Evidence of exposure to SARS-CoV-2 in cats and dogs from households in Italy

AbstractSARS-CoV-2 originated in animals and is now easily transmitted between people. Sporadic detection of natural cases in animals alongside successful experimental infections of pets, such as cats, ferrets and dogs, raises questions about the susceptibility of animals under natural conditions of pet ownership. Here we report a large-scale study to assess SARS-CoV-2 infection in 817 companion animals living in northern Italy, sampled at a time of frequent human infection. No animals tested PCR positive. However, 3.4% of dogs and 3.9% of cats had measurable SARS-CoV-2 neutralizing antibody titers, with dogs from COVID-19 positive households being significantly more likely to test positive than those from COVID-19 negative households. Understanding risk factors associated with this and their potential to infect other species requires urgent investigation.One Sentence SummarySARS-CoV-2 antibodies in pets from Italy.</jats:sec

IMPRoving Outcomes for children exposed to domestic ViolencE (IMPROVE): an evidence synthesis

BackgroundExposure to domestic violence and abuse (DVA) during childhood and adolescence increases the risk of negative outcomes across the lifespan.ObjectivesTo synthesise evidence on the clinical effectiveness, cost-effectiveness and acceptability of interventions for children exposed to DVA, with the aim of making recommendations for further research.Design(1) A systematic review of controlled trials of interventions; (2) a systematic review of qualitative studies of participant and professional experience of interventions; (3) a network meta-analysis (NMA) of controlled trials and cost-effectiveness analysis; (4) an overview of current UK provision of interventions; and (5) consultations with young people, parents, service providers and commissioners.SettingsNorth America (11), the Netherlands (1) and Israel (1) for the systematic review of controlled trials of interventions; the USA (4) and the UK (1) for the systematic review of qualitative studies of participant and professional experience of interventions; and the UK for the overview of current UK provision of interventions and consultations with young people, parents, service providers and commissioners.ParticipantsA total of 1345 children for the systematic review of controlled trials of interventions; 100 children, 202 parents and 39 professionals for the systematic review of qualitative studies of participant and professional experience of interventions; and 16 young people, six parents and 20 service providers and commissioners for the consultation with young people, parents, service providers and commissioners.InterventionsPsychotherapeutic, advocacy, parenting skills and advocacy, psychoeducation, psychoeducation and advocacy, guided self-help.Main outcome measuresInternalising symptoms and externalising behaviour, mood, depression symptoms and diagnosis, post-traumatic stress disorder symptoms and self-esteem for the systematic review of controlled trials of interventions and NMA; views about and experience of interventions for the systematic review of qualitative studies of participant and professional experience of interventions and consultations.Data sourcesMEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, Applied Social Sciences Index and Abstracts, International Bibliography of the Social Sciences, Social Services Abstracts, Social Care Online, Sociological Abstracts, Social Science Citation Index, World Health Organization trials portal and clinicaltrials.gov.Review methodsA narrative review; a NMA and incremental cost-effectiveness analysis; and a qualitative synthesis.ResultsThe evidence base on targeted interventions was small, with limited settings and types of interventions; children were mostly &lt; 14 years of age, and there was an absence of comparative studies. The interventions evaluated in trials were mostly psychotherapeutic and psychoeducational interventions delivered to the non-abusive parent and child, usually based on the child’s exposure to DVA (not specific clinical or broader social needs). Qualitative studies largely focused on psychoeducational interventions, some of which included the abusive parent. The evidence for clinical effectiveness was as follows: 11 trials reported improvements in behavioural or mental health outcomes, with modest effect sizes but significant heterogeneity and high or unclear risk of bias. Psychoeducational group-based interventions delivered to the child were found to be more effective for improving mental health outcomes than other types of intervention. Interventions delivered to (non-abusive) parents and to children were most likely to be effective for improving behavioural outcomes. However, there is a large degree of uncertainty around comparisons, particularly with regard to mental health outcomes. In terms of evidence of cost-effectiveness, there were no economic studies of interventions. Cost-effectiveness was modelled on the basis of the NMA, estimating differences between types of interventions. The outcomes measured in trials were largely confined to children’s mental health and behavioural symptoms and disorders, although stakeholders’ concepts of success were broader, suggesting that a broader range of outcomes should be measured in trials. Group-based psychoeducational interventions delivered to children and non-abusive parents in parallel were largely acceptable to all stakeholders. There is limited evidence for the acceptability of other types of intervention. In terms of the UK evidence base and service delivery landscape, there were no UK-based trials, few qualitative studies and little widespread service evaluation. Most programmes are group-based psychoeducational interventions. However, the funding crisis in the DVA sector is significantly undermining programme delivery.ConclusionsThe evidence base regarding the acceptability, clinical effectiveness and cost-effectiveness of interventions to improve outcomes for children exposed to DVA is underdeveloped. There is an urgent need for more high-quality studies, particularly trials, that are designed to produce actionable, generalisable findings that can be implemented in real-world settings and that can inform decisions about which interventions to commission and scale. We suggest that there is a need to pause the development of new interventions and to focus on the systematic evaluation of existing programmes. With regard to the UK, we have identified three types of programme that could be justifiably prioritised for further study: psycho-education delivered to mothers and children, or children alone; parent skills training in combination with advocacy: and interventions involving the abusive parent/caregiver. We also suggest that there is need for key stakeholders to come together to explicitly identify and address the structural, practical and cultural barriers that may have hampered the development of the UK evidence base to date.Future work recommendationsThere is a need for well-designed, well-conducted and well-reported UK-based randomised controlled trials with cost-effectiveness analyses and nested qualitative studies. Development of consensus in the field about core outcome data sets is required. There is a need for further exploration of the acceptability and effectiveness of interventions for specific groups of children and young people (i.e. based on ethnicity, age, trauma exposure and clinical profile). There is also a need for an investigation of the context in which interventions are delivered, including organisational setting and the broader community context, and the evaluation of qualities, qualifications and disciplines of personnel delivering interventions. We recommend prioritisation of psychoeducational interventions and parent skills training delivered in combination with advocacy in the next phase of trials, and exploratory trials of interventions that engage both the abusive and the non-abusive parent.Study registrationThis study is registered as PROSPERO CRD42013004348 and PROSPERO CRD420130043489.FundingThe National Institute for Health Research Public Health Research programme.</jats:sec

