Amanita muscaria (fly agaric): from a shamanistic hallucinogen to the search for acetylcholine

The mushroom Amanita muscaria (fly agaric) is widely distributed throughout continental Europe and the UK. Its common name suggests that it had been used to kill flies, until superseded by arsenic. The bioactive compounds occurring in the mushroom remained a mystery for long periods of time, but eventually four hallucinogens were isolated from the fungus: muscarine, muscimol, muscazone and ibotenic acid. The shamans of Eastern Siberia used the mushroom as an inebriant and a hallucinogen. In 1912, Henry Dale suggested that muscarine (or a closely related substance) was the transmitter at the parasympathetic nerve endings, where it would produce lacrimation, salivation, sweating, bronchoconstriction and increased intestinal motility. He and Otto Loewi eventually isolated the transmitter and showed that it was not muscarine but acetylcholine. The receptor is now known variously as cholinergic or muscarinic. From this basic knowledge, drugs such as pilocarpine (cholinergic) and ipratropium (anticholinergic) have been shown to be of value in glaucoma and diseases of the lungs, respectively

Assessment of the effect of a comprehensive chest radiograph deep learning model on radiologist reports and patient outcomes: a real-world observational study.

OBJECTIVES: Artificial intelligence (AI) algorithms have been developed to detect imaging features on chest X-ray (CXR) with a comprehensive AI model capable of detecting 124 CXR findings being recently developed. The aim of this study was to evaluate the real-world usefulness of the model as a diagnostic assistance device for radiologists. DESIGN: This prospective real-world multicentre study involved a group of radiologists using the model in their daily reporting workflow to report consecutive CXRs and recording their feedback on level of agreement with the model findings and whether this significantly affected their reporting. SETTING: The study took place at radiology clinics and hospitals within a large radiology network in Australia between November and December 2020. PARTICIPANTS: Eleven consultant diagnostic radiologists of varying levels of experience participated in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Proportion of CXR cases where use of the AI model led to significant material changes to the radiologist report, to patient management, or to imaging recommendations. Additionally, level of agreement between radiologists and the model findings, and radiologist attitudes towards the model were assessed. RESULTS: Of 2972 cases reviewed with the model, 92 cases (3.1%) had significant report changes, 43 cases (1.4%) had changed patient management and 29 cases (1.0%) had further imaging recommendations. In terms of agreement with the model, 2569 cases showed complete agreement (86.5%). 390 (13%) cases had one or more findings rejected by the radiologist. There were 16 findings across 13 cases (0.5%) deemed to be missed by the model. Nine out of 10 radiologists felt their accuracy was improved with the model and were more positive towards AI poststudy. CONCLUSIONS: Use of an AI model in a real-world reporting environment significantly improved radiologist reporting and showed good agreement with radiologists, highlighting the potential for AI diagnostic support to improve clinical practice

Protecting eyewitness evidence: Examining the efficacy of a self-administered interview tool

Given the crucial role of eyewitness evidence, statements should be obtained as soon as possible after an incident. This is not always achieved due to demands on police resources. Two studies trace the development of a new tool, the Self-Administered Interview (SAI), designed to elicit a comprehensive initial statement. In Study 1, SAI participants reported more correct details than participants who provided a free recall account, and performed at the same level as participants given a Cognitive Interview. In Study 2, participants viewed a simulated crime and half recorded their statement using the SAI. After a delay of 1 week, all participants completed a free recall test. SAI participants recalled more correct details in the delayed recall task than control participants

Cost-Effective Strategies for Mitigating a Future Influenza Pandemic with H1N1 2009 Characteristics

Background: We performed an analysis of the cost-effectiveness of pandemic intervention strategies using a detailed, individual-based simulation model of a community in Australia together with health outcome data of infected individuals gathered during 2009–2010. The aim was to examine the cost-effectiveness of a range of interventions to determine the most cost-effective strategies suitable for a future pandemic with H1N1 2009 characteristics. Methodology/Principal Findings: Using transmissibility, age-stratified attack rates and health outcomes determined from H1N1 2009 data, we determined that the most cost-effective strategies involved treatment and household prophylaxis using antiviral drugs combined with limited duration school closure, with costs ranging from $632 to$777 per case prevented. When school closure was used as a sole intervention we found the use of limited duration school closure to be significantly more cost-effective compared to continuous school closure, a result with applicability to countries with limited access to antiviral drugs. Other social distancing strategies, such as reduced workplace attendance, were found to be costly due to productivity losses. Conclusion: The mild severity (low hospitalisation and case fatality rates) and low transmissibility of H1N1 2009 meant that health treatment costs were dominated by the higher productivity losses arising from workplace absence due to illness and childcare requirements following school closure. Further analysis for higher transmissibility but with the same, mild severit

Copper Chaperone for Cu/Zn Superoxide Dismutase is a sensitive biomarker of mild copper deficiency induced by moderately high intakes of zinc

