Imperial College London

Dr Charlotte-Eve Short

Faculty of MedicineDepartment of Infectious Disease

Academic Clinical Lecturer
 
 
 
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VD4, Variety wingNorfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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42 results found

Short C-E, 2023, Comparative analysis of vaginal microbiota sampling using menstrual cups and high vaginal swabs in pregnant women living with HIV-1 infection, Frontiers in Cellular and Infection Microbiology, Vol: 13, ISSN: 2235-2988

Background: Menstrual cups (MCs) are increasingly used to collect cervicovaginal secretions to characterise vaginal mucosal immunology, in conjunction with high vaginal swabs (HVS) for metataxonomics, particularly in HIV transmission studies. We hypothesised that both methods of collecting bacterial biomass are equivalent for 16S rRNA gene sequencing.Material and Methods: Cervicovaginal fluid (CVF) samples from 16 pregnant women with HIV-1 (PWWH) were included to represent the major vaginal bacterial community state types (CST I-V). Women underwent sampling during the second trimester by liquid amies HVS followed by a MC (Soft disc™) and samples were stored at -80°C. Bacterial cell pellets obtained from swab elution and MC (500 µL, 1 in 10 dilution) were resuspended in 120 µL PBS for DNA extraction. Bacterial 16S rRNA gene sequencing was performed using V1-V2 primers and were analysed using MOTHUR. Paired total DNA, bacterial load, amplicon read counts, diversity matrices and bacterial taxa were compared by sampling method using MicrobiomeAnalyst, SPSS and R.Results: The total DNA eluted from one aliquot of diluted CVF from an MC was similar to that of a HVS (993ng and 609ng, p=0.18); the mean bacterial loads were also comparable for both methods (MC: 8.0 log10 16S rRNA gene copies versus HVS: 7.9 log10 16S rRNA gene copies, p=0.27). The mean number of sequence reads generated from MC samples was lower than from HVS (MC: 12730; HVS:14830, p=0.05). The α-diversity metrices were similar for both techniques; MC Species Observed: 41 (range 12-96) versus HVS: 47 (range 16-96), p=0.15; MC Inverse Simpson Index: 1.98 (range 1.0-4.0) versus HVS: 0.48 (range 1.0-4.4), p=0.22). The three most abundant species observed were: Lactobacillus iners, Lactobacillus crispatus and Gardnerella vaginalis. Hierarchical clustering of relative abundance data showed that samples obtained using different techniques in an individual clustered in the same CST group.

Journal article

Fink DL, Callaby H, Luintel A, Beynon W, Bond H, Lim EY, Gkrania-Klotsas E, Heskin J, Bracchi M, Rathish B, Milligan I, O'Hara G, Rimmer S, Peters JR, Payne L, Mody N, Hodgson B, Lewthwaite P, Lester R, Woolley SD, Sturdy A, Whittington A, Johnson L, Jacobs N, Quartey J, Ai Payne B, Crowe S, Elliott IA, Harrison T, Cole J, Beard K, Cusack T-P, Jones I, Banerjee R, Rampling T, Specialist and High Consequence Infectious Diseases Centres Network for Monkeypox, Dunning Jet al., 2023, Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study., Lancet Infectious Diseases, Vol: 23, Pages: 589-597, ISSN: 1473-3099

BACKGROUND: The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. METHODS: In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. FINDINGS: 156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30-44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3 (IQR 349-828).

