Search

Inborn errors of immunity (IEI) are genetically driven disorders. With the advancement of sequencing technologies, a rapidly increasing number of gene defects has been identified, thereby mirroring the high heterogeneity in immunological and clinical presentations observed in patients. However, for a large majority of patients, no causative single nucleotide variant (SNV) or small indel can be identified using next-generation sequencing. First studies have shown that also copy number variants (CNVs) can cause IEI. Unfortunately, CNVs are not well examined in many routine diagnostic settings and the aim of this study was to assess the number of clinically relevant chromosomal losses and gains in a large cohort. We identified a total of 20 CNVs using whole exome sequencing data of a cohort of 191 patients with a suspected IEI. A definite molecular diagnosis could be made in five patients (2.6%), including pathogenic deletions affecting ICOS, TNFAIP3, and 22q11.2. CNVs of uncertain significance were observed in fifteen patients (7.9%), including deletions of 11q22.1q22.3 and 16p11.2 but also duplications affecting entire or parts of genes previously associated with IEI. Importantly, five patients carrying a CNV of uncertain significance also carried pathogenic or likely pathogenic SNVs (PIK3R1, NFKB1, NLRC4, DOCK2), or SNVs of unknown significance (NFKB2). This cooccurrence of SNVs and CNVs suggests modifying effects in some patients, and functional follow-up is warranted now in order to better understand phenotypic heterogeneity. In summary, the diagnostic yield of IEI can be increased substantially by evaluating CNVs, which allows an improved therapeutic management in those patients.

Transgender men and women in Nigeria experience many barriers in accessing HIV prevention and treatment services, particularly given the environment of transphobia (including harassment, violence and discrimination) and punitive laws in the country. HIV epidemic control in Nigeria requires improving access to and quality of HIV services for key populations at high risk, including transgender men and women. We assessed how stigma influences HIV services for transgender people in Lagos, Nigeria.In-depth interviews (IDIs) and focus group discussions were conducted with transgender men (n = 13) and transgender women (n = 25); IDIs were conducted with community service organization (CSO) staff (n = 8) and healthcare providers from CSO clinics and public health facilities (n = 10) working with the transgender population in March 2021 in Lagos. Content analysis was used to identify how stigma influences transgender people's experiences with HIV services.Three main findings emerged. First, gender identity disclosure is challenging due to anticipated stigma experienced by transgender persons and fear of legal repercussions. Fear of being turned in to authorities was a major barrier to disclose to providers in facilities not affiliated with a transgender-inclusive clinic. Providers also reported difficulty in eliciting information about the client's gender identity. Second, respondents reported lack of sensitivity among providers about gender identity and conflation of transgender men with lesbian women and transgender women with being gay or men who have sex with men, the latter being more of a common occurrence. Transgender participants also reported feeling disrespected when providers were not sensitive to their pronoun of preference. Third, HIV services that are not transgender-inclusive and gender-affirming can reinforce stigma. Both transgender men and women spoke about experiencing stigma and being refused HIV services, especially in mainstream public health facilities, as opposed to transgender-inclusive CSO clinics.This study highlights how stigma impedes access to appropriate HIV services for transgender men and women, which can have a negative impact along the HIV care continuum. There is a need for transgender-inclusive HIV services and competency trainings for healthcare providers so that transgender clients can receive appropriate and gender-affirming HIV services.

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related to Tet2 loss of function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1β signaling. OBJECTIVE: To assess whether individuals with CHIP have greater cardiovascular event reduction in response to IL-1β neutralization in the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS). DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial took place from April 2011 to June 2017 at more than 1000 clinical sites in 39 countries. Targeted deep sequencing of genes previously associated with CHIP in a subset of trial participants using genomic DNA prepared from baseline peripheral blood samples were analyzed. All participants had prior myocardial infarction and elevated high-sensitivity C-reactive protein level above 0.20 mg/dL. Analysis took place between June 2017 and December 2021. INTERVENTIONS: Canakinumab, an anti–IL-1β antibody, given at doses of 50, 150, and 300 mg once every 3 months. MAIN OUTCOMES AND MEASURES: Major adverse cardiovascular events (MACE). RESULTS: A total of 338 patients (8.6%) were identified in this subset with evidence for clonal hematopoiesis. As expected, the incidence of CHIP increased with age; the mean (SD) age of patients with CHIP was 66.3 (9.2) years and 61.5 (9.6) years in patients without CHIP. Unlike other populations that were not preselected for elevated C-reactive protein, in the CANTOS population variants in TET2 were more common than DNMT3A (119 variants in 103 patients vs 86 variants in 85 patients). Placebo-treated patients with CHIP showed a nonsignificant increase in the rate of MACE compared with patients without CHIP using a Cox proportional hazard model (hazard ratio, 1.32 [95% CI, 0.86-2.04]; P = .21). Exploratory analyses of placebo-treated patients with a somatic variant in either TET2 or DNMT3A (n = 58) showed an equivocal risk for MACE (hazard ratio, 1.65 [95% CI, 0.97-2.80]; P = .06). Patients with CHIP due to somatic variants in TET2 also had reduced risk for MACE while taking canakinumab (hazard ratio, 0.38 [95% CI, 0.15-0.96]) with equivocal difference compared with others (P for interaction = .14). CONCLUSIONS AND RELEVANCE: These results are consistent with observations of increased risk for cardiovascular events in patients with CHIP and raise the possibility that those with TET2 variants may respond better to canakinumab than those without CHIP. Future studies are required to further substantiate this hypothesis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01327846

