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BACKGROUND: While it is now apparent clinical sequelae (long COVID) may persist after acute COVID-19, their nature, frequency and aetiology are poorly characterised. This study aims to regularly synthesise evidence on long COVID characteristics, to help inform clinical management, rehabilitation strategies and interventional studies to improve long-term outcomes. METHODS: A living systematic review. Medline, CINAHL (EBSCO), Global Health (Ovid), WHO Global Research on COVID-19 database, LitCovid and Google Scholar were searched till 17 March 2021. Studies including at least 100 people with confirmed or clinically suspected COVID-19 at 12 weeks or more post onset were included. Risk of bias was assessed using the tool produced by Hoy et al. Results were analysed using descriptive statistics and meta-analyses to estimate prevalence. RESULTS: A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case-control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function. CONCLUSION: Long COVID is a complex condition with prolonged heterogeneous symptoms. The nature of studies precludes a precise case definition or risk evaluation. There is an urgent need for prospective, robust, standardised, controlled studies into aetiology, risk factors and biomarkers to characterise long COVID in different at-risk populations and settings. PROSPERO REGISTRATION NUMBER: CRD42020211131.

Abstract Background This paper is a response to the suggestion by Sacristán et al that clinicians can increase their clinical freedom by undertaking individualised economic analyses that demonstrate that interventions, which at a population level do not reach conventional thresholds of cost-effectiveness, do so in particular patients. Discussion In this reply, I question the presumption that "clinical freedom" is necessarily desirable and go on to argue that, even if it is, the proposal that clinicians should do individualised economic evaluation is flawed. Firstly, the additional clinical choice that may be gained from individualised economic analyses that demonstrate that an intervention, generally considered not to be cost-effective, is cost-effective in a particular patient, is likely to be counterbalanced by other analyses that produce the converse result (i.e. that an intervention that is cost-effective at a population level may not be so in a particular patient) - a complementary consequence, which is ignored by Sacristán et al in their paper. Secondly, the skills and time required to do an individualised economic analysis are likely to exceed those of most clinicians. Thirdly, and most importantly, asking clinicians to make rationing judgements at the point of care is a threat to patient trust and can harm the doctor-patient relationship. Summary Individualised economic evaluations are neither a desirable nor feasible method for increasing clinical choice.

Abstract Background To evaluate the educational effects of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduates compared to a traditional lecture-based course of equivalent content. Methods We conducted a cluster randomised controlled trial in the Netherlands and the UK involving postgraduate trainees in six obstetrics and gynaecology departments. Outcomes (knowledge gain and change in attitude towards EBM) were compared between the clinically integrated e-learning course (intervention) and the traditional lecture based course (control). We measured change from pre- to post-intervention scores using a validated questionnaire assessing knowledge (primary outcome) and attitudes (secondary outcome). Results There were six clusters involving teaching of 61 postgraduate trainees (28 in the intervention and 33 in the control group). The intervention group achieved slightly higher scores for knowledge gain compared to the control, but these results were not statistically significant (difference in knowledge gain: 3.5 points, 95% CI -2.7 to 9.8, p = 0.27). The attitudinal changes were similar for both groups. Conclusion A clinically integrated e-learning course was at least as effective as a traditional lecture based course and was well accepted. Being less costly than traditional teaching and allowing for more independent learning through materials that can be easily updated, there is a place for incorporating e-learning into postgraduate EBM curricula that offer on-the-job training for just-in-time learning. Trial registration Trial registration number: ACTRN12609000022268.

