Activity of convalescent and vaccine serum against SARS-CoV-2 Omicron.

The Omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in November 2021 in South Africa and Botswana, as well as in a sample from a traveller from South Africa in Hong Kong1,2. Since then, Omicron has been detected globally. This variant appears to be at least as infectious as Delta (B.1.617.2), has already caused superspreader events3, and has outcompeted Delta within weeks in several countries and metropolitan areas. Omicron hosts an unprecedented number of mutations in its spike gene and early reports have provided evidence for extensive immune escape and reduced vaccine effectiveness2,4-6. Here we investigated the virus-neutralizing and spike protein-binding activity of sera from convalescent, double mRNA-vaccinated, mRNA-boosted, convalescent double-vaccinated and convalescent boosted individuals against wild-type, Beta (B.1.351) and Omicron SARS-CoV-2 isolates and spike proteins. Neutralizing activity of sera from convalescent and double-vaccinated participants was undetectable or very low against Omicron compared with the wild-type virus, whereas neutralizing activity of sera from individuals who had been exposed to spike three or four times through infection and vaccination was maintained, although at significantly reduced levels. Binding to the receptor-binding and N-terminal domains of the Omicron spike protein was reduced compared with binding to the wild type in convalescent unvaccinated individuals, but was mostly retained in vaccinated individuals.

Immunity to Seasonal Coronavirus Spike Proteins Does Not Protect from SARS-CoV-2 Challenge in a Mouse Model but Has No Detrimental Effect on Protection Mediated by COVID-19 mRNA Vaccination.

Seasonal coronaviruses have been circulating widely in the human population for many years. With increasing age, humans are more likely to have been exposed to these viruses and to have developed immunity against them. It has been hypothesized that this immunity to seasonal coronaviruses may provide partial protection against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it has also been shown that coronavirus disease 2019 (COVID-19) vaccination induces a back-boosting effects against the spike proteins of seasonal betacoronaviruses. In this study, we tested if immunity to the seasonal coronavirus spikes from OC43, HKU1, 229E, or NL63 would confer protection against SARS-CoV-2 challenge in a mouse model, and whether pre-existing immunity against these spikes would weaken the protection afforded by mRNA COVID-19 vaccination. We found that mice vaccinated with the seasonal coronavirus spike proteins had no increased protection compared to the negative controls. While a negligible back-boosting effect against betacoronavirus spike proteins was observed after SARS-CoV-2 infection, there was no negative original antigenic sin-like effect on the immune response and protection induced by SARS-CoV-2 mRNA vaccination in animals with pre-existing immunity to seasonal coronavirus spike proteins. IMPORTANCE The impact that immunity against seasonal coronaviruses has on both susceptibility to SARS-CoV-2 infection as well as on COVID-19 vaccination is unclear. This study provides insights into both questions in a mouse model of SARS-CoV-2.

Keep your cool: Overwintering physiology in response to urbanization in the acorn ant, Temnothorax curvispinosus.

Winter presents a challenge for survival, yet temperate ectotherms have remarkable physiological adaptations to cope with low-temperature conditions. Under recent climate change, rather than strictly relaxing pressure on overwintering survival, warmer winters can instead disrupt these low-temperature trait-environment associations, with negative consequences for populations. While there is increasing evidence of physiological adaptation to contemporary warming during the growing season, the effects of winter warming on physiological traits are less clear. To address this knowledge gap, we performed a common garden experiment using relatively warm-adapted versus cold-adapted populations of the acorn ant, Temnothorax curvispinosus, sampled across an urban heat island gradient, to explore the effects of winter conditions on plasticity and evolution of physiological traits. We found no evidence of evolutionary divergence in chill coma recovery nor in metabolic rate at either of two test temperatures (4 and 10 °C). Although we found the expected plastic response of increased metabolic rate under the 10 °C acute test temperature as compared with the 4 °C test temperature, this plastic response, (i.e., the acute thermal sensitivity of metabolic rate), was not different across populations. Surprisingly, we found that winter-acclimated urban ant populations exhibited higher heat tolerance compared with rural ant populations, and that the magnitude of divergence was comparable to that observed among growing-season acclimated ants. Finally, we found no evidence of differences between populations with respect to changes in colony size from the beginning to the end of the overwintering experiment. Together, these findings indicate that despite the evolution of higher heat tolerance that is often accompanied by losses in low-temperature tolerance, urban acorn ants have retained several components of low-temperature physiological performance when assessed under ecologically relevant overwintering conditions. Our study suggests the importance of measuring physiological traits under seasonally-relevant conditions to understand the causes and consequences of evolutionary responses to contemporary warming.