Journal article

Preda VG, Roberts LA, Quinlan RA, Short C-E, Taylor GP, Marchesi JRet al., 2023, Antiretroviral therapy (ART) inhibits the growth of cervicovaginal microbiome species in vitro: potential role in preterm birth (PTB), British HIV Association, Publisher: Wiley, Pages: 11-11, ISSN: 1464-2662

Conference paper

Preda VG, Roberts LA, Quinlan RA, Short C-ES, Taylor GP, Marchesi JRet al., 2023, Antiretroviral therapy (ART) inhibits the growth of cervicovaginal microbiome species in vitro: potential role in preterm birth (PTB), Publisher: WILEY, Pages: 11-11, ISSN: 1464-2662

Conference paper

Burnham KL, Maher AK, Jones EM, Tan MMH, Saputil RC, Baillon L, Selck C, Giang N, Arguello R, Pillay C, Thorley E, Short CE, Quinlan R, Barclay WS, Cooper N, Taylor GP, Davenport EE, Dominguez-Villar Met al., 2022, Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19, Nature Communications, Vol: 13, Pages: 1-17, ISSN: 2041-1723

Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14+ monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals. Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathogen sensing ex vivo leads to defects in pro-inflammatory cytokine and type-I IFN production in moderate COVID-19 cases, together with defects in glycolysis. COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology.

Journal article

Shiva F, Short C-E, Goldmeier D, Winston Aet al., 2022, Predictive value of neurological symptoms in persons with suspected neurosyphilis, SEXUALLY TRANSMITTED INFECTIONS, Vol: 98, Pages: 228-229, ISSN: 1368-4973

Journal article

Khan M, Rosadas C, Katsanovskaja K, Weber ID, Shute J, Ijaz S, Marchesin F, McClure E, Elias S, Flower B, Gao H, Quinlan R, Short C, Rosa A, Roustan C, Moshe M, Taylor GP, Elliott P, Cooke GS, Cherepanov P, Parker E, McClure MO, Tedder RSet al., 2022, Simple, sensitive, specific self-sampling assay secures SARS-CoV-2 antibody signals in sero-prevalence and post-vaccine studies, Scientific Reports, Vol: 12, ISSN: 2045-2322

At-home sampling is key to large scale seroprevalence studies. Dried blood spot (DBS) self-sampling removes the need for medical personnel for specimen collection but facilitates specimen referral to an appropriately accredited laboratory for accurate sample analysis. To establish a highly sensitive and specific antibody assay that would facilitate self-sampling for prevalence and vaccine-response studies. Paired sera and DBS eluates collected from 439 sero-positive, 382 sero-negative individuals and DBS from 34 vaccine recipients were assayed by capture ELISAs for IgG and IgM antibody to SARS-CoV-2. IgG and IgM combined on DBS eluates achieved a diagnostic sensitivity of 97.9% (95%CI 96.6 to 99.3) and a specificity of 99.2% (95% CI 98.4 to 100) compared to serum, displaying limits of detection equivalent to 23 and 10 WHO IU/ml, respectively. A strong correlation (r = 0.81) was observed between serum and DBS reactivities. Reactivity remained stable with samples deliberately rendered inadequate, (p = 0.234) and when samples were accidentally damaged or 'invalid'. All vaccine recipients were sero-positive. This assay provides a secure method for self-sampling by DBS with a sensitivity comparable to serum. The feasibility of DBS testing in sero-prevalence studies and in monitoring post-vaccine responses was confirmed, offering a robust and reliable tool for serological monitoring at a population level.

Journal article

Rosadas C, Khan M, Parker E, Marchesin F, Katsanovskaja K, Sureda-Vives M, Fernandez N, Randell P, Harvey R, Lilley A, Harris BH, Zuhair M, Fertleman M, Ijaz S, Dicks S, Short C-E, Quinlan R, Taylor GP, Hu K, McKay P, Rosa A, Roustan C, Zuckerman M, El Bouzidi K, Cooke G, Flower B, Moshe M, Elliott P, Spencer AJ, Lambe T, Gilbert SC, Kingston H, Baillie JK, Openshaw PJ, G Semple M, ISARIC4C Investigators, Cherepanov P, O McClure M, S Tedder Ret al., 2022, Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility, Journal of Virological Methods, Vol: 302, ISSN: 0166-0934

Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD). This class and species neutral assay showed a specificity of 100% on 825 pre COVID-19 samples and a potential sensitivity of 99.6% on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralisation and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations. The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.

Journal article

Short C-E, Quinlan R, Preda V, Wang X, Smith A, Marchesi J, Lee Y, MacIntyre D, Bennett P, Taylor Get al., 2021, Vaginal microbiota, genital inflammation and extracellular matrix remodelling collagenase: MMP-9 in pregnant women with HIV, a potential preterm birth mechanism warranting further exploration, Frontiers in Cellular and Infection Microbiology, Vol: 11, Pages: 1-14, ISSN: 2235-2988

Background: Pregnant women living with HIV infection (PWLWH) have elevated rates of preterm birth (PTB) in which HIV and cART are implicated. PWLWH also have a high prevalence of adverse vaginal microbiota, which associate with genital tract inflammation. The mechanism underlying PTB in PWLWH is unknown. We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria. Material and Methods: Cervical vaginal fluid (CVF) collected by a soft cup and high vaginal swabs (HVS) were obtained from PWLWH and HIV uninfected pregnant women (HUPW) at three antenatal time points. Maternal characteristics, cART exposure, and pregnancy outcome were recorded. Concentrations of MMP-9, TIMP-1 and ten cytokines were measured by immunoassays. Vaginal microbiota composition was determined through 16S rRNA amplicon sequencing. MMP-9, TIMP-1 and cytokine concentrations were compared by HIV status, cART, and prematurity and in PWLWH correlations with polymorphonuclear leucocytes, cytokines and bacterial genera were explored. Results: CVF was available for 50 PWLWH (108 samples) and 12 HUPW (20 samples) between gestation weeks 14-38. Thirty-six PWLWH conceived on cART and 14 initiated post-conception. There were five and one PTB outcomes in PWLWH and HUPW respectively. PWLWH had higher mean CVF concentrations of MMP-9 (p<0.001) and TIMP-1 (p=0.035) in the second trimester compared with HUPW with a similar trend in the third trimester. PWLWH also had higher CVF values of cytokines: IL-1b, IL-8, IL-12 and TNF-a in both trimesters compared to HUPW (p≤0.003). In PWLWH, MMP-9 positively correlated with TIMP-1 (r=0.31, p=0.002) and CVF polymorphonuclear leucocytes (r=0.57, p=0.02). Correlations were observed between MMP-9 and three cytokines: IL-1b(r=0.61), IL-8(r=0.57) and TNF-a(r=0.64), p<

Journal article

Rosa A, Pye VE, Graham C, Muir L, Seow J, Ng KW, Cook NJ, Rees-Spear C, Parker E, dos Santos MS, Rosadas C, Susana A, Rhys H, Nans A, Masino L, Roustan C, Christodoulou E, Ulferts R, Wrobel AG, Short C-E, Fertleman M, Sanders RW, Heaney J, Spyer M, Kjaer S, Riddell A, Malim MH, Beale R, MacRae J, Taylor GP, Nastouli E, van Gils MJ, Rosenthal PB, Pizzato M, McClure MO, Tedder RS, Kassiotis G, McCoy LE, Doores KJ, Cherepanov Pet al., 2021, SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity, Science Advances, Vol: 7, Pages: 1-14, ISSN: 2375-2548

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo–electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.

Journal article

Pereira C, Harris B, Di Giovannantonio M, Rosadas C, Short C-E, Quinlan R, Sureda-Vives M, Fernandez N, Day-Weber I, Khan M, Marchesin F, Katsanovskaja K, Parker E, Taylor G, Tedder R, McClure M, Dani M, Fertleman Met al., 2021, Antibody response to SARS-CoV-2 infection is not associated with Post-COVID-19 Syndrome in healthcare workers, Journal of Infectious Diseases, Vol: 223, Pages: 1671-1676, ISSN: 0022-1899

It is currently unknown how Post-COVID-19 Syndrome (PCS) may affect those infected with SARS-CoV-2. This longitudinal study reports on healthcare staff who tested positive for SARS-CoV-2 between March-April 2020 and follows their antibody titres and symptomatology. Over half (n=21/38) had PCS at 7-8 months. There was no statistically significant difference between initial RT-PCR viral titres or serial antibody levels between those who did and did not develop PCS. This study highlights the relative commonality of PCS in healthcare workers and this should be considered in vaccination scheduling and workforce planning to allow adequate frontline staffing numbers.

Journal article

Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, Liew F, Russell CD, Moore SC, Fairfield C, Carter E, Abrams S, Short C, Thaventhiran T, Bergstrom E, Gardener Z, Ascough S, Chiu C, Docherty AB, Hunt D, Crow YJ, Solomon T, Taylor GP, Turtle L, Harrison EM, Dunning J, Semple MG, Baillie JK, Openshaw PJMet al., 2021, Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19, Science Immunology, Vol: 6, Pages: 1-17, ISSN: 2470-9468

While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.

Journal article

Short C-E, Brown R, Quinlan R, Lee Y, Smith A, Marchesi J, Shattock R, Bennett P, Taylor G, MacIntyre Det al., 2021, Lactobacillus-depleted vaginal microbiota in pregnant women living with HIV-1 infection are associated with increased local inflammation and preterm birth, Frontiers in Cellular and Infection Microbiology, Vol: 10, ISSN: 2235-2988

Background: Pregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. We set out to explore factors associated with gestational age at delivery of PWLWH in a UK population.Methods: Prospective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored.Findings: There was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1β.Interpretation: There is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population.

Journal article

Rosa A, Pye VE, Graham C, Muir L, Seow J, Ng KW, Cook NJ, Rees-Spear C, Parker E, Dos Santos MS, Rosadas C, Susana A, Rhys H, Nans A, Masino L, Roustan C, Christodoulou E, Ulferts R, Wrobel A, Short C-E, Fertleman M, Sanders RW, Heaney J, Spyer M, Kjær S, Riddell A, Malim MH, Beale R, MacRae JI, Taylor GP, Nastouli E, van Gils MJ, Rosenthal PB, Pizzato M, McClure MO, Tedder RS, Kassiotis G, McCoy LE, Doores KJ, Cherepanov Pet al., 2021, SARS-CoV-2 recruits a haem metabolite to evade antibody immunity., medRxiv

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.

Journal article

Harris BHL, Zuhair M, di Giovannantonio M, Rosadas C, Short C-E, Thaventhiran T, Quinlan R, Taylor A, Calvez R, Taylor GP, Tedder RS, McClure MO, Fertleman Met al., 2021, Asymptomatic COVID-19 in a rehabilitation facility: evolution of the presence of nasopharyngeal SARS-CoV-2 and serological antibody responses, The Journal of Infectious Diseases, Vol: 223, Pages: 192-196, ISSN: 0022-1899

At the start of the UK COVID-19 epidemic, this rare point prevalence study reveals ⅓ of patients in a London inpatient rehabilitation unit were found to be infected with SARS-CoV 2, but asymptomatic (n=15/45). We report on eight patients in detail, including their clinical stability, the evolution of their nasopharyngeal viral RT-PCR burden and their antibody levels over time revealing the infection dynamics by RT-PCR and serology during the acute phase. Notably, a novel serological test for antibodies against the receptor binding domain of SARS40 CoV-2 (anti-RBD) showed 100% of our asymptomatic cohort remained seropositive between 3 to 6 weeks post-diagnosis.

Journal article

Harris BHL, Zuhair M, Di Giovannantonio M, Rosadas C, Khan M, Short C-E, Thaventhiran T, Quinlan R, Taylor A, Calvez R, Taylor GP, Tedder RS, McClure MO, Fertleman Met al., 2021, Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in a rehabilitation facility: evolution of the presence of nasopharyngeal SARS-CoV-2 and serological antibody responses., Journal of Infectious Diseases, Vol: 223, Pages: 192-196, ISSN: 0022-1899

At the start of the UK coronavirus disease 2019 epidemic, this rare point prevalence study revealed that one-third of patients (15 of 45) in a London inpatient rehabilitation unit were found to be infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but asymptomatic. We report on 8 patients in detail, including their clinical stability, the evolution of their nasopharyngeal viral reverse-transcription polymerase chain reaction (RT-PCR) burden, and their antibody levels over time, revealing the infection dynamics by RT-PCR and serology during the acute phase. Notably, a novel serological test for antibodies against the receptor binding domain of SARS-CoV-2 showed that 100% of our asymptomatic cohort remained seropositive 3-6 weeks after diagnosis.

Journal article

Tedder RS, Parker E, Sureda-Vives M, Fernandez N, Randell P, Marchesin F, Katsanovskaja K, Harvey R, Lilley A, Harris BHL, Zuhair M, Fertleman M, Ijaz S, Dicks S, Short C-E, Quinlan R, Taylor GP, McKay P, Hu K, Rosa A, Roustan C, Zuckerman M, El Bouzidi K, Cooke G, Flower B, Moshe M, Elliott P, Spencer AJ, Lambe T, Gilbert SC, Kingston H, Baillie JK, Openshaw P, Semple M, Cherepanov P, McLure Met al., 2021, Detection and quantification of antibody to SARS-CoV-2 receptor binding domain provides enhanced sensitivity, specificity and utility, Publisher: Elsevier BV

Background: Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity.Methods: The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA) provides the most sensitive format. It has been exploited in a novel hybrid manner employing an S1 solid-phase preferentially presenting RBD once solid-phase bound, coupled with a labelled RBD conjugate, used in a two-step sequential assay.Findings: This assay showed a specificity of 100% on 825 pre COVID-19 samples and a potential sensitivity of 99.6% on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralisation and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine. The early response at presentation with illness, elevated responsiveness with disease severity, detection of asymptomatic seroconversion and persistence after the loss of antibody to the nucleoprotein (anti-NP) are all documented.Trial Registration: The ISARIC WHO CCP-UK study was registered at https://www.isrctn.com/ISRCTN66726260 and designated an Urgent Public Health Research Study by NIHR.Interpretation: The hybrid DABA displays the attributes necessary for an antibody test to be used in both clinical and reference serology. It allows the neutralising antibody response to be inferred early in infection and potentially in vaccine recipients. It is also of sufficient sensitivity to be used to provide serological confirmation of prior infection and provides a more secure measure for seroprevalence studies in the population generally than does anti-NP based on the Architect platform.Funding: This work is variously supported by grants from: the National I

Working paper

Thwaites R, Sevilla Uruchurtu AS, Siggins M, Liew F, Russell C, Moore S, Carter E, Abrams S, Short C-E, Thaventhiran T, Bergstrom E, Gardener Z, Ascough S, Chiu C, Docherty A, Hunt D, Crow Y, Solomon T, Taylor G, Turtle L, Harrison E, Semple M, Baillie K, Openshaw PJMet al., 2020, Elevated antiviral, myeloid and endothelial inflammatory markers in severe COVID-19, Publisher: medRxiv

Introductory paragraph</h4> The mechanisms that underpin COVID-19 disease severity, and determine the outcome of infection, are only beginning to be unraveled. The host inflammatory response contributes to lung injury, but circulating mediators levels fall below those in classical ‘cytokine storms’. We analyzed serial plasma samples from 619 patients hospitalized with COVID-19 recruited through the prospective multicenter ISARIC clinical characterization protocol U.K. study and 39 milder community cases not requiring hospitalization. Elevated levels of numerous mediators including angiopoietin-2, CXCL10, and GM-CSF were seen at recruitment in patients who later died. Markers of endothelial injury (angiopoietin-2 and von-Willebrand factor A2) were detected early in some patients, while inflammatory cytokines and markers of lung injury persisted for several weeks in fatal COVID-19 despite decreasing antiviral cytokine levels. Overall, markers of myeloid or endothelial cell activation were associated with severe, progressive, and fatal disease indicating a central role for innate immune activation and vascular inflammation in COVID-19.

