Ancient and historical DNA in conservation policy

Although genetic diversity has been recognized as a key component of biodiversity since the first Convention on Biological Diversity (CBD) in 1993, it has rarely been included in conservation policies and regulations. Even less appreciated is the role that ancient and historical DNA (aDNA and hDNA, respectively) could play in unlocking the temporal dimension of genetic diversity, allowing key conservation issues to be resolved, including setting baselines for intraspecies genetic diversity, estimating changes in effective population size (N-e), and identifying the genealogical continuity of populations. Here, we discuss how genetic information from ancient and historical specimens can play a central role in preserving biodiversity and highlight specific conservation policies that could incorporate such data to help countries meet their CBD obligations.Peer reviewe

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Management of mixed cod stocks in the transition zone between the North Sea and the Baltic Sea: How can this be achieved efficiently? (FABBIO)

The project ”Management of mixed cod stocks in the transition zone between the North Sea and the Baltic Sea: How can this be achieved most efficiently?” focused on one of the key challenges for assessment and management of fish stocks: Movement of individuals and stocks mixing. The project focused on resolving issues of stock mixing in cod stocks between the North Sea (Subarea 4), Skagerrak (SD 20), Kattegat (SD 20), the western Baltic (Belt Sea (SD 22), and Sound (SD 23)), and the eastern Baltic Sea (SDs 24 – 32). The project was funded by European Maritime and Fisheries Fund and the Danish Fisheries Agency. The activities in the project involved providing new biological knowledge on genetic and ecological connectivity, advancing methods, and providing a tool to evaluate the impact of stock mixing on stock assessment.Genetic identification of populationsFull genome resequencing data revealed marked genetic differences between samples of fish at spawning time collected in the North Sea, eastern Baltic Sea and the transition zone between the two areas (i.e. SD 21-SD 24). In contrast, we found limited divergence between spawning fish collected in the southern Kattegat, Belt Sea, Sound and Arkona Sea (SD 24, spring), suggesting that these fish belong to the same biological population, identifying a total of three major biological units for management in this system. Weaker gradient signals within the transition zone may be related to introgression in the hybrid zone from parental populations in the North Sea and eastern Baltic Sea, and they are much weaker than any difference observed between the three populations. Future sampling may refine these analyses, in particular regarding the relationship between spawning fish in the transition zone. However, they are not expected to change the overall relationship and magnitude of differentiation between the three populations presented in the currentreport.Genetic identification of population mixingThrough the use of a panel of genetic markers specifically designed to identify population of origin in a scenario with three baselines (North Sea, transition zone, eastern Baltic Sea, as supported by the genomic analyses above) we analyzed samples collected across the full transition zone to estimate proportions from the three baseline populations. The results confirmed previous findings of substantial mixing in the Kattegat and Arkona Sea, with North Sea fish and transition zone fish mixing in Kattegat and eastern Baltic Sea fish and transition zone fish mixing in the Arkona Sea. We also confirmed the gradient of mixing in the Kattegat, with higher proportions of North Sea fish in the northern parts of the area. In contrast, we found limited mixing in the Belt Sea and the Sound where fish appeared to be primarily of transition zone origin. While data for older age classes were limited, we also found evidence for higher proportions of North Sea fish among younger age classes, as also reported in previous studies.Natal origin and movements of adultsThis project investigated the natal origin and adult movements of cod in the transition zone, focusing on spatial differences in the chemical composition (the chemical “fingerprint”) recorded in the cod’s otoliths. Examining the elements analyzed in this study, it becomes apparent that they reflect gradients in environmental conditions and physiological processes, aligning with known mechanisms of otolith biomineralization. Therefore, otolith chemistry proves to be a suitable method for assessing the movement patterns of fish in the transition zone.The analyses of the otolith cores, representing the natal origin of cod, revealed spatial variations in their chemical fingerprint, indicating at least three different clusters (= spawning areas). Without baseline samples from cod larvae, it is not possible to identify where these spawning areas are, but combined with knowledge of known spawning areas, the results suggested that the cod originated primarily from the North Sea (concentrated in the Skagerrak and northern Kattegat), the Southern Kattegat (spread throughout Kattegat and partly in the Sound and Belt Sea), and the Belt Sea (predominantly found in the Belt Sea and the Sound). The contribution of the spawning area clusters varies significantly among different year classes of cod, indicating fluctuations in the relative contribution of cod originating from each spawning area.Cod inhabiting the Skagerrak and northern Kattegat regions either exhibit a similar chemical fingerprint throughout their lives or exhibit extensive mixing. Generally, these cod populations do not migrate south into the western Baltic Sea. However, some cod in the southernmost Kattegat display a Belt Sea/Sound signal throughout their lives, which is likely not due to movements but rather due to the incomplete alignment of environmental gradients with the boundaries of management areas. In contrast, the Belt Sea region predominantly hosts cod that remain resident throughout their lives, with minimal movements observed. In contrast, cod