Inherent versus induced protein flexibility: Comparisons within and between apo and holo structures.

Understanding how ligand binding influences protein flexibility is important, especially in rational drug design. Protein flexibility upon ligand binding is analyzed herein using 305 proteins with 2369 crystal structures with ligands (holo) and 1679 without (apo). Each protein has at least two apo and two holo structures for analysis. The inherent variation in structures with and without ligands is first established as a baseline. This baseline is then compared to the change in conformation in going from the apo to holo states to probe induced flexibility. The inherent backbone flexibility across the apo structures is roughly the same as the variation across holo structures. The induced backbone flexibility across apo-holo pairs is larger than that of the apo or holo states, but the increase in RMSD is less than 0.5 Å. Analysis of χ1 angles revealed a distinctly different pattern with significant influences seen for ligand binding on side-chain conformations in the binding site. Within the apo and holo states themselves, the variation of the χ1 angles is the same. However, the data combining both apo and holo states show significant displacements. Upon ligand binding, χ1 angles are frequently pushed to new orientations outside the range seen in the apo states. Influences on binding-site variation could not be easily attributed to features such as ligand size or x-ray structure resolution. By combining these findings, we find that most binding site flexibility is compatible with the common practice in flexible docking, where backbones are kept rigid and side chains are allowed some degree of flexibility.

Examining the functional range of commercially available low-cost airborne particle sensors and consequences for monitoring of indoor air quality in residences.

Low-cost airborne particle sensors are gaining attention for monitoring human exposure to indoor particulate matter. This study aimed to establish the concentrations at which these commercially available sensors can be expected to report accurate concentrations. We exposed five types of commercial integrated devices and three types of "bare" low-cost particle sensors to a range of concentrations generated by three different sources. We propose definitions of upper and lower bounds of functional range based on the relationship between a given sensor's output and that of a reference instrument during a laboratory experiment. Experiments show that the lower bound can range from approximately 3 to 15 µg/m3 . At greater concentrations, sensor output deviates from linearity at approximately 300-3000 µg/m3 . We also conducted a simulation campaign to analyze the effect of this limitation on functional range on the accuracy of exposure readings given by these devices. We estimate that the upper bound results in minimal inaccuracy in exposure quantification, and the lower bound can result in as much as a 50% error in approximately 10% of US homes.

Intragroup xenophobic attitudes, ethnic identity, and substance use among Latinx adolescents.

This study examined intragroup xenophobic attitudes, ethnic identity, and substance use (N = 905). Drawing on cognitive dissonance theory, we hypothesized that intragroup xenophobic attitudes among Latinx individuals would be associated with higher levels of substance use (SU) in early adulthood and that ethnic identity would increase the strength of that association. We found that in 10th grade, xenophobic attitudes were higher among respondents with lower ethnic identity, a longer family history in the United States, and less stress. In a longitudinal analysis, SU in emerging adulthood was highest among males, those reporting higher stress in 10th grade, and those with a longer family history in the United States. There was a significant interaction of ethnic identity and xenophobia on substance use (ß = -.12, p < .001), indicating that substance use was higher among Latinxs with low ethnic identity who harbor xenophobic attitudes. Findings are explained using system justification theory because intragroup xenophobia appears to operate as a coping strategy that is maladaptive for Latinx individuals reporting low ethnic identity but somehow useful to those with high ethnic identity.

