The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has brought distinct challenges to the care of children and adolescents globally. Unusually for a respiratory viral infection, children and adolescents are at much lower risk from symptomatic coronavirus disease 2019 (COVID-19) than any other age group. The near-global closure of schools in response to the pandemic reflected the reasonable expectation from previous respiratory virus outbreaks that children would be a key component of the transmission chain. However, emerging evidence suggests that this is most likely not the case. A minority of children experience a postinfectious inflammatory syndrome, the pathology and long-term outcomes of which are poorly understood. However, relative to their risk of contracting disease, children and adolescents have been disproportionately affected by lockdown measures, and advocates of child health need to ensure that children’s rights to health and social care, mental health support, and education are protected throughout subsequent pandemic waves.
Evidence from contact-tracing studies suggest that children and teenagers are less susceptible to SARS-CoV-2 infection than adults; however, community swabbing and seroprevalence studies conducted outside of outbreak settings suggest that infection rates are similar to those in older age groups (1–3). Only half of children and teenagers with antibodies against SARS-CoV-2 have experienced symptoms, and there is growing evidence that there is a broad range of presentations, emphasizing the limitations of community-based prevalence studies based on testing only children with respiratory symptoms. Hospitalization for severe acute COVID-19 in children is rare, but among these pediatric inpatients, respiratory symptoms are more apparent than in infected children in the community (4). Case fatality in hospitalized children is, fortunately, relatively low at 1% (compared with 27% across all ages) (4).
The reason for the lower burden of symptomatic disease in children is not yet clear. Upper airway expression of angiotensin-converting enzyme 2 (ACE2), a receptor for the SARS-CoV-2 spike protein, increases with age, and higher ACE2 expression correlates with being positive for SARS-CoV-2 genomic RNA in swabs of upper respiratory tracts from symptomatic children, but not with viral load (5). An alternative proposal is the absence in children of maladaptive immune responses that lead to acute respiratory distress syndrome (ARDS) in older age groups (6), but there are likely other unidentified mechanisms.
Understanding the nature of immune responses in children is important given the rare, but potentially severe, multisystem inflammatory syndrome observed in more than 1000 children and adolescents in multiple countries during the first wave of COVID-19 (7). Known variously as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), multisystem inflammatory syndrome in children (MIS-C), or Kawasaki-like disease, the illness presents with persistent fever accompanied, to a variable extent, by gastrointestinal symptoms, rash, and conjunctival inflammation. Laboratory markers of inflammation are very high, and myocarditis is a distinct, and potentially fatal, feature. Children and young people with PIMS-TS are more likely to have antibodies to SARS-CoV-2 than evidence of virus from nasal swabs, with presentations usually 4 to 6 weeks after infection. The cardiac involvement initially led to this condition being described as a variant of Kawasaki disease (in which an unknown trigger leads to an inflammatory disease, resulting in coronary artery inflammation). However, a comprehensive case series clearly delineated PIMS-TS from Kawasaki disease, with children who experience PIMS-TS being substantially older and with increased circulating concentrations of ferritin (a marker of inflammation) and D-dimer and troponin (markers of cardiovascular damage), which are rarely seen in Kawasaki disease (8). A dominant feature of PIMS-TS is myocarditis, transient myocardial dysfunction, and shock, which are present in approximately half of UK and U.S. case series (8, 9).
In the UK, a Delphi national consensus statement has recently been proposed (10) to guide investigation and management of this condition, which focuses on supportive care and enrolling patients into a specific arm of the RECOVERY randomized controlled trial to evaluate the use of corticosteroids and intravenous immunoglobulin in patients with acute PIMS-TS. Fortunately, fatalities are rare [occurring in 10 of the 570 cases reported to the U.S. Centers for Disease Control and Prevention between March and July 2020, and none of 52 cases in a UK series (4, 9)]. However, the long-term consequences are unknown, and all children and teenagers who experience PIMS-TS require ongoing cardiac review. Proposed mechanisms for this illness have focused on a maladaptive acquired immune response to SARS-CoV-2 infection, and a dysregulated humoral immune response is suggested by increased antibodies against multiple, non–SARS-CoV-2, respiratory viruses in severe MIS-C but not mild MIS-C or acute COVID-19 (5).
Understanding this response is crucial when considering the risks and benefits of immunizing children against COVID-19, should a vaccine become available. Of the vaccines being tested in clinical trials, none have yet been administered to children, with priority instead being given, appropriately, to older age groups. The most advanced candidate, ChAdOX1-nCOV-19, is currently in phase 2 and 3 studies that include a pediatric arm for 5 to 12 year olds (NCT04400838), receiving half the full adult dose in this study. However, this study arm is not currently active and will commence enrolment only once the safety profile in adults is more complete. Given the low rates of disease in children, they are likely to be a low priority to receive a vaccine unless it is definitively shown that (i) children have an important role in the transmission of the virus and (ii) the vaccine reduces viral shedding (and hence reduces transmission).
To what extent do children transmit SARS-CoV-2? Recent reports that young children acutely unwell with COVID-19 have concentrations of viral RNA in nasal aspirates that are similar to, or higher, than adults (5) raised concerns that their role in transmission may have been underestimated. However, one of these studies compared children within the first week of illness with adults with more than 7 days of symptoms, when viral load is expected to be reduced (5). Such studies need to be interpreted with consideration of the very low numbers of children with symptomatic COVID-19.
Of greater concern is the possibility that viral shedding could be occurring from asymptomatic children and that, given schools “bridge” households, this could create a pool of ongoing viral circulation responsible for introductions of virus to the pupils’ homes and beyond. Understanding this issue is fundamental to resolving what has been an unprecedented global disruption to primary (children of ∼5 to 11 years) and secondary (children aged 11 to 18 years) education. Given the near universal closing of schools in conjunction with other lockdown measures, it has been difficult to determine what benefit, if any, closing schools has over other interventions. However, there is some reassurance: Multiple studies of contacts of primary and secondary school children with known SARS-CoV-2 infection showed minimal onward transmission in schools (3). Furthermore, after the reopening of primary schools in the UK, only 1 of 23,358 nasal swabs taken from children in June 2020 had detectable SARS-CoV-2, giving an estimate of 3.9 cases per 100,000 students (2). Looked at from another perspective, when household outbreaks of infection have occurred, it appears that children were responsible for only a small minority of household introductions of the virus. Also, recent surveys found that reopening of schools in a number of European countries in April and May had no clear impact on community transmission, with cases continuing to fall in most countries after reopening (11).
Nevertheless, recent experiences of substantial outbreaks of COVID-19 related to children and teenagers show that there is no room for complacency. In May, an Israeli secondary school was shut shortly after a postlockdown reopening after the identification of two symptomatic students independently infected with SARS-CoV-2. A subsequent schoolwide testing campaign revealed that 153 (13.2%) students and 25 (16.6%) staff had detectable SARS-CoV-2 infection, and contact tracing revealed a further 87 cases in non–school attendees (12). Although formal studies were not conducted to definitively show school-based transmission, potential contributory factors included a heat wave that led to extensive use of air-conditioning and exemptions from face mask wearing, relatively crowded classrooms (with 35 to 38 per class with 1.1 to 1.3 m2 between students), and shared schoolyard and outdoor spaces.
As schools in the Northern Hemisphere reopen after summer holidays, risk mitigation strategies adopted to variable degrees include creating separate cohorts (or “bubbles”) within schools that interact minimally with each other, use of face masks in crowded areas (if not the classroom itself ), and regular screening of students and staff. The coming months will provide an invaluable opportunity to identify which of these measures are most effective at minimizing transmission, to generate a standard “best practice” that balances young peoples’ rights to an education with the need to protect the broader community from further transmission. However, it is inevitable that there will be students attending school while infected with SARS-CoV-2, and likely there will be some school outbreaks, with the frequency of these events reflecting levels of community transmission. Regardless, it is hard to support the opening of retail and hospitality sectors while schools remain shut, as occurred in many countries earlier this year.
School closures and attendant loss of other protective systems for children (such as limited social care and health visiting) highlight the indirect, but very real, harms being disproportionately borne by children and teenagers as a result of measures to mitigate the COVID-19 pandemic. In the UK, it is estimated that the impact on education thus far may lead to a quarter of the national workforce having lower skills and attainment for a generation after the mid-2020s, leading to the loss of billions of dollars in national wealth (11). Additionally, there are a variety of other harms to children’s health, including the risk of reemergence of vaccine-preventable diseases such as measles because of disruptions to immunization programs.
There are many other areas of potential indirect harm to children, including an increase in home injuries (accidental and nonaccidental) when children have been less visible to social protection systems because of lockdowns. In Italy, hospitalizations for accidents at home increased markedly during the COVID-19 lockdown and potentially posed a higher threat to children’s health than COVID-19 (13). UK pediatricians report that delay in presentations to hospital or disrupted services contributed to the deaths of equal numbers of children that were reported to have died with SARS-CoV-2 infection (14). Many countries are seeing evidence that mental health in young people has been adversely affected by school closures and lockdowns. For example, preliminary evidence suggests that deaths by suicide of young people under 18 years old increased during lockdown in England (15).
The role of children in transmission of SARS-CoV-2 remains unclear; however, existing evidence points to educational settings playing only a limited role in transmission when mitigation measures are in place, in marked contrast to other respiratory viruses. In the event of seemingly inevitable future waves of COVID-19, there is likely to be further pressures to close schools. There is now an evidence base on which to make decisions, and school closures should be undertaken with trepidation given the indirect harms that they incur. Pandemic mitigation measures that affect children’s wellbeing should only happen if evidence exists that they help because there is plenty of evidence that they do harm.
Deep abiotic weathering of pyrite
Getting rid of fool’s gold
Pyrite, also called fool’s gold, is an iron sulfide mineral that is very commonly found in rock but is almost nonexistent in sediments today. Pyrite oxidizes quickly and is a major source of sulfur to the ocean, but it is also a proxy for the oxygen content historically in Earth’s atmosphere. Gu et al. conducted a set of detailed observations of the pyrite oxidation process in a shale unit. The authors found that erosion tied to fracturing is just as important as the oxygen content for the dissolution process. They developed a model that helps determine the conditions in Earth’s past for which pyrite might have been stable and the role of microorganisms in the oxidation process.
Science, this issue p. eabb8092
Oxidative weathering of pyrite, the most abundant sulfide mineral in Earth’s crust, is coupled to the biogeochemical cycles of sulfur, oxygen, carbon, and iron. Pyrite oxidation is key to these cycles because of its high reactivity with oxygen. Before the Great Oxidation Event (GOE), atmospheric oxygen concentrations were low on early Earth and pyrite was exposed at Earth’s surface, allowing erosion into sediments that were preserved in river deposits. Today, it oxidizes at depth in most rocks and is often not exposed at the land surface. To understand pyrite weathering through geologic time, researchers extrapolate the reaction kinetics based on studies from the laboratory or in acid mine drainage. Such work has emphasized the important role of microorganisms in catalyzing pyrite oxidation. But to interpret the oxidation rates of pyrite on early Earth requires knowledge of the rate-limiting step of the oxidation as it occurs naturally in rocks.
We investigated the oxidation of pyrite in micrometer-sized grains, in centimeter-sized rock fragments, and in meter-scale boreholes at a small, well-studied catchment in a critical-zone observatory. Our goal was to determine the reaction mechanism of pyrite weathering in rocks as it occurs today. The slow-eroding catchment is underlain by shale, the most common rock type exposed on Earth. We determined weathering profiles of pyrite through chemical and microscopic analysis.
At the ridgelines of the shale watershed, most pyrite oxidation occurs within a 1-m-thick reaction zone ∼16 m below land surface, just above the depth of water table fluctuation. This is the reaction front at the borehole scale. Only limited oxidation occurs in halos around a few fractures at deeper depths. Above the depth where pyrite is 100% oxidized in all boreholes, rock fracture density and porosity are generally higher than below. However, the narrow parts of pore openings called pore throats remain small enough in oxidizing shale to limit access of microorganisms to the pyrite surface. During oxidation, iron oxides pseudomorphically replace the pyrite grains. High-resolution transmission electron microscopy (TEM) reveals that the oxidation front at grain scale is defined by a sharp interface between pyrite and an iron (oxyhydr)oxide (Fh) that is either ferrihydrite or feroxyhyte. This Fh then transforms into a banded structure of iron oxides that ultimately alter to goethite in outer layers. This complex oxidative transformation progresses inward from fractures when observed at clast scale.
