Ninety-one Pango lineages, including those of five variants of concern (VOC), were identified. Genetic analysis revealed at least 260 introductions to the CMS from other global regions. For each of the 17 CMS, the percentage of reported COVID-19 cases sequenced by the COVID-19 IMPACT laboratory ranged from 0·02% to 3·80% (median = 1·12%). Sequences submitted to GISAID by our study represented 73·3% of all SARS-CoV-2 sequences from the 17 CMS available on the database up to December 31st 2021. Increased staffing, process and infrastructural improvement over the course of the project helped reduce turnaround times for reporting to originating institutions and sequence uploads to GISAID. Insights from our genomic surveillance network in the Caribbean region directly influenced non-pharmaceutical countermeasures in the CMS countries. However, limited availability of associated surveillance and clinical data made it challenging to contextualise the observed SARS-CoV-2 diversity and evolution, highlighting the need for development of infrastructure for collecting and integrating genomic sequencing data and sample-associated metadata.The COVID-19 pandemic highlighted the importance of global genomic surveillance to monitor the emergence and spread of SARS-CoV-2 variants and inform public health decision-making. Until December 2020 there was minimal capacity for viral genomic surveillance in most Caribbean countries. To overcome this constraint, the COVID-19: Infectious disease Molecular epidemiology for PAthogen Control & Tracking (COVID-19 IMPACT) project was implemented to establish rapid SARS-CoV-2 whole genome nanopore sequencing at The University of the West Indies (UWI) in Trinidad and Tobago (T&T) and provide needed SARS-CoV-2 sequencing services for T&T and other Caribbean Public Health Agency Member States (CMS). Using the Oxford Nanopore Technologies MinION sequencing platform and ARTIC network sequencing protocols and bioinformatics pipeline, a total of 3610 SARS-CoV-2 positive RNA samples, received from 17 CMS, were sequenced  Pathogen genomic sequencing and related analytical approaches have proved to be invaluable tools for healthcare providers and public health decision-makers during the COVID-19 pandemic , 3 to thWhile the pandemic brought the value of genomic surveillance to the forefront, it also highlighted countries and regions lacking the required infrastructure and capacity . In the Specifically, COVID-19 IMPACT aimed to implement Oxford Nanopore Technology (ONT) MinION sequencing and ARTIC network open-source protocols and bioinformatic pipelines to generate baseline data on SARS-CoV-2 lineages circulating in the Caribbean. In doing this, the project sought to address questions relating to SARS-CoV-2 evolution and transmission within the region; and to respond to questions from local and regional public health bodies relating to COVID-19 control. For example, regarding the relative contribution to COVID-19 incidence of local transmission versus imported cases, whether clusters of cases were linked or the result of distinct, independent chains of transmission, or risks associated with different modes of importation.COVID-19 IMPACT aimed to process 800 samples over two years and generated its first SARS-CoV-2 whole genome sequences in December 2020, two weeks prior to the first report of the emergence of the first variant of concern (VOC) . The emepersonal communication). Also, the sequencing information provided by the IMPACT laboratory informed Grenada’s decision to not reinstitute travel restrictions in March of 2021 as newly identified VOCs were identified in multiple countries at that time, demonstrating that further restrictions would be ineffective. , personal communication).During the project’s first year, the T&T MoH and regional health ministries in 16 other CMS  relied on the COVID-19 IMPACT project for the generation, analysis and interpretation of genomic data on SARS-CoV-2 lineages circulating within the region. The effectiveness of this initiative was demonstrated by the rapid detection and reporting of VOCs in several CMS, which informed public health policy and decision-making for economic reopening, international travel restrictions and work policies. For example, in T&T, in order to slow the introduction of the gamma, delta and omicron VOCs to the general population, until community spread was confirmed, sequencing results were used to guide the enforcement of more stringent isolation criteria for individuals entering the country in whom new VOCs were detected , th 2020 to December 31st 2021, highlighting challenges and successes that can inform the necessary future development of pathogen genomic surveillance in the Caribbean and other less well-resourced regions.The COVID-19 IMPACT laboratory at the UWI is now a designated Pan American Health Organization (PAHO) reference sequencing laboratory (PAHO-RSL) and part of the COVID-19 Genomic Surveillance Regional Network. As at July 30, 2022 the project has processed over 4,800 clinical samples and contributed 3,999 sequences from the Caribbean sub-region to GISAID. More recently, it has provided training and technical support to laboratories in other CMS and institutions in building their own WGS capacity. Here, we describe the results of SARS-CoV-2 genomic surveillance efforts by the COVID-19 IMPACT project from December 5https://carpha.org/Who-We-Are/Member-States) and (ii) the Trinidad Public Health Laboratory (TPHL) which, as the reference laboratory for the T&T MoH, receives samples for SARS-CoV-2 confirmatory testing from T&T’s five regional health authorities (RHAs) as well as from private laboratories offering SARS-CoV-2 RT-PCR testing. At CARPHA, RNA extraction was carried out using the Qiagen QiaAmp Viral RNA Mini kit  as per the manufacturer’s guidelines while the RT-PCR was performed on the Applied BioSystems QuantStudio Dx platforms using the Charité- Berlin  protocol for the detection of the E-gene. This protocol utilises the AgPath- ID Ambion One-Step RT-PCR kit  and primer and probes ordered through Integrated DNA Technologies. At the TPHL, RNA extraction was carried out using the Tiangen TIANamp Virus DNA/RNA Kit  and RT-PCR carried out using the BGI 2019-nCoV: Real-Time Fluorescent RT-PCR kit , as well as the GeneXpert System and Xpert Xpress SARS-CoV-2 RT-PCR kit. In addition to prospectively collected samples, viral RNA extracted from SARS-CoV-2 RT-PCR positive samples collected prior to the implementation of the project during the first wave of COVID-19 in T&T (August to October 2020) were obtained retrospectively from TPHL.De-identified viral RNA extracted from samples positive for SARS-CoV-2 by real-time PCR (RT-PCR) were received by the COVID-19 IMPACT project laboratory at the UWI from (i) CARPHA, a regional public health body which serves 26 member states (A SARS-CoV-2 genome sequencing requisition form was developed for the project in consultation with the T&T MoH see  to captuhttps://dx.doi.org/10.17504/protocols.io.bbmuik6w), with version 3 used prior to 28th October 2021 and version 4 thereafter. The libraries were sequenced using a MinION sequencing device until October 2021 after which sequencing was carried out using the GridION device . Consensus sequences were generated using the ARTIC Network CoV-2019 novel coronavirus bioinformatics protocol, version 1.1.0. Reads passing quality control in MinKNOW were filtered using the ARTIC guppyplex tool (version 5.0.16) to retain only reads 400–700bp long and then assembled into consensus sequences using nanopolish (version 1.2.1) [https://artic.network/ncov-2019/ncov2019-bioinformatics-sop.html].DNA libraries were prepared from viral RNA extracts using the ARTIC Network nCoV-2019 version 3 LoCost sequencing protocol and nCoV-2019 primer panel for cDNA amplification (https://pangolin.cog-uk.io/) for sequences generated up until October 21st 2021 and using the most recent version of the Pangolin COVID-19 command-line tool . Overall, 91 lineages were identified, including lineages corresponding to all VOCs  and VOIs . 2 = 0·86; Slope = 1·2 x10-3). Hence, a Bayesian timescale phylogenetic reconstruction was performed, which resulted in an estimated median evolutionary rate of 8·39 x 10−4 substitutions per site per year [95% (highest posterior density) HPD: 8·28 x 10−4–8·51 x 10−4], in line with previous estimates [Phylogenetic analysis revealed the new genome sequences clustered along diverse lineages of SARS-CoV-2, most prominently with VOCs, confirming genome sequence designations obtained using Pangolin. After removal of 59 molecular clock outliers, a strong temporal signal was identified in the dataset  where both the project laboratory and CARPHA headquarters are located. The numbers and proportions of samples received from the remaining 16 CMS were as follows: Anguilla , Antigua and Barbuda , Bahamas , Barbados , Bermuda , British Virgin Islands , Cayman Islands , Dominica , Grenada , Guyana , Jamaica , Montserrat , Saint Kitts and Nevis , Saint Lucia , Saint Vincent and the Grenadines , and Turks and Caicos Islands .For those CMS for which at least 75 samples were sequenced , the distribution of lineages detected over time is shown in The percentage of reported COVID-19 cases that were sequenced for each EW per CMS is shown in The exact dates of sample collection and receipt at the sequencing laboratory were available for 3,459 of the 3,610 samples sequenced. For T&T, the majority of samples  was received within one week of collection, while for samples originating outside of T&T, most took two or more weeks to arrive at the laboratory . Most saOf all samples assigned to a Pango lineage, 2,864 (96·8%) were uploaded to GISAID. Overall, most  were uploaded more than three weeks after the sequences were generated and only 13·5% (n = 218) within one week  with litOut of the 3,610 samples sequenced, 3,004 had been received accompanied by the Ct value obtained during confirmatory RT-PCR. Sending institutions were asked to send samples with Ct values <28 and 82·5%  of those samples sequenced met this criterion including 66·9%  in the 10–25 range. However, while most of these yielded sequences with genome coverage over 75%, there were many samples with low Ct values that performed poorly and vice versa . There wThe rapid evolution of SARS-CoV-2 and repeated emergence of lineages with altered epidemiological characteristics of public health significance , has emphasised the importance of comprehensive and sustained genomic surveillance and the need to enhance capacity in settings where this is currently limited. This is especially important in regions such as the Caribbean, where no such capacity previously existed. The COVID-19 IMPACT project was initiated at the UWI in T&T, in December 2020 in order to address this gap. The project was conceptualised and initially funded as a research project that would implement local capacity for virus whole genome sequencing and would sequence a maximum of 800 retrospective and prospective SARS-CoV-2 samples in order to establish baseline information of viral diversity and evolution in the region, and assist public health bodies with targeted investigations.de facto public health