The impact of heat exposure on reduced gestational age in pregnant women in North Carolina, 2011-2015.

Research on the impact of heat on pregnant women has focused largely on outcomes following extreme temperature events, such as particular heat waves or spells of very cold weather on pregnant women. Consistently, the literature has shown a statistically significant relationship between heat with shortened gestational age with studies concentrated largely in the western states of the USA or other nations. The association between heat and shortened gestational age has not been examined in the Southeastern US where maternal outcomes are some of the most challenging in the nation. Unlike previous studies that focus on the impacts of a single heat wave event, this study seeks to understand the impact of high heat over a 5-year period during the annual warm season (May-September). To achieve this goal, a case-crossover study design is employed to understand the impact of heat on preterm labor across regions in North Carolina (NC). Temperature thresholds for impact and the underlying relationships between preterm labor and heat are investigated using generalized additive models (GAM). Gridded temperature data (PRISM) is used to establish exposure classifications. The results reveal significant impacts to pregnant women exposed to heat with regional variations. The exposure variable with the most stable and significant result was minimum temperature, indicating high overnight temperatures have the most impact on preterm birth. The magnitude of this impact varies across regions from a 1% increase in risk to 6% increase in risk per two-degree increment above established minimum temperature thresholds.

Inhibition of type I interferon induction and signalling by mosquito-borne flaviviruses.

The Flavivirus genus (Flaviviridae family) contains a number of important human pathogens, including dengue and Zika viruses, which have the potential to cause severe disease. In order to efficiently establish a productive infection in mammalian cells, flaviviruses have developed key strategies to counteract host immune defences, including the type I interferon response. They employ different mechanisms to control interferon signal transduction and effector pathways, and key research generated over the past couple of decades has uncovered new insights into their abilities to actively decrease interferon antiviral activity. Given the lack of antivirals or prophylactic treatments for many flaviviral infections, it is important to fully understand how these viruses affect cellular processes to influence pathogenesis and disease outcome. This review will discuss the strategies mosquito-borne flaviviruses have evolved to antagonise type I interferon mediated immune responses.

Recent improvements to Binding MOAD: a resource for protein-ligand binding affinities and structures.

For over 10 years, Binding MOAD (Mother of All Databases; http://www.BindingMOAD.org) has been one of the largest resources for high-quality protein-ligand complexes and associated binding affinity data. Binding MOAD has grown at the rate of 1994 complexes per year, on average. Currently, it contains 23,269 complexes and 8156 binding affinities. Our annual updates curate the data using a semi-automated literature search of the references cited within the PDB file, and we have recently upgraded our website and added new features and functionalities to better serve Binding MOAD users. In order to eliminate the legacy application server of the old platform and to accommodate new changes, the website has been completely rewritten in the LAMP (Linux, Apache, MySQL and PHP) environment. The improved user interface incorporates current third-party plugins for better visualization of protein and ligand molecules, and it provides features like sorting, filtering and filtered downloads. In addition to the field-based searching, Binding MOAD now can be searched by structural queries based on the ligand. In order to remove redundancy, Binding MOAD records are clustered in different families based on 90% sequence identity. The new Binding MOAD, with the upgraded platform, features and functionalities, is now equipped to better serve its users.

Monitoring of chimerism following allogeneic haematopoietic stem cell transplantation (HSCT): technical recommendations for the use of short tandem repeat (STR) based techniques, on behalf of the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping Chimerism Working Group.

Analysis of short tandem repeats (STR) is the predominant method for post-transplant monitoring of donor engraftment. It can enable early detection of disease relapse, level of engraftment and provide useful information on the graft-versus-host disease (GVHD)/graft-versus-tumour (GVT) effect, facilitating therapeutic intervention. Harmonization and standardization of techniques and result interpretation is essential to reduce the impact of laboratory variability on both clinical management and the results of multi-centre clinical trials. However, the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) has highlighted significant issues inherent in STR testing that impact upon inter- and intra- laboratory variation. We present here consensus best practice guidelines and recommendations for STR chimerism testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 11 UK and Eire clinical laboratories. This document uses data obtained from the UK NEQAS LI Post-Stem Cell Transplant (SCT) Chimerism Monitoring Programme.

