Current evidence for COVID-19 therapies: a systematic literature review.

Effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. A systematic review was conducted to identify clinical trials of pharmacological interventions for COVID-19 published between 1 December 2019 and 14 October 2020. Data regarding efficacy of interventions, in terms of mortality, hospitalisation and need for ventilation, were extracted from identified studies and synthesised qualitatively. In total, 42 clinical trials were included. Interventions assessed included antiviral, mucolytic, antimalarial, anti-inflammatory and immunomodulatory therapies. Some reductions in mortality, hospitalisation and need for ventilation were seen with interferons and remdesivir, particularly when administered early, and with the mucolytic drug, bromhexine. Most studies of lopinavir/ritonavir and hydroxychloroquine did not show significant efficacy over standard care/placebo. Dexamethasone significantly reduced mortality, hospitalisation and need for ventilation versus standard care, particularly in patients with severe disease. Evidence for other classes of interventions was limited. Many trials had a moderate-to-high risk of bias, particularly in terms of blinding; most were short-term and some included low patient numbers.This review highlights the need for well-designed clinical trials of therapeutic interventions for COVID-19 to increase the quality of available evidence. It also emphasises the importance of tailoring interventions to disease stage and severity for maximum efficacy.

Assessing the effect of hypoxia on cardiac metabolism using hyperpolarized 13 C magnetic resonance spectroscopy.

Hypoxia plays a role in many diseases and can have a wide range of effects on cardiac metabolism depending on the extent of the hypoxic insult. Noninvasive imaging methods could shed valuable light on the metabolic effects of hypoxia on the heart in vivo. Hyperpolarized carbon-13 magnetic resonance spectroscopy (HP 13 C MRS) in particular is an exciting technique for imaging metabolism that could provide such information. The aim of our work was, therefore, to establish whether hyperpolarized 13 C MRS can be used to assess the in vivo heart's metabolism of pyruvate in response to systemic acute and chronic hypoxic exposure. Groups of healthy male Wistar rats were exposed to either acute (30 minutes), 1 week or 3 weeks of hypoxia. In vivo MRS of hyperpolarized [1-13 C] pyruvate was carried out along with assessments of physiological parameters and ejection fraction. Hematocrit was elevated after 1 week and 3 weeks of hypoxia. 30 minutes of hypoxia resulted in a significant reduction in pyruvate dehydrogenase (PDH) flux, whereas 1 or 3 weeks of hypoxia resulted in a PDH flux that was not different to normoxic animals. Conversion of hyperpolarized [1-13 C] pyruvate into [1-13 C] lactate was elevated following acute hypoxia, suggestive of enhanced anaerobic glycolysis. Elevated HP pyruvate to lactate conversion was also seen at the one week timepoint, in concert with an increase in lactate dehydrogenase (LDH) expression. Following three weeks of hypoxic exposure, cardiac metabolism of pyruvate was comparable with that observed in normoxia. We have successfully visualized the effects of systemic hypoxia on cardiac metabolism of pyruvate using hyperpolarized 13 C MRS, with differences observed following 30 minutes and 1 week of hypoxia. This demonstrates the potential of in vivo hyperpolarized 13 C MRS data for assessing the cardiometabolic effects of hypoxia in disease.

Tools for structured team communication in pre-registration health professions education: a Best Evidence Medical Education (BEME) review: BEME Guide No. 41.

INTRODUCTION: Calls for the inclusion of standardized protocols for information exchange into pre-registration health professions curricula have accompanied their introduction into clinical practice. In order to help clinical educators respond to these calls, we have reviewed educational interventions for pre-registration students that incorporate one or more of these ?tools for structured communication?. METHODS: Searches of 10 databases (1990?2014) were supplemented by hand searches and by citation searches (to January 2015). Studies evaluating an intervention for pre-registration students of any clinical profession and incorporating at least one tool were included. Quality of included studies was assessed using a checklist of 11 indicators and a narrative synthesis of findings undertaken. RESULTS: Fifty studies met our inclusion criteria. Of these, 21 evaluated the specific effect of a tool on educational outcomes, and 27 met seven or more quality indicators. CONCLUSIONS: Pre-registration students, particularly those in the US, are learning to use tools for structured communication either in specific sessions or integrated into more extensive courses or programmes; mostly 'Situation Background Assessment Recommendation' and its variants. There is some evidence that learning to use a tool can improve the clarity and comprehensiveness of student communication, their perceived self-confidence and their sense of preparedness for clinical practice. There is, as yet, little evidence for the transfer of these skills to the clinical setting or for any influence of teaching approach on learning outcomes. Educators will need to consider the positioning of such learning with other skills such as clinical reasoning and decision-making.

Preconditioning of Cardiosphere-Derived Cells With Hypoxia or Prolyl-4-Hydroxylase Inhibitors Increases Stemness and Decreases Reliance on Oxidative Metabolism.

Cardiosphere-derived cells (CDCs), which can be isolated from heart explants, are a promising candidate cell source for infarcted myocardium regeneration. However, current protocols used to expand CDCs require at least 1 month in vitro to obtain sufficient cells for transplantation. We report that CDC culture can be optimized by preconditioning the cells under hypoxia (2% oxygen), which may reflect the physiological oxygen level of the stem cell niche. Under hypoxia, the CDC proliferation rate increased by 1.4-fold, generating 6 × 10(6) CDCs with higher expression of cardiac stem cell and pluripotency gene markers compared to normoxia. Furthermore, telomerase (TERT), cytokines/ligands involved in stem cell trafficking (SDF/CXCR-4), erythropoiesis (EPO), and angiogenesis (VEGF) were increased under hypoxia. Hypoxic preconditioning was mimicked by treatment with two types of hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitors (PHDIs): dimethyloxaloylglycine (DMOG) and 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid (BIC). Despite the difference in specificity, both PHDIs significantly increased c-Kit expression and activated HIF, EPO, and CXCR-4. Furthermore, treatment with PHDIs for 24 h increased cell proliferation. Notably, all hypoxic and PHDI-preconditioned CDCs had decreased oxygen consumption and increased glycolytic metabolism. In conclusion, cells cultured under hypoxia could have potentially enhanced therapeutic potential, which can be mimicked, in part, by PHDIs.

Investigating mitochondrial metabolism in contracting HL-1 cardiomyocytes following hypoxia and pharmacological HIF activation identifies HIF-dependent and independent mechanisms of regulation.

Hypoxia is a consequence of cardiac disease and downregulates mitochondrial metabolism, yet the molecular mechanisms through which this occurs in the heart are incompletely characterized. Therefore, we aimed to use a contracting HL-1 cardiomyocyte model to investigate the effects of hypoxia on mitochondrial metabolism. Cells were exposed to hypoxia (2% O2) for 6, 12, 24, and 48 hours to characterize the metabolic response. Cells were subsequently treated with the hypoxia inducible factor (HIF)-activating compound, dimethyloxalylglycine (DMOG), to determine whether hypoxia-induced mitochondrial changes were HIF dependent or independent, and to assess the suitability of this cultured cardiac cell line for cardiovascular pharmacological studies. Hypoxic cells had increased glycolysis after 24 hours, with glucose transporter 1 and lactate levels increased 5-fold and 15-fold, respectively. After 24 hours of hypoxia, mitochondrial networks were more fragmented but there was no change in citrate synthase activity, indicating that mitochondrial content was unchanged. Cellular oxygen consumption was 30% lower, accompanied by decreases in the enzymatic activities of electron transport chain (ETC) complexes I and IV, and aconitase by 81%, 96%, and 72%, relative to controls. Pharmacological HIF activation with DMOG decreased cellular oxygen consumption by 43%, coincident with decreases in the activities of aconitase and complex I by 26% and 30%, indicating that these adaptations were HIF mediated. In contrast, the hypoxia-mediated decrease in complex IV activity was not replicated by DMOG treatment, suggesting HIF-independent regulation of this complex. In conclusion, 24 hours of hypoxia increased anaerobic glycolysis and decreased mitochondrial respiration, which was associated with changes in ETC and tricarboxylic acid cycle enzyme activities in contracting HL-1 cells. Pharmacological HIF activation in this cardiac cell line allowed both HIF-dependent and independent mitochondrial metabolic changes to be identified.

Levels of reflective thinking and patient safety: an investigation of the mechanisms that impact on student learning in a single cohort over a 5 year curriculum.

Existing research into learning about patient safety focuses on identifying how educational interventions improve educational outcomes but few studies offer evidence that inform educators about the mechanisms involved in learning about patient safety. The current evidence based in undergraduates is also limited to outcomes that relate to knowledge and skills. A realist approach involving three cycles of data collection in a single cohort of students over 5 years used different outcomes in Kirkpatrick's framework to identify the mechanisms that influence students learning about patient safety. Data source 1. Focus groups identified an overarching theoretical model of the mechanisms that influence patient safety learning for medical students. Data source 2 Identified if the mechanisms from data source 1 could be demonstrated at the outcome level of knowledge and attitudes. Data source 3 Established associations between mechanisms and outcomes at skills and behavioural level, in a standardised simulated ward setting. Data source 1: The interpretation of data from seven focus groups involving sixty students identified reflection at two levels of Mezirow's descriptions; reflection and critical reflection as mechanisms that influence learning about error. Data source 2: Sixty-one students participated. The associations found, reflection and knowledge of actions to take for patient safety, r = 0.44 (P = 0.00) and critical reflection and intentions regarding patient safety, r = 0.40 (P = 0.00) Data source 3: Forty-eight students participated. The correlation identified associations between critical reflection and planned changes following feedback was, r = 0.48 (P = 0.00) and reflection and knowledge based errors r = -0.30 (P = 0.03). A realist approach identified two different levels of reflection were associated with different patient safety outcomes for this cohort of students. Critical reflection was associated with attitudes and reflection was associated with knowledge of actions and error behaviours. These findings give educators greater depth of information about the role of reflection in patient safety.

Real-time situation awareness assessment in critical illness management: adapting the situation present assessment method to clinical simulation.

BACKGROUND: Situation awareness (SA) is a human factor of critical importance to patient safety. Simulation training aims to examine and debrief human factors; however, SA cannot be directly observed. This has led to the development of SA measurement tools. The Situation Present Assessment Method (SPAM) measures SA in real-time without the need to pause the scenario. The SPAM process involves the delivery of queries to the participant who must answer them accurately and quickly. The latency between the query being asked and answer being received represents SA. METHOD: Two query delivery procedures are described in the literature: query delivery by telephone and in person. These procedures were piloted in simulation teaching with final-year medical students. The scenarios were videotaped and reviewed by the investigators to evaluate each procedure. Our evaluation of the existing SPAM procedures led us to adapt the method by developing a bespoke application, which delivers queries via a personal digital assistant (PDA), calculates the latency data and presents it to the instructor. RESULTS: Presented by telephone, queries tended to disrupt the 'flow' of the simulation. The 'in person' procedure was not disruptive; however, participants found it difficult to distinguish queries from other dialogue. The PDA represented a compromise between these two techniques: generating data without disrupting the scenario. CONCLUSIONS: The use of SPAM is feasible in clinical simulation. By using handheld technology, SA data are made available to the instructor for use in debrief; this expands the utility of SPAM to the field of medical education.

Metabolic adaptation to chronic hypoxia in cardiac mitochondria.

Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11% oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17-18%, and with pyruvate were decreased by 29-15%, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions.

The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity.

Hypoxic and oxidant stresses can coexist in biological systems, and oxidant stress has been proposed to activate hypoxia pathways through the inactivation of the 'oxygen-sensing' hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases. Here, we show that despite reduced sensitivity to cellular hypoxia, the HIF asparaginyl hydroxylase--known as FIH, factor inhibiting HIF--is strikingly more sensitive to peroxide than the HIF prolyl hydroxylases. These contrasting sensitivities indicate that oxidant stress is unlikely to signal hypoxia directly to the HIF system, but that hypoxia and oxidant stress can interact functionally as distinct regulators of HIF transcriptional output.

A questionnaire study of GPs' and patients' beliefs about the different components of patient centredness.

Much research has explored the interaction between doctor and patient in the consultation and patient centredness has generally emerged as the preferred mode of consultation style. The present study aimed to examine and compare general practitioners' (GPs) and patients' beliefs about the importance of the different aspects of patient centred behaviour in a consultation. Matched questionnaires were completed by 410 patients (response rate=76.5%) and 64 GPs (response rate=85.3%) from practices around London concerning aspects of patient centredness operationalized in terms of doctor receptiveness, patient involvement, the affective content of the relationship and information giving. The results showed that GPs and patients showed similar beliefs about involving the patient in decision making, aspects of doctor receptiveness and the importance of the patient's own feelings in the consultation. However, GPs believed that it was less important to focus only on the patient's main problem, and more important to acknowledge their own feelings and avoid medical language. Further, GPs rated doctor receptiveness and the affective content of the relationship overall as more important for a good consultation than the patients. The patients also consistently rated information giving as more important than the GPs. To conclude, GPs rated the doctor receptiveness and affective components of patient centredness as more important than patients whereas patients showed greater endorsement of information indicating that although patient centredness may currently be the preferred style of consultation, doctors and patients prefer different aspects of this behaviour.