Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis

Abnormal development of multiciliated cells is a hallmark of a variety of human conditions associated with chronic airway diseases, hydrocephalus and infertility. Multiciliogenesis requires both activation of a specialized transcriptional program and assembly of cytoplasmic structures for large-scale centriole amplification that generates basal bodies. It remains unclear, however, what mechanism initiates formation of these multiprotein complexes in epithelial progenitors. Here we show that this is triggered by nucleocytoplasmic translocation of the transcription factor E2f4. After inducing a transcriptional program of centriole biogenesis, E2f4 forms apical cytoplasmic organizing centres for assembly and nucleation of deuterosomes. Using genetically altered mice and E2F4 mutant proteins we demonstrate that centriole amplification is crucially dependent on these organizing centres and that, without cytoplasmic E2f4, deuterosomes are not assembled, halting multiciliogenesis. Thus, E2f4 integrates nuclear and previously unsuspected cytoplasmic events of centriole amplification, providing new perspectives for the understanding of normal ciliogenesis, ciliopathies and cancer

TYK2 Protein-Coding Variants Protect against Rheumatoid Arthritis and Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits

Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10-21), A928V (rs35018800, OR = 0.53, P = 1.2x10-9), and I684S (rs12720356, OR = 0.86, P = 4.6x10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6x10-18), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases

An Adverse Outcome Pathway for Sensitization of the Respiratory Tract by Low-Molecular-Weight Chemicals: Building Evidence to Support the Utility of In Vitro and In Silico Methods in a Regulatory Context

Sensitization of the respiratory tract is an important occupational health challenge, and understanding the mechanistic basis of this effect is necessary to support the development of toxicological tools to detect chemicals that may cause it. Here we use the adverse outcome pathway (AOP) framework to organize information that may better inform our understanding of sensitization of the respiratory tract, building on a previously published skin sensitization AOP, relying on literature evidence linked to low-molecular-weight organic chemicals and excluding other known respiratory sensitizers acting via different molecular initiating events. The established key events (KEs) are as follows: (1) covalent binding of chemicals to proteins, (2) activation of cellular danger signals (inflammatory cytokines and chemokines and cytoprotective gene pathways), (3) dendritic cell activation and migration, (4) activation, proliferation, and polarization of T cells, and (5) sensitization of the respiratory tract. These events mirror the skin sensitization AOP but with specific differences. For example, there is some evidence that respiratory sensitizers bind preferentially to lysine moieties, whereas skin sensitizers bind to both cysteine and lysine. Furthermore, exposure to respiratory sensitizers seems to result in cell behavior for KEs 2 and 3, as well as the effector T cell response, in general skewing toward cytokine secretions predominantly associated with T helper 2 (Th2) response. Knowledge gaps include the lack of understanding of which KE(s) drive the Th2 polarization. The construction of this AOP may provide insight into predictive tests that would in combination support the discrimination of respiratory-sensitizing from non- and skin-sensitizing chemicals, a clear regulatory need

Developing a competency-based curriculum in HIV for nursing schools in Haiti

<p>Abstract</p> <p>Background</p> <p>Preparing health workers to confront the HIV/AIDS epidemic is an urgent challenge in Haiti, where the HIV prevalence rate is 2.2% and approximately 10 100 people are taking antiretroviral treatment. There is a critical shortage of doctors in Haiti, leaving nurses as the primary care providers for much of the population. Haiti's approximately 1000 nurses play a leading role in HIV/AIDS prevention, care and treatment. However, nurses do not receive sufficient training at the pre-service level to carry out this important work.</p> <p>Methods</p> <p>To address this issue, the Ministry of Health and Population collaborated with the International Training and Education Center on HIV over a period of 12 months to create a competency-based HIV/AIDS curriculum to be integrated into the 4-year baccalaureate programme of the four national schools of nursing.</p> <p>Results</p> <p>Using a review of the international health and education literature on HIV/AIDS competencies and various models of curriculum development, a Haiti-based curriculum committee developed expected HIV/AIDS competencies for graduating nurses and then drafted related learning objectives. The committee then mapped these learning objectives to current courses in the nursing curriculum and created an 'HIV/AIDS Teaching Guide' for faculty on how to integrate and achieve these objectives within their current courses. The curriculum committee also created an 'HIV/AIDS Reference Manual' that detailed the relevant HIV/AIDS content that should be taught for each course.</p> <p>Conclusion</p> <p>All nursing students will now need to demonstrate competency in HIV/AIDS-related knowledge, skills and attitudes during periodic assessment with direct observation of the student performing authentic tasks. Faculty will have the responsibility of developing exercises to address the required objectives and creating assessment tools to demonstrate that their graduates have met the objectives. This activity brought different administrators, nurse leaders and faculty from four geographically dispersed nursing schools to collaborate on a shared goal using a process that could be easily replicated to integrate any new topic in a resource-constrained pre-service institution. It is hoped that this experience provided stakeholders with the experience, skills and motivation to strengthen other domains of the pre-service nursing curriculum, improve the synchronization of didactic and practical training and develop standardized, competency-based examinations for nursing licensure in Haiti.</p

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Vet Med Update, 2015 September

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