Analytical Method for Measuring Cosmogenic (35)S in Natural Waters.

Cosmogenic sulfur-35 in water as dissolved sulfate ((35)SO4) has successfully been used as an intrinsic hydrologic tracer in low-SO4, high-elevation basins. Its application in environmental waters containing high SO4 concentrations has been limited because only small amounts of SO4 can be analyzed using current liquid scintillation counting (LSC) techniques. We present a new analytical method for analyzing large amounts of BaSO4 for (35)S. We quantify efficiency gains when suspending BaSO4 precipitate in Inta-Gel Plus cocktail, purify BaSO4 precipitate to remove dissolved organic matter, mitigate interference of radium-226 and its daughter products by selection of high purity barium chloride, and optimize LSC counting parameters for (35)S determination in larger masses of BaSO4. Using this improved procedure, we achieved counting efficiencies that are comparable to published LSC techniques despite a 10-fold increase in the SO4 sample load. (35)SO4 was successfully measured in high SO4 surface waters and groundwaters containing low ratios of (35)S activity to SO4 mass demonstrating that this new analytical method expands the analytical range of (35)SO4 and broadens the utility of (35)SO4 as an intrinsic tracer in hydrologic settings.

Virus-like particles of louping ill virus elicit potent neutralizing antibodies targeting multimers of viral envelope protein.

Louping ill virus (LIV) is a tick-borne flavivirus that predominantly causes disease in livestock, especially sheep in the British Isles. A preventive vaccine, previously approved for veterinary use but now discontinued, was based on an inactivated whole virion that likely provided protection by induction of neutralizing antibodies recognizing the viral envelope (E) protein. A major disadvantage of the inactivated vaccine was the need for high containment facilities for the propagation of infectious virus, as mandated by the hazard group 3 status of the virus. This study aimed to develop high-efficacy non-infectious protein-based vaccine candidates. Specifically, soluble envelope protein (sE), and virus-like particles (VLPs), comprised of the precursor of membrane and envelope proteins, were generated, characterized, and studied for their immunogenicity in mice. Results showed that the VLPs induced more potent virus neutralizing response compared to sE, even though the total anti-envelope IgG content induced by the two antigens was similar. Depletion of anti-monomeric E protein antibodies from mouse immune sera suggested that the neutralizing antibodies elicited by the VLPs targeted epitopes spanning the highly organized structure of multimer of the E protein, whereas the antibody response induced by sE focused on E monomers. Thus, our results indicate that VLPs represent a promising LIV vaccine candidate.

Short-lived natural radionuclides as tracers in hydrogeological studies - A review.

Fundamental approaches to the study of groundwater rely on investigating the spatial and temporal distribution of stable and radioactive isotopes and other anthropogenic compounds in natural waterbodies. The most often used tracers for estimating groundwater flow paths and residence times, groundwater/surface water interaction as well as tracing chemical (contamination) sources include stable isotopes of water (δ 18O and δ 2H), radiocarbon (14C; t1/2 = 5730 a), tritium (3H; t1/2 = 12.43 a) as well as unreactive fluorine-containing gases (e.g., chlorofluorocarbons CCl3F or CFC-11; CCl2F3 or CFC-12; C2Cl3F3 or CFC-113; and SF6). While gas tracers are usually referred to as transient tracers and are appropriate for investigating modern flow systems, the isotopic tracers are often used to investigated paleo or regional flow systems. Stable isotopes of water can also be used to investigate groundwater/surface water interactions. Another, thus far been less frequently used group of groundwater tracers, are cosmo- and geo- genic short-lived radioisotopes. These isotopes are uniquely suited for studying a wide range of groundwater problems that have short time scales including high aquifer vulnerability to quantitative and qualitative impacts and groundwater discharge to surface waters. Here, we discuss and compare the applications of radio­sulphur (35S; half-life t1/2 = 87 d), radio­beryllium (7Be; t1/2 = 53 d), radio­phosphorus (32/33P; combined t1/2 = 33 d), natural tritium (3H; t1/2 = 12.43 a), radon (222Rn; t1/2 = 3.8 d) and short-lived radium (224/223Ra; combined t1/2 = 5.2 d). The paper discusses the principles of the individual tracer methods, focusing on the isotopes' input functions or values, on sampling techniques, and on methods of analyses. Case studies that applied a combined use of the tracers are referred to for readers who wish to learn more about the application of the so far underused cosmo- and geo- genic radioisotopes as aquatic tracers.