laboratory, meant a dramatic increase in samples submitted to the sequencing laboratory, pressure to minimise turnaround times and the need for rapid implementation of more formal sample handling and reporting procedures, initially with very limited human resources and infrastructure (Successful implementation of the project in a relatively short time frame was greatly facilitated by (i) pre-existing local expertise in viral genomics and phylogenetics at the UWI, (ii) early commitment to the project by the T&T MoH and CARPHA, (ii) the UWI project laboratory’s prior collaborative research links with local and regional public health bodies (i.e. TPHL and CARPHA), and with international partners, (iv) CARPHA’s rapid engagement and receipt of commitment from other CMS, and (v) open access to global scientific expertise, relevant protocols and scientific publications see . Howevertructure . With adWithin the first year, 3,610 samples from 17 CMS were sequenced, analysed, and the results returned to the CMS of origin to inform public health policy as necessary. A large diversity of SARS-CoV-2 lineages were detected, including VOCs and VOIs designated at the time and with at least 260 introductions originating from non-CMS. The estimated tMRCA of late 2019 based on the study data set is consistent with previous estimates for SARS-CoV-2 emergence –34. HoweIt is important for genomic surveillance sampling to be appropriately targeted and sufficiently extensive to detect the early emergence and expansion of new lineages . Vavrek Further, for the vast majority of samples received by the project laboratory, no information was provided to indicate to which, if any, of the targeted sequencing categories the samples belonged, making it difficult to determine the extent to which sampling criteria were being met. This is in part because the study did not anticipate the scale and direction in which it would develop, and , only date of sample collection, geographic origin, sample type and Ct value were requested and agreed by CARPHA and the T&T MoH. The additional information required to confirm and contextualise the sequencing effort is available within the respective government public health institutions. However, retrieval remains a major challenge because the institutions involved have differing platforms for sample and data management, as well as different policies and arrangements for data sharing. CARPHA does not share data from CMS without their explicit permission, so access would necessarily require agreement from each of them. In the case of T&T, the MoH agreed to share these and other non-identifying metadata, but staffing limitations within the ministry severely hindered retrieval. Also, since the ethical approval granted by the T&T MoH specified that samples must be de-identified before being sent to UWI, UWI staff could not carry out the data retrieval themselves.th 2020 to December 31st 2021 varied from 0·02% to 3·80%, with a median of 1·12%. Based on data from the GISAID Submission Tracker, this is considerably lower than rates achieved by countries such as Denmark and the United Kingdom which, as of March 7th 2022, had sequenced and shared approximately 14% and 12% of their cases respectively. For sixteen of the CMS, the rate achieved by the COVID-19 IMPACT laboratory does not represent the total genomic surveillance effort during the specified period, as those CMS intermittently submitted SARS-CoV-2 positive samples to extra-regional laboratories for sequencing. Also, having established in-house sequencing capacity in late 2021, CARPHA began offering sequencing services to its member states in December of 2021. Interestingly, while the overall median percentage of reported COVID-19 cases sequenced by the COVID-19 IMPACT laboratory during the time period in question was 1·12%, the lowest percentages of reported cases were sequenced during the latter half of 2021 (median 0.99 vs. a median of 1.14 for 2020 and a median of 1.63 for January to June 2021). This decrease may in part be explained by sequencing services being offered by CARPHA in late-2021 as well as some Caribbean countries having established in-house sequencing capacity also during late-2021. Nevertheless, overall, the COVID-19 IMPACT laboratory accounted for the majority (73·3%) of the SARS-CoV-2 sequences on GISAID for the 17 CMS up to December 31st 2021, albeit with the percentage of sequences originating from the COVID-19 project varying widely among CMS. While it was not possible to determine a specific date of introduction for the different VOCs and VOIs in each country, in some cases the first detection of a VOC/VOI in a country via sequencing by the Project IMPACT laboratory was in samples collected up to 2 months before a reported surge in COVID-19 cases occurred in the respective country.With the exception of Montserrat (which sequenced 32.6% of 46 cases reported during the study period), the percentage of reported COVID-19 cases sequenced by the COVID-19 IMPACT laboratory for each CMS between December 5The total number of samples and the frequency at which samples were received for sequencing varied widely among the 17 CMS, with the least (n = 4) from the Cayman Islands, and most (n = 2597) from T&T. Only 7 countries had more than 75 sequences uploaded to GISAID and for three of these , few or no samples from epidemic wave peaks were sent to the COVID-19 IMPACT laboratory for sequencing. Several factors may have influenced this variability in total and weekly sequencing effort via the COVID-19 IMPACT project. For example, resource limitations necessitated the implementation of a limit on the number of samples per month per country. Recognizing that at any given time CMS were not equally affected, this limit was not routinely upheld. Some countries sent many more samples than the prescribed limit while others may have observed the limit even during peak periods. The very low number or absence of samples representing epidemic wave peaks may also reflect the fact that healthcare services were overwhelmed during these peaks and did not have the resources to dedicate effort to genomic surveillance. Alternatively, having confirmed the presence of a VOC (prior to an epidemic peak), countries may have deemed it unnecessary to continue sequencing. Finally, in the case of the Cayman Islands, in-country sequencing capacity was developed in early 2021 and they stopped sending samples to the project at that point.The critical contributions of global genomic surveillance in elucidating and understanding the epidemiological characteristics of SARS-CoV-2 lineages and in informing public health responses are as much dependent on rapid and open sharing of genomic sequence data, primarily via GISAID , 37 as tThe project was initially funded through a UWI grant initiative that covered the sequencing of about 800 samples by a limited laboratory team  who were responsible for all stages, from sample receipt to GISAID upload. Faster laboratory turnaround times and GISAID upload were facilitated when WHO/PAHO support added five members to the laboratory team in June 2021 and a sixth in September 2021. The sixth had the required expertise in bioinformatics and computer coding to automate the analysis, reporting and upload processes which contributed to an increase in the proportion of sequences uploaded within one week and the clearing of a backlog Click here for additional data file.S2 Figth 2020 to December 31st 2021 a total of 3610 samples were sequenced. Sufficient coverage was obtained for 2975  to enable assignment to a Pango lineage. The numbers below the pie charts indicate respectively the number of sequences and lineages identified in each country, as at December 31, 2021. Ninety-one individual lineages were identified, including all 5 VOCs  and two VOIs . Sub lineages for the VOCs and VOIs identified are grouped together using the WHO classifications. VOC = Variants of Concern. VOI = Variants of Interest. Map base layer modified from Serafy et al. 2015 [https://doi.org/10.1371/journal.pone.0142022.g001).For each of the 17 CARPHA territories participating in Project IMPACT  the percentage of each lineage identified is indicated in a pie chart. The percentage of sequences from each country for which insufficient coverage was obtained to be able to assign a Pango lineage is not shown. From December 5al. 2015  (License(TIF)Click here for additional data file.S3 FigIn panels A-D samples originating from T&T are indicated in blue and samples originating from non-T&T CMS are indicated in pink. (A) Time taken for samples to be received at the COVID-19 IMPACT laboratory after collection. Date of sample collection and date of receipt at the sequencing laboratory were available for 3463 samples sent for sequencing. (B) Time taken for sequencing to be reported once samples have been received by the COVID-19 IMPACT laboratory. This includes time for storage upon receipt, sample processing and library preparation, sequencing and bioinformatics pipeline analysis. Regardless of the sending institution, results for all T&T samples (n = 2596) were reported to the T&T MoH while results for samples coming from CARPHA were reported to CARPHA (n = 1670). Where multiple reports were made (e.g. T&T samples received from CARPHA reported to both CARPHA and T&T MoH) the earliest report date was used. (C) Time taken for results to be reported once having been processed and sequenced. Results for all T&T samples  were reported to the T&T MoH while results for samples coming from CARPHA (n = 1670) were reported to CARPHA. Where multiple reports were made, the earliest report date was used. (D) Time from date sequenced to upload to the GISAID database. 2828 sequences were uploaded to GISAID as at December 31 2021 (E) Time taken for sequences to be uploaded to the GISAID database after sequencing per week, for samples originating from Trinidad and Tobago and non-Trinidad and Tobago countries. The time taken in days for sequences (n = 2864) to be uploaded to GISAID after generation is indicated for sequences generated from T&T samples (left) and non-T&T samples (right). On the x-axis the time of sample collection  is indicated for the samples from which the sequences were derived. T&T = Trinidad and Tobago. T&T MoH = Trinidad and Tobago Ministry of Health. CARPHA = Caribbean Regional Health Agency.(TIF)Click here for additional data file.S4 FigPercentage Genome Coverage of SARS-CoV-2 Sequences retrieved versus (A) Ct Value and (B) Sample Age. Samples originating from Trinidad and Tobago (T&T) are indicated in blue while those from other CARPHA member states (CMS) (overseas) are indicated in green. The median of the frequency distribution for percentage of the SARS-CoV-2 genome retrieved (89%) is indicated by the red line and the maximum Ct value specified in the criteria for sequencing (Ct = 28) is indicated by the black line was requested for samples to be sent for sequencing. Sample age is the length of time from the date a sample was collected from a COVID-19 case to the date the sample was sequenced.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 File(R)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(PDF)Click here for additional data file.


Evidence for efficacy of single, high-dose liposomal amphotericin B (LAmB) in HIV-associated cryptococcal meningitis and histoplasmosis is growing. No systematic review has examined the safety of this regimen across multiple studies.We systematically searched Medline, Scopus, and the Cochrane Library from inception to April 2023 for studies reporting grade 3 and 4 adverse events (AEs) with single high-dose LAmB vs traditional amphotericin regimens for HIV-associated fungal infections.Three trials (n = 946) were included. Compared with traditional regimens, single high-dose LAmB was associated with equivalent risk of grade 3 and 4 AEs  and lower overall risk of grade 4 AEs , grade 4 renal  and grade 4 hematological AEs .Single, high-dose LAmB is associated with a lower risk of life-threatening AEs compared with other World Health Organization–endorsed amphotericin B–based regimens in invasive HIV–related fungal infection. Evidence for the efficacy of single high-dose liposomal amphotericin B  in HIV-associated fungal infections is growing. In 2022, the World Health Organization (WHO) adopted single high-dose LAmB as the cornerstone of first-line induction treatment for HIV-associated cryptococcal meningitis  after thLAmB is a lipid-based polyene formulation of amphotericin that received US Food and Drug Administration approval in 1997 . LAmB haThe AMBITION trial noted fewer grade 3 or 4 adverse events (AEs) in participants receiving single high-dose LamB compared with those receiving amphotericin B deoxycholate (DAmB) . LAmB, dTo date, no systematic review has tried to summarize AE data associated with single high-dose LAmB across trials. We conducted a systematic review and meta-analysis to pool data from the existing literature to determine if treatment with a single high-dose LAmB, when used for induction treatment of invasive fungal infections in people with HIV, carries a lower risk of serious adverse events compared with treatment with a traditional WHO-approved formulation or dosing of amphotericin B.We searched Medline (PubMed), Scopus, and the Cochrane Library (Wiley) from inception to April 2023 for relevant studies. We included studies that (1) compared single high-dose LAmB with alternative WHO guideline–recommended induction amphotericin B regimen for treatment of invasive fungal infection in people with HIV; (2) reported serious or life-threatening (grade 3 and 4) adverse events for each group at the conclusion of, or shortly after, induction therapy; and (3) were published in English. We assessed AEs at a minimum of 2 weeks after start of treatment to account for all AEs that may be seen during the entirety of induction therapy (2 weeks). One study [To locate relevant studies in Medline, we used exploded MeSH terms and keywords to generate sets for the following themes: liposomal amphotericin B, HIV infection, administration, and dosage. We then used the Boolean term “AND” to find their intersection. The search strategy was designed with the support of a biomedical librarian (H.B.B.). This basic approach was modified to search each electronic database. Details of the structure and findings of each electronic search strategy can be found in the Abstracts were screened based on title and abstract by 2 investigators independently  using Rayyan . Full-teFull-text data extraction and risk of bias assessment were performed independently by 2 investigators . A standardized data collection form was used to abstract relevant information from included studies such as clinical outcomes and risk of bias. One study included in the analysis  was not As a result of the small number of studies identified, a formal funnel plot is not included. Instead, we used a qualitative approach to comment on whether publication bias was a potential risk among included studies.P value <.10 and inconsistency (I2) >50%.After data extraction, we used a random-effects model to calculate pooled risk ratios (RRs) with 95% CIs using RevMan 5.4 . We chosTo calculate the risk ratios for our primary outcome, we used the following approach. Our numerator included the number of people experiencing grade 3 and 4 AEs in the study group. Our denominator included the total number of people in that study group who were at risk for the outcome. The method of grading AEs was noted. One paper  did not We categorized individually reported AEs into 3 categories: renal , hematological , and infusion-related . One study [Our secondary outcome included 10-week mortality. When data were available on 10-week mortality, we selected the intention-to-treat results for the analysis.After duplicate removal, 2052 abstracts were screened based on title and abstract. Thirty-five citations were selected for full-text review, and 3 studies were included . The chaRisk of bias assessment is available for review in the Compared with controls, patients who received single high-dose LAmB were less likely overall to develop grade 4 AEs , grade 4 renal AEs , or grade 4 hematological AEs , the most severe, life-threatening AEs .Patients who received single high-dose LAmB were as likely to develop the combined outcome of grade 3 or 4 AE , grade 3 and 4 hematological AE , and infusion-related AE of any severity . Those who received single high-dose LAmB were less likely to develop grade 3 and 4 renal AEs  .Ten-week mortality between the 2 groups did not differ  . HeterogOur systematic review and meta-analysis found that single high-dose LAmB—as induction therapy for cryptococcal meningitis or disseminated histoplasmosis in people with HIV—was associated with a lower risk of life-threatening (grade 4) adverse events compared with alternative WHO-recommended amphotericin-based regimens. This difference was driven by a reduction in grade 4 renal and hematologic adverse events.Our findings may be particularly pertinent for routine hospital settings in low- and middle-income countries (LMICs), where the ability to monitor and respond to severe AEs is less robust. Furthermore, in such settings, there may be lower adherence to strategies to minimize amphotericin B–associated toxicities . In 1 obOur findings may also have implications for using single high-dose LAmB in induction therapy in well-resourced contexts, where there is growing advocacy for this dosing strategy . One limThe pharmacodynamic and pharmacokinetic differences between LAmB and DAmB may explain their differing safety profiles and provide reassurance regarding the efficacy of single high-dose LAmB. LAmB is released more slowly than DAmB, with a lower initial volume of distribution . Less LAThe pharmacodynamic index most predictive of amphotericin efficacy is the ratio of maximal concentration to minimum inhibitory concentration (Cmax/MIC) . The lipThe strengths of our study include a comprehensive search of the literature that included conference abstracts and other unpublished literature. Another strength is the biological plausibility: Considering that the total exposure to amphotericin B is lower with the single, high-dose LAmB strategy, it is not surprising that there is less toxicity. We also observed low heterogeneity in most adverse event categories, supporting a consistency of effect. Although the Pasqualotto study excluded patients with creatinine >1.5 times the upper limit of normal while the 2 Jarvis studies did not exclude for renal dysfunction, reassuringly only 5 out of 882 participants in the Pasqualotto study were excluded due to high creatinine. This suggests that there may be low heterogenicity in the baseline patient characteristics across trials, despite the fact that they had different fungal infections.Our study has several limitations. First, as a result of a large number of patients included in 1 study comparing single high-dose LAmB with DAmB , our resCost is an important driver of antifungal use in LMICs. For example, in South Africa in 2016, the cost of LAmB was US$160 per 50-mg vial, >60 times the cost of amphotericin B deoxycholate . Our stuThis study adds further evidence to support the use of single high-dose LAmB over other alternative regimens to treat cryptococcal meningitis or histoplasmosis in people with HIV in resource-limited settings. Single high-dose LAmB is safer than traditional amphotericin B–based regimens when used for induction therapy to treat cryptococcal meningitis and histoplasmosis in people with HIV.ofad472_Supplementary_DataClick here for additional data file.


However, if no new policies are applied and technology developments follow historical trends, year-2050 global net aviation CO2 is still likely to be well above industry goals, including the goal of carbon-neutral growth from 2019, even when the demand effects of the pandemic are accounted for.The COVID-19 pandemic had a dramatic impact on aviation in 2020, and the industry’s future is uncertain. In this paper, we consider scenarios for recovery and ongoing demand, and discuss the implications of these scenarios for aviation emissions-related policy, including the Carbon Offsetting and Reduction Scheme for International Aviation (CORSIA) and the EU Emissions Trading Scheme (ETS). Using the Aviation Integrated Model (AIM2015), a global aviation systems model, we project how long-term demand, fleet, and emissions projections might change. Depending on recovery scenario, we project cumulative aviation fuel use to 2050 might be up to 9% below that in scenarios not including the pandemic. The majority of this difference arises from reductions in relative global income levels. Around 40% of modeled scenarios project no offset requirement in either the CORSIA pilot or first phases; however, because of its more stringent emissions baseline (based on reductions from year 2004–2006 CO Impacts on aviation-dependent industries, such as tourism, are similarly large. The International Civil Aviation Organization (ICAO) estimate year-2020 global scheduled passenger numbers were reduced by 60% . Weekly European air traffic volumes were 90% below year-2019 levels in April 2020 and remain 64% below year 2019 levels in May 2021 , with Eurocontrol projections implying year-2020 traffic just below half of year-2019 values . Although 2020 RPK impacts were at a similar 60%–70% level across all world regions, 2021 IATA RPK projections anticipate more regional divergence, with faster RPK recovery in North and Latin America (40%–50% below year-2019 levels) and slower recovery in Europe and the Middle East (65%–70% below year-2019 levels) . For comparison, the 2003 SARS epidemic led to 8% yearly RPK reduction in affected regions, with 6 months of disruption, peak monthly RPK reduction of 35%, and $6 billion lost revenue .The COVID-19 pandemic has had an extreme impact on global aviation. The International Air Transport Association (IATA) estimates the global aviation industry lost over $100 billion in 2020 alone . Rapid expansion comes at the cost of increasing environmental impacts , with some studies suggesting that, because of difficulties in reducing within-sector CO2, aviation may become one of the highest-emitting sectors by 2050 . The challenge of reducing aviation’s environmental impact has led to policy action on national, regional, and international levels , most notably ICAO’s Carbon Offsetting and Reduction Scheme for International Aviation (CORSIA) and aviation’s inclusion in the EU Emissions Trading Scheme (ETS). In both schemes, CO2 emissions above a given baseline are subject to a carbon price which funds corresponding reductions in other sectors. Additionally, depending on carbon costs, airlines may decide to adopt lower-emissions technologies themselves. In response to the COVID-19 pandemic, the CORSIA baseline  has been changed to refer only to 2019 . Initial analysis has shown that this change will likely result in a zero offset requirement for the pilot phase of CORSIA and offsetting requirements to 2035 might be reduced by up to three-quarters from a no-COVID baseline, if demand recovery follows IATA projections .This reduction is even more dramatic when pre-pandemic anticipated growth trends are considered. Global aviation RPK demand has grown on average over 5% per year since 1980. Industry projections anticipated 4%–5% per year increases over the next 20 years . Historically, routes vacated by collapsed airlines were typically taken up by other airlines , suggesting networks and competition may return to pre-pandemic conditions over the longer term provided profits can still be made. Other airlines have received government bailouts to continue operating, with over $100 billion state aid globally for aviation industry-related entities . Aircraft storage is a common response to demand downturns. Although some aircraft are retired from storage, others resume service once demand increases again . For very large and/or quad-engine aircraft such as the Boeing 747, Airbus A380, and Airbus A340, increased storage may combine with the end of production runs to accelerate existing system trends away from their use. Increased financial constraints on airlines may also incentivize abandonment of sustainability measures .Airline bankruptcies and retirements may continue to affect the sector even during recovery, because the mix of aircraft and operators has changed. The initial crisis period was associated both with airline bankruptcies  and scrappage and/or storage of older and larger aircraft . Reductions in oil price are typically passed on to passengers via lower ticket prices, stimulating demand; however, because many airlines hedge fuel costs, this effect may have a lag of 1–2 years . The short duration of the oil price fall means that any ongoing impacts are likely to be small. Low oil prices combined with capital constraints may also reduce airline incentives to invest in fuel-saving technologies. Historically, low oil price has been associated with lower ambition in fuel-saving technology development, although conditional bail-out programs for affected industries  may mitigate this. The impact of COVID-19 on carbon prices has been smaller. Initially, the EU ETS European Union Allowance (EUA) price fell by around 30% , but has since recovered to above pre-pandemic levels, driven in part by the EU ETS Market Stability Reserve . However, longer-term effects on EUA prices are possible if lower projected gross domestic product (GDP) reduces energy demand. Similarly, international carbon credit (CER) prices remain around recent levels under $1/tCO2 .Oil prices in 2020 stabilized at around $40/bbl, well below pre-pandemic projections of around $60/bbl, but have recovered in 2021 . This is an area of considerable uncertainty and potentially high impact. As yet it is impossible to quantify long-term impacts on business travel, though there are early indications that reductions are likely . Business passengers were around 30% of year-2007 UK totals, and this proportion has been declining over time . Separately, it has been suggested that aviation demand growth may decouple from GDP growth as aviation systems mature and/or because of environmental campaigns such as the flight-shaming movement, which encourage individuals to fly less . However, a comparison of income elasticities of aviation demand from different world regions suggests systematic differences between more and less mature aviation systems are not straightforwardly identifiable with current estimates .Longer-term changes in attitudes to aviation arising from the pandemic could occur because flying is perceived as less safe, or from increased use of videoconferencing to substitute business travel. Although demand downturns caused by previous disruptive events associated with ongoing safety concerns  were relatively short-lived, there is evidence of longer-term impacts on post-9/11 US domestic demand . Although demand impacts caused by border closures, movement restrictions, and fear of contagion may be relatively short-lived, the income impacts of the pandemic are likely to be longer term. The April 2021 update to the International Monetary Fund (IMF)’s World Economic Outlook  estimates that global GDP fell 3.3% in 2020 and will recover by 6% in 2021. Similarly, the World Bank  estimates a 4.3% fall in year-2020 global GDP and recovery of 4% in 2021. Longer-term projections are necessarily based on scenarios for how the pandemic progresses; however, ongoing offsets in GDP per capita from pre-pandemic projections are typical. This is similar to the impact of the 2008 financial crisis; IMF analysis  suggests that, 10 years later, 85% of economies that experienced a banking crisis in 2008 were still operating at output levels below pre-crisis trends. IMF estimates  suggest that global GDP will remain 2%–4.5% lower than pre-pandemic projections in 2025. Aviation passenger and freight demand can be strongly affected by changes in income , so it is likely that ongoing offsets in GDP projections will also affect long-term aviation projections; for example, the 2008 financial crisis was associated with a 2-year demand offset from pre-crisis trends . Because ongoing GDP impacts are likely to differ by country and will be affected by factors such as vaccine availability and the extent and type of outbreak control measures, ongoing demand impacts will likely differ by country as well.Historically, aviation demand has been sensitive to developments in global incomes , may affect aviation demand, fleet, and emissions over long timescales, affecting the likelihood of reaching emissions targets and the functioning of emissions-reduction policy. In this paper, we use a global aviation systems model to investigate scenarios for how the post-COVID-19 aviation sector might develop to 2050, and what implications these scenarios have for aviation emissions policies, both in specific cases  and more generally in relation to cumulative CO). AIM2015 models current and future interactions between passengers, airlines, airports, and other stakeholders. The basic model structure is shown in ).To project aviation demand and emissions with and without the COVID-19 pandemic, we use an updated version of the open-source global aviation systems model AIM2015 . Historically, Europe accounted for over 90% of global non-scheduled traffic; a “typical” charter flight travels between a European regional airport and a resort . Several papers and reports provide information about size distributions and typical proportion of unscheduled flights by region and type of origin and destination airport (–). These are used to generate scaling factors per route type  to account for additional unscheduled flights.Unscheduled flights consist mainly of charter flights and on-demand air services . In 2015, they accounted for 217 billion RPK, or 5% of global international RPK, although this proportion is declining . This includes freight carried in freighter aircraft and in the holds of passenger aircraft . Less information is available about air freight than is available for passengers. For this paper, we follow the same simple approach as in ICF Consulting et al.  to provide an estimate of air freight-related emissions. 2015 base year country-pair air freight flows are derived from national and international databases where available  and otherwise estimated from country-level totals combined with typical hold freight flows . For hold freight, the constraint on available capacity is often volume rather than weight. As such, we assume that typical passenger-to-freight ratios in passenger aircraft per route group  represent what is practically achievable, and that additional freight per country-pair flow beyond what can be carried in passenger aircraft at these ratios is carried in freighter aircraft. Freighter fleets and utilization are derived from fleet databases  and freight-specific operating costs are taken from literature estimates . The technology composition of the freighter fleet is assumed similar to that for passenger aircraft of the same size and manufacture year. Freighter conversion from passenger aircraft is accounted for by conversion curves . Changes in air freight demand resulting from changes in country-level GDP and country-pair level operating costs are accounted for via literature elasticity estimates . Freighter flights are not assigned to individual airports but aggregated to country-pair level, with flight distance assumed typical of the average flight between each country-pair. For the pandemic period, where extra freighter flights are required as a result of the reduction in passenger aircraft hold freight capacity, it is assumed they will be provided by stored freighter aircraft (if available) or otherwise by stored passenger aircraft with technology characteristics typical of the passenger fleet, approximating the case where passenger aircraft have been used to provide all-freight operations . This approach is calibrated by a similar backcasting exercise to that carried out in Dray et al. , and, although approximate, produces similar freight RTK, demand growth rates, and cost/RTK estimates to industry projections . We neglect transhipment-related and airport-specific effects and interactions with other transport modes.Air freight accounted for around 24% of global RTK in 2018  is already modeled in AIM. However, as discussed above, the COVID-19 pandemic has likely accelerated existing trends away from Very Large Aircraft (VLA). The Airbus A380 and Boeing 747 are due to end production before 2023, with no scheduled replacement. To simulate this, we restrict airline purchases and modeled technology development in the VLA size class from 2021 onward; as the fleet declines through retirements, demand that would have been served by VLAs is typically served by twin-aisle aircraft at higher frequency but lower per-flight CO), driven by border closures, quarantine regulations, and distancing requirements. It is likely some movement restrictions will extend into late 2021 and potentially beyond, depending how the pandemic progresses. The extent and duration of these effects is highly uncertain. To generate scenarios for these impacts, we introduce demand damping factors for the immediate recovery period, applied separately for domestic and international passenger and freight demand. For 2020, these factors are estimated directly from available data on yearly average demand reductions . After 2020, we follow a scenario-based approach where the assumed extent of movement restrictions is consistent with the recovery scenario, as discussed below.The largest short-term impact of the pandemic on aviation arises from travel restrictions. International RPK was 98% below year-2019 levels in May 2020 . To account for this, passenger load factors are also adjusted when the damping factor is applied, with the amount of adjustment taken from IATA data on typical load factors for routes with strongly reduced demand . Because airlines lose money operating at low load factors, this is not sustainable over the long term and we assume that, when the damping factor is removed, load factors will return to pre-pandemic trends.Passenger damping factors apply to numbers of true origin–ultimate destination passengers per city-pair. In practice, flights are reduced by a smaller amount, with many operating at low load factors . As in Dray et al. , we consider SSP1, 2, and 4 as High-growth, Mid-growth, and Low-growth scenarios. These scenarios are paired with long-term energy price scenarios consistent with their broad storylines: the International Energy Agency (IEA) Sustainable Development Scenario (SDS) and Stated Policies Scenario (STEPS) for High (SSP1) and Mid (SSP2), and Energy Information Administration (EIA) “low economic growth” projections for Low . However, to explore an illustrative case where changes in attitudes to aviation might cause significantly less demand growth than projected, we also run IPCC’s very low economic growth case SSP3 with an additional demand decoupling component (“Decoupling” scenario), using decreases in income elasticities over time similar to Department for Transport . Second, modeling the impact of COVID-19 on aviation requires projections for how the pandemic will affect GDP and energy prices. IMF provides country-level projections for 2020 and 2021, and global scenarios for how developments to 2025 may deviate from a no-pandemic baseline . We run the four scenarios with and without COVID-19 impacts. For the scenario runs which include COVID-19, we adjust GDP and oil prices between 2020 and 2025 in line with the projections of IMF , using actual values for 2020 and differences from a no-pandemic baseline for later years, and running the “High” long-term growth scenario with the IMF’s “Upside” scenario and the “Decoupling” scenario with the IMF’s “Downside” scenario . These combinations are not intended to imply that individual recovery scenarios are likely to lead to specific ongoing GDP scenarios, but rather an attempt to cover the range of potential futures (from “rapid recovery followed by high growth” to “prolonged recovery followed by weak growth”) which may be relevant for aviation policy outcomes. Model inputs per scenario with and without COVID-19 are shown in To address these uncertainties, we use two approaches. For the main set of model runs, we use a scenario-based approach to define internally consistent sets of model inputs. Three scenario components are required. First, long-term population and income growth rates are derived from the Intergovernmental Panel on Climate Change (IPCC) Shared Socioeconomic Pathway (SSP) scenario set ; for SSP3, we additionally extend applied damping factors to 2025 to simulate a prolonged movement restriction scenario based on the low end of IATA short-term impact projections . Air freight demand has reduced by much less than passenger demand. For 2020 a drop in global trade volumes of 13% to 32% has been projected . Because hold freight capacity in passenger aircraft has dropped by a larger factor than this, COVID-19 has driven an effective short-term shift toward freighter aircraft, with some passenger aircraft temporarily repurposed for freight-only flights , and we apply damping factors to freight demand for 2020 only.Passenger damping factors to account for closed connections for 2020 and 2021 are derived from IATA data and projections . To assess how uncertainties in GDP, population, and energy prices may affect outcomes, we also run a set of 500 model runs with global GDP per capita growth rates drawn from distributions estimated by Department for Transport , including a range of COVID-19 GDP adjustments between the “Upside” and “Downside” scenarios from IMF . We also include population growth rate distributions from United Nations , although these have relatively little effect on outcomes because of the smaller uncertainty range in population growth rates and lower model sensitivity .Scenario modeling allows the development of self-consistent storylines about how the future may develop. However, it may miss future developments which are within the uncertainty range in developments in different parameters, but do not form part of the specific storylines investigated. In general, GDP/capita is the scenario variable which has the largest impact on aviation demand. Recent research has suggested the SSP scenarios may understate the full range of uncertainty in future GDP developments . For reference, the IPCC very high (SSP5) growth scenario is also shown for GDP/capita.For these projections, oil prices and pandemic period damping factors are drawn from a uniform distribution across the full range of those modeled in the scenario-based projections. Year-2050 distributions of GDP/capita, population, and oil price for these model runs are shown in 2 . EU Aviation sector Allowances (EUAAs) are allocated to cover emissions below this baseline, 85% of which are freely allocated via benchmarking or the new entrants’ reserve, and 15% of which are auctioned. Emissions above the baseline must be accounted for via the purchase of allowances (EUAs) from other sectors. The aviation cap will decrease by a Linear Reduction Factor (LRF) of 2.2% per year from 2021 to 2030, in line with other ETS sectors , though the LRF may be increased as part of the “Fit for 55” package . In 2019, around 48% of EU ETS-eligible direct aviation CO2 was above the baseline. This means that a 50% reduction in aviation demand at constant aircraft utilization by type and load factor would likely take emissions below the baseline. However, both aircraft utilization by type and load factors have changed substantially. The future scope of the scheme, as well as the continuation of the LRF past 2030 and free allowance allocation, are under regular review and may be subject to change . For this analysis, we assume that the EU ETS continues to apply to intra-EEA flights  and that the same LRF and auctioning percentage continue to apply through to 2050.The EU ETS currently applies to intra-European Economic Area (EEA) flights. An aviation emissions baseline is set corresponding to 95% of average year 2004–2006 aviation CO2 baseline. This has recently been adjusted to a year-2019 baseline only . As noted by several authors , a 2019 baseline would imply no offsets under CORSIA until demand recovers, potentially leading to zero offset requirements in the pilot and/or first phases of the scheme. Initially, all airlines on eligible routes pay carbon costs under CORSIA corresponding to the amount by which total scheme emissions are above the baseline. From 2030 on, the scheme shifts to a combination of global and individual airline responsibility for growth in emissions. This shift effectively lowers the baseline slightly, as under individual responsibility airlines that can reduce their own emissions below the baseline have zero offset requirements rather than lowering the offset requirement for others. We assume participation throughout all phases of the scheme is limited to those countries that have indicated to ICAO that they will participate, that is, excluding India, China, Brazil, Russia, and Vietnam, and that the scheme is continued to 2050.For CORSIA, global international aviation between participating countries was initially intended to be offset above an average year 2019–2020 direct aviation CO) (reaching around $150/tCO2 by 2050); following Department of Energy & Climate Change , when a range of carbon prices is used, we consider values beween the baseline and a higher trend reaching the upper-end values modeled in European Commission  in 2050 (around $430/tCO2).Different carbon prices apply to both schemes. Because the EU ETS is a carbon trading scheme, EU ETS carbon prices are a function of the cost of emissions reductions achievable across participating sectors and geographical regions. They are therefore sensitive to assumptions about the future level of ambition of the scheme and technical implementation details such as the Market Stability Reserve. As a baseline, we use carbon price projections from European Commission (2 ($1.2/tCO2) for the pilot and first phases of CORSIA, with the potential to rise to €4–10/tCO2 ($5–12/tCO2) if additional constraints on vintage or vulnerability are applied . We use this lower price trend as a baseline and the upper price trend as an upper limit where a range of values is modeled. However, because the CORSIA carbon price applies only to emissions above the baseline, the effective carbon price that airlines will pay is much lower than this, and the exact value chosen for CORSIA carbon price has little impact on outcomes.CORSIA Eligible Unit (CEU) prices are likely to reflect the cost of international carbon credits (CERs). Fearnehough et al. project that the cost of CER-type credits is likely to remain under €1/tCO). The next generation of aircraft designs is expected in the 2030–2035 time period  and these designs will likely dominate the year-2050 fleet. Although substantial research is ongoing into alternatives to conventional aircraft, including electric and hydrogen-fueled concepts, technology and infrastructure constraints likely mean that the full global potential of these designs is realizable only after 2050 without additional policy support; where literature estimates project significant aviation decarbonization before this date, this is typically assumed to arise via low-carbon drop-in fuels (either biofuels or power-to-liquids) or via offsets in other sectors . For this paper, we assume “business-as-usual”-type technology developments, that is, a kerosene-fueled next generation of aircraft, using technology and cost characteristics from ATA & Ellondee . For the main scenario runs, central values of these characteristics are used; where distributions of input values are assumed, we use triangular distributions bounded by the “optimistic” and “pessimistic” scenarios provided. Following Climate Change Committee , we assume up to 10% aviation biofuel use, with cost characteristics given by the cost curve model used in Dray et al. . The impact on outcomes of deviating from these (relatively conservative) technology assumptions are discussed below.The technological makeup of the global aircraft fleet in 2050 is uncertain. Because the typical lifetime of an aircraft to scrappage is 30 years, in the absence of a change in retirement behavior many aircraft delivered in 2020 will still be operating in 2050 , pre-COVID-19 industry projections  and alternative post-COVID-19 projections  are also shown. Black lines indicate COVID-19-adjusted scenarios; gray lines the corresponding scenarios without adjustment. For the final panel, (j), the level of net CO2 emissions consistent with carbon-neutral growth from 2019  is also shown. Because we assume a range of recovery scenarios, one impact of COVID-19 is an increase in the uncertainty range of demand and emissions outcomes. This in turn increases the challenges associated with planning for system recovery and future growth. However, all combinations of scenarios have year-2050 demand and emissions below those in the corresponding no-COVID-19 case, reflecting assumed offsets in economic growth. For the three main scenarios, which do not consider demand decoupling from GDP growth, RPK demand growth in the 2030–2050 period returns to values not far below recent growth trends (2.5%–3.8%/year). For the Decoupling scenario, which includes slow recovery, slow growth, and modest demand decoupling from economic growth, RPK grows in this period at 2.2%/year, a rate at which improvements in conventional technology could feasibly be fast enough for global CO2 emissions growth to be close to zero . Underlying growth rates and pandemic impacts vary by country and region. For example, scenario projections anticipate average year 2019–2050 RPK growth of 3.4%–5.1% in China (3.5%–5.2% without the impact of COVID-19), 2.0%–3.5% in the United States (2.1%–3.6% without the impact of COVID-19), and 2.5%–4.6% in Brazil (2.8%–4.8% without the impact of COVID-19).A summary of key global output metrics to 2050 with and without COVID-19 adjustment is shown in 2 per RPK flown; although this is also affected by changes in fleet composition and route type, the overall short-term impact on CO2/RPK that we project is an increase . Freight tonne-km (FTK) decreases by a relatively small amount, but the proportion of freight flown in freighter aircraft increases significantly over the 2020–2021 period before returning to more typical historical values.Over the short term, the largest impacts on aviation demand and emissions arise from border closures and other movement restrictions; these affect international passenger totals and RPK most strongly. Flights and fuel use are less affected owing to reductions in passenger load factor flown and owing to freighter-related components. Similarly, decreases in passenger load factor temporarily increase CO2 in the COVID-19-adjusted scenarios is 1260–2180 Mt, which is around 5%–7% below the corresponding non-COVID-19 cases.Of the different mechanisms discussed above by which the pandemic may affect long-term aviation demand and emissions, by far the largest direct impact comes from assumed offsets in economic growth leading to lower demand. By 2050, this channel of impact is responsible for nearly all differences between the COVID-19 and corresponding non-COVID-19 cases. In contrast, fuel burn impacts related to aircraft retirements during the pandemic are typically small and/or short-lived; over the longer term, there are small differences in fleet fuel efficiency compared with the corresponding non-COVID-19 cases as a result of a combination of lower demand growth leading to slower fleet turnover, reduced pandemic period demand for new aircraft displacing some new aircraft purchases to later dates, and small changes in aircraft size choice. These factors lead in combination to 0.5%–0.8% lower year-2050 fleet fuel use per revenue tonne-km (RTK) in the COVID-19 scenarios. By 2050, global projected direct aviation CO2 including the effect of offsets and allowances purchased from other sectors (panel [j]), under the assumption that CORSIA offsets equate to real, additional, and permanent reductions in CO2. This represents a lower limit in net climate impact as, historically, CERs have been of only limited additionality —however, CORSIA-eligible credits have additional requirements designed to improve this situation. 2 in 2050 under the “business-as-usual” policy and technology assumptions used here .), we project year-2019 global direct aviation CO2 of just over 900 Mt. Long-term net global aviation CO2 remains above this value in 91% of model runs, even once the impact of CORSIA and the EU ETS is considered. This reflects several factors. First, CORSIA excludes domestic aviation, so rises in domestic aviation CO2 (excluding EU ETS participants) are not subject to offsets. Second, CORSIA covers international routes between participating countries, so non-participation of individual states excludes all flights to and from those states. Although the EU ETS includes domestic flights and has a more stringent target, it covers only around 7% of global aviation CO2 at current scope. Third, under most combinations of input parameters long-term demand continues to grow. For the Decoupling scenario, year-2050 net aviation CO2 is only around 20% above year-2019 values, and at the low end of the model runs using probabilistic inputs, net aviation CO2 remains around or slightly below year-2019 values. None of the combinations of parameters investigated results in IATA’s target of year-2050 aviation CO2 emissions being half of year-2005 values  being met, with the lowest projected year-2050 net aviation CO2 being around 600 Mt. Meeting this goal would require significant changes in technology and/or aviation fuels, or significantly more stringent offset-related policy . As noted by Department for Transport , there is also a “long tail” of high emissions outcomes where long-term economic growth rates after the recovery period are on the upper end of those projected. As discussed above, the main impact of the COVID-19 pandemic on meeting year-2050 emissions targets is likely to be the extent to which the pandemic offsets or reduces global demand trends. In the case that economic recovery is rapid and attitudes to aviation do not change , the pandemic has limited impact on year-2050 emissions.Similarly to ICCT (b)–(d) of ). Because of different demand growth and participation assumptions, our estimated totals are typically lower than this, though we see similar offset totals (up to around 2380 Mt) in the long upper tail of probabilistic model runs. Offset totals are highly sensitive to demand growth and, to a lesser extent, technology characteristics. Under three of four COVID-19 scenarios investigated, and for 58% of the COVID-19 model runs with probabilistic inputs, we find zero or close to zero offsetting requirement during the pilot phase. For the Decoupling scenario, and for 37% of probabilistic COVID-19 scenarios, we find zero offsetting requirement in the CORSIA first phase as well, that is, CORSIA scope emissions remain below year-2019 values in these scenarios until at least 2026. For CORSIA’s second phase, all investigated scenarios have at least some offsetting requirement; this is driven by the switch toward individual rather than global-level offsetting requirements. However, 23% of probabilistic model runs have total second-phase offsetting requirements below 100 Mt—well below pre-COVID-19, high-participation, high-growth projections. Under these circumstances, CORSIA would have little impact on global aviation emissions, with slowing of net aviation CO2 growth driven largely by demand growth slowing relative to the rate of technological improvements.In panels  but, owing primarily to the EU ETS, net intra-EEA aviation CO2 decreases on average by 1.7%–2.5%/year over this time period (1.6%–2.4%/year for scenarios without COVID-19). Panel (e) of We project that European aviation COf) of ). Using this metric, we project reductions in cumulative net aviation CO2 by around 6%–9% from the no-COVID-19 case for the scenario model runs, depending primarily on the speed and extent of long-term economic recovery. Although none of the scenarios modeled here are consistent with net zero in the aviation sector , these reductions may still make emissions reductions that depend on finite resources  easier to achieve.Finally, panel , this may lead to reductions in anticipated cumulative year 2020–2050 global aviation CO2 of around 6%–9% compared with an equivalent case without the pandemic, and 2%–10% reductions in cumulative 2020–2050 airline profit. One impact of COVID-19 is to increase the already large level of uncertainty in relation to future aviation emissions , highlighting the importance of aviation emissions policy that is responsive to future developments.In this paper, we used systems modeling to generate initial scenarios for the long-term impacts the COVID-19 pandemic may have on aviation, in particular on emissions mitigation policy. Although outcomes are highly uncertain, both scenario-based modeling and projections using probabilistic inputs suggest some long-term impacts are likely. We find that long-term impacts from pandemic-induced fleet changes are likely small, but COVID-19-related economic impacts may translate into offsets in demand growth. In the case that these follow the pessimistic end of recovery projections . Under these assumptions, the aviation industry is unlikely to meet year-2050 targets. Even carbon-neutral growth from 2019, a relatively unambitious target, is missed in 91% of the COVID-19-adjusted probabilistic model runs, and all COVID-19-adjusted scenarios. No model runs meet the IATA target of halving year-2050 aviation CO2 relative to year-2005 levels. To meet or go beyond these targets, the reductions in typical demand growth modeled here are not sufficient. The extent to which radical technological change is achievable represents another degree of uncertainty to be explored if the aviation sector is to join others in decarbonizing. This includes the extent to which more ambitious policy on offsets, fuels  or alternative aircraft technologies can address the potential gap between targets and projections. Similarly, there is a need for future work which explores the extent to which changes in attitudes to aviation may affect ongoing demand for flights, and how this interacts with global and regional income levels by trip purpose, which is a key area of uncertainty in future projections.These model runs assume relatively conservative developments in aircraft and fuel technologies, consistent with recent historical trends and some projections of future developments (