BACKGROUND: Small increases in zinc (Zn) consumption above recommended amounts have been shown to reduce copper (Cu) status in experimental animals and humans. Recently, we have reported that copper chaperone for Cu/Zn superoxide dismutase (CCS) protein level is increased in tissues of overtly Cu-deficient rats and proposed CCS as a novel biomarker of Cu status. METHODS: Weanling male Wistar rats were fed one of four diets normal in Cu and containing normal (30 mg Zn/kg diet) or moderately high (60, 120 or 240 mg Zn/kg diet) amounts of Zn for 5 weeks. To begin to examine the clinical relevance of CCS, we compared the sensitivity of CCS to mild Cu deficiency, induced by moderately high intakes of Zn, with conventional indices of Cu status. RESULTS: Liver and erythrocyte CCS expression was significantly (P < 0.05) increased in rats fed the Zn-60 and/or Zn-120 diet compared to rats fed normal levels of Zn (Zn-30). Erythrocyte CCS expression was the most sensitive measure of reduced Cu status and was able to detect a decrease in Cu nutriture in rats fed only twice the recommended amount of Zn. Liver, erythrocyte and white blood cell CCS expression showed a significant (P < 0.05) inverse correlation with plasma and liver Cu concentrations and caeruloplasmin activity. Unexpectedly, rats fed the highest level of Zn (Zn-240) showed overall better Cu status than rats fed a lower level of elevated Zn (Zn-120). Improved Cu status in these rats correlated with increased duodenal mRNA expression of several Zn-trafficking proteins (i.e. MT-1, ZnT-1, ZnT-2 and ZnT-4). CONCLUSION: Collectively, these data show that CCS is a sensitive measure of Zn-induced mild Cu deficiency and demonstrate a dose-dependent biphasic response for reduced Cu status by moderately high intakes of Zn

Do comprehensive deep learning algorithms suffer from hidden stratification? A retrospective study on pneumothorax detection in chest radiography

ObjectivesTo evaluate the ability of a commercially available comprehensive chest radiography deep convolutional neural network (DCNN) to detect simple and tension pneumothorax, as stratified by the following subgroups: the presence of an intercostal drain; rib, clavicular, scapular or humeral fractures or rib resections; subcutaneous emphysema and erect versus non-erect positioning. The hypothesis was that performance would not differ significantly in each of these subgroups when compared with the overall test dataset.DesignA retrospective case–control study was undertaken.SettingCommunity radiology clinics and hospitals in Australia and the USA.ParticipantsA test dataset of 2557 chest radiography studies was ground-truthed by three subspecialty thoracic radiologists for the presence of simple or tension pneumothorax as well as each subgroup other than positioning. Radiograph positioning was derived from radiographer annotations on the images.Outcome measuresDCNN performance for detecting simple and tension pneumothorax was evaluated over the entire test set, as well as within each subgroup, using the area under the receiver operating characteristic curve (AUC). A difference in AUC of more than 0.05 was considered clinically significant.ResultsWhen compared with the overall test set, performance of the DCNN for detecting simple and tension pneumothorax was statistically non-inferior in all subgroups. The DCNN had an AUC of 0.981 (0.976–0.986) for detecting simple pneumothorax and 0.997 (0.995–0.999) for detecting tension pneumothorax.ConclusionsHidden stratification has significant implications for potential failures of deep learning when applied in clinical practice. This study demonstrated that a comprehensively trained DCNN can be resilient to hidden stratification in several clinically meaningful subgroups in detecting pneumothorax.</jats:sec

The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8+ T cell recognition of endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 c1-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV c2-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8+ T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed

Prevalence of Buruli Ulcer in Akonolinga Health District, Cameroon: Results of a Cross Sectional Survey

As long as there is no strategy to prevent Buruli ulcer, the early detection and treatment of cases remains the most promising control strategy. Buruli ulcer is most common in remote rural areas where people have little contact with health structures. Information on the number of existing cases in the population and where they go to seek treatment is important for project planning and evaluation. Health structure based surveillance systems cannot provide this information, and previous prevalence surveys did not provide information on spatial distribution and coverage. We did a survey using centric systematic area sampling in a Health District in Cameroon to estimate prevalence and project coverage. We found the method was easy to use and very useful for project planning. It identified priority areas with relatively high prevalence and low coverage and provided an estimate of the number of existing cases in the population of the health district. The active case finding component of the method used served as an awareness campaign and was an integrated part of the project, creating a network of health delegates trained on Buruli ulcer

The association between air travel and deep vein thrombosis: Systematic review & meta-analysis

BACKGROUND: Air travel has been linked with the development of deep vein thrombosis (DVT) since the 1950s with a number of plausible explanations put forward for causation. No systematic review of the literature exploring this association has previously been published. METHODS: A comprehensive search was undertaken (Data bases searched were: MEDLINE, EMBASE, Cochrane Library) for studies that estimated both the incidence and the risk of DVT in air travellers relative to non-air travellers. RESULTS: In total 254 studies were identified but only six incidence studies and four risk studies met inclusion criteria justifying their use in a systematic review. Incidence of symptomatic DVT ranged from (0%) in one study to (0.28%) which was reported in pilots over ten years. The incidence of asymptomatic DVT ranged from (0%) to (10.34%). Pooled odds ratios for the two case control studies examining the risk of DVT following air travel were 1.11 (95% CI: 0.64–1.94). Pooled odds ratios for all models of travel including two studies of prolonged air travel (more than three hours) were 1.70 (95% CI: 0.89–3.22). CONCLUSION: We found no definitive evidence that prolonged (more than 3-hours) travel including air travel, increases the risk of DVT. There is evidence to suggest that flights of eight hours or more increase the risk of DVT if additional risk factors exist

One way or another? Criminal investigators' beliefs regarding the disclosure of evidence in interviews with suspects in England and Wales

The research base concerning interviews with suspects remains to be comprehensively developed. For example, the extant literature provides differing views regarding how best to undertake the important interview task of disclosing evidence. In the current study, using a self-report questionnaire, 224 investigators based in England and Wales were asked as to their own preferred methods. Most respondents advocated a gradual method of disclosing evidence, stating that this approach would better reveal inconsistencies and obtain a complete version of events (similar to the reasoning of those who preferred disclosing evidence later). Those who advocated revealing evidence early stated this approach would more likely elicit confessions. Several respondents would not commit to one single method, arguing that their chosen strategy was contextually dependent. The study’s findings suggest that it remains arguable as to whether there is one best approach to evidence disclosure and/or whether particular circumstances should influence interviewing strategies