Protective effect and molecular mechanisms of human non-neutralizing cross-reactive spike antibodies elicited by SARS-CoV-2 mRNA vaccination.

Neutralizing antibodies correlate with protection against SARS-CoV-2. Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection from disease progression. Non-neutralizing antibodies cannot directly protect from infection but may recruit effector cells thus contribute to the clearance of infected cells. Also, they often bind conserved epitopes across multiple variants. We characterized 42 human mAbs from COVID-19 vaccinated individuals. Most of these antibodies exhibited no neutralizing activity in vitro but several non-neutralizing antibodies protected against lethal challenge with SARS-CoV-2 in different animal models. A subset of those mAbs showed a clear dependence on Fc-mediated effector functions. We determined the structures of three non-neutralizing antibodies with two targeting the RBD, and one that targeting the SD1 region. Our data confirms the real-world observation in humans that non-neutralizing antibodies to SARS-CoV-2 can be protective.

Sequential Infection with Influenza A Virus Followed by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Leads to More Severe Disease and Encephalitis in a Mouse Model of COVID-19.

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly influenza viruses, is a global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected with influenza A virus (IAV) followed by SARS-CoV-2 and the host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 alone. The sequentially infected mice showed reduced SARS-CoV-2 RNA synthesis, yet exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to the singly infected or control mice. Sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz Tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis, albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by IAV inhibits SARS-CoV-2. Interestingly, infection with an attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest coinfection ('twinfection') is deleterious and mitigation steps should be instituted as part of the comprehensive public health and management strategy of COVID-19.

The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection.

SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia.

Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations.

Molecular genetic assays for the detection of the JAK2 V617F (c.1849G>T) and other pathogenetic mutations within JAK2 exon 12 and MPL exon 10 are part of the routine diagnostic workup for patients presenting with erythrocytosis, thrombocytosis or otherwise suspected to have a myeloproliferative neoplasm. A wide choice of techniques are available for the detection of these mutations, leading to potential difficulties for clinical laboratories in deciding upon the most appropriate assay, which can lead to problems with inter-laboratory standardization. Here, we discuss the most important issues for a clinical diagnostic laboratory in choosing a technique, particularly for detection of the JAK2 V617F mutation at diagnosis. The JAK2 V617F detection assay should be both specific and sensitive enough to detect a mutant allele burden as low as 1-3%. Indeed, the use of sensitive assays increases the detection rate of the JAK2 V617F mutation within myeloproliferative neoplasms. Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2 V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays. Molecular results should be considered in the context of clinical findings and other haematological or laboratory results.

Trauma-Informed Care on mental health wards: the impact of Power Threat Meaning Framework Team Formulation and Psychological Stabilisation on self-harm and restrictive interventions.

Aim: The aim of this evaluation was to assess the impact of introducing a model of Trauma-Informed Care (TIC), comprising weekly Power Threat Meaning Framework (PTMF) Team Formulation and weekly Psychological Stabilisation staff training, to a National Health Service (NHS) adult acute inpatient mental health unit over a four-year period. Method: A retrospective service evaluation design was employed to assess for differences in the number of incidents of self-harm, seclusion and restraint in the four-year period following the introduction of TIC, when compared to the year prior. Results: Significant reductions were demonstrated in the monthly number of incidents of self-harm (p < 0.01; r = 0.42), seclusion (p < 0.05; r = 0.30) and restraint (p < 0.05; d = 0.55) following the introduction of TIC. Conclusion: Findings suggest that PTMF Team Formulation and Psychological Stabilisation training can contribute to significant reductions in self-harm and restrictive interventions (seclusion and restraint) on adult mental health wards. Qualitative interviews with staff and service users from the unit will support a better understanding of the mechanisms of this change. Further research, employing a randomised control trial design, could increase the validity and generalisability of findings. However, the ethical implications of withholding potentially beneficial practices from a control group would need to be considered.