Under today’s atmosphere, pyrite oxidation, rate-limited by diffusion of oxygen at the grain scale, is regulated by fracturing at clast scale. As pyrite is oxidized at borehole scale before reaching the land surface in most landscapes today, the oxidation rate is controlled by the movement of pyrite upward, which is in turn limited by the rate of erosion. Comparisons of shale landscapes with different erosion rates reveal that fracture spacing varies with erosion rate, so this suggests that fracture spacing may couple the landscape-scale to grain-scale rates. Microbial acceleration of oxidation globally today is unlikely in low-porosity rocks because pyrite oxidation usually occurs at depth, where pore throats limit access, as observed here for shales. Before the GOE, the rate of pyrite oxidation was instead controlled by the slower reaction kinetics in the presence of lower atmospheric oxygen concentrations. At that time, therefore, pyrite was exposed at the land surface, where microbial interaction could have accelerated the oxidation and acidified the landscape, as suggested by others. Our work highlights the importance of fracturing and erosion in addition to atmospheric oxygen as a control on the reactivity of this ubiquitous iron sulfide.
Pyrite oxidation was studied from the molecular (TEM) scale of the pyrite―Fe oxide interface through clast and borehole scales to extrapolate to landscapes. The rate of oxidation of pyrite, limited at grain scale by oxygen diffusion through the shale matrix, is regulated at larger scales by fracturing and erosion.
Pyrite is a ubiquitous iron sulfide mineral that is oxidized by trace oxygen. The mineral has been largely absent from global sediments since the rise in oxygen concentration in Earth’s early atmosphere. We analyzed weathering in shale, the most common rock exposed at Earth’s surface, with chemical and microscopic analysis. By looking across scales from 10−9 to 102 meters, we determined the factors that control pyrite oxidation. Under the atmosphere today, pyrite oxidation is rate-limited by diffusion of oxygen to the grain surface and regulated by large-scale erosion and clast-scale fracturing. We determined that neither iron- nor sulfur-oxidizing microorganisms control global pyrite weathering fluxes despite their ability to catalyze the reaction. This multiscale picture emphasizes that fracturing and erosion are as important as atmospheric oxygen in limiting pyrite reactivity over Earth’s history.
Moving heart elements and cells
Transposable elements comprise a large percentage of the human genome, with the endogenous retrovirus (ERV) subclass representing more than 8%. Using human pluripotent stem cell–derived cardiomyocytes and bioengineered micropatterning to recapitulate cardiogenesis, Wilson et al. found evidence that the primate-specific ERV MER41 is involved in primate heart development. A MER41-derived long noncoding RNA called BANCR is exclusively expressed in the fetal heart. When BANCR is eliminated, cardiomyocyte migration is disrupted. The cardiogenic transcription factor TBX5 and Hippo signaling factors TEAD4/YAP1 bind to a BANCR enhancer during fetal development. A related analysis in mouse shows that heart size increases with embryo BANCR knock-in.
Dev. Cell 54, 694 (2020).
Obesity and inflammation
Accumulation of fat cells (shown in yellow in this micrograph) may be promoted by gene variants linked to inflammation.
IMAGE: DAVID M. PHILLIPS/SCIENCE SOURCE
Obesity is associated with chronic inflammation, which can trigger other diseases such as atherosclerosis, type 2 diabetes, and even cancer. There appears to be a genetic component to excess fat accumulation, and studies suggest that inflammatory gene variants may contribute. Karunakaran et al. found that single-nucleotide polymorphisms in the human receptor-interacting serine/threonine-protein kinase 1 gene (RIPK1) increase its expression and are causally associated with obesity. RIPK1 is a key regulator of inflammatory responses and cell death. Silencing of Ripk1 in mice on a high-fat diet reduced fat mass, body weight, and inflammatory responses in adipose tissue. This suggests that RIPK1-mediated inflammation (and possibly other functions) contribute to obesity and that RIPK1 could be a therapeutic target.
Nat. Metab. 10.1038/s42255-020-00279-2 (2020).
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