Tenosynovial giant cell tumors (TGCTs) are characterized by rearrangements of CSF1, thought to drive overexpression of macrophage colony-stimulating factor (CSF1), thereby promoting tumor growth and recruitment of non-neoplastic mononuclear and multinucleated inflammatory cells. While fusions to collagen promoters have been described, the mechanism of CSF1 overexpression has been unclear in a majority of cases. Two cohorts of TGCT were investigated for CSF1 rearrangements using fluorescence in situ hybridization (FISH) and either RNA-seq or DNA-seq with Sanger validation. The study comprised 39 patients, including 13 localized TGCT, 21 diffuse TGCT, and five of unspecified type. CSF1 rearrangements were identified by FISH in 30 cases: 13 translocations, 17 3' deletions. Sequencing confirmed CSF1 breakpoints in 28 cases; in all 28 the breakpoint was found to be downstream of exon 5, replacing or deleting a long 3' UTR containing known miRNA and AU-rich element negative regulatory sequences. We also confirmed the presence of CBL exon 8-9 mutations in six of 21 cases. In conclusion, TGCT in our large cohort were characterized by variable alterations, all of which led to truncation of the 3' end of CSF1, instead of the COL6A3-CSF1 fusions previously reported in some TGCTs. The diversity of fusion partners but consistent integrity of CSF1 functional domains encoded by exons 1-5 support a hypothesis that CSF1 overexpression results from transcription of a truncated form of CSF1 lacking 3' negative regulatory sequences. The presence of CBL mutations affecting the linker and RING finger domain suggests an alternative mechanism for increased CSF1/CSF1R signaling in some cases.

There seems little doubt that Low-Cost Carriers (LCCs) have had a substantial impact on the tourism sector, with the generation of volumes of tourists to emerging and mature destinations. However, little is known about how the tourists' profile depends on the influence exercised by an LCC in the decision-making process for visiting a certain destination. This is the focus of this study which main aim is to identify and understand two types of travellers: travellers who visited the destination mainly due to the availability of low-cost flights, and travellers who declare they would have visited the destination anyway using different means. Methodologically, we adopt the Causal Chain Approach to measure the causation link between the availability of low-cost flight routes and tourists' decisions to visit a certain destination. Our empirical case study examines the profile of travellers using a Ryanair route from East Midlands airport (England) to Reus airport (Catalonia).

We present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific-filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.

In assessing the economic impact of a cultural event or attraction, the number of visits caused by the event or attraction is the pivotal variable. In the instance of many visitors, the causal impact is neither absent nor complete, but partial. The authors develop a method of assessing directly the aggregate causal impact of a cultural event or attraction and apply this in four case studies of culture in market towns. There emerges a pattern in the way economic impact comes about.

It is generally believed that consumption of film and television products can induce tourism to destinations featured. We review the literature relating to this, examine it from the perspective of mass communications theory and develop a general causal model to measure the influence of screen products on visitor numbers. The model is quantified by way of a survey at two popular UK destinations. Our conclusions are that the contributions of screen products to visitor numbers are fractional, diffuse and substantial. We further find that the magnitude of the effect differs greatly between destinations and that this is related to background causes independent of screen effects.

Question de femme ou question d'être? Y a-t-il un être au féminin ou une manière d'être femme? Des femmes interrogent la psychanalyse. Cet article propose un retour sur la notion de castration et sur les développements entourant la signification du phallus. L'expérience de la castration est présentée comme étant étroitement liée au processus de la sexuation et à la constitution même du sujet parlant. Cet article tente de faire état de la position féminine, qui questionne la castration. La psychanalyse n'apporte pas une réponse, elle pose une limite : celle de l'ordre symbolique dans lequel l'être parlant est inscrit. En deçà de cette limite de la castration, il reste à construire pour chaque femme et chaque homme, dans le Québec contemporain, un espace pour le désir., It is a matter of being woman or simply of being? Is there actually a feminine way to be? Here, women put psychanalysis into question. This article suggests a return to the notion of castration and to the developments surrounding the significance of the phallus. The castration experience is presented as being closely liked to the process of sexualization and to the individual's self-realization. The authors advance the woman's point of view, which questions castration. They find that psychoanalysis does not provide an answer, but imposes a limit: that of a symbolic order in which the individual must fit. Within the limiting phenomenon of castration, there remains the need for every man and woman in contemporary Québec society to share a sense of desire.

PurposeExplores the development of online learning in UK higher education as a case study to illustrate the difficulties created by an over‐reliance on technology push and a failure to understand and respond to market needs.Design/methodology/approachDraws on a variety of published secondary sources and the authors' own experience of working with the UK e‐University (UKeU).FindingsArgues that the development of online learning as a substitute for more traditional forms of delivery has been limited. For both e‐learning in general and for the UKeU in particular, the comparatively limited adoption of online learning beyond the campus‐based model is explained by failure to understand the market and a focus on what is technologically possible rather than what customers want.Research limitations/implicationsPresents a single case study developed from secondary sources and personal experience.Practical implicationsModels of online learning that exclude any face‐to‐face contact may have limited market opportunities, but blended models offer considerable potential both on and off campus. Investments and development costs of online learning are such that reusability or recycling of learning material has to be built into the production process if the benefits are to be fully realised.Originality/valuePrevious studies of e‐learning in the UK have not been driven by a marketing perspective. This study therefore delivers valuable intelligence for marketing educators considering their own options for investing in online learning development. In general, it provides further evidence of the importance of using market intelligence to inform the development and launch of product and service innovations.