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis

Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology

Clinically active Crohn's disease in the presence of a low C-reactive protein

Objective. Clinical interest in C-reactive protein (CRP) - a component of the innate immune system - has focused mainly on its worth as an indicator of disease activity. There has been a resurgence of interest in CRP in the Crohn's disease ( CD) literature because several trials of new treatments for active CD have been characterized by both a large proportion of patients with low CRP ( &lt; 10 mg/l) at entry to the trials and by a negative therapeutic outcome. It is therefore of interest to study the clinical characteristics of patients who are thought to have at the same time both active CD and a low CRP. Material and methods. Patients were prospectively recruited as part of the Brisbane IBD clinical and research programme. Subjects were included in the low CRP group only if there were complete datasets for CRP on all occasions of active CD, and CRP was &lt; 10 mg/l. Active disease was defined as CD activity index (CDAI) &gt; 200. The low CRP group was compared with patients in the raised CRP group for a range of clinical variables as well as the major NOD2 variants. Results. There were data sets for 223 CD patients, with a mean disease duration of 12 years. Of these, 22 patients fulfilled the criteria for low CRP. The low CRP group ( group 1) showed significant differences for disease site (p &lt; 0.01) and for BMI (p = 0.006) compared to the raised CRP group ( group 2). Specifically, group 1 had a predominance of pure ileal disease (95% versus 53%) and lack of pure colonic disease (0% versus 24%) compared to group 2, and their BMI was significantly lower (20.3 kg/m(2) versus 25.0 kg/m(2)). Groups 1 and 2 did not differ with respect to Vienna behaviour at diagnosis, smoking, appendicectomy, extra-intestinal manifestations of CD, or NOD2 SNP variants. There was a trend for low CRP patients with previous ileal resection to evolve to a stricturing phenotype. Fat wrapping was noted in 11/13 (85%) of low CRP patients undergoing ileal resections. Conclusions. Patients with CD and a persistently low CRP in the face of active disease were characterized by an almost exclusive ileal disease distribution and a low BMI, compared to those with a raised CRP. These patients had a similar frequency and distribution of NOD2/CARD15 variants. Stricturing ( v inflammatory or penetrating) behaviour may explain some low CRP. Despite the abnormally low BMI, fat wrapping was noted in the majority of low CRP patients undergoing ileal resection