HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium

Background: While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection. Methods and Findings: To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions—an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of 13C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A. Conclusions: These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation

Information gaps in surveillance data and effects on the Ghanaian response to the Ebola outbreak in West Africa

Background: Complete and accurate information on disease occurrence is crucial for effective public health response to disease outbreaks. In response to the 2014 Ebola epidemic in West Africa, Ghana intensified surveillance for the disease across the country. However, the case definition provided by the Ministry of Health was not uniformly applied at all reporting health facilities.Objective: This paper analyses the accompanying Case Record Forms (CRFs) submitted to Noguchi Memorial Institute for Medical Research to determine its completeness and appropriateness for instituting an effective response to the epidemic.Methods: We determined the proportions of completeness in reporting for all criteria provided by the MOH for the clinical diagnosis of Ebola. New indicators were generated to measure the completeness of each variable. Tables and graphs of completeness of indicators were produced and presented.Results: Of the 156 samples, 69% were from males. Approximately 4.5% had no record for age. The date of specimen collection was filled for 96%; 34.6% (54) did not have date of onset of symptoms. In 37.8% (59) of cases, location was blank. In 12% of cases, no symptoms were recorded and about 30% had no record of fever. Travel history, especially to affected areas, was missing for 40.4%.Conclusions: Gaps on CRFs can significantly reduce the utility of results of laboratory analysis for outbreak control. Although all the samples analysed were negative for Ebola Virus, the high proportion of missing data on the forms should be a source of concern. We recommend that frontline health staff be trained on the importance of capturing all information required on the form.Source of funding: The funding for the analysis of suspected samples were provided partially by Ghana Health Servce and research funding from Noguchi Memorial Institute for Medical ResearchKeywords: Ebola Virus Disease, Data Gaps, Ghana, Ministry of Health, Symptom

Application of the pMHC array to characterise tumour antigen specific T cell populations in leukaemia patients at disease diagnosis

Immunotherapy treatments for cancer are becoming increasingly successful, however to further improve our understanding of the T-cell recognition involved in effective responses and to encourage moves towards the development of personalised treatments for leukaemia immunotherapy, precise antigenic targets in individual patients have been identified. Cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen specific T-cell populations naturally circulating in patients and normal donors. We have developed the pMHC array to detect CD8+ T-cell populations in leukaemia patients that recognise epitopes within viral antigens (cytomegalovirus (CMV) and influenza (Flu)) and leukaemia antigens (including Per Arnt Sim domain 1 (PASD1), MelanA, Wilms’ Tumour (WT1) and tyrosinase). We show that the pMHC array is at least as sensitive as flow cytometry and has the potential to rapidly identify more than 40 specific T-cell populations in a small sample of T-cells (0.8–1.4 x 106). Fourteen of the twenty-six acute myeloid leukaemia (AML) patients analysed had T cells that recognised tumour antigen epitopes, and eight of these recognised PASD1 epitopes. Other tumour epitopes recognised were MelanA (n = 3), tyrosinase (n = 3) and WT1126-134 (n = 1). One of the seven acute lymphocytic leukaemia (ALL) patients analysed had T cells that recognised the MUC1950-958 epitope. In the future the pMHC array may be used provide point of care T-cell analyses, predict patient response to conventional therapy and direct personalised immunotherapy for patients

Osteopathology and insect traces in the Australopithecus africanus skeleton StW 431

We present the first application of high-resolution micro computed tomography in an analysis of both the internal and external morphology of the lumbar region of StW 431 – a hominin skeleton recovered from Member 4 infill of the Sterkfontein Caves (South Africa) in 1987. The lumbar vertebrae of the individual present a number of proliferative and erosive bony processes, which were investigated in this study. Investigations suggest a complex history of taphonomic alteration to pre-existing spinal degenerative joint disease (SDJD) as well as post-mortem modification by an unknown insect. This study is in agreement with previous pathological diagnoses of SDJD which affected StW 431 and is the first time insect traces on this hominin are described. The results of this analysis attest to the complex series of post-mortem processes affecting the Sterkfontein site and its fossil assemblages

SARS-CoV-2 detection among international air travellers to Ghana during mandatory quarantine

Objectives: To determine the prevalence of SARS-CoV-2 detection among international travellers to Ghana during mandatory quarantine.Design: A retrospective cross-sectional study.Setting: Air travellers to Ghana on 21st and 22nd March 2020.Participants: On 21st and 22nd March 2020, a total of 1,030 returning international travellers were mandatorily quarantined in 15 different hotels in Accra and tested for SARS-CoV-2. All of these persons were included in the study.Main outcome measure: Positivity for SARS-CoV-2 by polymerase chain reaction.Results: The initial testing at the beginning of quarantine found 79 (7.7%) individuals to be positive for SARS-CoV-2. In the exit screening after 12 to 13 days of quarantine, it was discovered that 26 of those who tested negative for SARS-CoV-2 in the initial screening subsequently tested positive.Conclusions: Ghana likely averted an early community spread of COVID-19 through the proactive approach to quarantine international travellers during the early phase of the pandemic

Data management during COVID-19 outbreak response in Ghana: a reference laboratory perspective on key issues and measures