in the Sound region show a connection with the Belt Sea. The majority of cod immigrate from the Belt Sea to the Sound before the age of 3 and tend to remain resident there. However, occasional Belt Sea signals detected at irregular intervals suggest some movement in and out of the Sound.The combined analysis of natal origin and adult movements provided valuable insights into the dynamics of the cod population in the transition zone. While cod in this zone may originate from different spawning areas, they are largely resident within the respective management areas as adults. Consequently, the project results suggested the presence of an ecological stock separation into two distinct stocks: The Skagerrak/Kattegat and the Belt Sea/Sound.Stock mixing: Combining genetics and otolith chemistryCollectively, the compilation of knowledge gained from historical data and new samples, from genome sequencing and otolith chemistry, indicate that there is considerable genetic and ecological structuring of cod between the North Sea and the Baltic Sea, with three genetically distinct populations: 1. North Sea, 2. eastern Baltic Sea and 3. transition zone (Kattegat, Belt Sea, Sound and Arkona Sea). The geographic distribution of these populations overlap in the Kattegat and Arkona Sea, respectively. While it was not possible to detect genetic differentiation in the transition zone, otolith chemistry revealed considerable ecological stock structuring. This scenario is consistent with considerable exchange of individuals between areas, presumably as a result of drift of early life stages. While cod in the transition zone may originate from different spawning areas (two apparently distinct areas were identified), they are largely resident within the geographical areas they settle into as adults. This leads to stock structuring in the transition zone with an ecological separation into two distinct components: 1. the (eastern) Skagerrak and the Kattegat, 2. the Belt Sea and the Sound.For cod in Belt Sea, the Sound and the spring-spawners in the Arkona Sea, the combined genetic and otolith chemistry results thus indicate that the current management area for western Baltic is appropriate. In the Kattegat, the spatially and temporally variable mixing dynamics with the North Sea need to be considered for a sustainable management of the stock, similarly to the mixing scenario with the eastern Baltic cod in the Arkona Sea. Recommendations as to what type of stock assessment approach is most suitable for this complex system of genetic and ecological stock structuring is not within the scope of this project.Impact of fish movements and stock mixing on stock assessmentThis project implemented the prototype of a simulation tool to evaluate migration impacts on stock assessment and propose mitigation strategies. While functional, the tool can be improved with documentation, user-friendly implementations, and inclusion of additional factors. Simulations highlighted challenges in specifying complex scenarios and limited data availability. Migration patterns affected assessment data. Closing parts of the norther Kattegat, for example, showed potential for stock recovery. A cost-benefit analysis compared genetic samples and otolith shape analysis for stock composition estimation. Precision and cost influenced the choice between methods. Note that the analysis did not consider sample collection or baseline costs. Given the new biological knowledge on genetic and ecological stock structure, movement patterns in the transition zone from the North Sea to the eastern Baltic, this will be the next focus area for the application of this tool.Potential management scenariosBased on the collective genetics, otolith chemistry and modelling simulation results from this project, we have identified three different scenarios for how stock mixing could be implemented in stock assessment and management for cod stocks in the transition zone:• Area-based assessment and management – current scenario. This is a status quo scenario, where current practices are continued with two distinct stocks in the transition zone: Kattegat and the western Baltic Sea (Belt Sea, Sound and Arkona Sea), with separate stock assessments and TACs, irrespective of genetic population. Stock mixing of eastern/wester Baltic cod in the Arkona Sea is already implemented in stock assessment. By not addressing stock mixing of North Sea/Kattegat populations, the severely declined Kattegat population is at risk of local depletion.• Area-based assessment and management – updated scenario. This scenario implies continuing with current practices of separate stock assessments for the current management areas Kattegat and western Baltic Sea (Belt Sea, Sound and Arkona Sea). In addition to the stock mixing of eastern/wester Baltic cod in the Arkona Sea the mixing of North Sea and Kattegat cod in the Kattegat should be addressed in a similar approach. This scenario disregards the fact that cod in the transition zone are genetically the same population, but would on the other hand reflect the ecological stock structuring, and thereby minimize the risk of local depletion of population components.• Population-based stock assessment and management. A population-based approach to stock assessment would require cod from the Kattegat, Belt Sea, Sound and Arkona Sea to be combined into a single stock representing the genetic “transitions zone population”. Stock mixing proportions in the transition zone population would need to be estimated for these areas, based on a genetic split of commercial and survey data. Subsequently, TACs can be allocated to exiting management areas, but should be informed by genetic estimates of mixing proportions in the different management areas to link estimated harvest rates in geographical areas to the stock assessments/advice for the underlying biological populations. components not accounted for with genetic split data, ii) how to allocate area-specific TACs, and iii) how to deal with social and political considerations

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trialResearch in context

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols