLA, and tyrosine phosphorylation of Syk is preserved. A similar set of results is seen with the second-generation inhibitor, acalabrutinib. The differential effect of Btk inhibition in CLEC-2 relative to GPVI signalling is explained by the positive feedback role involving Btk itself, as well as ADP and thromboxane A2 mediated activation of P2Y12 and TP receptors, respectively. This feedback role is not seen in mouse platelets and, consistent with this, CLEC-2-mediated activation is blocked by high but not by low concentrations of ibrutinib. Nevertheless, thrombosis was absent in 8 out of 13 mice treated with ibrutinib. These results show that Btk inhibitors selectively block activation of human platelets by CLEC-2 relative to GPVI suggesting that they can be used at ‘low dose’ in patients to target CLEC-2 in thrombo-inflammatory disease

Biophysical Characteristics Reveal Neural Stem Cell Differentiation Potential

Distinguishing human neural stem/progenitor cell (huNSPC) populations that will predominantly generate neurons from those that produce glia is currently hampered by a lack of sufficient cell type-specific surface markers predictive of fate potential. This limits investigation of lineage-biased progenitors and their potential use as therapeutic agents. A live-cell biophysical and label-free measure of fate potential would solve this problem by obviating the need for specific cell surface markers

Neural correlates of a single-session massage treatment

The current study investigated the immediate neurophysiological effects of different types of massage in healthy adults using functional magnetic resonance imaging (fMRI). Much attention has been given to the default mode network, a set of brain regions showing greater activity in the resting state. These regions (i.e. insula, posterior and anterior cingulate, inferior parietal and medial prefrontal cortices) have been postulated to be involved in the neural correlates of consciousness, specifically in arousal and awareness. We posit that massage would modulate these same regions given the benefits and pleasant affective properties of touch. To this end, healthy participants were randomly assigned to one of four conditions: 1. Swedish massage, 2. reflexology, 3. massage with an object or 4. a resting control condition. The right foot was massaged while each participant performed a cognitive association task in the scanner. We found that the Swedish massage treatment activated the subgenual anterior and retrosplenial/posterior cingulate cortices. This increased blood oxygen level dependent (BOLD) signal was maintained only in the former brain region during performance of the cognitive task. Interestingly, the reflexology massage condition selectively affected the retrosplenial/posterior cingulate in the resting state, whereas massage with the object augmented the BOLD response in this region during the cognitive task performance. These findings should have implications for better understanding how alternative treatments might affect resting state neural activity and could ultimately be important for devising new targets in the management of mood disorders

A mutation in Nischarin causes otitis media via LIMK1 and NF-κB pathways

Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-κB pathways in the development of chronic OM

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes