Imperial College London

DrPanteleimonTakis

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Research Associate
 
 
 
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p.takis Website

 
 
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Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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60 results found

Gouveia GJ, Head T, Cheng LL, Clendinen CS, Cort JR, Du X, Edison AS, Fleischer CC, Hoch J, Mercaldo N, Pathmasiri W, Raftery D, Schock TB, Sumner LW, Takis PG, Copié V, Eghbalnia HR, Powers Ret al., 2024, Perspective: use and reuse of NMR-based metabolomics data: what works and what remains challenging., Metabolomics, Vol: 20

BACKGROUND: The National Cancer Institute issued a Request for Information (RFI; NOT-CA-23-007) in October 2022, soliciting input on using and reusing metabolomics data. This RFI aimed to gather input on best practices for metabolomics data storage, management, and use/reuse. AIM OF REVIEW: The nuclear magnetic resonance (NMR) Interest Group within the Metabolomics Association of North America (MANA) prepared a set of recommendations regarding the deposition, archiving, use, and reuse of NMR-based and, to a lesser extent, mass spectrometry (MS)-based metabolomics datasets. These recommendations were built on the collective experiences of metabolomics researchers within MANA who are generating, handling, and analyzing diverse metabolomics datasets spanning experimental (sample handling and preparation, NMR/MS metabolomics data acquisition, processing, and spectral analyses) to computational (automation of spectral processing, univariate and multivariate statistical analysis, metabolite prediction and identification, multi-omics data integration, etc.) studies. KEY SCIENTIFIC CONCEPTS OF REVIEW: We provide a synopsis of our collective view regarding the use and reuse of metabolomics data and articulate several recommendations regarding best practices, which are aimed at encouraging researchers to strengthen efforts toward maximizing the utility of metabolomics data, multi-omics data integration, and enhancing the overall scientific impact of metabolomics studies.

Journal article

Powers R, Andersson ER, Bayless AL, Brua RB, Chang MC, Cheng LL, Clendinen CS, Cochran D, Copié V, Cort JR, Crook AA, Eghbalnia HR, Giacalone A, Gouveia GJ, Hoch JC, Jeppesen MJ, Maroli AS, Merritt ME, Pathmasiri W, Roth HE, Rushin A, Sakallioglu IT, Sarma S, Schock TB, Sumner LW, Takis P, Uchimiya M, Wishart DSet al., 2024, Best practices in NMR metabolomics: Current state, TrAC - Trends in Analytical Chemistry, Vol: 171, ISSN: 0165-9936

A literature survey was conducted to identify current practices used by NMR metabolomics investigators when conducting and reporting their metabolomics studies. A total of 463 papers from 2020 to 80 papers from 2010 were selected from PubMed and were manually analyzed by a team of investigators to assess the extent and completeness of the experimental procedures and protocols reported. A significant number of the papers did not report on essential experimental details, incompletely stated which statistical methods were used, improperly applied supervised multivariate statistical analyses, or lacked validation of statistical models. A large diversity of protocols and software were identified, which suggests a lack of consensus and a relatively limited use of commonly agreed upon standards for conducting and reporting NMR metabolomics studies. The overall intent of the survey is to inform and encourage the NMR metabolomics community to develop and adopt best practices for the field.

Journal article

Routy B, Lenehan JG, Miller WH, Jamal R, Messaoudene M, Daisley BA, Hes C, Al KF, Martinez-Gili L, Punčochář M, Ernst S, Logan D, Belanger K, Esfahani K, Richard C, Ninkov M, Piccinno G, Armanini F, Pinto F, Krishnamoorthy M, Figueredo R, Thebault P, Takis P, Magrill J, Ramsay L, Derosa L, Marchesi JR, Parvathy SN, Elkrief A, Watson IR, Lapointe R, Segata N, Haeryfar SMM, Mullish BH, Silverman MS, Burton JP, Maleki Vareki Set al., 2024, Author Correction: Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial., Nat Med, Vol: 30

Journal article

Forlano R, Martinez-Gili L, Takis P, Miguens Blanco J, Liu T, Triantafyllou E, Skinner C, Loomba R, Thursz M, Marchesi JR, Mullish BH, Manousou Pet al., 2024, Disruption of gut barrier integrity and host-microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus, Gut Microbes, Vol: 16, ISSN: 1949-0976

Aberration of the “gut-liver axis” contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.

Journal article

Alexander J, Powell N, Marchesi J, Camuzeaux S, Chekmeneva E, Jimenez B, Sands Cet al., 2024, Considerations for peripheral blood transport and storage during large-scale multicentre metabolome research, Gut, Vol: 73, Pages: 379-383, ISSN: 0017-5749

Journal article

Michael BD, Dunai C, Needham EJ, Tharmaratnam K, Williams R, Huang Y, Boardman SA, Clark JJ, Sharma P, Subramaniam K, Wood GK, Collie C, Digby R, Ren A, Norton E, Leibowitz M, Ebrahimi S, Fower A, Fox H, Tato E, Ellul MA, Sunderland G, Held M, Hetherington C, Egbe FN, Palmos A, Stirrups K, Grundmann A, Chiollaz A-C, Sanchez J-C, Stewart JP, Griffiths M, Solomon T, Breen G, Coles AJ, Kingston N, Bradley JR, Chinnery PF, Cavanagh J, Irani SR, Vincent A, Baillie JK, Openshaw PJ, Semple MG, ISARIC4C Investigators, COVID-CNS Consortium, Taams LS, Menon DKet al., 2023, Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses, Nature Communications, Vol: 14, ISSN: 2041-1723

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

Journal article

Takis PG, Aggelidou VA, Sands CJ, Louka Aet al., 2023, Mapping of 1H NMR chemical shifts relationship with chemical similarities for the acceleration of metabolic profiling: application on blood products, Magnetic Resonance in Chemistry, Vol: 61, Pages: 759-769, ISSN: 0749-1581

One-dimensional (1D) proton-nuclear magnetic resonance (1H-NMR) spectroscopy is an established technique for the deconvolution of complex biological sample types via the identification/quantification of small molecules. It is highly reproducible and could be easily automated for small to large-scale bioanalytical, epidemiological, and in general metabolomics studies. However, chemical shift variability is a serious issue that must still be solved in order to fully automate metabolite identification. Herein, we demonstrate a strategy to increase the confidence in assignments and effectively predict the chemical shifts of various NMR signals based upon the simplest form of statistical models (i.e., linear regression). To build these models, we were guided by chemical homology in serum/plasma metabolites classes (i.e., amino acids and carboxylic acids) and similarity between chemical groups such as methyl protons. Our models, built on 940 serum samples and validated in an independent cohort of 1,052 plasma-EDTA spectra, were able to successfully predict the 1H NMR chemical shifts of 15 metabolites within ~1.5 linewidths (Δv1/2) error range on average. This pilot study demonstrates the potential of developing an algorithm for the accurate assignment of 1H NMR chemical shifts based solely on chemically defined constraints.

Journal article

Roper KJ, Thomas J, Albalawi W, Maddocks E, Dobson S, Alshehri A, Barone FG, Baltazar M, Semple MG, Ho A, Turtle L, ISARIC4C Consortium, Paxton WA, Pollakis Get al., 2023, Quantifying neutralising antibody responses against SARS-CoV-2 in dried blood spots (DBS) and paired sera, Scientific Reports, Vol: 13, ISSN: 2045-2322

The ongoing SARS-CoV-2 pandemic was initially managed by non-pharmaceutical interventions such as diagnostic testing, isolation of positive cases, physical distancing and lockdowns. The advent of vaccines has provided crucial protection against SARS-CoV-2. Neutralising antibody (nAb) responses are a key correlate of protection, and therefore measuring nAb responses is essential for monitoring vaccine efficacy. Fingerstick dried blood spots (DBS) are ideal for use in large-scale sero-surveillance because they are inexpensive, offer the option of self-collection and can be transported and stored at ambient temperatures. Such advantages also make DBS appealing to use in resource-limited settings and in potential future pandemics. In this study, nAb responses in sera, venous blood and fingerstick blood stored on filter paper were measured. Samples were collected from SARS-CoV-2 acutely infected individuals, SARS-CoV-2 convalescent individuals and SARS-CoV-2 vaccinated individuals. Good agreement was observed between the nAb responses measured in eluted DBS and paired sera. Stability of nAb responses was also observed in sera stored on filter paper at room temperature for 28 days. Overall, this study provides support for the use of filter paper as a viable sample collection method to study nAb responses.

Journal article

Routy B, Lenehan JG, Miller WH, Jamal R, Messaoudene M, Daisley BA, Hes C, Al KF, Martinez-Gili L, Punčochář M, Ernst S, Logan D, Belanger K, Esfahani K, Richard C, Ninkov M, Piccinno G, Armanini F, Pinto F, Krishnamoorthy M, Figueredo R, Thebault P, Takis P, Magrill J, Ramsay L, Derosa L, Marchesi JR, Parvathy SN, Elkrief A, Watson IR, Lapointe R, Segata N, Haeryfar SMM, Mullish BH, Silverman MS, Burton JP, Maleki Vareki Set al., 2023, Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial, Nature Medicine, ISSN: 1546-170X

Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899.

Journal article

Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, GenOMICC Investigators, SCOURGE Consortium, ISARICC Investigators, 23andMe COVID-19 Team, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, Baillie JKet al., 2023, GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 617, Pages: 764-768, ISSN: 0028-0836

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Journal article

Goldswain H, Dong X, Penrice-Randal R, Alruwaili M, Shawli GT, Prince T, Williamson MK, Raghwani J, Randle N, Jones B, Donovan-Banfield I, Salguero FJ, Tree JA, Hall Y, Hartley C, Erdmann M, Bazire J, Jearanaiwitayakul T, Semple MG, Openshaw PJM, Baillie JK, ISARIC4C Investigators, Emmett SR, Digard P, Matthews DA, Turtle L, Darby AC, Davidson AD, Carroll MW, Hiscox JAet al., 2023, The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection, Genome Biology, Vol: 24, ISSN: 1474-7596

BACKGROUND: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. RESULTS: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. CONCLUSIONS: These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

Journal article

Stebbing J, Takis PG, Sands CJ, Maslen L, Lewis MR, Gleason K, Page K, Guttery D, Fernandez-Garcia D, Primrose L, Shaw JAet al., 2023, Comparison of phenomics and cfDNA in a large breast screening population: the Breast Screening and Monitoring Study (BSMS), Oncogene, Vol: 42, Pages: 825-832, ISSN: 0950-9232

To assess their roles in breast cancer diagnostics, we aimed to compare plasma cell-free DNA (cfDNA) levels with the circulating metabolome in a large breast screening cohort of women recalled for mammography, including healthy women and women with mammographically detected breast diseases, ductal carcinoma in situ and invasive breast cancer: the Breast Screening and Monitoring Study (BSMS). In 999 women, plasma was analyzed by nuclear magnetic resonance (NMR) and Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) and then processed to isolate and quantify total cfDNA. NMR and UPLC-MS results were compared with data for 186 healthy women derived from the AIRWAVE cohort. Results showed no significant differences between groups for all metabolites, whereas invasive cancers had significantly higher plasma cfDNA levels than all other groups. When stratified the supervised OPLS-DA analysis and total cfDNA concentration showed high discrimination accuracy between invasive cancers and the disease/medication-free subjects. Furthermore, comparison of OPLS-DA data for invasive breast cancers with the AIRWAVE cohort showed similar discrimination between breast cancers and healthy controls. This is the first report of agreement between metabolomics and plasma cfDNA levels for discriminating breast cancer from healthy subjects in a true screening population. It also emphasizes the importance of sample standardization. Follow on studies will involve analysis of candidate features in a larger validation series as well as comparing results with serial plasma samples taken at the next routine screening mammography appointment. The findings here help establish the role of plasma analysis in the diagnosis of breast cancer in a large real-world cohort.

Journal article

Harvey N, Takis PG, Lindon JC, Li JV, Jiménez Bet al., 2023, Optimization of diffusion-ordered NMR spectroscopy experiments for high-throughput automation in human metabolic phenotyping, Analytical Chemistry, Vol: 95, Pages: 3147-3152, ISSN: 0003-2700

The diffusion-ordered nuclear magnetic resonance spectroscopy (DOSY) experiment allows the calculation of diffusion coefficient values of metabolites in complex mixtures. However, this experiment has not yet been broadly used for metabolic profiling due to lack of a standardized protocol. Here we propose a pipeline for the DOSY experimental setup and data processing in metabolic phenotyping studies. Due to the complexity of biological samples, three experiments (a standard DOSY, a relaxation-edited DOSY, and a diffusion-edited DOSY) have been optimized to provide DOSY metabolic profiles with peak-picked diffusion coefficients for over 90% of signals visible in the one-dimensional 1H general biofluid profile in as little as 3 min 36 s. The developed parameter sets and tools are straightforward to implement and can facilitate the use of DOSY for metabolic profiling of human blood plasma and urine samples.

Journal article

Augustin A, Le Guennec A, Umamahesan C, Kendler-Rhodes A, Tucker RM, Chekmeneva E, Takis P, Lewis M, Balasubramanian K, DeSouza N, Mullish BH, Taylor D, Ryan S, Whelan K, Ma Y, Ibrahim M, Bjarnason I, Hayee BH, Charlett A, Dobbs SM, Dobbs RJ, Weller Cet al., 2023, Faecal metabolite deficit, gut inflammation and diet in Parkinson’s disease: integrative analysis indicates inflammatory response syndrome, Clinical and Translational Medicine, Vol: 13, ISSN: 2001-1326

Background:Gut-brain axis is widely implicated in the pathophysiology of Parkinson's disease (PD). We take an integrated approach to considering the gut as a target for disease-modifying intervention, using continuous measurements of disease facets irrespective of diagnostic divide.Methods:We characterised 77 participants with diagnosed-PD, 113 without, by dietary/exogenous substance intake, faecal metabolome, intestinal inflammation, serum cytokines/chemokines, clinical phenotype including colonic transit time. Complete-linkage hierarchical cluster analysis of metabolites discriminant for PD-status was performed.Results:Longer colonic transit was linked to deficits in faecal short-chain-fatty acids outside PD, to a ‘tryptophan-containing metabolite cluster’ overall. Phenotypic cluster analysis aggregated colonic transit with brady/hypokinesia, tremor, sleep disorder and dysosmia, each individually associated with tryptophan-cluster deficit. Overall, a faster pulse was associated with deficits in a metabolite cluster including benzoic acid and an imidazole-ring compound (anti-fungals) and vitamin B3 (anti-inflammatory) and with higher serum CCL20 (chemotactic for lymphocytes/dendritic cells towards mucosal epithelium). The faster pulse in PD was irrespective of postural hypotension. The benzoic acid-cluster deficit was linked to (well-recognised) lower caffeine and alcohol intakes, tryptophan-cluster deficit to higher maltose intake. Free-sugar intake was increased in PD, maltose intake being 63% higher (p = .001). Faecal calprotectin was 44% (95% CI 5%, 98%) greater in PD [p = .001, adjusted for proton-pump inhibitors (p = .001)], with 16% of PD-probands exceeding a cut-point for clinically significant inflammation compatible with inflammatory bowel disease. Higher maltose intake was associated with exceeding this calprotectin cut-point.Conclusions:Emerging picture is of (i) clinical phenotype being described by deficits in microbial metabolites essenti

Journal article

Liew F, Talwar S, Cross A, Willett B, Scott S, Logan N, Siggins M, Swieboda D, Sidhu J, Efstathiou C, Moore S, Davis C, Mohamed N, Nunag J, King C, Thompson AAR, Rowland-Jones S, Docherty A, Chalmers J, Ho L-P, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard L, Wootton D, Dunachie S, Quint J, Evans R, Wain L, Fontanella S, de Silva T, Ho A, Harrison E, Baillie JK, Semple MG, Brightling C, Thwaites R, Turtle L, Openshaw Pet al., 2023, SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination, EBioMedicine, Vol: 87, Pages: 1-14, ISSN: 2352-3964

Background:Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.Methods:In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.Findings:Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination.Interpretation:The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.Funding:This

Journal article

Routy B, Lenehan J, Daisley B, Messaoudene M, Al K, Richard C, Miller W, Jamal R, Ernst S, Logan D, Belanger K, Gili LM, Mullish B, Takis P, Samayoa CH, Ninkov M, Parvathy SN, Lambert C, Elkrief A, Lapointe R, Haeryfar M, Burton J, Silverman M, Maleki Set al., 2022, 614 Microbiome modification with fecal microbiota transplant from healthy donors before anti-PD1 therapy reduces primary resistance to immunotherapy in advanced and metastatic melanoma patients, SITC 37th Annual Meeting (SITC 2022), Publisher: BioMed Central, ISSN: 2051-1426

Conference paper

Vink E, Davis C, MacLean A, Pascall D, McDonald SE, Gunson R, Hardwick HE, Oosthuyzen W, Openshaw PJM, Baillie JK, Semple MG, Ho Aet al., 2022, Viral coinfections in hospitalized Coronavirus disease 2019 patients recruited to the international severe acute respiratory and emerging infections consortium WHO clinical characterisation protocol UK study, Open Forum Infectious Diseases, Vol: 9, Pages: 1-10, ISSN: 2328-8957

BackgroundWe conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity.MethodsMultiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge.ResultsA coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity.ConclusionsViral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward.

Journal article

Takis PG, Vuckovic I, Tan T, Denic A, Lieske JC, Lewis MR, Macura Set al., 2022, NMRpQuant: an automated software for large scale urinary total protein quantification by one-dimensional 1H NMR profiles, Bioinformatics, Vol: 38, Pages: 4437-4439, ISSN: 1367-4803

Summary1H nuclear magnetic resonance (NMR) spectroscopy is an established bioanalytical technology for metabolic profiling of biofluids in both clinical and large-scale population screening applications. Recently, urinary protein quantification has been demonstrated using the same 1D 1H NMR experimental data captured for metabolic profiling. Here, we introduce NMRpQuant, a freely available platform that builds on these findings with both novel and further optimized computational NMR approaches for rigorous, automated protein urine quantification. The results are validated by interlaboratory comparisons, demonstrating agreement with clinical/biochemical methodologies, pointing at a ready-to-use tool for routine protein urinalyses.Availability and implementationNMRpQuant was developed on MATLAB programming environment. Source code and Windows/macOS compiled applications are available at https://github.com/pantakis/NMRpQuant, and working examples are available at https://doi.org/10.6084/m9.figshare.18737189.v1.

Journal article

Norris T, Razieh C, Zaccardi F, Yates T, Islam N, Gillies CL, Chudasama Y, Rowlands A, Davies MJ, McCann GP, Banerjee A, Lam CSP, Docherty AB, Openshaw PJM, Baillie JK, Semple MG, Lawson CA, Khunti Ket al., 2022, Impact of cardiometabolic multimorbidity and ethnicity on cardiovascular/renal complications in patients with COVID-19, Heart, Vol: 108, Pages: 1200-1208, ISSN: 1355-6037

Objective Using a large national database of people hospitalised with COVID-19, we investigated the contribution of cardio-metabolic conditions, multi-morbidity and ethnicity on the risk of in-hospital cardiovascular complications and death.Methods A multicentre, prospective cohort study in 302 UK healthcare facilities of adults hospitalised with COVID-19 between 6 February 2020 and 16 March 2021. Logistic models were used to explore associations between baseline patient ethnicity, cardiometabolic conditions and multimorbidity (0, 1, 2, >2 conditions), and in-hospital cardiovascular complications (heart failure, arrhythmia, cardiac ischaemia, cardiac arrest, coagulation complications, stroke), renal injury and death.Results Of 65 624 patients hospitalised with COVID-19, 44 598 (68.0%) reported at least one cardiometabolic condition on admission. Cardiovascular/renal complications or death occurred in 24 609 (38.0%) patients. Baseline cardiometabolic conditions were independently associated with increased odds of in-hospital complications and this risk increased in the presence of cardiometabolic multimorbidity. For example, compared with having no cardiometabolic conditions, 1, 2 or ≥3 conditions was associated with 1.46 (95% CI 1.39 to 1.54), 2.04 (95% CI 1.93 to 2.15) and 3.10 (95% CI 2.92 to 3.29) times higher odds of any cardiovascular/renal complication, respectively. A similar pattern was observed for all-cause death. Compared with the white group, the South Asian (OR 1.19, 95% CI 1.10 to 1.29) and black (OR 1.53 to 95% CI 1.37 to 1.72) ethnic groups had higher risk of any cardiovascular/renal complication.Conclusions In hospitalised patients with COVID-19, cardiovascular complications or death impacts just under half of all patients, with the highest risk in those of South Asian or Black ethnicity and in patients with cardiometabolic multimorbidity.

Journal article

Chasapi SA, Karagkouni E, Kalavrizioti D, Vamvakas S, Zompra A, Takis PG, Goumenos DS, Spyroulias GAet al., 2022, NMR-based metabolomics in differential diagnosis of Chronic Kidney Disease (CKD) subtypes, Metabolites, Vol: 12, Pages: 1-14, ISSN: 2218-1989

Chronic Kidney Disease (CKD) is considered as a major public health problem as it can lead to end-stage kidney failure, which requires replacement therapy. A prompt and accurate diagnosis, along with the appropriate treatment, can delay CKD’s progression, significantly. Herein, we sought to determine whether CKD etiology can be reflected in urine metabolomics during its early stage. This is achieved through the analysis of the urine metabolic fingerprint from 108 CKD patients by means of Nuclear Magnetic Resonance (NMR) spectroscopy metabolomic analysis. We report the first NMR—metabolomics data regarding the three most common etiologies of CKD: Chronic Glomerulonephritis (IgA and Membranous Nephropathy), Diabetic Nephropathy (DN) and Hypertensive Nephrosclerosis (HN). Analysis aided a moderate glomerulonephritis clustering, providing characterization of the metabolic fluctuations between the CKD subtypes and control disease. The urine metabolome of IgA Nephropathy reveals a specific metabolism, reflecting its different etiology or origin and is useful for determining the origin of the disease. In contrast, urine metabolomes from DN and HN patients did not reveal any indicative metabolic pattern, which is consistent with their fused clinical phenotype. These findings may contribute to improving diagnostics and prognostic approaches for CKD, as well as improving our understanding of its pathology.

Journal article

Correia GDS, Takis PG, Sands CJ, Kowalka AM, Tan T, Turtle L, Ho A, Semple MG, Openshaw PJM, Baillie JK, Takáts Z, Lewis MRet al., 2022, 1H NMR Signals from urine excreted protein are a source of bias in probabilistic quotient normalization, Analytical Chemistry, Vol: 94, Pages: 6919-6923, ISSN: 0003-2700

Normalization to account for variation in urinary dilution is crucial for interpretation of urine metabolic profiles. Probabilistic quotient normalization (PQN) is used routinely in metabolomics but is sensitive to systematic variation shared across a large proportion of the spectral profile (>50%). Where 1H nuclear magnetic resonance (NMR) spectroscopy is employed, the presence of urinary protein can elevate the spectral baseline and substantially impact the resulting profile. Using 1H NMR profile measurements of spot urine samples collected from hospitalized COVID-19 patients in the ISARIC 4C study, we determined that PQN coefficients are significantly correlated with observed protein levels (r2 = 0.423, p < 2.2 × 10–16). This correlation was significantly reduced (r2 = 0.163, p < 2.2 × 10–16) when using a computational method for suppression of macromolecular signals known as small molecule enhancement spectroscopy (SMolESY) for proteinic baseline removal prior to PQN. These results highlight proteinuria as a common yet overlooked source of bias in 1H NMR metabolic profiling studies which can be effectively mitigated using SMolESY or other macromolecular signal suppression methods before estimation of normalization coefficients.

Journal article

Takis P, Vuckovic I, Macura S, 2022, NMRpQuant

NMRpQuant is a freely available software for the automated total urinary protein via 1D 1H NMR urine profiles.(check the associated paper: https://doi.org/10.1093/bioinformatics/btac502)

Software

Närhi F, Moonesinghe SR, Shenkin SD, Drake TM, Mulholland RH, Donegan C, Dunning J, Fairfield CJ, Girvan M, Hardwick HE, Ho A, Leeming G, Nguyen-Van-Tam JS, Pius R, Russell CD, Shaw CA, Spencer RG, Turtle L, Openshaw PJM, Baillie JK, Harrison EM, Semple MG, Docherty AB, ISARIC4C investigatorset al., 2022, Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study., The Lancet Digital Health, Vol: 4, Pages: e220-e234, ISSN: 2589-7500

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70-0·89], p=0·0001, for 70-79 years; 0·52 [0·46-0·58], p<0·0001, for >80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75-80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant wom

Journal article

Dejnirattisai W, Huo J, Zhou D, Zahradník J, Supasa P, Liu C, Duyvesteyn HME, Ginn HM, Mentzer AJ, Tuekprakhon A, Nutalai R, Wang B, Dijokaite A, Khan S, Avinoam O, Bahar M, Skelly D, Adele S, Johnson SA, Amini A, Ritter TG, Mason C, Dold C, Pan D, Assadi S, Bellass A, Omo-Dare N, Koeckerling D, Flaxman A, Jenkin D, Aley PK, Voysey M, Costa Clemens SA, Naveca FG, Nascimento V, Nascimento F, Fernandes da Costa C, Resende PC, Pauvolid-Correa A, Siqueira MM, Baillie V, Serafin N, Kwatra G, Da Silva K, Madhi SA, Nunes MC, Malik T, Openshaw PJM, Baillie JK, Semple MG, Townsend AR, Huang K-YA, Tan TK, Carroll MW, Klenerman P, Barnes E, Dunachie SJ, Constantinides B, Webster H, Crook D, Pollard AJ, Lambe T, OPTIC Consortium, ISARIC4C Consortium, Paterson NG, Williams MA, Hall DR, Fry EE, Mongkolsapaya J, Ren J, Schreiber G, Stuart DI, Screaton GRet al., 2022, SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses, Cell, Vol: 185, Pages: 467-484.e15, ISSN: 0092-8674

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

Journal article

de Silva TI, Liu G, Lindsey BB, Dong D, Moore SC, Hsu NS, Shah D, Wellington D, Mentzer AJ, Angyal A, Brown R, Parker MD, Ying Z, Yao X, Turtle L, Dunachie S, COVID-19 Genomics UK COG-UK Consortium, Maini MK, Ogg G, Knight JC, ISARIC4C Investigators, Peng Y, Rowland-Jones SL, Dong Tet al., 2021, The impact of viral mutations on recognition by SARS-CoV-2 specific T cells., iScience, Vol: 24, Pages: 103353-103353, ISSN: 2589-0042

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

Journal article

Takis P, Lewis M, 2021, PROCESSING 1H-NMR SPECTRAL DATA

Patent

Wickenhagen A, Sugrue E, Lytras S, Kuchi S, Noerenberg M, Turnbull ML, Loney C, Herder V, Allan J, Jarmson I, Cameron-Ruiz N, Varjak M, Pinto RM, Lee JY, Iselin L, Palmalux N, Stewart DG, Swingler S, Greenwood EJD, Crozier TWM, Gu Q, Davies EL, Clohisey S, Wang B, Maranhao Costa FT, Santana MF, de Lima Ferreira LC, Murphy L, Fawkes A, Meynert A, Grimes G, Filho JLDS, Marti M, Hughes J, Stanton RJ, Wang ECY, Ho A, Davis I, Jarrett RF, Castello A, Robertson DL, Semple MG, Openshaw PJM, Palmarini M, Lehner PJ, Baillie JK, Rihn SJ, Wilson SJet al., 2021, A prenylated dsRNA sensor protects against severe COVID-19, Science, Vol: 374, Pages: 1-18, ISSN: 0036-8075

Journal article

Drake TM, Riad AM, Fairfield CJ, Egan C, Knight SR, Pius R, Hardwick HE, Norman L, Shaw CA, McLean KA, Thompson AAR, Ho A, Swann OV, Sullivan M, Soares F, Holden KA, Merson L, Plotkin D, Sigfrid L, de Silva TI, Girvan M, Jackson C, Russell CD, Dunning J, Solomon T, Carson G, Olliaro P, Nguyen-Van-Tam JS, Turtle L, Docherty AB, Openshaw PJ, Baillie JK, Harrison EM, Semple MG, ISARIC4C investigatorset al., 2021, Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study, The Lancet, Vol: 398, Pages: 223-237, ISSN: 0140-6736

BACKGROUND: COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK. METHODS: We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities. FINDINGS: Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were

Journal article

COVID-19 Host Genetics Initiative, 2021, Mapping the human genetic architecture of COVID-19, Nature, Vol: 600, Pages: 472-477, ISSN: 0028-0836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Journal article

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