A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome.

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q- syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q- syndrome

The PHF21B gene is associated with major depression and modulates the stress response

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.M-L Wong, M Arcos-Burgos, S Liu, J I Vélez, C Yu, B T Baune, M C Jawahar, V Arolt, U Dannlowski, A Chuah, G A Huttley, R Fogarty, M D Lewis, S R Bornstein, and J Licini

Evaluation of the McGrath® MAC videolaryngoscope in a tertiary teaching hospital

Background: Videolaryngoscopes have become increasingly popular in recent years for use in both normal and difficult airways. Despite this trend, their benefit remains controversial. The McGrath® MAC videolaryngoscope (Aircraft Medical Ltd, Edinburgh, UK) is used for first line or rescue intubation, and for training in videolaryngoscopy intubation. We conducted a prospective observational study to assess the performance of the McGrath® MAC. Methods: We evaluated the use of the McGrath® MAC videolaryngoscope from January 2016 to April 2016. We recruited 500 adult patients undergoing elective surgery requiring endotracheal intubation. Data was collected via an online survey. The primary outcome was the success of intubation with the McGrath® MAC. Secondary outcomes included the ease of the McGrath® MAC insertion, best glottic view, ease of tracheal tube insertion, number of intubation attempts, evidence of airway trauma, quality of view, adjunct used, airway manoeuvres used, quality of image on monitor screen and overall impression of the device. Results: A total of 428 responses were analysed. The overall success rate was 97.9% (95% confidence interval 96.0–99.0%). The success rate for those with predictors of difficult airway was 95.5% (95% confidence interval 87.6–99.5%). Easy scope insertion was reported by 97.2% of anaesthetists and 89.7% reported easy tube insertion. Some of our cases (1.9%) were complicated by airway trauma involving superficial oropharyngeal or lip injury. Conclusion: The McGrath® MAC videolaryngoscope is a good choice for a videolaryngoscope, conferring advantages of a high intubation success rate, ease of laryngoscope insertion and ease of intubation. It is suitable for use in predicted difficult airways

Epidural analgesia in a paediatric teaching hospital: Trends, developments, and a brief review of literature

Introduction: Continuous epidural analgesia has proven to be a good tool in the anaesthetist’s quest to provide excellent pain relief for an extended perioperative period. Pharmaceutical advances provide us with a larger array of both local anaesthetic (LA) drugs and additives that can prolong the duration or enhance the quality of analgesia, or both. The avoidance of LA toxicity is of paramount importance for safe prescription, especially in the high-risk neonatal and infant cohort, and all patients stand to benefit from ‘safer’ LA agents and adjuvants that promote the use of a lowered concentration of epidural LA infusions. We present a descriptive review of trends in epidural prescription and technique in our hospital. Methods: Our observational study was conducted over a period of 19 years in a tertiary paediatric teaching hospital. Prospectively collected data that included patient demographics, level of epidural catheter insertion, LA drugs and adjuvants used, as well as postoperative infusion rates, were then analysed retrospectively. Results: There was a decline in the use of paediatric epidural analgesia. Over the study period, we also observed a shift in preference of LAs and adjuvant drugs toward safer alternatives. Conclusion: Paediatric epidural analgesia is gradually being superseded by other analgesic modalities with superior safety profiles (e.g. peripheral neural blockade). However, indications remain for its continued use, and anaesthetists should be familiar with its technical aspects and pitfalls

Evaluating the internalisation of the intrinsic role of health advocacy of student pharmacists in a new integrated Bachelor of Pharmacy curriculum: a mixed-methods study

Abstract To keep up with the contemporary health landscape, there is an imperative need for healthcare professionals to practise health advocacy through health promotion on the individual, population, and systems levels. In the Academic Year of 2020/2021, the National University of Singapore (NUS) Department of Pharmacy implemented a new spiral curriculum integrating basic, clinical, and systems sciences with one of its aims to deepen students’ health advocacy internalisation and prepare them as future health advocates. A mixed-methods approach was adopted. Questionnaires were disseminated across three time-points to elicit students’ levels of internalisation of health advocacy, which were then categorised into levels, and a Mann–Whitney U test was conducted. In comparison with prematriculation, no significant difference was found after students underwent the first year of the curriculum, while a significant difference was found after students underwent two years of the curriculum. Semi-structured interviews were also conducted after each Academic Year to gain deeper insights into the questionnaire results. Thematic analysis of the interviews revealed that curricular integration in the first year was perceived to be lacking. However, with learnt knowledge constantly reinforced and more experiential learning opportunities incorporated throughout the second year, students found the integrated curriculum beneficial in instilling confidence to practise health advocacy. This study offers insights into the prospects of a spiral integrated curriculum in imparting health advocacy, and may even suggest its potential to be applied to other educational settings. Future follow-up studies can also be conducted on the same study population to evaluate long-term impacts and areas for improvement of the curriculum

Preparing your intensive care unit for the COVID-19 pandemic: practical considerations and strategies

The coronavirus disease 2019 (COVID-19) has rapidly evolved into a worldwide pandemic. Preparing intensive care units (ICU) is an integral part of any pandemic response. In this review, we discuss the key principles and strategies for ICU preparedness. We also describe our initial outbreak measures and share some of the challenges faced. To achieve sustainable ICU services, we propose the need to 1) prepare and implement rapid identification and isolation protocols, and a surge in ICU bed capacity; (2) provide a sustainable workforce with a focus on infection control; (3) ensure adequate supplies to equip ICUs and protect healthcare workers; and (4) maintain quality clinical management, as well as effective communication.