Non-Covid papers: “Let’s keep in touch!”

Non-Covid papers: “Let’s keep in touch!”

“Let’s keep in touch!” is a phrase commonly used to indicate a social bond formed between people. Ideally, such bonds are maintained even across long distances and over the passage of time. Today, keeping in touch is easy, whether through a call, a text message, social media or the now omnipresent virtual meeting. However, what traces might remain of signs of social relationships from 50,000 years ago, and why is investigating these ancient relationships useful? Researchers now present data suggesting that small beads made of ostrich eggshell (OES) and fashioned into jewellery were exchanged between groups across eastern and southern Africa as part of long-distance social connections over the past 50,000 years. These relationships, across immense distances, then broke down about 33,000 years ago — around the same time as major climate changes occurred — and were renewed only about 2,000 years ago, the authors suggest:

https://www.nature.com/articles/d41586-021-03681-2

Archaeologists have long suggested that the placement of human remains in tombs during the Stone Age of northwestern Europe reflects one of the ways in which kinship was created and negotiated. Biological descent is presumed to have played a part, but relatively few cases of close genetic relationships have previously been uncovered from these tombs. This is partly because only a couple of studies have investigated the genetic lineage of multiple burials from the same site. Now, an innovative study of a chambered tomb at Hazleton North in southwestern Britain has analysed the genomes of 35 out of at least 41 people, including 22 adults, buried there over the course of a century. A team now reveal notable information about the social relationships between these individuals, who lived around 5,700 years ago. The authors’ findings provide a uniquely high-resolution, multigenerational and spatio-temporal analysis of the connections between the people who were interred together in the monument:

https://www.nature.com/articles/d41586-021-03799-3

During the twentieth century, our knowledge of the past was revolutionized by the introduction of radiocarbon dating, by the calibration of radiocarbon data to calendar dates using wood controls of known age and by advances in dating increasingly small samples. Now, another radiocarbon revolution is under way. There is a growing trend in harnessing calibration data that can be pinpointed to an individual year — measured using single rings of individual trees. For the years for which such calibration data exist, the most-recent international radiocarbon calibration curve, called IntCal20, represents a principal advance over the previously used approach (which often combined several tree rings for calibration analysis). Separate teams now report how this method was used to clarify the timelines of two key Viking sites:

https://www.nature.com/articles/d41586-021-03769-9

Much of the current debate surrounding the location and timing of the emergence of modern human behaviour focuses on Africa during the Middle Stone Age (MSA), which lasted from about 320,000 to 30,000 years ago. The first known appearances of a suite of modern human innovations relating to technology, social organization, symbolism and exploitation of the landscape and resources occurred in Africa during this period. This time frame is also associated with the earliest known hominin fossils placed in the modern human lineage. The emergence of more-complex behaviours surrounding the treatment of the dead is often framed in the broader context of an increase in symbolic capabilities. A group now present a convincing case for the intentional burial of a young child in eastern Africa, at Panga ya Saidi, a cave in Kenya. The authors’ meticulous recording of this archaeological evidence has revealed the earliest known human burial in Africa, and the whole world:

https://www.nature.com/articles/d41586-021-00805-6

Around the year 2300 BC, a man now nicknamed the Amesbury Archer was buried with exceptional riches near the ancient stone monument Stonehenge in southern England. The Amesbury Archer and the items buried with him provide a snapshot of a culture in the south of Britain that used metal and created distinctive ceramics, known as Bell Beaker pottery. This man was also an immigrant: analysis of oxygen isotopes in the enamel layers of his teeth that had formed in childhood suggested he originated from the Alps in central Europe. A group analyse his genome and those of hundreds of other ancient individuals buried across Britain, as well as in continental Europe, to unravel Britain’s migratory past with unprecedented granularity:

https://www.nature.com/articles/d41586-021-03770-2

Analysis of ancient DNA from one of the best-preserved Neolithic tombs in Britain has revealed that most of the people buried there were from five continuous generations of a single extended family. By analysing DNA extracted from the bones and teeth of 35 individuals entombed at Hazleton North long cairn in the Cotswolds-Severn region, the research team was able to detect that 27 of them were close biological relatives. The group lived approximately 5700 years ago:

https://www.nature.com/articles/s41586-021-04241-4

Mathematicians have been developing theories by studying examples throughout history. For instance, by looking at a cube and a pyramid, one might realize that the number of vertices, edges and faces are related. A mathematician recognizes such a pattern, extends it to more-general shapes, and then starts to think about why this relationship might hold. Parts of this process involve computations, for which mathematical software has been useful since it first became available in the 1960s. However, human creativity enables mathematicians to instinctively understand where to look for emerging patterns. A team now describe a way of using artificial intelligence (AI) techniques to help with the creative core of the mathematical-research process:

https://www.nature.com/articles/s41586-021-04086-x

Rogue planets are elusive cosmic objects that have masses comparable to those of the planets in our Solar System but do not orbit a star, instead roaming freely on their own. Not many were known until now, but a team of astronomers, using data from several European Southern Observatory (ESO) telescopes and other facilities, have just discovered at least 70 new rogue planets in our galaxy. This is the largest group of rogue planets ever discovered, an important step towards understanding the origins and features of these mysterious galactic nomads:

https://www.nature.com/articles/s41550-021-01513-x

Astronomers have produced the most comprehensive image of radio emission from the nearest actively feeding supermassive black hole to Earth. The emission is powered by a central black hole in the galaxy Centaurus A, about 12 million light years away. When viewed from Earth, the eruption from Centaurus A now extends eight degrees across the sky, the length of 16 full Moons laid side by side:

https://www.nature.com/articles/s41550-021-01553-3

MIT aerospace engineers are testing a concept for a hovering rover that levitates by harnessing the moon's natural charge. The design uses tiny ion beams to charge up the vehicle and the surface underneath, with little power needed. Such an ion boost could be strong enough to levitate a 2-pound vehicle on the moon and large asteroids:

https://arc.aiaa.org/doi/10.2514/1.A35001

Three studies report data on the lunar samples brought back by China’s robotic Chang’e-5 mission — the first mission to return samples since the Soviet Union’s Luna 24 mission in 1976. These data extend our knowledge of volcanic eruptions on the Moon and provide information on the cause of the volcanism that cannot be obtained from orbit. The results raise questions about the structure and thermal evolution of the lunar interior, and improve methods for estimating the age of planetary surfaces throughout the inner Solar System. They demonstrate that samples returned from previously unvisited regions of the lunar surface can prompt a revision of models of lunar evolution that were developed on the basis of the Apollo and Luna samples. An explanation must now be sought for how the lunar interior was hot enough to drive volcano eruptions two billion years ago:

https://www.nature.com/articles/d41586-021-03547-7

Many satellites have electric propulsion thrusters, which generate thrust by using electrical energy to accelerate the ions of a propellant gas. However, the choice of gas presents a problem. A group report a successful demonstration of an iodine-ion thruster in space — offering a cheaper and simpler alternative to other gases. The design removes the need for bulky high-pressure tanks and complex gas-feed systems, providing a thruster that is not only remarkably simple, light and inexpensive, but also efficient. The authors found that the electric current in the beam of ions ejected from the plasma source for iodine was nearly 50% stronger than the current generated using xenon. This propulsion thruster could be a game-changer for networked systems of small satellites, which are more agile and resilient than are those operating alone:

https://www.nature.com/articles/d41586-021-03384-8

Earth’s annual orbit around the Sun displays variations in what is known as eccentricity — in which the planet’s orbit varies between a more-circular and a more-elliptical path. These cycles of eccentricity occur approximately every 100,000 and 400,000 years, and are caused by the gravitational pull of other planets. A team have uncovered a phenomenon that challenges our understanding of the effects of Earth’s orbital eccentricity. The authors automated the process of characterization of intricate structures called calcite liths, which are produced by single-celled phytoplankton. Their work resulted in the observation that a high eccentricity of Earth’s orbit leads to high diversity of phytoplankton, and vice versa, as observed over the past 2.8 million years. Exploring the rhythm of orbital variations across the evolution of the tree of life will undoubtedly unveil greater detail regarding the intricate feedbacks between life, the carbon cycle and climate:

https://www.nature.com/articles/d41586-021-03549-5

Microbial communities tend to use the most energy-rich and most easily metabolized compounds that they have at their disposal. This leads to a progressive enrichment of compounds that are difficult to break down and that provide little energy, particularly in the absence of oxygen or other inorganic electron acceptors. Under these conditions, the use of hydrocarbons, molecules consisting of carbon and hydrogen, such as alkanes, has been thought to rely entirely on a collaboration (known as syntrophy) between bacteria that break down these compounds into acetate and molecular hydrogen (H2), and microorganisms called methanogenic archaea that use the molecules to produce methane (CH4), the simplest hydrocarbon. A team overturn this long-standing account of a division of labour in the methanogenic degradation of hydrocarbons by reporting that a single type of microorganism can degrade various large hydrocarbons into methane:

https://www.nature.com/articles/d41586-021-03729-3

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. A group 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

Electrons typically propagate without interacting in graphene, a single layer of carbon atoms arranged in a honeycomb lattice. But when three sheets of graphene are stacked on top of one another so that their lattices are aligned but offset — forming rhombohedral trilayer graphene — an electric field can be used to induce interactions between the electrons. Two teams report that these interactions give rise to ferromagnetism, the type of magnetism found in iron magnets, and superconductivity (zero electrical resistance). These states have already been observed in other trilayer configurations known as moiré systems, but rhombohedral trilayer graphene is more structurally stable than these materials, and has a simpler lattice structure. Rhombohedral trilayer graphene is also easier to obtain because it exists in nature, whereas moiré systems need to be engineered:

https://www.nature.com/articles/d41586-021-02773-3

An ultraviolet-light beam directs the formation of solid mineral nanoparticles in a carefully tailored solution, sculpting ‘flowers’ and other intricate shapes. In the natural world, minerals can self-assemble into exquisite architectures, such as the skeletons of corals. To replicate this process in the laboratory, a team chose a molecule called ketoprofen, which releases carbon dioxide when exposed to UV light, and mixed it with a solution of barium and silicate ions. Using a custom-built device, the authors focused a narrow spot of UV light within the solution. The ketoprofen molecules in the vicinity of the light generated carbon dioxide, which combined with nearby barium ions to produce barium carbonate nanocrystals. This, in turn, caused the precipitation of silicon dioxide and the formation of a barium–silica nanocomposite mineral. Crucially, the researchers could guide the mineral’s blossoming structure to curl, fold or turn around a corner by projecting the spot of light in a particular shape or by varying the reaction’s condition, such as the light intensity or the solution temperature. When the authors moved the light beam through the solution, a wand of mineral materialized:

https://onlinelibrary.wiley.com/doi/10.1002/adma.202107843

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. Now researchers 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

Much like fluorescence microscopy, stimulated Raman scattering (SRS) gain microscopy is an optical imaging method capable of generating high-resolution maps of biological tissues. The contrast in SRS images derives from the characteristic vibrations of the sample’s molecules, which enable tissue imaging without the need to label samples with fluorescent dyes. SRS is gaining ground as a biomedical imaging tool, but the minimum molecular concentrations that it can detect are higher than those that can be detected using fluorescence microscopy, thus limiting its scope. Finding ways to fundamentally improve the detection sensitivity of this technique has been challenging. A group now describe an approach for boosting sensitivity through quantum-enhanced suppression of noise in the SRS signal:

https://www.nature.com/articles/d41586-021-01514-w

According to the WHO, cardiovascular diseases are the world’s leading cause of death. The development and progression of cardio-vascular disease (CVD) could be influenced by a perturbation in the balance of haematopoiesis, the process by which blood cells (including immune cells) are generated from haematopoietic stem and progenitor cells (HSPCs). Indeed, inflammatory blood cells that are derived from haematopoietic progenitor cells in the bone marrow have been implicated in cardiovascular disorders such as athero-sclerosis, a condition in which cholesterol builds up in the arteries; myo-cardial infarction (heart attack); and ischaemia, a form of heart failure that results from a lack of oxygen supply. This relationship between the cardiac and haemato-poietic systems was thought to be unidirectional. A team provide evidence from individuals with CVD, as well as from mouse models of such disease, suggesting that the crosstalk between the cardio-vascular system and the bone marrow is bidirectional:

https://www.nature.com/articles/d41586-021-03550-y

The complexity of a tumour’s evolving cellular population poses an obstacle to successful therapy. A group present data that pinpoint some of the mechanisms underlying the ability of cancers to evolve to a more aggressive and treatment-resistant form:

https://www.nature.com/articles/s41586-021-04206-7

The cardinal feature of blood stem cells is their ability to regenerate the body’s entire blood and immune systems. The process is known as haematopoiesis, and the cells are better known as haematopoietic stem cells (HSCs). In developing embryos, HSCs shuffle around distinct anatomical sites, with blood circulation enabling their trafficking. After birth, these cells reside in specialized niches in the bone marrow that support their quiescence and self-renewal. Throughout life, HSCs are released from the bone marrow to replenish blood cells in a circadian pattern that is under the control of involuntary nerves. Pain-sensing nerves also make connections with the bone marrow, but can these neurons mobilize HSCs, too? Now a group address this question and identify a surprising role for chilli peppers:

https://www.nature.com/articles/d41586-020-03577-7

The acquisition of mutations in blood-forming (haematopoietic) stem cells can lead to a process called clonal haematopoiesis, in which subpopulations of mutant blood cells arise. This phenomenon can be a treacherous contributor to the progression of leukaemia and death. A group now provide evidence that clonal haematopoiesis is also common in people who have solid tumours. In these people, the phenomenon is associated with increased age, tobacco use and radiation therapy, is correlated with an increased risk of leukaemia, and is linked to reduced overall survival:

https://www.nature.com/articles/549465a

Broadly neutralizing antibodies (bnAbs) targeting epitopes of the influenza virus hemagglutinin (HA) have the potential to provide near universal protection against influenza virus infection. However, viral mutants that escape bnAbs have been reported. The identification of bnAb classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Researchers report a distinct class of bnAbs targeting a discrete membrane-proximal anchor epitope of the HA stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with pandemic-threat H2 and H5 viruses. Antibodies targeting this anchor epitope utilize a highly restricted repertoire, which encodes for two public binding motifs that make extensive contacts with conserved residues in the fusion peptide. Moreover, anchor epitope-targeting B cells are common in the human memory B cell (MBC) repertoire and were recalled in humans by an oil-in-water adjuvanted chimeric HA (cHA) vaccine, a potential universal influenza virus vaccine. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of bnAbs that are widespread in the human MBC pool:

https://www.nature.com/articles/s41586-021-04356-8

Covid papers:

A group report a super-spreading event of Omicron infections amongst triple-vaccinated healthcare workers, infecting 21 of 33 attending a private gathering in the Faroe Islands.

https://www.medrxiv.org/content/10.1101/2021.12.22.21268021v1

In late November 2021, an outbreak of Omicron SARS-CoV-2 following a Christmas party with 117 attendees was detected in Oslo, Norway. They observed an attack rate of 74% and most cases developed symptoms. As at 13 December, none have been hospitalised. Most participants were 30–50 years old. Ninety-six percent of them were fully vaccinated. These findings corroborate reports that the Omicron variant may be more transmissible, and that vaccination may be less effective in preventing infection compared with Delta:

https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.50.2101147

Omicron seems to be at least equally infectious than B.1.617.2 (Delta), has already caused super spreader events3 and has outcompeted Delta within weeks in several countries and metropolitan areas. A team investigated the neutralizing and binding activity of sera from convalescent, mRNA double vaccinated, mRNA boosted, convalescent double vaccinated, and convalescent boosted individuals against wild type, B.1.351 and B.1.1.529 SARS-CoV-2 isolates. Neutralizing activity of sera from convalescent and double vaccinated participants was undetectable to very low against B.1.1.529 while neutralizing activity of sera from individuals who had been exposed to spike three or four times was maintained, albeit at significantly reduced levels. Binding to the B.1.1.529 receptor binding domain (RBD) and N-terminal domain (NTD) was reduced in convalescent not vaccinated individuals, but was mostly retained in vaccinated individuals:

https://www.nature.com/articles/d41586-021-03846-z

Although Omicron is very capable of evading antibodies and causing reinfections/breakthroughs, it barely evades T-cells at all, meaning vaxxed or recovered people are likely to retain very good protection against severe disease. They studied neutralizing antibodies and T-cell responses to SARS-CoV-2 D614G (wildtype, WT), and the B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants of concern (VOC) in a cohort of 60 health care workers (HCW) after immunisation with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273 or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which significantly decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralisation assays with authentic virus showed consistent cross-neutralisation of the Beta and Delta variants in study participants, but Omicron-specific responses were significantly lower or absent (up to a 34-fold decrease compared to D614G). Notably, BNT162b2 booster vaccination after either two mRNA-1273 immunisations or Ad26.COV.2 priming partially restored neutralisation of the Omicron variant, but responses were still up to-17-fold decreased compared to D614G. CD4+ T-cell responses were detected up to 6 months after all vaccination regimens; S-specific T-cell responses were highest after mRNA-1273 vaccination. No significant differences were detected between D614G- and variant-specific T-cell responses, including Omicron, indicating minimal escape at the T-cell level. This study shows that vaccinated individuals retain T-cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations may be needed to further restore Omicron cross-neutralisation by antibodies:

https://www.medrxiv.org/content/10.1101/2021.12.26.21268380v1

But, researchers report the persistence of viable SARS-CoV-2 in patients treated with sotrovimab and the rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab, the one mAb that work(ed) with Omicron:

https://www.medrxiv.org/content/10.1101/2021.12.18.21267628v1

A report shows the Johnson&Johnson vaccine demonstrates 85% effectiveness against hospitalisation in South Africa when Omicron was dominant. A second, separate analysis of the immune response to different vaccine regimens, conducted by Beth Israel Deaconess Medical Center (BIDMC), demonstrated that a heterologous booster (different vaccine) of the JNJ COVID-19 vaccine in individuals who initially received the Pfizer vaccine generated a 41-fold increase in neutralizing antibody responses and a 5-fold increase in CD8+ T-cells to Omicron by four weeks following the boost. While a homologous boost with Pfizer generated a 17-fold increase in neutralizing antibodies and a 1.4-fold increase in CD8+ T-cells by four weeks following the boost. Thus, both neutralizing antibodies and CD8+ T-cells were higher four weeks after the boost with the Johnson & Johnson vaccine than with the Pfizer vaccine:

https://www.nejm.org/doi/full/10.1056/NEJMc2119358?

A group show that vaccine effectiveness is significantly reduced against the Omicron variant in association with neutralising antibody responses from dual and triple recipients of the BNT162b2 (Pfizer), ChAdOx1 (Astra Zeneca) and mRNA-1273 (Moderna) COVID-19 vaccines. Further, using live virus culture and viral pseudotypes, they describe an altered entry pathway that favours endosomal fusion over the TMPRSS2-dependent, cell surface fusion utilised by all previous variants of SARS-CoV-2. In summary, Omicron exhibits significant antigenic and biological changes that underpin immune evasion and hyper-transmissibility and could affect the pathogenesis and clinical severity of disease:

https://www.gla.ac.uk/media/Media_829360_smxx.pdf

Last month, researchers reported that up to 40% of deer populations in Illinois, Michigan, Pennsylvania, and New York had antibodies to the coronavirus:

https://www.pnas.org/content/118/47/e2114828118

Another group found active SARS-CoV-2 infections in at least 30% of deer tested across Iowa in 2020:

https://www.biorxiv.org/content/10.1101/2021.10.31.466677v2

Accounting for under-detection of infection, infection seasonality, nonpharmaceutical interventions, and vaccination, we estimate that the majority of South Africans had been infected by SARS-CoV-2 before the Omicron wave. Based on findings for Gauteng province, Omicron is estimated 100.3% (95% CI: 74.8 - 140.4%) more transmissible than the ancestral SARS-CoV-2 and 36.5% (95% CI: 20.9 - 60.1%) more transmissible than Delta; in addition, Omicron erodes 63.7% (95% CI: 52.9 - 73.9%) of the population immunity, accumulated from prior infections and vaccination, in Gauteng”. The senior author says: “That’s not something that should apply directly to other countries, like the U.S., because it’s very specific to the South African context,” said Shaman. Different strains took off there, leading to an immunological history not as relevant to the Northern Hemisphere. “How much immune erosion we can expect here will be hard to say,” said Shaman. “However, we’re talking about large numbers, so we could imagine it’s going to be pretty potent at running by the immunity of people who’ve already been infected or vaccinated in most places it shows up”:

https://www.medrxiv.org/content/10.1101/2021.12.19.21268073v1

To develop therapies against emerging variants, it is important to understand the viral biology and the effect of mutations. However, this is challenging because live virus can only be studied in a few laboratories that meet stringent safety standards. Now a team describe a virus-like particle (VLP) that comprises the four SARS-CoV-2 structural proteins, but instead of packaging viral RNA, it packages messenger RNA (mRNA) that expresses a reporter protein. The amount of reporter expressed in receiver cells depends on the efficiency of packaging and assembly in the producer cells and the efficiency of entry into receiver cells. Mutations in the nucleocapsid protein that are found in more transmissible variants increase mRNA packaging and expression. The VLPs provide a platform for studying the effect of mutations in the structural proteins and for screening therapeutics:

https://www.science.org/doi/10.1126/science.abl6184

A group provide evidence that SARS-CoV-2 spreads through cell–cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell–cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting enzyme 2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralisation by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis:

https://www.pnas.org/content/119/1/e2111400119

The Omicron variant encodes 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Now researchers show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for convalescent and vaccinated individuals, but this loss was less pronounced after a third vaccine dose. Most receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only 3 out of 29 mAbs retaining unaltered potency, including the ACE2-mimicking S2K146 mAb. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs neutralized Omicron through recognition of antigenic sites outside the RBM, including sotrovimab, S2X259 and S2H97. The magnitude of Omicron-mediated immune evasion marks a major SARS-CoV-2 antigenic shift. Broadly neutralizing mAbs recognizing RBD epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers:

https://www.nature.com/articles/d41586-021-03825-4

A team investigated whether Omicron escapes antibody neutralisation in South Africans vaccinated with Pfizer BNT162b2. They also investigated if Omicron requires the ACE2 receptor to infect cells. They isolated and sequence confirmed live Omicron virus from an infected person in South Africa and compared plasma neutralisation of Omicron relative to an ancestral SARS-CoV-2 strain, observing that Omicron still required ACE2 to infect. For neutralisation, blood samples were taken soon after vaccination from participants who were vaccinated and previously infected or vaccinated with no evidence of previous infection. Neutralisation of ancestral virus was much higher in infected and vaccinated versus vaccinated only participants but both groups showed a 22-fold escape from vaccine elicited neutralisation by the Omicron variant. However, in the previously infected and vaccinated group, the level of residual neutralisation of Omicron was similar to the level of neutralisation of ancestral virus observed in the vaccination only group. These data support the notion that, provided high neutralisation capacity is elicited by vaccination/boosting approaches, reasonable effectiveness against Omicron may be maintained:

https://www.nature.com/articles/d41586-021-03824-5

Researchers found B.1.1.529 to be markedly resistant to neutralisation by serum not only from convalescent patients, but also from individuals vaccinated with one of the four widely used COVID-19 vaccines. Even serum from persons vaccinated and boosted with mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies to all known epitope clusters on the spike protein, we noted that the activity of 17 of the 19 antibodies tested were either abolished or impaired, including ones currently authorized or approved for use in patients. In addition, we also identified four new spike mutations (S371L, N440K, G446S, and Q493R) that confer greater antibody resistance to B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2:

https://www.nature.com/articles/d41586-021-03826-3

The rapid development of vaccines has been crucial in battling the ongoing COVID-19 pandemic. However, access challenges remain, breakthrough infections occur, and emerging variants present increased risk. Developing antiviral therapeutics is therefore a high priority for the treatment of COVID-19. Some drug candidates in clinical trials act against the viral RNA-dependent RNA polymerase, but there are other viral enzymes that have been considered good targets for inhibition by drugs. A group report the discovery and characterisation of a drug against the main protease involved in the cleavage of polyproteins involved in viral replication. The drug, PF-07321332, can be administered orally, has good selectivity and safety profiles, and protected against infection in a mouse model. In a phase 1 clinical trial, the drug reached concentrations expected to inhibit the virus based on in vitro studies. It also inhibited other coronaviruses, including severe acute respiratory syndrome coronavirus 1 and Middle East respiratory syndrome coronavirus, and could be in the armoury against future viral threats:

https://www.science.org/doi/10.1126/science.abl4784

Researchers asked to what extent did the COVID-19 pandemic reduce access to surgical care, and were racial and ethnic minority groups more likely to have reduced access to surgical care? In this cohort study of more than 13 million inpatient and outpatient surgical encounters in 767 US hospitals in a hospital administrative database, surgical use was 13% lower in 2020 compared with 2019, with the greatest decrease concentrated in elective surgical procedures. While Black and Hispanic patients experienced a reduction in surgical encounters, White patients experienced the greatest reduction in surgical encounters. Despite severe and persistent disruptions to health systems during the COVID-19 pandemic, racial and ethnic minority groups did not experience a disproportionate decrease in access to surgical care:

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2787470

How did hospitalisations and racial and ethnic disparities in hospitalisation outcomes change during the COVID-19 pandemic among patients with traditional Medicare? In this cohort study using 100% traditional Medicare inpatient data, comprising 31 771 054 beneficiaries and 14 021 285 hospitalisations from January 2019 through February 2021, the decline in non–COVID-19 and emergence of COVID-19 hospitalisations during the pandemic was qualitatively similar among beneficiaries of different racial and ethnic minority groups. In-hospital mortality for patients with COVID-19 was higher in racial and ethnic minority groups than in White patients, driven by a Hispanic-White gap; mortality among non-COVID-19 hospitalisations also differentially increased among patients in racial and ethnic minority groups relative to White patients, driven by an increased Black-White gap. Racial and ethnic disparities in mortality were evident among COVID-19 hospitalisations and widened among non–COVID-19 hospitalisations among Medicare beneficiaries, motivating greater attention to health equity:

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2787469

Is exposure to incarceration associated with a long-term increase in mortality rate, and does this association differ by race? In this cohort study of 7974 individuals who were followed up from 1979 to 2018, incarceration was associated with a 65% higher mortality rate among Black participants. Among non-Black participants, incarceration was not associated with mortality. These findings suggest that racial disparities in the association of incarceration with mortality, as well as in rates of exposure to incarceration, may partially explain the lower life expectancy of the non-Hispanic Black population in the US:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787436

Next, are youths with a history of incarceration at increased risk of early mortality compared with youths with no history of incarceration? In this cohort study of 3645 previously incarcerated youths, the all-cause mortality rate was 5.9 times higher in previously incarcerated youths than the rate observed in general population, Medicaid-enrolled youths. Homicide was the leading cause of death among formerly incarcerated youths, accounting for more deaths than all other causes combined. These findings suggest that delinquency and violence prevention strategies that incorporate a culturally informed approach and consider sex and developmental level are critical to reduce early mortality in this high-risk youth population:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787434

Studies have attempted to estimate the extent of hesitancy worldwide. One survey of nearly 45,000 participants in 12 countries — conducted before COVID-19 vaccines started being rolled out, and published in July — found that hesitancy was lower in the 10 low- and middle-income nations than in Russia and the United States. But researchers say that the situation has changed throughout the pandemic. In Nepal, for example, where the study found acceptance was highest (97%), the pace of vaccination has slowed, despite only 40% of adults having received one dose:

https://www.nature.com/articles/d41586-021-01987-9

Researchers asked what is the association between COVID-19 testing and case rates on residential college campuses? In this cohort study of 18 Connecticut colleges and universities, infrequent COVID-19 testing of residential students was not associated with decreased transmission, whereas testing of residential students twice per week was associated with decreased transmission during the 2020-2021 academic year. Findings suggest that twice-weekly COVID-19 testing of residential students may serve as an effective infection mitigation strategy at colleges and universities:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787433

Researchers now report the results of a double-blind, randomised, placebo-controlled, endpoint-case driven, phase 3, clinical trial of a single dose of an adenovirus type 5 vectored vaccine (CanSino Biologics, Tianjin, China) in adults 18 years and older. The study involved 18,363 vaccinated and 18,354 unvaccinated participants from Argentina, Chile, Mexico, Pakistan, and Russia, with recruitment beginning in September, 2020, and continuing until the endpoint of 150 COVID-19 cases was reached in January, 2021. Efficacy against PCR-confirmed COVID-19 was 57·5% (95% CI 39·7–70·0; p=0·0026) and 91·7% (95% CI 36·1–98·9) against severe COVID-19. Similar efficacy numbers have been reported in clinical trials of the Oxford AstraZeneca chimpanzee adenovirus vectored vaccine (62·1% in recipients of the standard dose) and the Jansen, Johnson & Johnson adenovirus type 26 vectored vaccine (66·9% against COVID-19 and 76·7% against severe COVID-19). Serious adverse events were relatively rare, and the rates did not differ between vaccine and placebo groups. Given differences in the timing, geographical region, study cohorts, and circulating variants, these three vaccines appear to have broadly similar safety and efficacy profiles. Most previous phase 3 clinical trials of COVID-19 vaccines have found that there is a lag period of roughly 14 days between vaccination and the start of protection. They report a similar lag period of approximately 12 days:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02834-8/fulltext

Death reporting in India. Between March 1, 2020, and June 30, 2021, 87,870 deaths were registered in areas of Chennai district represented by the 2011 census, exceeding expected deaths by 25 990 (95% uncertainty interval 25 640–26 360) or 5·18 (5·11–5·25) excess deaths per 1000 people. Stratified by age, excess deaths numbered 21·02 (20·54–21·49) excess deaths per 1000 people for individuals aged 60–69 years, 39·74 (38·73–40·69) for those aged 70–79 years, and 96·90 (93·35–100·16) for those aged 80 years or older. Neighbourhoods with lower socioeconomic status had 0·7% to 2·8% increases in pandemic-associated mortality per 1 SD increase in each measure of community disadvantage, due largely to a disproportionate increase in mortality within these neighbourhoods during the second wave. Conversely, differences in excess mortality across communities were not clearly associated with socioeconomic status measures during the first wave. For each increase by 1 SD in measures of community disadvantage, neighbourhoods had 3·6% to 8·6% lower pandemic-associated mortality during the first 4 weeks of India's country-wide lockdown, before widespread SARS-CoV-2 circulation was underway in Chennai. The greatest reductions in mortality during this early lockdown period were observed among men aged 20–29 years, with 58% (54–62) fewer deaths than expected from pre-pandemic trends. Mortality in Chennai increased substantially but heterogeneously during the COVID-19 pandemic, with the greatest burden concentrated in disadvantaged communities. Reported COVID-19 deaths greatly underestimated pandemic-associated mortality:

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00746-5/fulltext

The ACTIV-3 Therapeutics for Inpatients with COVID-19 (TICO) platform was developed to assess multiple candidate mAbs in individuals hospitalised with moderate or severe COVID-19 within 12 days of symptom onset. Now, the ACTIV-3 TICO Study Group report the results of two neutralising mAb treatments (sotrovimab and BRII-196 plus BRII-198) that were provided in addition to standard of care, typically including remdesivir and corticosteroids, in a double-blind, randomised fashion, predominantly before the availability of SARS-CoV-2 vaccines, and were compared with a pooled placebo group. Enrolment into the trial was stopped early after a prespecified interim futility analysis in 536 participants in the modified intention-to-treat population found no improvement in odds of favourable pulmonary outcome scores on day 5 after infusion with either sotrovimab or BRII-196 plus BRII-198 compared with placebo. By day 90, no difference was seen in the primary endpoint of sustained clinical recovery with either sotrovimab or BRII-196 plus BRII-198 compared with placebo, and composite safety outcomes were similar across the three groups:

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00762-3/fulltext

Does colchicine prevent intubation and mortality in hospitalized patients with COVID-19 pneumonia? In this randomized clinical trial of 1279 patients hospitalized with COVID-19, patients allocated to receive colchicine plus usual care or to usual care alone demonstrated no significant difference in the coprimary outcome of mechanical ventilation or 28-day mortality. This randomized clinical trial found that colchicine did not significantly reduce the need for mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787585

Lung autopsy studies, which include analyses of plasma samples from 6 of the patients, demonstrate how SARS-CoV-2 not only spreads in the lungs and damages them, but also how it affects immune system responses. The researchers determined that SARS-CoV-2 infected respiratory epithelial cells, which aid in generating and repairing lung tissue, via a different process than influenza. According to the authors, fatal influenza often results from secondary bacterial co-pathogenesis, unlike fatal COVID-19, which produces pulmonary damage and associated immune responses so severe that coinfection isn’t necessary for the disease to become deadly. Individuals who died more than 20 days following initial COVID-19 symptoms exhibited high levels of pulmonary fibrosis. Furthermore, several individuals had widespread thrombosis, and each had diffuse alveolar damage—a potentially fatal condition that prevents adequate oxygenation of the blood and ultimately stiffens the lungs, according to the study. All autopsied individuals died between March and July 2020, within 3 to 47 days of symptom onset; they were also diagnosed with at least 1 high-risk factor associated with severe COVID-19. The researchers concluded that their findings may help to predict case severity and recovery among people who are elderly or have obesity or diabetes when they develop COVID-19. The authors noted that the links they uncovered between disease processes and patients’ comorbidities such as diabetes may provide insight into tailoring existing COVID-19 therapeutics based on the stage of the illness:

https://www.science.org/doi/10.1126/scitranslmed.abj7790

It is not fully understood why COVID-19 is typically milder in children. To examine differences in response to SARS-CoV-2 infection in children and adults, a group analysed paediatric and adult COVID-19 patients and healthy controls (total n=93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In healthy paediatric airways, they observed cells already in an interferon-activated state, that upon SARS-CoV-2 infection was further induced especially in airway immune cells. They postulate that higher paediatric innate interferon-responses restrict viral replication and disease progression. The systemic response in children was characterised by increases in naive lymphocytes and a depletion of natural killer cells, while in adults cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. They provide evidence that dendritic cells initiate interferon signalling in early infection, and identify novel epithelial cell states that associate with COVID-19 and age. Their matching nasal and blood data showed a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were massively reduced in paediatric patients. Together, they provide several mechanisms that explain the milder clinical syndrome observed in children:

https://www.nature.com/articles/s41586-021-04345-x

Next, researchers 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. They 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

A team evaluated the relative performance of saliva and mid-turbinate swabs as RT-PCR samples for the Delta and Omicron variants. The positive percent agreement (PPA) of saliva swabs and mid-turbinate swabs to a composite standard was 71% (95% CI: 53-84%) and 100% (95% CI: 89-100%), respectively, for the Delta variant. However, for the Omicron variant saliva and mid-turbinate swabs had a 100% (95% CI: 90-100%) and 86% (95% CI: 71-94%) PPA, respectively. This finding supports ex-vivo data of altered tissue tropism from other labs for the Omicron variant. Reassessment of the diagnostic testing standard-of-care may be required as the Omicron variant become the dominant variant worldwide:

https://www.medrxiv.org/content/10.1101/2021.12.22.21268246v1

Is substantial weight loss achieved with weight loss surgery associated with improved risk and severity of COVID-19 infection in patients with obesity? In this cohort study of 11,809 patients with obesity, the rates of positive SARS-CoV-2 test results were comparable among patients in the surgical group and control group. However, previous weight loss surgery was significantly associated with a 49% lower risk of hospitalisation, 63% lower risk of need for supplemental oxygen, and 60% lower risk of severe disease during a 12-month period after contracting COVID-19 infection. The findings from this study show an association between weight loss achieved with surgery and improved outcomes of COVID-19 infection, suggesting that obesity can be a modifiable risk factor for the severity of COVID-19 infection:

https://jamanetwork.com/journals/jamasurgery/fullarticle/2787613

What is an ideal balance between alternative care modalities implemented during the COVID-19 pandemic and traditional care in the post-pandemic care model? This survey study of 1529 chronically ill adults found that patients would choose alternative care (ie. teleconsultations, symptom-checkers, and remote monitoring) over the traditional care equivalent for 22% to 52% of their future needs. The study identified 67 care activities, patient characteristics, and characteristics of alternative care modalities for which patients considered it appropriate to replace traditional with alternative care. Alternative care modalities implemented during the pandemic could be used to deliver nearly half of patients’ post-pandemic care:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787586

Researchers found that patients with covid-19 admitted to hospital and those managed in the community had higher GP consultation rates for most symptoms and diseases, received more prescriptions, and were more likely to use healthcare resources after covid-19 than in the 12 months before infection, although the rates in the two groups differed. For example, although the rates for primary care consultations for symptoms such as fatigue, breathlessness, and palpitations were similar between the two groups, patients in the community were more likely to consult their GP because of loss of taste and smell and muscle pain; patients admitted to hospital were more likely to report ongoing problems related to nausea and delirium. Although healthcare use increased in both groups after covid-19 relative to levels before the pandemic, the increase was higher in patients admitted to hospital for all types of healthcare use. Nevertheless, healthcare use in the group managed in the community increased by 18% after covid-19 compared with levels before the pandemic, highlighting the need for adequate ongoing provision of care for this population:

https://www.bmj.com/content/375/bmj-2021-065834

The objective of a study was to assess the effectiveness and safety of rosuvastatin plus colchicine, emtricitabine/tenofovir in Columbia. In a large randomised trial, the combined use of all the drugs reduces the risk of 28-day mortality and the need for invasive mechanical ventilation in hospitalized patients with pulmonary compromise from COVID-19. More randomized controlled trials are needed to compare the effectiveness and cost of treatment with this combination versus other drugs that have been shown to reduce mortality from SARS-CoV-2 infection and its usefulness in patients with chronic statin use:

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00523-X/fulltext

A group describe how they used Twitter to investigate vaccine-induced side effects:

https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00378-1/fulltext

 


Justin Stebbing
Managing Director

 

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