The COVID-19 pandemic caused by SARS-CoV-2 is an important subject for global health. Ghana experienced lowmoderate transmission of the disease when the first case was detected in March 12, 2020 until the middle of July when the number of cases begun to drop. By August 24, 2020, the country's total number of confirmed cases stood at 43,622, with 263 deaths. By the same time, the Noguchi Memorial Institute for Medical Research (NMIMR) of the University of Ghana, the primary testing centre for COVID-19, had tested 285,501 with 28,878 confirmed cases. Due to database gaps, there were initial challenges with timely reporting and feedback to stakeholders during the peak surveillance period. The gaps resulted from mismatches between samples and their accompanying case investigation forms, samples without case investigation forms and vice versa, huge data entry requirements, and delayed test results. However, a revamp in data management procedures, and systems helped to improve the turnaround time for reporting results to all interested parties and partners. Additionally, inconsistencies such as multiple entries and discrepant patient-sample information were resolved by introducing a barcoding electronic capture system. Here, we describe the main challenges with COVID-19 data management and analysis in the laboratory and recommend measures for improvement

Exploring Talent Identification in Australian Rules Football: The Nuances of the Athlete Recruitment Process

The process of talent identification and recruitment is a key element of the elite athlete talent pathway. As such, it is important to understand the information and specific processes used by expert recruiters to inform talent identification decisions. Therefore, the purpose of this study was to examine the perspectives of talent identifiers in relation to their conceptions of talent and the information they collect and interpret to inform their talent identification decisions. Participating in the study were 13 heads of recruitment at elite Australian Football League clubs. They were deemed experts in their field and were responsible for the selection and recruitment of players at their respective clubs. Data were collected through semi-structured interviews conducted via teleconferencing, with thematic analysis used to identify key themes. Thematic analysis of interview data generated two first order themes: (1) Understanding Talent and (2) Talent Identification Process. Four second order themes emerged from the data: (1a) Defining Talent, (1b) Athlete Attributes, (2a) Talent List Development, and(2b) Recruiter Tasks. From these second order themes, 12 associated third order themes were produced (e.g., projecting growth/athlete potential, initial identification process, refining the list, and the final decision). In particular, the findings highlight how the recruiters assess talent based on game performance and athlete intent (i.e., "giving 100%"), rather than performance at physical testing sessions, and the psychological profile of the athletes. Overall, the findings emphasize the complexity associated with elite-level talent identification and provide insight for practitioners and researchers aiming to understand and explain the talent identification process

Exploring Talent Identification in Australian Rules Football: The Nuances of the Athlete Recruitment Process

The process of talent identification and recruitment is a key element of the elite athlete talent pathway. As such, it is important to understand the information and specific processes used by expert recruiters to inform talent identification decisions. Therefore, the purpose of this study was to examine the perspectives of talent identifiers in relation to their conceptions of talent and the information they collect and interpret to inform their talent identification decisions. Participating in the study were 13 heads of recruitment at elite Australian Football League clubs. They were deemed experts in their field and were responsible for the selection and recruitment of players at their respective clubs. Data were collected through semi-structured interviews conducted via teleconferencing, with thematic analysis used to identify key themes. Thematic analysis of interview data generated two first order themes: (1) Understanding Talent and (2) Talent Identification Process. Four second order themes emerged from the data: (1a) Defining Talent, (1b) Athlete Attributes, (2a) Talent List Development, and(2b) Recruiter Tasks. From these second order themes, 12 associated third order themes were produced (e.g., projecting growth/athlete potential, initial identification process, refining the list, and the final decision). In particular, the findings highlight how the recruiters assess talent based on game performance and athlete intent (i.e., "giving 100%"), rather than performance at physical testing sessions, and the psychological profile of the athletes. Overall, the findings emphasize the complexity associated with elite-level talent identification and provide insight for practitioners and researchers aiming to understand and explain the talent identification process

Core pinning by intragranular nanoprecipitates in polycrystalline MgCNi_3

The nanostructure and magnetic properties of polycrystalline MgCNi_3 were studied by x-ray diffraction, electron microscopy, and vibrating sample magnetometry. While the bulk flux-pinning force curve F_p(H) indicates the expected grain-boundary pinning mechanism just below T_c = 7.2 K, a systematic change to pinning by a nanometer-scale distribution of core pinning sites is indicated by a shift of F_p(H) with decreasing temperature. The lack of scaling of F_p(H) suggests the presence of 10 to 20% of nonsuperconducting regions inside the grains, which are smaller than the diameter of fluxon cores 2xi at high temperature and become effective with decreasing temperature when xi(T) approaches the nanostructural scale. Transmission electron microscopy revealed cubic and graphite nanoprecipitates with 2 to 5 nm size, consistent with the above hypothesis since xi(0) = 6 nm. High critical current densities, more than 10^6 A/cm^2 at 1 T and 4.2 K, were obtained for grain colonies separated by carbon. Dirty-limit behavior seen in previous studies may be tied to electron scattering by the precipitates, indicating the possibility that strong core pinning might be combined with a technologically useful upper critical field if versions of MgCNi_3 with higher T_c can be found.Comment: 5 pages, 6 figures, submitted to PR