Real-time estimation of immunological responses against emerging SARS-CoV-2 variants in the UK: a mathematical modelling study.

BACKGROUND: The emergence of SARS-CoV-2 variants and COVID-19 vaccination have resulted in complex exposure histories. Rapid assessment of the effects of these exposures on neutralising antibodies against SARS-CoV-2 infection is crucial for informing vaccine strategy and epidemic management. We aimed to investigate heterogeneity in individual-level and population-level antibody kinetics to emerging variants by previous SARS-CoV-2 exposure history, to examine implications for real-time estimation, and to examine the effects of vaccine-campaign timing. METHODS: Our Bayesian hierarchical model of antibody kinetics estimated neutralising-antibody trajectories against a panel of SARS-CoV-2 variants quantified with a live virus microneutralisation assay and informed by individual-level COVID-19 vaccination and SARS-CoV-2 infection histories. Antibody titre trajectories were modelled with a piecewise linear function that depended on the key biological quantities of an initial titre value, time the peak titre is reached, set-point time, and corresponding rates of increase and decrease for gradients between two timing parameters. All process parameters were estimated at both the individual level and the population level. We analysed data from participants in the University College London Hospitals-Francis Crick Institute Legacy study cohort (NCT04750356) who underwent surveillance for SARS-CoV-2 either through asymptomatic mandatory occupational health screening once per week between April 1, 2020, and May 31, 2022, or symptom-based testing between April 1, 2020, and Feb 1, 2023. People included in the Legacy study were either Crick employees or health-care workers at three London hospitals, older than 18 years, and gave written informed consent. Legacy excluded people who were unable or unwilling to give informed consent and those not employed by a qualifying institution. We segmented data to include vaccination events occurring up to 150 days before the emergence of three variants of concern: delta, BA.2, and XBB 1.5. We split the data for each wave into two categories: real-time and retrospective. The real-time dataset contained neutralising-antibody titres collected up to the date of emergence in each wave; the retrospective dataset contained all samples until the next SARS-CoV-2 exposure of each individual, whether vaccination or infection. FINDINGS: We included data from 335 participants in the delta wave analysis, 223 (67%) of whom were female and 112 (33%) of whom were male (median age 40 years, IQR 22-58); data from 385 participants in the BA.2 wave analysis, 271 (70%) of whom were female and 114 (30%) of whom were male (41 years, 22-60); and data from 248 participants in the XBB 1.5 wave analysis, 191 (77%) of whom were female, 56 (23%) of whom were male, and one (<1%) of whom preferred not to say (40 years, 21-59). Overall, we included 968 exposures (vaccinations) across 1895 serum samples in the model. For the delta wave, we estimated peak titre values as 490·0 IC50 (95% credible interval 224·3-1515·9) for people with no previous infection and as 702·4 IC50 (300·8-2322·7) for people with a previous infection before omicron; the delta wave did not include people with a previous omicron infection. For the BA.2 wave, we estimated peak titre values as 858·1 IC50 (689·8-1363·2) for people with no previous infection, 1020·7 IC50 (725·9-1722·6) for people with a previous infection before omicron, and 1422·0 IC50 (679·2-3027·3) for people with a previous omicron infection. For the XBB 1.5 wave, we estimated peak titre values as 703·2 IC50 (415·0-3197·8) for people with no previous infection, 1215·9 IC50 (511·6-7338·7) for people with a previous infection before omicron, and 1556·3 IC50 (757·2-7907·9) for people with a previous omicron infection. INTERPRETATION: Our study shows the feasibility of real-time estimation of antibody kinetics before SARS-CoV-2 variant emergence. This estimation is valuable for understanding how specific combinations of SARS-CoV-2 exposures influence antibody kinetics and for examining how COVID-19 vaccination-campaign timing could affect population-level immunity to emerging variants. FUNDING: Wellcome Trust, National Institute for Health Research University College London Hospitals Biomedical Research Centre, UK Research and Innovation, UK Medical Research Council, Francis Crick Institute, and Genotype-to-Phenotype National Virology Consortium.

Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource.

BACKGROUND: Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear and hampers our understanding of tissue homeostasis and cancer development. RESULTS: Here, we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and non-cancer somatic evolution in 122 cancer types and 12 non-cancer tissues. Mapping the alterations of these genes in 7953 pan-cancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and non-cancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. CONCLUSIONS: Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and non-cancer somatic drivers, their literature support, and properties are accessible in the Network of Cancer Genes and Healthy Drivers resource at http://www.network-cancer-genes.org/ .

Author Correction: Scalable and robust SARS-CoV-2 testing in an academic center.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Trends in Aortic Valve Replacement Procedures Between 2009 and 2015: Has Transcatheter Aortic Valve Replacement Made a Difference?

BACKGROUND: This study reports trends in volume and adverse events associated with isolated aortic valve procedures performed in Medicare beneficiaries between 2009 and 2015. METHODS: This retrospective study used the annual fiscal year Medicare Provider Analysis and Review file to identify all Medicare beneficiaries undergoing an isolated aortic valve procedure. Outcome measures included three mortality rates and nine in-hospital adverse events. The final study population consisted of 233,660 hospitalizations. RESULTS: During the study period, Medicare beneficiaries undergoing an aortic valve procedure increased from 22,076 to 49,362, for an average annual growth rate of 14.45%. Transcatheter aortic valve replacement (TAVR) procedures per 100,000 Medicare beneficiaries grew from 10.7 in 2012 to 41.1 in 2015. Overall, in-hospital mortality rates, cumulative 30-day mortality rates, and 90-day postdischarge mortality rates declined annually during the study period. However, the 90-day mortality rate for TAVR was nearly double the rate for the tissue surgical aortic valve replacement group. Nearly 68% of Medicare beneficiaries experienced at least one in-hospital adverse event during their index hospitalization. Medicare beneficiaries undergoing TAVR had the lowest observed adverse events rates among the aortic valve procedures in 2015. CONCLUSIONS: The total number of Medicare beneficiaries undergoing isolated aortic valve procedures increased from 47.5 to 88.9 per 100,000 Medicare beneficiaries during the study period. Aortic valve procedures increased significantly during this study period primarily due to the increase in TAVR, with clinical outcomes improving as well. Although long-term outcomes of TAVR are still under investigation, these results are promising.

The Epichloë festucae antifungal protein has activity against the plant pathogen Sclerotinia homoeocarpa, the causal agent of dollar spot disease.

Epichloë spp. are naturally occurring fungal endophytic symbionts of many cool-season grasses. Infection by the fungal endophytes often confers biotic and abiotic stress tolerance to their hosts. Endophyte-mediated disease resistance is well-established in the fine fescue grass Festuca rubra subsp. rubra (strong creeping red fescue) infected with E. festucae. Resistance to fungal pathogens is not an established effect of endophyte infection of other grass species, and may therefore be unique to the fine fescues. The underlying mechanism of the disease resistance is unknown. E. festucae produces a secreted antifungal protein that is highly expressed in the infected plant tissues and may therefore be involved in the disease resistance. Most Epichloë spp. do not have a gene for a similar antifungal protein. Here we report the characterization of the E. festucae antifungal protein, designated Efe-AfpA. The antifungal protein partially purified from the apoplastic proteins of endophyte-infected plant tissue and the recombinant protein expressed in the yeast Pichia pastoris was found to have activity against the important plant pathogen Sclerotinia homoeocarpa. Efe-AfpA may therefore be a component of the disease resistance seen in endophyte-infected strong creeping red fescue.

Incremental Hospital Cost and Length-of-stay Associated With Treating Adverse Events Among Medicare Beneficiaries Undergoing Cervical Spinal Fusion During Fiscal Year 2013 and 2014.

STUDY DESIGN: A retrospective study. OBJECTIVE: To report the incremental hospital resources consumed with treating adverse events experienced by Medicare beneficiaries undergoing a two or three vertebrae level cervical spinal fusion. SUMMARY OF BACKGROUND DATA: Hospitals are increasingly at financial risk for patients experiencing adverse events due "pay for performance." Little is known about incremental resources consumed when treating patients who experienced an adverse event after cervical spinal fusions. METHODS: Fiscal years 2013 and 2014 Medicare Provider Analysis and Review file was used to identify 86,265 beneficiaries who underwent 2 or 3 vertebrae level cervical spinal fusion. International Classification of Diseases 9th Clinical Modification diagnostic and procedure codes were used to identify 10 adverse events. This study estimated both the observed and risk-adjusted incremental hospital resources consumed (cost [2014 US $] and length-of-stay) in treating beneficiaries experiencing each adverse event. RESULTS: Overall, 6.2% of beneficiaries undergoing cervical spinal fusion experienced at least one of the study's adverse events. Beneficiaries experiencing any complication consumed significantly more hospital resources (incremental cost of $28,638) and had longer length-of-stay (incremental stays of 9.1 days). After adjusting for patient demographics and comorbid conditions, incremental cost of treating adverse events ranged from $42,358 (infection) to $10,100 (dural tear). CONCLUSION: Adverse events frequently occur and add substantially to the hospital costs of patients undergoing cervical spinal fusion. Shared decision-making instruments should clearly provide these risk estimates to the patient before surgical consideration. Investment in activities that have been shown to reduce specific adverse events is warranted, and this study may allow health systems to prioritize performance improvement areas. LEVEL OF EVIDENCE: 3.

Functional characterization of salicylate hydroxylase from the fungal endophyte Epichloë festucae.

Epichloë spp. are symbiotic fungal endophytes of many cool season grasses. The presence of the fungal endophytes often confers insect, drought, and disease tolerance to the host grasses. The presence of the fungal endophytes within the host plants does not elicit host defense responses. The molecular basis for this phenomenon is not known. Epichloë festucae, the endophyte of Festuca rubra, expresses a salicylate hydroxylase similar to NahG from the bacterium Pseudomonas putida. Few fungal salicylate hydroxylase enzymes have been reported. The in planta expression of an endophyte salicylate hydroxylase raised the possibility that degradation of plant-produced salicylic acid is a factor in the mechanism of how the endophyte avoids eliciting host plant defenses. Here we report the characterization of the E. festucae salicylate hydroxylase, designated Efe-shyA. Although the fungal enzyme has the expected activity, based on salicylic acid levels in endophyte-free and endophyte-infected plants it is unlikely that expression of the endophyte salicylate hydroxylase is a factor in the lack of a host defense response to the presence of the fungal endophyte.

Horizontal gene transfer of a bacterial insect toxin gene into the Epichloë fungal symbionts of grasses.

Horizontal gene transfer is recognized as an important factor in genome evolution, particularly when the newly acquired gene confers a new capability to the recipient species. We identified a gene similar to the makes caterpillars floppy (mcf1 and mcf2) insect toxin genes in Photorhabdus, bacterial symbionts of nematodes, in the genomes of the Epichloë fungi, which are intercellular symbionts of grasses. Infection by Epichloë spp. often confers insect resistance to the grass hosts, largely due to the production of fungal alkaloids. A mcf-like gene is present in all of the Epichloë genome sequences currently available but in no other fungal genomes. This suggests the Epichloë genes were derived from a single lineage-specific HGT event. Molecular dating was used to estimate the time of the HGT event at between 7.2 and 58.8 million years ago. The mcf-like coding sequence from Epichloë typhina subsp. poae was cloned and expressed in Escherichia coli. E. coli cells expressing the Mcf protein were toxic to black cutworms (Agrotis ipsilon), whereas E. coli cells containing the vector only were non-toxic. These results suggest that the Epichloë mcf-like genes may be a component, in addition to the fungal alkaloids, of the insect resistance observed in Epichloë-infected grasses.

SOLiD-SAGE of endophyte-infected red fescue reveals numerous effects on host transcriptome and an abundance of highly expressed fungal secreted proteins.

One of the most important plant-fungal symbiotic relationships is that of cool season grasses with endophytic fungi of the genera Epichloë and Neotyphodium. These associations often confer benefits, such as resistance to herbivores and improved drought tolerance, to the hosts. One benefit that appears to be unique to fine fescue grasses is disease resistance. As a first step towards understanding the basis of the endophyte-mediated disease resistance in Festuca rubra we carried out a SOLiD-SAGE quantitative transcriptome comparison of endophyte-free and Epichloë festucae-infected F. rubra. Over 200 plant genes involved in a wide variety of physiological processes were statistically significantly differentially expressed between the two samples. Many of the endophyte expressed genes were surprisingly abundant, with the most abundant fungal tag representing over 10% of the fungal mapped tags. Many of the abundant fungal tags were for secreted proteins. The second most abundantly expressed fungal gene was for a secreted antifungal protein and is of particular interest regarding the endophyte-mediated disease resistance. Similar genes in Penicillium and Aspergillus spp. have been demonstrated to have antifungal activity. Of the 10 epichloae whole genome sequences available, only one isolate of E. festucae and Neotyphodium gansuense var inebrians have an antifungal protein gene. The uniqueness of this gene in E. festucae from F. rubra, its transcript abundance, and the secreted nature of the protein, all suggest it may be involved in the disease resistance conferred to the host, which is a unique feature of the fine fescue-endophyte symbiosis.