We investigated whether changes in engagement in home-based creative activities were associated with changes in depressive symptoms, anxiety symptoms and life satisfaction during the COVID-19 pandemic, aiming to replicate findings from the UK in a USA sample.3725 adults were included from the COVID-19 Social Study in the USA, a panel study collecting data weekly during the COVID-19 pandemic. We measured engagement in eight types of creative leisure activities on the previous weekday between April and September 2020. Data were analysed using fixed effects regression models.Increased time spent gardening was associated with reductions in depressive and anxiety symptoms and enhanced life satisfaction. Spending more time doing woodwork/DIY and arts/crafts were also associated with enhanced life satisfaction. However, more time watching television, films or other similar media (not for information on COVID-19) was associated with increased depressive symptoms. Other creative activities were not associated with mental health or well-being.Some findings differ from evidence obtained in the UK, demonstrating the importance of replicating research across countries. Our findings should also be considered when formulating guidelines for future stay-at-home directives, enabling individuals to stay well despite the closure of public resources. During the COVID-19 pandemic in the UK, spending more time doing outdoor activities and creative hobbies was associated with improvements in depression, anxiety and life satisfaction.In the US, increases in time spent doing gardening, woodwork and DIY, and arts and crafts were longitudinally associated with improvements in mental health and wellbeing during the COVID-19 pandemic.Our findings demonstrate the importance of replicating research across countries, exploring how cultural or contextual nuances affect the associations between creative engagement and health outcomes. Future guidelines for stay-at-home directives should consider the role of creative leisure activities.Given the widespread stay-at-home orders during the COVID-19 pandemic, identifying activities that people engaged in at home and that helped to support their mental health and well-being is a key priority.In the USA, cross-sectional studies have found that self-reported decreases in leisure activities, compared with before the pandemic, were associated with higher depressive symptoms and lower well-being.Therefore, in this study, we aimed to replicate findings from the UK in a USA sample, with a focus on creative activities. There is extensive prepandemic longitudinal evidence that creative activities are beneficial for mental and physical health.https://github.com/UCL-BSH/CSSUserGuide; This panel study was a USA extension of the UK COVID-19 Social Study run by UCL (10.1136/jech-2022-219653.supp1Supplementary dataParticipants reported how long they had spent on the last weekday engaging in (1) reading for pleasure, (2) arts/crafts activities , (3) digital arts activities , (4) gardening, (5) watching television, films, Netflix or similar, (6) listening to the radio or music, (7) doing DIY (do-it-yourself), woodwork, metal work, model making or similar and (8) another hobby not already mentioned. Time spent on each activity was categorised as none, low (<30 min) or high (≥30 min).Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9).Most demographic, socioeconomic and health-related covariates were measured at baseline in this study , diagnosed mental health problem, diagnosed physical health problem or disability). However, several COVID-19-related factors were reported in each wave. We measured  whether participants: had ever been diagnosed with or suspected having COVID-19; had been in contact with someone with COVID-19 in the last week; had lost their job, partner lost their job or had a major cut to household income due to changes in employment; were unable to pay bills, rent or mortgage, or were evicted or lost accommodation; had face-to-face contact or a phone or video call with another person for 15 min or more. We also measured whether participants’ isolation status .Fixed effects models tested the longitudinal associations of engagement in creative leisure activities with mental health and well-being. This approach uses only within-individual variation to examine how change in activity engagement is related to change in mental health within individuals over time. All time-invariant factors are accounted for automatically, even if unobserved. We standardised all outcomes and tested three models, using depressive symptoms, anxiety symptoms and life satisfaction as separate outcomes, including all leisure activities simultaneously. We then adjusted these fixed effects models for time-varying covariates.In sensitivity analyses, we first tested whether the associations between leisure activities, mental health and well-being differed according to baseline employment status. We then included a combined index of time spent on creative hobbies  to allow comparison to previous research.After weighting, 49% of the sample were aged 30–59 years, 59% were female and 81% were white . ParticiThe largest reduction in depressive symptoms was for participants who increased their time spent gardening from none to less than 30 min per day . More thGardening was the only activity associated with changes in anxiety symptoms. Only increasing time spent gardening to less than 30 min per day was associated with lower anxiety symptoms, and this association was maintained after adjusting for time-varying covariates.Increases in time spent doing arts/crafts, gardening and doing woodwork/DIY were associated with higher life satisfaction. The largest improvement was for participants who increased their time spent doing woodwork/DIY from none to more than 30 min per day. Increasing from no gardening and not doing arts/crafts to more than 30 min per day was also associated with improved life satisfaction. Adjusting for time-varying covariates did not alter these associations.There was no evidence that any of the associations between time on spent on creative leisure activities, depressive or anxiety symptoms, or life satisfaction differed according to employment status . AdditioIn the USA, during the COVID-19 pandemic, increased time spent on gardening was associated with reductions in depressive and anxiety symptoms and enhanced life satisfaction. Spending more time doing woodwork/DIY and arts/crafts were also associated with improvements in life satisfaction. However, spending more than half an hour per day watching television or other similar media was associated with increases in depressive symptoms.During the UK COVID-19 lockdown, increases in watching television were also associated with higher depressive symptoms, but not anxiety symptoms or life satisfaction.Evidence that gardening was associated with mental health and well-being is in line with findings from the UK lockdownThe lack of evidence for associations between other creative leisure activities and mental health and well-being was unexpected. During the UK lockdown, creative hobbies, reading for pleasure and listening to music were associated with reduced depressive and anxiety symptoms and enhanced life satisfaction.This study has several strengths, including the large sample, with follow-ups over 12 waves during the first 5 months of the COVID-19 pandemic. We measured longitudinal changes in time spent on leisure activities instead of relying on self-reported changes in engagement (compared with before the pandemic) as in previous cross-sectional studies.During the COVID-19 pandemic in the USA, doing gardening, woodwork/DIY and arts/crafts had the most potential to improve mental health and well-being. Despite the similarity of our approach to previous research, our findings differ from evidence obtained in the UK.


Coronavirus disease 2019 (COVID-19) mRNA vaccines are associated with an increased risk of myocarditis using hospital discharge diagnoses as an outcome. The validity of these register-based diagnoses is uncertain.Patient records for subjects < 40 years of age and a diagnosis of myocarditis in the Swedish National Patient Register were manually reviewed. Brighton Collaboration diagnosis criteria for myocarditis were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy. Poisson regression was used to estimate incidence rate ratios, comparing the register-based outcome variable to validated outcomes. Interrater reliability was assessed by a blinded re-evaluation.Overall, 95.6% (327/342) of cases registered as myocarditis were confirmed . Of the 4.4% (15/342) cases reclassified as no myocarditis or as insufficient information, two cases had been exposed to the COVID-19 vaccine no more than 28 days before the myocarditis diagnosis, two cases were exposed >28 days before admission and 11 cases were unexposed to the vaccine. The reclassification had only minor impact on incidence rate ratios for myocarditis following COVID-19 vaccination. In total, 51 cases were sampled for a blinded re-evaluation. Of the 30 randomly sampled cases initially classified as either definite or probably myocarditis, none were re-classified after re-evaluation. Of the in all 15 cases initially classified as no myocarditis or insufficient information, 7 were after re-evaluation re-classified as probable or possible myocarditis. This re-classification was mostly due to substantial variability in electrocardiogram interpretation.This validation of register-based diagnoses of myocarditis by manual patient record review confirmed the register diagnosis in 96% of cases and had high interrater reliability. Reclassification had only a minor impact on the incidence rate ratios for myocarditis following COVID-19 vaccination. A large study based on nationwide health registers in Denmark, Finland, Norway and Sweden has demonstrated that both first and second doses of mRNA Coronavirus disease 2019 (COVID-19) vaccines are associated with an increased risk of myocarditis and pericarditis , electrocardiogram (ECG), echocardiography, serum biomarkers for myocardial injury, magnetic resonance imaging (MRI) and/or endomyocardial biopsy . There aThe aim of this study was to validate the accuracy of a myocarditis diagnosis when based on ICD-10 hospital discharge diagnoses in the Swedish National Patient Register, applying the proposed Brighton Collaboration criteria in a structured manual review of patient records.To enable pharmacoepidemiological studies of the COVID-19 vaccines, the Swedish Medical Products Agency has set up a regularly updated dynamic nationwide register-based study cohort (CoVacSafe-SE). This research database has been generated from individual-level linkage of COVID-19 vaccination exposure data to other national health data registers . It primFor validation of ICD-10 diagnoses of myocarditis, registered in the Swedish National Patient Register and linked to CoVacSafe-SE, we selected individuals 12–39 years old having an incident hospital discharge diagnosis of myocarditis identified during the study period from 27 December 2020 to 13 November 2021. These selection criteria are identical to those in the Nordic study on SARS-CoV-2 vaccination and myocarditis  I400, I401, I408, I409, I411, I418 or I514 after an in-hospital stay. Diagnoses in CoVacSafe-SE originate from exact person-based linkage to the Swedish National Patient register using the unique personal identification number .Patient records covering the hospital separation where a myocarditis diagnosis occurred first were requested from that specific hospital department. Brighton Collaboration criteria for the level of evidence were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy to verify the diagnosis of myocarditis. A structured electronic questionnaire was developed to capture the basic information required for the application of the Brighton Collaboration criteria for the level of evidence (see variable list in Table S1) . AccordiTo evaluate interrater reliability, we randomly selected 15 records  from each Brighton Collaboration level for re-evaluation in a new round of patient record review. The same group of raters was used, but each rater could only reassess patient records reviewed by another rater in the first round of manual record review. Also in this second round of review, the contracted senior cardiologist could be consulted at the discretion of the individual rater.Based on the results of the patient record review we described the extent and pattern of reclassification and calculated the positive predictive value of a register-based diagnosis with 95% confidence interval (CI).possible (level 1–3) or probable (level 1–2). As only a random selection of myocarditis cases unexposed to the COVID-19 vaccine was validated, a random selection of unexposed myocarditis cases not validated was reclassified proportionate to the reclassification in the validated subset. Starting follow-up on 27 December 2020, we used Poisson regression to estimate incidence rate ratios (IRRs) with 95% CIs, comparing rates of myocarditis in 28-day risk periods after the administration date of the first and second dose of a COVID-19 vaccine to rates in unvaccinated periods, using time-varying exposures. Identical modelling of covariates as in the Nordic study was used  of the exposed cases and 188 (98.4%) of the randomly selected cases unexposed to the COVID-19 vaccine . In this population, 273 were males and 69 were females. Overall, unexposed cases tended to be more non-specific with a more complex clinical presentation. A lower proportion had elevated markers for myocardial damage and in more than half of these cases, no results from echocardiography were available . The chaAfter the patient record review, 95.6% (327/342) of the cases registered as myocarditis in the Swedish National Patient Register were confirmed as having myocarditis , while 4.4% (15/342) were reclassified as not having myocarditis . Of thespossible, the results were only marginally different compared to using the original register diagnosis . In all, 21 cases were initially classified as Brighton Collaboration level 3–5, of which all were sampled for re-evaluation. Among these 21 cases, eight out of the 12 reclassifications by a new rater had a direct impact on the binary outcome variable. After re-evaluation 12 of these 21 cases were classified within the Brighton Collaboration levels of evidence of at least possible (level 1–3).In total, 51 cases were sampled for a blinded re-evaluation . Of the Approximately 4% of the cases registered as myocarditis in the Swedish National Patient Register during the study period were reclassified as not having myocarditis. The proportion reclassified was slightly higher in the group unexposed to the COVID-19 vaccine compared to those exposed to the vaccine. When the risk for myocarditis related to COVID-19 vaccines was estimated, differences in the strength of association were minor when using an outcome measure based on the patient record review, compared to using the original register diagnosis.Before the COVID-19 pandemic, Swedish national register data have indicated a slightly increasing trend in the background incidence of myocarditis in subjects aged ≥16 years during the period 2000–2014 . During There are currently no internationally accepted consensus criteria for myocarditis. We used the recently proposed Brighton collaboration criteria as the basis for the manual patient record review . Other cIt may be difficult to apply myocarditis criteria to information extracted from patient records. Endomyocardial biopsy results are considered as a key component but are rarely justified in cases of uncomplicated myocarditis and has limited sensitivity . In our It is therefore important to look for interrater variability in a validation based on patient record review such as in the present study. The patient record review was not straightforward. Interrater reliability was very high in the Brighton Collaboration level 1 and level 2. However, interrater reliability was much lower in the 21 cases initially classified as level 3 to level 5, most likely related to the evaluation of electrocardiograms. This is not unexpected as substantial variability in ECG interpretation has been observed for physicians at all training levels, even after educational interventions –15. SeveIn a previous single-centre validation 507 electronic case records with a discharge diagnosis of myocarditis were systematically reviewed, and 421 (83.0%) could be verified as acute myocarditis . The redOur study has some notable limitations. The patient record review was not blinded to vaccine exposure status. It was considered unfeasible to reliably blind the reviewers. Redaction of the extracts from patient records would signal vaccination status or if too extensive threaten the overall clinical assessment of the case. Furthermore, our study design does not allow evaluation of potentially false negative cases as this would require a large sample of health-care contacts with plausible symptoms but without a diagnosis of myocarditis in the Patient Register. This limits the ability to generate estimates of sensitivity and specificity, which would have been helpful for quantitative bias analysis. Some caution must also be exerted before generalisation to other countries since coding practices for hospital discharge diagnoses may differ, and to age groups not represented in our study population.This validation of register-based diagnoses of myocarditis by manual patient record review confirmed the register diagnosis in 96% of cases and had high interrater reliability. Among the few cases not classified as definite or probable interrater reliability was much lower, mostly due to substantial variability in electrocardiogram interpretation. Reclassification had only minor impact on the incidence rate ratios for myocarditis following COVID-19 vaccination.Dr Sundström reported participating in research funded by governmental agencies, universities, Astellas Pharma, Janssen Biotech, AstraZeneca, Pfizer, Roche, (then) Abbott Laboratories, (then) Schering-Plough, UCB Nordic and Sobi, with all funds paid to Karolinska Institutet, outside the submitted work.Dr Grünewald reported being involved in the European Medicines Agency regulatory assessment of Comirnaty; being previously employed at a drug development consultancy firm with cross-product responsibilities and being involved on a project for pertussis vaccines funded by Sanofi Pasteur, Merck Sharp & Dohme Corp, and GlaxoSmithKline at the Swedish Agency of Infectious Disease Control.Dr Ljung reported receiving grants from Sanofi Aventis paid to his institution outside the submitted work and receiving personal fees from Pfizer outside the submitted work.This research was conducted as a pharmacovigilance activity by the Medical Products Agency, which is a Swedish Government agency. The study did not receive any external funding.https://orcid.org/0000-0002-8850-7863Rolf Gedeborg https://orcid.org/0000-0002-0654-4530Rickard Ljung https://orcid.org/0000-0002-1738-0834Björn Zethelius https://orcid.org/0000-0003-2337-3371Anders Sundström https://orcid.org/0000-0002-8806-5778Kai Eggers https://orcid.org/0000-0003-1460-4078Nils Feltelius https://orcid.org/0000-0002-9280-8140Maria Grünewald Click here for additional data file.


Consequently, HIV counselling settings should implement suicide risk reduction initiatives. Physical activity (PA) counselling could be a relevant add-on intervention. The aim of this secondary analysis from a single-arm pre- and post-study exploring the efficacy of PA counselling for HIV/AIDS patients with mental health problems was to investigate the efficacy of PA counselling on reducing suicidal ideation.out of 41 participants in an 8-week PA counselling intervention, 15 participants reported suicidal ideation. These 15  participants completed the Patient Health Questionnaire-9 (PHQ-9), Alcohol Use Disorder Identification Test -10 (AUDIT-10), and the Simple Physical Activity Questionnaire (SIMPAQ) pre- and immediately post-intervention.the prevalence of suicidal ideation (PHQ-9 item 9≥1) dropped to 20% post-intervention, i.e. only three patients with HIV still reported suicidal ideation. Also, following the intervention significant (P<0.05) increases in walking and incidental PA (SIMPAQ) levels, and reductions in depressive and alcohol abuse symptoms were observed.our data demonstrate that PA counselling might be promising in reducing suicidal ideation in most HIV patients in low-resourced settings. Randomized controlled trials are warranted to confirm these beneficial findings. Mental health and HIV/AIDS are strongly interlinked. One is affecting  and predRecently, the role of lifestyle psychiatry has been acknowledged as a promising non-pharmacological intervention for reducing the burden of poor mental health ,17. PhysIn a pilot study , we demoStudy design: this is a secondary analysis of a pre-test/post-test study without a control group  were included in this secondary analysis study. Four patients had a paid job, no single patient was taking psychotropic medication. The median body mass index was 23.3 (IQR=4.0). One participant smoked and reported to smoke on average one cigarette per day. Two patients complained of leg pain, three patients reported chronic asthma, three chronic cardiovascular symptoms, four chronic low back pain and four chronic joint pain. Five patients reported multi-morbidity, i.e. two or more chronic conditions.Changes in clinical variables following the 8-week physical activity counselling: between baseline and 8 weeks of counselling, the prevalence of suicidal ideation reduced from 100 to 20.0% (P=0.001). Only three participants reported suicidal ideation post-intervention. Other changes in time of the clinical characteristics are presented in To the best of our knowledge, the current study is the first to indicate that in a remote fishing community an 8-week physical activity counselling program using a SDT and motivational interviewing framework reduces levels of suicidal ideation. An interesting observation is that only women with HIV/AIDS reported suicidal ideation in the current study. Recently, a gender-based meta-analysis found that the prevalence of suicide/suicidal ideation is higher among women compared to men . TherefoOur study adds to the existing literature that lifestyle interventions might be a potential strategy to reduce suicide risk in low-resourced settings, and in particular for women. A secondary finding was that in the fifteen included patients with suicidal ideation the levels of depression and alcohol abuse also reduced, and levels of physical activity increased. One of the potential underlying mechanisms for the reduced suicidal ideation therefore might be these reductions in symptomatology, which are known risk factors for suicidal risk -46. TherLimitations and future research: the findings of the present study should however be interpreted with caution due to some methodological limitations. First, although suicidal ideation reported via item 9 of the PHQ-9 is a robust predictor of suicide attempts and deaths regardless of age, and this for increased risk for two years [wo years , it shouwo years . Fourth,Despite the reported limitations, it can be concluded that in the majority of patients with HIV/AIDS and a co-morbid mental disorder, suicidal ideation reduced following a physical activity counselling program based on SDT principles and a motivational interviewing framework. Reductions in suicidal ideation are accompanied with reductions in depression and alcohol abuse and increases in physical activity levels. Benefits can be obtained within 8 weeks and in challenging low-resourced settings such as in the Ugandan fishing community in our study.Compared to the general population, people living with HIV/AIDS have a 100-fold higher risk of completed suicide;HIV counselling centers are knowledgeable about suicide and associated risk factors, but report challenges in assessing and managing individuals with suicide risk;Physical activity is a low-cost lifestyle intervention which could be promising in reducing suicidal risk.In the majority of patients with HIV/AIDS and a co-morbid mental disorder, suicidal ideation reduces following a physical activity counselling program;The self-determination theory principles and a motivational interviewing framework can be successfully implemented in physical activity interventions in low-resourced settings;Reductions in suicidal ideation are accompanied with reductions in depression and alcohol abuse.