Abstract Background We developed and evaluated the outcomes of an e-learning course for evidence based medicine (EBM) training in postgraduate medical education in different languages and settings across five European countries. Methods We measured changes in knowledge and attitudes with well-developed assessment tools before and after administration of the course. The course consisted of five e-learning modules covering acquisition (formulating a question and search of the literature), appraisal, application and implementation of findings from systematic reviews of therapeutic interventions, each with interactive audio-visual learning materials of 15 to 20 minutes duration. The modules were prepared in English, Spanish, German and Hungarian. The course was delivered to 101 students from different specialties in Germany (psychiatrists), Hungary (mixture of specialties), Spain (general medical practitioners), Switzerland (obstetricians-gynaecologists) and the UK (obstetricians-gynaecologists). We analysed changes in scores across modules and countries. Results On average across all countries, knowledge scores significantly improved from pre- to post-course for all five modules (p < 0.001). The improvements in scores were on average 1.87 points (14% of total score) for module 1, 1.81 points (26% of total score) for module 2, 1.9 points (11% of total score) for module 3, 1.9 points (12% of total score) for module 4 and 1.14 points (14% of total score) for module 5. In the country specific analysis, knowledge gain was not significant for module 4 in Spain, Switzerland and the UK, for module 3 in Spain and Switzerland and for module 2 in Spain. Compared to pre-course assessment, after completing the course participants felt more confident that they can assess research evidence and that the healthcare system in their country should have its own programme of research about clinical effectiveness. Conclusion E-learning in EBM can be harmonised for effective teaching and learning in different languages, educational settings and clinical specialties, paving the way for development of an international e-EBM course.

Abstract Background Over the last years key stake holders in the healthcare sector have increasingly recognised evidence based medicine (EBM) as a means to improving the quality of healthcare. However, there is considerable uncertainty about the best way to disseminate basic knowledge of EBM. As a result, huge variation in EBM educational provision, setting, duration, intensity, content, and teaching methodology exists across Europe and worldwide. Most courses for health care professionals are delivered outside the work context ('stand alone') and lack adaptation to the specific needs for EBM at the learners' workplace. Courses with modern 'adaptive' EBM teaching that employ principles of effective continuing education might fill that gap. We aimed to develop a course for post-graduate education which is clinically integrated and allows maximum flexibility for teachers and learners. Methods A group of experienced EBM teachers, clinical epidemiologists, clinicians and educationalists from institutions from eight European countries participated. We used an established methodology of curriculum development to design a clinically integrated EBM course with substantial components of e-learning. An independent European steering committee provided input into the process. Results We defined explicit learning objectives about knowledge, skills, attitudes and behaviour for the five steps of EBM. A handbook guides facilitator and learner through five modules with clinical and e-learning components. Focussed activities and targeted assignments round off the learning process, after which each module is formally assessed. Conclusion The course is learner-centred, problem-based, integrated with activities in the workplace and flexible. When successfully implemented, the course is designed to provide just-in-time learning through on-the-job-training, with the potential for teaching and learning to directly impact on practice.

Abstract Background A variety of definitions of evidence-based practice (EBP) exist. However, definitions are in themselves insufficient to explain the underlying processes of EBP and to differentiate between an evidence-based process and evidence-based outcome. There is a need for a clear statement of what Evidence-Based Practice (EBP) means, a description of the skills required to practise in an evidence-based manner and a curriculum that outlines the minimum requirements for training health professionals in EBP. This consensus statement is based on current literature and incorporating the experience of delegates attending the 2003 Conference of Evidence-Based Health Care Teachers and Developers ("Signposting the future of EBHC"). Discussion Evidence-Based Practice has evolved in both scope and definition. Evidence-Based Practice (EBP) requires that decisions about health care are based on the best available, current, valid and relevant evidence. These decisions should be made by those receiving care, informed by the tacit and explicit knowledge of those providing care, within the context of available resources. Health care professionals must be able to gain, assess, apply and integrate new knowledge and have the ability to adapt to changing circumstances throughout their professional life. Curricula to deliver these aptitudes need to be grounded in the five-step model of EBP, and informed by ongoing research. Core assessment tools for each of the steps should continue to be developed, validated, and made freely available. Summary All health care professionals need to understand the principles of EBP, recognise EBP in action, implement evidence-based policies, and have a critical attitude to their own practice and to evidence. Without these skills, professionals and organisations will find it difficult to provide 'best practice'.