Delivering the precision oncology paradigm: reduced R&D costs and greater return on investment through a companion diagnostic informed precision oncology medicines approach.

BACKGROUND: Precision oncology medicines represent a paradigm shift compared to non-precision oncology medicines in cancer therapy, in some situations delivering more clinical benefit, and potentially lowering healthcare costs. We determined whether employing a companion diagnostic (CDx) approach during oncology medicines development delivers effective therapies that are within the cost constraints of current health systems. R&D costs of developing a medicine are subject to debate, with average estimates ranging from $765 million (m) to $4.6 billion (b). Our aim was to determine whether precision oncology medicines are cheaper to bring from R&D to market; a secondary goal was to determine whether precision oncology medicines have a greater return on investment (ROI). METHOD: Data on oncology medicines approved between 1997 and 2020 by the US Food and Drug Administration (FDA) were analysed from the Securities and Exchange Commission (SEC) filings. Data were compiled from 10-K, 10-Q, and 20-F financial performance filings on medicines' development costs through their R&D lifetime. Clinical trial data were split into clinical trial phases 1-3 and probability of success (POS) of trials was calculated, along with preclinical costs. Cost-of-capital (CoC) approach was applied and, if appropriate, a tax rebate was subtracted from the total. RESULTS: Data on 42 precision and 29 non-precision oncology medicines from 56 companies listed by the National Cancer Institute which had complete data available were analysed. Estimated mean cost to deliver a new oncology medicine was $4.4b (95% CI, $3.6-5.2b). Costs to bring a precision oncology medicine to market were $1.1b less ($3.5b; 95% CI, $2.7-4.5b) compared to non-precision oncology medicines ($4.6b; 95% CI, $3.5-6.1b). The key driver of costs was POS of clinical trials, accounting for a difference of $591.3 m. Additional data analysis illustrated that there was a 27% increase in return on investment (ROI) of precision oncology medicines over non-precision oncology medicines. CONCLUSION: Our results provide an accurate estimate of the R&D spend required to bring an oncology medicine to market. Deployment of a CDx at the earliest stage substantially lowers the cost associated with oncology medicines development, potentially making them available to more patients, while staying within the cost constraints of cancer health systems.

The Stereotypic Response of the Pulmonary Vasculature to Respiratory Viral Infections: Findings in Mouse Models of SARS-CoV-2, Influenza A and Gammaherpesvirus Infections.

The respiratory system is the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 19 (COVID-19) where acute respiratory distress syndrome is considered the leading cause of death. Changes in pulmonary blood vessels, among which an endothelialitis/endotheliitis has been particularly emphasized, have been suggested to play a central role in the development of acute lung injury. Similar vascular changes are also observed in animal models of COVID-19. The present study aimed to determine whether the latter are specific for SARS-CoV-2 infection, investigating the vascular response in the lungs of mice infected with SARS-CoV-2 and other respiratory viruses (influenza A and murine gammaherpesvirus) by in situ approaches (histology, immunohistology, morphometry) combined with RNA sequencing and bioinformatic analysis. Non-selective recruitment of monocytes and T and B cells from larger muscular veins and arteries was observed with all viruses, matched by a comparable transcriptional response. There was no evidence of endothelial cell infection in any of the models. Both the morphological investigation and the transcriptomics approach support the interpretation that the lung vasculature in mice mounts a stereotypic response to alveolar and respiratory epithelial damage. This may have implications for the treatment and management of respiratory disease in humans.