Non-COVID papers

Non-COVID papers

Non-COVID papers:

Standard quantum theory contains square roots of negative numbers. But how essential are these ‘imaginary’ numbers? A way of disproving analogous theories that omit them has been proposed — and confirmed experimentally. The square root of a negative number could easily be regarded as a curious mathematical construction that has little bearing on real life. Indeed, the French polymath René Descartes gave such numbers the derogatory name ‘imaginary’, reserving the term ‘real numbers’ for those that occur on an ordinary number line. However, since the development of quantum theory nearly a century ago, it has seemed likely that complex numbers — which combine imaginary and real numbers — are deeply embedded in the structure of the physical world. Indeed, the imaginary unit that represents the square root of minus one occurs prominently in the basic equations of quantum theory. A team now show how experiments could strengthen the evidence that complex numbers are key to describing the quantum world, by eliminating a class of theory that contains only real numbers. And two versions of the experiment they propose have already been implemented:

https://www.nature.com/articles/d41586-021-03678-x

An optical device designed to control the properties of electron waves inside an electron microscope demonstrates that clever platforms for integrated photonics need not be powered by expensive laser systems. The wavelength of an electron can be up to 100,000 times shorter than that of a photon, which means that microscopes that use electrons to illuminate a sample are able to resolve much smaller structures than can those that use light. But electrons and photons also work together: interactions with photons can be used to modulate the wave-like nature of electrons, changing the energy spectrum of the electron beam in a way that could be useful for tailored microscopy. However, these electron–photon interactions are weak, and usually require high-power laser sources. A  group now report an optical platform for manipulating the properties of electron waves using a light source that is not much more powerful than an average laser pointer. The low light power required of this device, together with its integrated design, make it readily applicable to many existing electron microscopes:

https://www.nature.com/articles/d41586-021-03767-x

Graphene is a single layer of carbon atoms arranged in a honeycomb lattice. Thin, flexible, transparent and metallic, it therefore forms an ideal material for many applications, especially for a type of electronics known as spintronics. In spintronic devices, the magnetic moment (spin) of an electron can be just as useful as its charge for storing information and performing logic operations. It has been predicted that when graphene is shaped into nanoribbons, with zigzag edges that are stabilized by carbon–hydrogen bonds, it should exhibit magnetic states that show particular promise for carbon-based electronics. However, a clear experimental demonstration of this magnetism in nanoribbons that are long enough to be technologically relevant has not been possible. Now researchers overcome this hurdle — reporting the synthesis and characterization of zigzag graphene nanoribbons in which carbon atoms spaced at regular intervals along the edges have been replaced by nitrogen atoms:

https://www.nature.com/articles/d41586-021-03768-w

Machine learning (ML) is increasingly being used as an advisory tool to guide antibacterial drug searches. Such methods typically use large training datasets and require extensive prior study of structure-activity relationships. ML models have proven to be effective within previously studied classes of antibiotics, but their predictive power is significantly limited when the task is to find candidate molecules that do not resemble known antibiotics. Tiihonen et al. present a general ML framework that does not rely on prior knowledge of the mechanism of antibiotic action. Their ML model developed for conjugated oligoelectrolyte molecules successfully predicted their antimicrobial activity against E. coli K12 and could potentially be applied to other understudied antibiotic classes:

https://pubs.acs.org/doi/10.1021/jacs.1c05055

For the first time, astronomers have detected a massive stream of charged gas erupting from the surface of a young, Sun-like star — offering a glimpse of the harsh conditions faced by any surrounding planets. Solar flares are huge explosions on the Sun’s surface that are often accompanied by eruptions made of filaments of hot, ionized gas. Some Sun-like stars exhibit extra-powerful versions of solar flares called superflares, but filament eruptions associated with such superflares had not been seen until now. A group were observing a young, Sun-like star in April 2020 when they detected a superflare about 20 times more energetic than the largest solar flares. Roughly 30 minutes later, the team found evidence of a filament eruption — the first linked to a superflare on a Sun-like star. The authors’ observations suggest that some of the matter in the filament was expelled into space in an event known as a coronal mass ejection. The team says that the results could lead to a better understanding of how filament eruptions and coronal mass ejections influence the evolution of stars and planets:

https://www.nature.com/articles/s41550-021-01532-8

Ocean ‘heatwaves’ are becoming increasingly common even in the frigid Arctic, where these events are more extreme, and possibly more damaging, than those in warmer seas farther south. Climate warming means that marine heatwaves — when ocean temperatures soar for extended periods — are getting more frequent and severe, threatening aquatic species and ecosystems unaccustomed to prolonged warm spells. The Pacific, Atlantic and Indian oceans are all feeling the squeeze, but few studies exist on the strength of heatwaves in the Arctic Ocean. Researchers analysed records of sea-surface temperatures in the Arctic from 1982 to 2020. They found that extreme warm spells have become more frequent and long-lasting, and that ocean-temperature anomalies are even more pronounced in the Arctic than in tropical and subtropical regions. Rapidly rising air temperatures in the Arctic and the associated retreat of sea ice both seem to contribute to amplified marine heatwaves in the region’s seas:

https://agupubs.onlinelibrary.wiley.com/doi/epdf/10.1029/2021GL095590

Crossing the Thames was never more rhythmic than it was on 10 June 2000, when London’s Millennium Bridge opened and then visibly rocked as pedestrians ambled across. The bridge’s motion has been cited as evidence of the dangers of synchronized walking — everyone seemed to move in unison, supposedly tapping into the resonant frequency of the bridge and causing it to sway. But a new study bolsters an alternative idea: that pedestrians’ natural walking behaviour was enough to cause the bridge to wobble. This motion, in turn, made it look as if everyone was walking in step. Researchers modelled the physics of bridge crossing and found that a large-enough crowd can get a bridge rocking regardless of how synchronized individuals’ steps are. Moreover, the swaying becomes worse as walkers adjust their gaits to keep their footing, adding more energy to the swinging system. The findings hint that, with enough people crossing at a time, certain bridges could be unstable over a larger range of frequencies than other models suggest, the team says:

https://www.nature.com/articles/s41467-021-27568-y

Some of the small, plain songbirds known as Darwin’s finches might protect their young from flesh-eating parasites just by staying in the nest. The more than a dozen bird species that astonished Charles Darwin on the Galapagos Islands are icons of evolutionary biology, but they are now under threat from the avian vampire fly (Philornis downsi), an introduced parasite that lays its eggs in the finches’ nests. Once the young birds hatch, P. downsi larvae crawl into the hatchlings’ beaks to feast on the baby birds’ flesh and blood. On average, P. downsi infestations kill 55% of young birds each year. To understand how parents protect their broods, a group gathered data, spanning 21 years, from more than 200 nests of finches of the Camarhynchus and Geospiza genera. After the fledglings flew the coop, the researchers counted the number of P. downsi larvae in the discarded nest. The team found fewer larvae in the nests in which female finches spent the longest time brooding the hatchlings. This correlation was strongest when the male nesting partner provided food deliveries to the nest, allowing the female to stay put:

https://royalsocietypublishing.org/doi/10.1098/rspb.2021.1668

With an 11–12-metre wingspan, comparable to that of a small plane, the winged reptile Quetzalcoatlus northropi must have cast a fearsome shadow as it flew above what is now Texas, 70 million years ago. It remains the largest known flying animal, but relatively few bones of it have been found and almost nothing about it has been published. Now a team have provided details of Q. northropi by analysing its smaller cousin, Quetzalcoatlus lawsoni, of which hundreds of bones have been found1. The team suggests that the bigger species could have used its long jaws, which taper to narrow, toothless points, like chopsticks to pluck prey from wetlands or meadows, as if it were a colossal heron. The team’s analysis suggests that the animal’s forelimbs could not have helped to propel it forwards when it walked, but could have been used like ungainly ski poles. To take to the air, the reptile probably dropped to a crouch, then leapt up so that its wingtips could clear the ground during what must have been a formidable wing stroke:

https://www.tandfonline.com/doi/full/10.1080/02724634.2020.1780247

A 1,600-year-old lyre found in modern Kazakhstan matches musical instruments seen in Anglo-Saxon burials of the first millennium AD, suggesting that technology transfer occurred across thousands of kilometres in antiquity. Soviet-era excavations in the Kazakh region of Dzhetyasar retrieved an ancient wooden object that was later identified as a stringed musical instrument from around the fourth century AD. When re-examining the object, a group found that it closely resembles lyres discovered in early medieval cemeteries in England and Germany, including one from the renowned seventh-century English burial Sutton Hoo. The Kazakh lyre is long and shallow, and has a single-piece soundbox with a curved bottom and hollow arms, which are connected at the top by a crossbar, a shape and technology that were thought to be unique to Western Europe. Because Dzhetyasar was on the Silk Road, an ancient trade route linking Europe to China, the finding suggests that the design for the lyre travelled along this route to or from Kazakhstan. These cultural exchanges might have been an example of early musical technology transfers between the West and the East:

https://www.nature.com/articles/d41586-021-03685-y

A fat-laden designer molecule keeps monkeys from becoming infected with an HIV-like virus, offering the potential that it could be used to treat AIDS and prevent HIV infection. Existing drugs reduce the amount of HIV in a person’s body but do not eradicate the virus and therefore must be taken indefinitely. Seeking a more effective drug, a group combined amino acids and cholesterol, a type of fat, to create a molecule called LP-98. When given to rhesus macaques (Macaca mulatta), LP-98 protected the animals from becoming infected with simian immunodeficiency virus (SIV), which is closely related to HIV. The compound also prevented infection with a hybrid virus combining elements of HIV and SIV. When LP-98 was given to monkeys infected with this hybrid, the virus in their bodies fell to levels too low to be detected and remained undetectable in several animals even after they stopped receiving the compound:

https://linkinghub.elsevier.com/retrieve/pii/S0092867421013829

Gastric cancer is a highly aggressive disease. Researchers now present clinical data that point to a way to improve outcomes for people who have this type of tumour by combining immunotherapy with anti-HER therapy:

https://www.nature.com/articles/d41586-021-03458-7

Researchers established a mouse model that replicates features of the weight change that occurs after smoking cessation in humans. These animals gained less weight during smoke exposure, and their weight returned to the non-smoking baseline after exposure ceased. The authors demonstrate that microbiota-dependent factors affect how much weight is regained. They found that administering antibiotics reduced the amount of weight regained, which suggests that a bacterial component of the microbiota targeted by antibiotics contributes to the process. This effect on the animals’ weight was maintained for weeks after antibiotic administration was halted, and the results were unaffected by changes in diet or differences in the original microbiota of mice obtained from various vendors:

https://www.nature.com/articles/d41586-021-03548-6

The gut microbiome can modulate the immune system and influence the therapeutic response of cancer patients, yet the mechanisms underlying the effects of microbiota are presently unclear. Researchers add to our understanding of how dietary habits affect microbiota and clinical outcomes to immunotherapy. In an observational study, the researchers found that melanoma patients reporting high fibre (prebiotic) consumption had a better response to checkpoint inhibitor immunotherapy compared with those patients reporting a low-fiber diet. The most marked benefit was observed for those patients reporting a combination of high fibre consumption and no use of over-the-counter probiotic supplements. These findings provide early insights as to how diet-related factors may influence the immune response:

https://www.science.org/doi/10.1126/science.aaz7015

Antibiotic resistance is a pervasive and increasing problem. A team show that glutamine promotes increase the influx and efficacy of a variety of antibiotics against multiple species of pathogenic Gram-negative bacteria. Mechanistically, glutamine promoted changes in nucleotide metabolism that led to the up-regulation of a two-component regulatory system, resulting in increased, nonspecific membrane permeability in bacteria having varied resistance mechanisms. Glutamine supplementation was also effective in mouse models of systemic or biofilm infection, suggesting a potential strategy to enhance antibiotic efficacy:

https://www.science.org/doi/10.1126/scitranslmed.abj0716

Eukaryotes encode five multiple-subunit, DNA-dependent RNA polymerases, of which Pol I, Pol II, and Pol III function as single units to produce cellular single-stranded RNA. The plant-specific Pol IV forms a complex with RDR2 (an RNA-dependent RNA polymerase) to produce double-stranded precursors of small interfering RNA essential for genomic DNA methylation. A group determined the cryo–electron microscopy structures of the Pol IV-RDR2 complex. The structures show that Pol IV and RDR2 connect their active centres through an inner RNA transfer channel and that Pol IV reverses transcription direction and hands over its transcript directly through the channel to RDR2 for the production of the second strand of the double-stranded RNA:

https://www.science.org/doi/10.1126/science.abj9184

Humans are animals, merely another lineage of great apes. However, we have diverged in significant ways from our ape cousins and we are perennially interested in how this happened. A team looked at energy intake and expenditure in modern hunter-gatherer societies and great apes. They found that we do not spend less energy while foraging or farming, but we do acquire more energy and at a faster rate than our ape cousins. This difference may have allowed our ancestors to spend more time in contexts that facilitated social learning and cultural development:

https://www.science.org/doi/10.1126/science.abf0130

Immune responses to pathogens are heightened in individuals previously exposed to pathogen-associated stimuli, a phenomenon known as innate immune training. This process is accomplished through metabolic reprogramming and epigenetic changes, but the underlying mechanisms are not fully understood. A team investigated the functional requirement of interleukin (IL)-17 receptor signalling in fibroblastic reticular cells (FRCs) in the development of protective antibody responses against gut infection and studied how innate immune training affects these responses. Mild gut inflammatory training before bacterial infection enhanced gut-protective antibody production and reduced colon inflammation. Inflammatory training required IL-17 signalling in FRCs and IL-10 production by B cells. These findings reveal a mechanism of innate immune training in FRCs for protection against gut infection:

https://www.science.org/doi/10.1126/sciimmunol.aao3669

Therapeutic treatments for metastatic cancer are an important unmet need. Studies have shown that the interaction between metadherin (MTDH) and staphylococcal nuclease domain-containing (1SND1) is important in tumour initiation, progression, and metastasis in mice. Shen et al. show that deletion of the Mtdh gene in established mammary tumors in mice suppressed tumor development, reduced metastasis, and improved survival. This effect was dependent on their interaction with SND1. The authors also found compounds that could disrupt the interaction by binding to SND1. Their lead molecule reduces tumour growth and lung metastasis in established mammary tumours in vivo. Preventing the MTDH–SND1 interaction also sensitizes mammary tumours to chemotherapy. This indicates that interfering with this protein-protein interaction could be a viable strategy for clinical investigation:

https://www.nature.com/articles/s43018-021-00279-5

Covid papers:

On top of the last UKHSA report, a paper from SA shows that on multivariable analysis, after controlling for factors associated with hospitalisation, individuals with SGTF infection had lower odds of being admitted to hospital compared to non-SGTF infections (adjusted odds ratio (aOR) 0.2, 95% confidence interval (CI) 0.1-0.3). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ between SGTF-infected individuals compared to non-SGTF individuals diagnosed during the same time period (aOR 0.7). Compared to earlier Delta infections, after controlling for factors associated with severe disease, SGTF-infected individuals had a lower odds of severe disease (aOR 0.3). Conclusion Early analyses suggest a reduced risk of hospitalisation among SGTF-infected individuals when compared to non-SGTF infected individuals in the same time period, and a reduced risk of severe disease when compared to earlier Delta-infected individuals. Some of this reduction is likely a result of high population immunity:

https://www.medrxiv.org/content/10.1101/2021.12.21.21268116v1

A Scottish study found that Omicron is two-thirds less likely to lead to hospitalisation. It also found that boosters provide strong protection against severe disease from Omicron:

https://www.research.ed.ac.uk/en/publications/severity-of-omicron-variant-of-concern-and-vaccine-effectiveness-

Another UK study concluded that Omicron infections are 40% less likely than Delta to result in hospital stays of one or more days:

https://www.imperial.ac.uk/media/imperial-college/medicine/mrc-gida/2021-12-22-COVID19-Report-50.pdf

Among the possible treatments for people just developing COVID-19 symptoms, antibody-rich plasma donated by recovered patients has taken a backseat to options such as monoclonal antibodies and antiviral pills. But a new clinical trial suggests it may deserve a bigger role. The trial results, posted today as a preprint, showed a transfusion of convalescent plasma cut rates of hospitalisation roughly in half—from 6.3% to 2.9%—in people treated early in the course of their infection with SARS-CoV-2. The treatment is currently authorized in the United States only for emergency use in certain hospitalized patients, but the researchers behind the study now say its use should be expanded. And they hope convalescent plasma will take a more prominent role in the fight against COVID-19 as the Omicron variant, shown to reduce the effectiveness of some monoclonal antibodies, becomes dominant. They argue it may be particularly useful in lower income countries that can’t afford or don’t have access to other treatments:

https://www.medrxiv.org/content/10.1101/2021.12.10.21267485v1

A paper reports on safety incidents in laboratories in China. The deaths of two people following a laboratory explosion at a Chinese university in October have raised alarm among researchers. The full circumstances that led to the deaths at the Nanjing University of Aeronautics and Astronautics (NUAA), in Jiangsu province, are not yet known — but they come amid wider concerns about safety in university teaching labs in China. The deaths are the latest in a series of fatalities caused by explosions in academic laboratories in China, often involving students in chemistry departments, that have been reported in recent years. Some researchers are optimistic that the situation is improving. But others say China’s government needs to do more to improve safety. In the recent incident, nine people were injured and two died as a result of an explosion just before 4 p.m. in the NUAA’s College of Materials Science and Technology, according to a Weibo post. Earlier this year, on 31 March, a graduate student was killed following an explosion at the Institute of Chemistry of the Chinese Academy of Sciences in Beijing. Previous lab blasts led to deaths of three students conducting a sewage-treatment experiment at Beijing Jiaotong University in December 2018; one death in the chemistry dept at Tsinghua University in Beijing in December 2015; and one death in a chemistry lab at the China University of Mining and Technology in Xuzhou in April 2015. It’s not possible to say what the cause was of any individual explosion and death without a full investigation report, none of which have been made public except for the incident at Beijing Jiaotong University, and some may not have been caused by negligence or lack of safety procedures. However, China has far more students than many other countries, so it's difficult to say if it has a larger number of lab-related deaths per capita and researchers note that lab safety is an issue in many countries. Some also question the idea that incidents are becoming more frequent in China and argue that serious accidents were probably happening 15–20 years ago as well, but they just weren’t reported publicly before the rise of social media:

https://www.sciencedirect.com/science/article/abs/pii/S0950423021002771?via%3Dihub

Does a heterologous SARS-CoV-2 vaccination strategy with the vector vaccine Ad26COVS1 result in a higher rate of antibody response compared with a homologous third dose of mRNA vaccine (mRNA-1273 or BNT162b2) in kidney transplant recipients who did not develop SARS-CoV-2 antibodies after 2 doses of an mRNA vaccine? This randomized clinical trial found that a third dose of SARS-CoV-2 vaccine in 197 kidney transplant recipients without antibodies after 2 doses of an mRNA vaccine induced an antibody response in 35% of the homologous (mRNA) group vs 42% of the heterologous (vector) group, with no statistically significant difference. The findings of this randomized clinical trial show that homologous and heterologous vaccination strategies for a third SARS-CoV-2 vaccine dose in kidney transplant recipients are comparable, with both mRNA and vector vaccines achieving seroconversion in more than one-third of kidney transplant recipients. However, given the high rate of non-responders after the third dose, additional strategies to induce an immune response in kidney transplant recipients are urgently needed:

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2787200

Is COVID-19 associated with severe gastrointestinal manifestations in children? In this multicentre cohort study of 685 Italian children with COVID-19, 10% showed severe gastrointestinal involvement characterized by diffuse adeno-mesenteritis, appendicitis, abdominal fluid collection, ileal intussusception, or pancreatitis. Children older than 5 years and those presenting with abdominal pain, leukopenia, or receiving a diagnosis of multisystem inflammatory syndrome were more likely to have severe gastrointestinal manifestations. Severe gastrointestinal involvement is not uncommon in children with COVID-19, and awareness about its frequency and presentation may help practitioners to appropriately manage children at risk of severe outcomes:

The above and the table below shows imaging findings:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787258

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal centre (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Even though Tfh-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high-affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. Indeed, we found by epitope mapping and BCR sequencing that Tfh cells focused the B cell response and therefore, in the absence of Tfh cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation:

https://www.science.org/doi/10.1126/sciimmunol.abl5652

Researchers developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 μg) SpFN vaccine, given twice 28 days apart, induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1. These potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates following high-dose SARS-CoV-2 respiratory challenge. The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates supports the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses:

https://www.science.org/doi/10.1126/scitranslmed.abi5735

Which eviction protections were associated with reduced mental distress among renters during the COVID-19 pandemic? In this cohort study assessing data from 2317 adult respondents of the Understanding Coronavirus in America Survey, moratoriums that blocked landlords from giving notice or filing for evictions were associated with a relative reduction in mental distress of approximately 13%, whereas protections that blocked only court hearings, judgments, and enforcement did not reduce distress significantly. Findings indicate that only moratoriums that blocked eviction notice and filing were associated with reduced renter distress, suggesting that to protect renters’ mental health, interventions should aim to prevent evictions before filing:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787245

Using healthcare data covering the entire Danish population, researchers did observe a strong association between vaccination with mRNA-1273 and myocarditis or myopericarditis, defined as the combined outcome of a hospital diagnosis of myocarditis or pericarditis, increased troponin levels, and a hospital stay lasting more than 24 hours. Vaccination with BNT162b2 was only associated with an overall increased rate of myocarditis or myopericarditis among female participants. In general, the rate of myocarditis or myopericarditis was about threefold to fourfold higher for mRNA-1273 vaccination than that for BNT162b2 vaccination. Nevertheless, the absolute number of events were low. Even in the youngest age group (12-39 years), the absolute rates of myocarditis or myopericarditis were 1.6 (95% confidence interval 1.0 to 2.6) and 5.7 (3.3 to 9.3) per 100 000 individuals within 28 days of BNT162b2 vaccination and mRNA-1273 vaccination, respectively. Clinical outcomes among vaccinated people with myocarditis or myopericarditis were predominantly mild:

https://www.bmj.com/content/375/bmj-2021-068665

Now a Kaiser Permanante California real world study. During the delta phase of the pandemic, breakthrough infections among fully vaccinated people have occurred, but the effectiveness of covid-19 vaccines against severe disease has remained robust. In this study, vaccine effectiveness against admission to hospital with the delta variant was high (97.6%). Only five fully vaccinated people with the delta variant were admitted to hospital, no fully vaccinated people with non-delta variants were admitted, and no deaths in hospital occurred among any fully vaccinated people. This finding is consistent with previous studies suggesting that fully vaccinated people with breakthrough infections tend to have attenuated viral load, fewer symptoms, and shorter duration of illness, although severe outcomes can still occur.  This study identified moderate waning of mRNA-1273 vaccine effectiveness against infection with the delta variant; effectiveness decreased from 94.1% in the 14-60 days after vaccination to 80.0% in the 151-180 days after vaccination:

https://www.bmj.com/content/375/bmj-2021-068848

Researchers identified 13 loci that were associated with SARS-CoV-2 infection and disease severity (Figure below), including 6 loci not reported in previous human genomics studies of COVID-19. Four loci affect general susceptibility to SARS-CoV-2, whereas nine were associated with disease severity. Two of the previously unassociated loci were discovered only when individuals with East Asian ancestry were included in the analysis, highlighting the value of including diverse populations in human genomics studies:

https://www.nature.com/articles/d41586-021-01773-7

A group show that the Omicron spike confers very significant evasion of vaccine elicited neutralising antibodies that is more pronounced for ChAdOx-1 adenovirus vectored vaccine versus BNT162b2 mRNA vaccine. Indeed neutralisation of Omicron was not detectable for the majority of individuals who had received two doses of ChAdOx-1. Third dose mRNA vaccination rescues neutralisation in the short term. Despite three mutations predicted to favour spike S1/S2 cleavage, observed cleavage efficiency is lower than for wild type Wuhan-1 D614G and Delta. We demonstrate significantly lower infectivity of lung organoids and Calu-3 lung cells expressing endogenous levels of ACE2 and TMPRSS2 but similar infection as compared to Delta when using H1299 lung epithelial cells. Importantly, fusogenicity of the Omicron spike is impaired, leading to marked reduction in syncitia formation. These observations indicate that Omicron has gained immune evasion properties whilst possibly modulating properties associated with replication and pathogenicity:

https://www.biorxiv.org/content/10.1101/2021.12.17.473248v1.full.pdf

Researchers asked what factors are associated with adverse effects after COVID-19 vaccination? In an online cohort study including 19,586 adults who received a COVID-19 vaccination, the factors most strongly associated with adverse effects were full vaccination dose, brand of vaccine, younger age, female sex, and having had COVID-19 before vaccination. Allergic reaction or anaphylaxis was reported in 0.3% of participants after partial vaccination and 0.2% of participants after full vaccination. These findings suggest that some individuals experience more adverse effects after COVID-19 vaccination, but serious adverse effects are rare:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787361

In a huge US study, vaccination status was associated with lower SARS-CoV-2 infection rates. Persons who received mRNA vaccines (BNT162b2 or mRNA-1273) had the lowest incidence rate at every point of the observational time, and unvaccinated persons in this cohort had the highest rate. Unvaccinated persons had 412%, 287%, and 159% more infections that people who received mRNA-1273, BNT162b2, or JNJ-78436735 vaccines, respectively. The observed incidence rate during the study period was 24.8% (unvaccinated), 15.6% (JNJ-78436735), 8.6% (BNT162b2), and 6.0% (mRNA-1273). The magnitude of SARS-CoV-2 risk for unvaccinated persons increased even more in July and August, parallel with the increasing prevalence of the Delta variant in the US. When restricted to fully vaccinated persons, the trend was nearly identical:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787363

COVID-19 mRNA vaccine immunogenicity and effectiveness are well established in adolescents. However, the effect of vaccination on multisystem inflammatory syndrome in children (MIS-C), a severe complication associated with SARS-CoV-2, has not yet been described. Summer 2021 in France was marked by both a fourth wave of COVID-19 cases due to the Delta variant, with a peak in August 2021, and by the recommendation of the French Public Health Agency to vaccinate children 12 years and older. Researchers estimated the risk of MIS-C among adolescents by COVID-19 vaccination status during September 2021 and October 2021. They found most adolescents with MIS-C for whom vaccination was indicated in France had not been vaccinated. These results suggest that COVID-19 mRNA vaccination was associated with a lower incidence of MIS-C in adolescents. The median of 25 days between single vaccine injection and MIS-C onset compared with a mean 28-day delay between SARS-CoV-2 infection and MIS-C onset suggests that, in most cases, SARS-CoV-2 infection occurred before or shortly after the vaccine injection, when immune response was incomplete. The absence of MIS-C cases in fully vaccinated children prevented calculation of an HR for this group, but suggests that 2 doses are warranted for efficient protection:

https://jamanetwork.com/journals/jama/fullarticle/2787495

Identifying which children and young people (CYP) are most vulnerable to serious infection due to SARS-CoV-2 is important to guide protective interventions. To address this question, a group used data for all hospitalisations in England among 0–17 year olds from 1 February 2019 to 31 January 2021. They examined how sociodemographic factors and comorbidities might be risk factors for pediatric intensive care unit (PICU) admission among hospitalisations due to the following causes: COVID-19 and pediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the first pandemic year (2020–2021); hospitalisations due to all other non-traumatic causes in 2020–2021; hospitalisations due to all non-traumatic causes in 2019–2020; and hospitalisations due to influenza in 2019–2020. Risk of PICU admission and death from COVID-19 or PIMS-TS in CYP was very low. They identified 6,338 hospitalisations with COVID-19, of which 259 were admitted to a PICU and eight CYP died. They identified 712 hospitalisations with PIMS-TS, of which 312 were admitted to a PICU and fewer than five CYP died. Hospitalisations with COVID-19 and PIMS-TS were more common among males, older CYP, those from socioeconomically deprived neighbourhoods and those who were of non-White ethnicity (Black, Asian, Mixed or Other). The odds of PICU admission were increased in CYP younger than 1 month old and decreased among 15–17 year olds compared to 1–4 year olds with COVID-19; increased in older CYP and females with PIMS-TS; and increased for Black compared to White ethnicity in patients with COVID-19 and PIMS-TS. Odds of PICU admission in COVID-19 were increased for CYP with comorbidities and highest for CYP with multiple medical problems. Increases in odds of PICU admission associated with different comorbidities in COVID-19 showed a similar pattern to other causes of hospitalisation examined and, thus, likely reflect background vulnerabilities. These findings identify distinct risk factors associated with PICU admission among CYP with COVID-19 or PIMS-TS that might aid treatment and prevention strategies:

https://www.nature.com/articles/s41591-021-01627-9

What is the risk of acute respiratory distress syndrome (ARDS) and death in patients with COVID-19 with metabolic syndrome? In this cohort study including 46,441 patients hospitalized for COVID-19, metabolic syndrome was associated with significantly increased odds of ARDS and death. With each metabolic syndrome criterion added from 1 to 4 criteria, the risk of ARDS significantly increased in an additive fashion. These findings suggest that metabolic syndrome and its associated comorbidities were critical risk factors associated with COVID-19–related ARDS and death:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787394

How have the mental health and well-being of older adults in England changed during the COVID-19 pandemic compared with pre-pandemic levels? This cohort study including 5146 older adults participating in the English Longitudinal Study of Ageing found that levels of depression, loneliness, and poor quality of life increased significantly during June and July 2020 compared with pre-pandemic levels and continued to deteriorate during the second national lockdown in November and December 2020, with further increases in anxiety symptoms from June and July 2020 to November and December 2020. Inequalities in experiences of mental ill health during the COVID-19 pandemic were evident, with women, individuals living alone, and those with less wealth being particularly vulnerable. Older individuals did not adapt well to the new psychosocial stressors introduced by the pandemic; policies should be in place for the immediate provision of targeted psychological interventions to support older people, and access to digital mental health services should be improved:

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2787196

Whether the use of remdesivir in symptomatic, non-hospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalisation is uncertain. A team conducted a randomized, double-blind, placebo-controlled trial involving non-hospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. A total of 562 patients who underwent randomisation and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19–related hospitalisation or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. Among non-hospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalisation or death than placebo:

https://www.nejm.org/doi/full/10.1056/NEJMoa2116846?

Do patients infected with the SARS-CoV-2 Delta variant experience more severe disease outcomes compared with those infected with the Beta variant? In this cohort study of 1427 persons infected with the Delta variant and 5353 persons infected with the Beta variant in Qatar, among 451 propensity score–matched pairs identified, persons infected with the Delta variant were more likely to be hospitalized (27.3% vs 20.0%) or to experience more severe disease outcomes. Infection with the Delta variant was independently associated with higher odds of experiencing any adverse outcome, and vaccination was associated with significantly reduced odds of severe disease outcomes. In this cohort study, infection with the Delta variant was more severe than infection with the Beta variant in persons in Qatar, although vaccination was highly protective against severe outcomes for both variants:

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2787492

Researchers’ results suggest a modest reduction in vaccine effectiveness against COVID-19 in Utah associated with the expansion of the Delta lineage in the state. This reduction in the effectiveness of available vaccines associated with the arrival of novel VOCs, rather than waning immunity, is concerning. These should serve as a caution throughout the US that the Delta variant can bring renewed outbreaks, even in highly vaccinated populations. If there is a consistent trend of increasing immune escape as new variants arise, it could eventually undermine the effectiveness of current vaccines and necessitate mass revaccination:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787438

A study aimed to assess the impact of COVID-19 on routine immunisation using triangulated data from global, country-based, and individual-reported sources obtained during the pandemic period. This report synthesised data from 170 countries and territories. Data sources included administered vaccine-dose data from January to December, 2019, and January to December, 2020, WHO regional office reports, and a WHO-led pulse survey administered in April, 2020, and June, 2020. Results were expressed as frequencies and proportions of respondents or reporting countries. Data on vaccine doses administered were weighted by the population of surviving infants per country. A decline in the number of administered doses of diphtheria–pertussis–tetanus-containing vaccine (DTP3) and first dose of measles-containing vaccine (MCV1) in the first half of 2020 was noted. The lowest number of vaccine doses administered was observed in April, 2020, when 33% fewer DTP3 doses were administered globally, ranging from 9% in the WHO African region to 57% in the South-East Asia region. Recovery of vaccinations began by June, 2020, and continued into late 2020. WHO regional offices reported substantial disruption to routine vaccination sessions in April, 2020, related to interrupted vaccination demand and supply, including reduced availability of the health workforce. Pulse survey analysis revealed that 45 (69%) of 65 countries showed disruption in outreach services compared with 27 (44%) of 62 countries with disrupted fixed-post immunisation services. The marked magnitude and global scale of immunisation disruption evokes the dangers of vaccine-preventable disease outbreaks in the future. Trends indicating partial resumption of services highlight the urgent need for ongoing assessment of recovery, catch-up vaccination strategy implementation for vulnerable populations, and ensuring vaccine coverage equity and health system resilience:

https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00512-X/fulltext

In a retrospective, population-based cohort study in Brazil and Scotland, researchers linked national databases from the EAVE II study in Scotland; and the COVID-19 Vaccination Campaign, Acute Respiratory Infection Suspected Cases, and Severe Acute Respiratory Infection/Illness datasets in Brazil) for vaccination, laboratory testing, clinical, and mortality data. They defined cohorts of adults (aged ≥18 years) who received two doses of ChAdOx1 nCoV-19 and compared rates of severe COVID-19 outcomes (ie. COVID-19 hospital admission or death) across fortnightly periods, relative to 2–3 weeks after the second dose. 1,972,454 adults received two doses of ChAdOx1 nCoV-19 in Scotland and 42,558,839 in Brazil, with longer follow-up in Scotland because two-dose vaccination began earlier in Scotland than in Brazil. In Scotland, RRs for severe COVID-19 increased to 2·01 (95% CI 1·54–2·62) at 10–11 weeks, 3·01 (2·26–3·99) at 14–15 weeks, and 5·43 (4·00–7·38) at 18–19 weeks after the second dose. The pattern of results was similar in Brazil, with RRs of 2·29 (2·01–2·61) at 10–11 weeks, 3·10 (2·63–3·64) at 14–15 weeks, and 4·71 (3·83–5·78) at 18–19 weeks after the second dose. In Scotland, vaccine effectiveness decreased from 83·7% (95% CI 79·7–87·0) at 2–3 weeks, to 75·9% (72·9–78·6) at 14–15 weeks, and 63·7% (59·6–67·4) at 18–19 weeks after the second dose. In Brazil, vaccine effectiveness decreased from 86·4% (85·4–87·3) at 2–3 weeks, to 59·7% (54·6–64·2) at 14–15 weeks, and 42·2% (32·4–50·6) at 18–19 weeks. They found waning vaccine protection of ChAdOx1 nCoV-19 against COVID-19 hospital admissions and deaths in both Scotland and Brazil, this becoming evident within three months of the second vaccine dose. Consideration needs to be given to providing booster vaccine doses for people who have received ChAdOx1 nCoV-19:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02754-9/fulltext

T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood. A group assessed neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with the Beta variant (dominant from November 2020 to May 2021) or infected prior to its emergence (first wave, Wuhan strain), to provide an overall measure of immune evasion. Researchers show that robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first wave patients. Using peptides spanning the Beta-mutated regions, they identified CD4 T cell responses targeting the wild type peptides in 12/22 first wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. Among the spike epitopes tested, they identified three epitopes containing the D215, L18, or D80 residues that were specifically recognized by CD4 T cells, and their mutated versions were associated with a loss of response. This study shows that in spite of loss of recognition of immunogenic CD4 epitopes, CD4 and CD8 T cell responses to Beta are preserved overall. These observations may explain why several vaccines have retained the ability to protect against severe COVID-19 even with substantial loss of neutralizing antibody activity against Beta:

https://www.science.org/doi/10.1126/scitranslmed.abj6824

Researchers used golden hamsters as a model to study the immune responses to SARS-CoV-2 infection. They found that SARS-CoV-2 infection induced immune responses different from influenza infection but could effectively lead to memory B and T cell responses. The generated memory T cells were able to protect against SARS-CoV-2 reinfection of animals with the same strain and a variant of concern. Despite immunity and protection to reinfection, hamsters with SARS-CoV-2 immune memory could still transmit the virus to naïve cage mates. Thus, golden hamsters represent a robust model for studying the immune responses to SARS-CoV-2 infection:

https://www.science.org/doi/10.1126/sciimmunol.abm3131

Merck conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalisation or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. A total of 1433 participants underwent randomisation; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalisation for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomisation, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. Early treatment with molnupiravir reduced the risk of hospitalisation or death in at-risk, unvaccinated adults with Covid-19:

https://www.nejm.org/doi/full/10.1056/NEJMoa2116044?query=recirc_mostViewed_railB_article

In another molnupiravir study, researchers evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and with symptom duration <7 days. Participants were randomized 1:1 to receive 200 mg molnupiravir or placebo, and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. Antiviral activity was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in nasopharyngeal swabs. Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR. Time to viral RNA clearance (primary endpoint) was decreased in the 800 mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank p-value=0.013). 92.5% of participants receiving 800 mg molnupiravir achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks). Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800 mg molnupiravir group compared with 16.7% of placebo group at day 3 of treatment (p =0.016). At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg molnupiravir compared with 11.1% of placebo recipients (p =0.034 and 0.027, respectively). Molnupiravir was well tolerated, with a similar number of adverse events across all doses:

https://www.science.org/doi/10.1126/scitranslmed.abl7430

Finally today, humans have infected a wide range of animals with SARS-CoV-2 viruses, but the establishment of a new natural animal reservoir has not been observed. Here, we document that free-ranging white-tailed deer (Odocoileus virginianus) are highly susceptible to infection with SARS-CoV-2 virus, are exposed to a range of viral diversity from humans, and are capable of sustaining transmission in nature. SARS-CoV-2 virus was detected by rRT-PCR in more than one-third (129/360, 35.8%) of nasal swabs obtained from Odocoileus virginianus in northeast Ohio (USA) during January-March 2021. Deer in 6 locations were infected with 3 SARS-CoV-2 lineages (B.1.2, B.1.582, B.1.596). The B.1.2 viruses, dominant in humans in Ohio at the time, infected deer in four locations. Probable deer-to-deer transmission of B.1.2, B.1.582, and B.1.596 viruses was observed, allowing the virus to acquire amino acid substitutions in the spike protein (including the receptor-binding domain) and ORF1 that are infrequently seen in humans. No spillback to humans was observed, but these findings demonstrate that SARS-CoV-2 viruses have the capacity to transmit in US wildlife, potentially opening new pathways for evolution. There is an urgent need to establish comprehensive “One Health” programs to monitor deer, the environment, and other wildlife hosts globally:

https://www.nature.com/articles/s41586-021-04353-x

 

Justin Stebbing
Managing Director

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