Abstract Future projections of southwestern African hydroclimate are highly uncertain. However, insights from past warm climates, like the Pliocene, can reveal mechanisms of future change and help benchmark models. Using leaf wax hydrogen isotopes to reconstruct precipitation (δDp) from Namibia over the past 5 million years, we find a long‐term depletion trend (−50‰). Empirical mode decomposition indicates this trend is linked to sea surface temperatures (SSTs) within the Benguela Upwelling System, but modulated by Indian Ocean SSTs on shorter timescales. The influence of SSTs on reconstructed regional hydroclimate is similar to that observed during modern Benguela Nin∼o events, which bring extreme flooding to the region. Isotope‐enabled simulations and PlioMIP2 results suggest that capturing a Benguela Nin∼o‐like state is key to accurately simulating Pliocene, and future, regional hydroclimate. This has implications for future regional climate, since an increased frequency of Benguela Nin∼os poses risk to the ecosystems and industries in the region.

Author(s): Madison G. Shankle [sup.1] [sup.2] , Natalie J. Burls [sup.3] , Alexey V. Fedorov [sup.1] [sup.4] , Matthew D. Thomas [sup.1] [sup.5] , Wei Liu [sup.6] , Donald E. [...], Ocean dynamics in the equatorial Pacific drive tropical climate patterns that affect marine and terrestrial ecosystems worldwide. How this region will respond to global warming has profound implications for global climate, economic stability and ecosystem health. As a result, numerous studies have investigated equatorial Pacific dynamics during the Pliocene (5.3-2.6 million years ago) and late Miocene (around 6 million years ago) as an analogue for the future behaviour of the region under global warming.sup.1-12. Palaeoceanographic records from this time present an apparent paradox with proxy evidence of a reduced east-west sea surface temperature gradient along the equatorial Pacific.sup.1,3,7,8--indicative of reduced wind-driven upwelling--conflicting with evidence of enhanced biological productivity in the east Pacific.sup.13-15 that typically results from stronger upwelling. Here we reconcile these observations by providing new evidence for a radically different-from-modern circulation regime in the early Pliocene/late Miocene.sup.16 that results in older, more acidic and more nutrient-rich water reaching the equatorial Pacific. These results provide a mechanism for enhanced productivity in the early Pliocene/late Miocene east Pacific even in the presence of weaker wind-driven upwelling. Our findings shed new light on equatorial Pacific dynamics and help to constrain the potential changes they will undergo in the near future, given that the Earth is expected to reach Pliocene-like levels of warming in the next century. New proxy data for ocean pH and an ocean-atmosphere model show that a radically different ocean circulation led to decoupling of ocean productivity and upwelling in the equatorial Pacific Ocean 3-6 million years ago.

End of 21st‐century hydroclimate projections suggest an expansion of subtropical dry zones, with Mediterranean and Sahel regions becoming much drier. However, paleobotanical assemblage evidence from the middle Miocene (17‐12 Ma), suggests both regions were instead humid environments. Here we show that by modifying regional sea surface temperatures (SST) in an Earth System Model (CESM1.2) simulation of the middle Miocene, the increased ocean evaporation and integrated water vapor flux overrides any drying effects associated with warming‐induced land‐surface evaporation driven by atmospheric CO2 concentrations. These modifications markedly reduce the bias in the model‐data comparison for this period. A vegetation model (BIOME4) forced with simulated climatologies predicts both regions were dominated by mixed forest, which is largely consistent with the paleobotanical record. This study unveils the potential for wetter subtropical Mediterranean climates associated with warming, presenting an alternative scenario from future drying projections with localized SST warming governing regional climate change. Plain Language Summary: Climate models project drier conditions over Europe and Northern Africa due to global warming. However, evidence from a past warm climate period, the middle Miocene (∼15 million years ago), finds wetter rather than drier environments. We refine climate model boundary conditions by reconstructing warmer ocean waters in the North Atlantic based on proxy evidence. The warmer ocean produces wetter environments by enhancing North Atlantic precipitation events and the North African monsoon. The increased rainfall and surface temperature cause a vegetation model to predict more forest coverage over Europe and Northern Africa, which is consistent with fossil evidence from ∼15 million years ago. This study unveils the potential for wetter climates associated with warming, presenting an alternative scenario from future drying projections, with localized sea surface warming governing regional climate. Key Points: Middle Miocene Europe rainfall discrepancy between herpetological (dry) and paleobotanical (wet) records complicate climate model validationSimulations that produce dry environments also produce cool North Atlantic sea surface temperatures which are inconsistent with proxiesSSTs informed by North Atlantic proxies produce wetter environments consistent with paleobotanical evidence [ABSTRACT FROM AUTHOR]

Although the majority of people with Covid-19 will experience mild to moderate symptoms and will recover fully, there is now increasing evidence that a significant proportion will experience persistent symptoms for months after the acute phase of the illness. These symptoms include, among others, fatigue, problems breathing, lack of smell and taste, headaches, and depression and anxiety. It is also clear the virus has lasting fluctuating multiorgan sequelae, including affecting not only the respiratory system but also the heart, liver, and nervous system. We present a protocol for a living systematic review that aims to synthesize the evidence on the prevalence and characteristics of post-acute COVID-19. The living systematic review will be updated regularly, approximately every 6 months, as new evidence emerges. We will include studies that follow up at least 100 people with Covid-19 at 12 or more weeks post Covid-19 onset, with no restrictions regarding country, setting, or language. We will use descriptive statistics and, for outcomes reported in two or more studies, we will use meta-analyses to estimate prevalence with 95% confidence intervals (CIs) using the exact method. Heterogeneity between estimates will be assessed using the I2 statistic. Our findings will also be presented as infographics to facilitate transcription to lay audiences. Ultimately, we aim to support the work of policy makers, practitioners, and patients when planning rehabilitation for those recovering from Covid-19. The protocol has been registered with PROSPERO ( CRD42020211131, 25/09/2020).

Background While it is now apparent clinical sequelae (long COVID) may persist after acute COVID-19, their nature, frequency and aetiology are poorly characterised. This study aims to regularly synthesise evidence on long COVID characteristics, to help inform clinical management, rehabilitation strategies and interventional studies to improve long-term outcomes.Methods A living systematic review. Medline, CINAHL (EBSCO), Global Health (Ovid), WHO Global Research on COVID-19 database, LitCovid and Google Scholar were searched till 17 March 2021. Studies including at least 100 people with confirmed or clinically suspected COVID-19 at 12 weeks or more post onset were included. Risk of bias was assessed using the tool produced by Hoy et al. Results were analysed using descriptive statistics and meta-analyses to estimate prevalence.Results A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case–control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function.Conclusion Long COVID is a complex condition with prolonged heterogeneous symptoms. The nature of studies precludes a precise case definition or risk evaluation. There is an urgent need for prospective, robust, standardised, controlled studies into aetiology, risk factors and biomarkers to characterise long COVID in different at-risk populations and settings.PROSPERO registration number CRD42020211131.

Although the majority of patients with COVID-19 will experience mild to moderate symptoms and will recover fully, there is now increasing evidence that a significant proportion will experience persistent symptoms for weeks or months after the acute phase of the illness. These symptoms include, among others, fatigue, problems in breathing, lack of smell and taste, headaches, and also depression and anxiety. It has also become clear that the virus has lasting effects not only on the respiratory system but also on other parts of the body, including the heart, liver, and the nervous system. In this paper we present a protocol for a living systematic review that aims to synthesize the evidence on the prevalence and duration of symptoms and clinical features of post-acute COVID-19 and its long-term complications. The living systematic review will be updated regularly, initially monthly with update cycles under continuous review as the pace of new evidence generated develops through the pandemic. We will include studies that follow up with COVID-19 patients who have experienced persistent mild, moderate or severe symptoms, with no restrictions regarding country, setting, or language. We will use descriptive statistics to analyse the data and our findings will be presented as infographics to facilitate transcription to lay audiences. Ultimately, we aim to support the work of policy makers, practitioners, and patients when planning rehabilitation for those recovering from COVID-19. The protocol has been registered with PROSPERO ( CRD42020211131, 25/09/2020).