Working paper

Short CS, Quinlan R, Bennett P, Shattock R, Taylor Get al., 2018, Optimising the collection of female genital tract fluid for cytokine analysis in pregnant women, Journal of Immunological Methods, Vol: 458, Pages: 15-20, ISSN: 0022-1759

Introduction: To better understand the immunology of pregnancy, study of female genital tract fluid (FGF) is desirable. However the optimum method of collection of FGF in pregnant women for immunological methods, specifically cytokine measurement, is unknown.Methods:A prospective study of HIV-uninfected pregnant women comparing two methods of FGF collection: polyvinyl acetal sponge collection of cervical fluid (CF) and menstrual cup collection of cervicovaginal fluid (CVF). Samples were collected at 3 time points across the second and third trimesters: 14-21, 22-25 and 26-31 weeks. Multiplex chemi-luminescent assays were used to measure: IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13 and TNF-α. Optimal methodology for cytokine normalisation (sample weight, volume and total protein) was explored. ResultsAll cytokines were measurable in both fluid types. IL-1β, IL-8 and IL-6 were detected at the highest concentrations (ranking order CF > CVF > plasma). CVF collection was simpler, provided the largest volume of sample (median 0.5g) with the potential for undiluted usage, and allowed for self-insertion. CF cytokine concentrations were intrinsically associated with sample weight and protein concentration however CVF cytokines were independent of these. Conclusion:Both methods of collection are robust for measurement of FGF cytokines during pregnancy. We recommend CVF collection using a menstrual cup as a viable option in pregnant women for high dimensional biological techniques.

Journal article

Buell KG, Puri A, Demontis MA, Short CL, Adonis A, Haddow J, Martin F, Dhasmana D, Taylor GPet al., 2016, Effect of pulsed methylprednisolone on pain, in patients with HTLV-1-associated myelopathy, PLOS One, Vol: 11, ISSN: 1932-6203

Journal article

Buell K, Puri A, Demontis MA, Short CL, Adonis A, Haddow J, Martin F, Dhasmana D, Taylor GPet al., 2015, Effect of pulsed methylprednisolone on disease severity, viral load and inflammation in patients with human T-lymphotropic virus type 1 associated myelopathy, RETROVIROLOGY, Vol: 12, ISSN: 1742-4690

Journal article

Short C-ES, Shaw SG, Fisher MJ, Gilleece YC, Walker-Bone Ket al., 2014, Comparison of peripheral forearm DXA and clinical risk factor screening using FRAX (R) to assess the risk of HIV-associated low bone mass: a cross-sectional study, Archives of Osteoporosis, Vol: 9, Pages: 1-6, ISSN: 1862-3522

SummaryThere is growing awareness that HIV infection is associated with low bone mass and fracture. DXA is a relatively scarce resource. Therefore, we evaluated two tools: peripheral DXA (pDXA) at the forearm and Fracture Risk Assessment Tool (FRAX®) to see which performed best at identifying men who should undergo DXA. In this setting, neither pDXA nor FRAX® showed good sensitivity and specificity for DXA.PurposeInfection with human immunodeficiency virus (HIV) is associated with an increased risk of low bone mineral density (BMD) and fractures. European guidance advocates screening using the FRAX® tool at diagnosis, on initiation of antiretroviral therapy and biannually thereafter in order to decide the need for DXA scanning. This cross-sectional study evaluates the performance of FRAX® and compares its sensitivity and specificity with that of another screening tool, peripheral forearm DXA (pDXA).MethodsHIV-infected men with varying exposure to antiretroviral therapies were recruited. FRAX® scores were calculated for all participants and everybody underwent pDXA scanning. Femoral neck and lumbar spine BMD was acquired on a Hologic QDR machine by an assessor blinded to the results of the FRAX® and pDXA.ResultsOne hundred and sixty-eight men (median age 45 years) were recruited with a median duration since HIV diagnosis of 74 months. In total, 21 % of subjects had either osteoporosis (aged ≥50 years) or BMD lower than expected for age (aged <50 years), according to axial DXA. Using a pDXA screening threshold of T ≤ −0.9, sensitivity was high (91 %) in defining those with the worst BMD on axial DXA but with poorer specificity (33 %). Alternately, using a threshold of T ≤ −2.7 reduced sensitivity (34 %) with an increase in specificity (91 %). FRAX® with HIV included as a secondary risk factor had poor sensitivity (31 %) and specificity (74 %) for detecting those with the poorest BMD on axi

Journal article

Samuel M, Bradshaw D, Perry M, Chan SY, Dhairyawan R, Byrne L, Smith K, Zhou J, Short CE, Naftalin C, Offodile N, Mandalia S, Roedling S, Shah R, Brook G, Poulton M, Rodgers M, Sarner L, Noble H, Hay P, Anderson J, Natha M, Hawkins D, Taylor G, de Ruiter Aet al., 2014, Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir., Infectious Diseases in Obstetrics & Gynecology, Vol: 2014, Pages: 961375-961375, ISSN: 1064-7449

INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.

Journal article

Short C-ES, Douglas M, Smith JH, Taylor GPet al., 2014, Preterm delivery risk in women initiating antiretroviral therapy to prevent HIV mother-to-child transmission, HIV Medicine, Vol: 15, Pages: 233-238, ISSN: 1464-2662

ObjectivesThe aim of the study was to describe the relationship between preterm delivery (PTD; < 37 weeks of gestation) and antiretroviral therapy in a single‐centre cohort of pregnant women with HIV infection.MethodsA retrospective analysis of data for 331 women who received care in a dedicated HIV antenatal clinic between 1996 and 2010 was carried out. Data on first CD4 cell count and viral load (HIV‐1 RNA copies/mL) recorded in pregnancy, class and timing of antiretroviral therapy, gestational age at delivery, and risk factors for and causes of PTD were available from a clinical database.ResultsOverall, 13.0% of deliveries were preterm, of which 53% were severe preterm (< 34 weeks of gestation). The lowest rate of PTD was observed in women treated with zidovudine monotherapy (6.2%). Higher rates of PTD were observed in women starting combination antiretroviral therapy (cART) in pregnancy compared with women conceiving while on cART [odds ratio (OR) 2.52; 95% confidence interval (CI) 1.22–5.20; P = 0.011]. Of the women who were eligible for zidovudine monotherapy on the basis of CD4 counts and HIV viral load but who were treated with short‐term cART to prevent HIV mother‐to‐child transmission, 28.6% delivered preterm. Women on short‐term cART remained at the highest risk of PTD compared with zidovudine monotherapy in multivariate analysis (OR 5.00; 95% CI 1.49–16.79; P = 0.015).ConclusionsThe causes of PTD are multiple and poorly understood. The timing of initiation and type of antiretroviral therapy administered during pregnancy appear to contribute to PTD risk. Understanding this association should improve the safety of antiretroviral therapy in pregnancy without increasing the risk of transmission.

Journal article

Short C-ES, Taylor GP, 2014, Antiretroviral therapy and preterm birth in HIV-infected women, Expert Review of Anti-infective Therapy, Vol: 12, Pages: 293-306, ISSN: 1478-7210

The use of combination antiretroviral therapy for the prevention of mother to child transmission of HIV infection has achieved vertical HIV transmission rates of <1%. The use of these drugs is not without risk to the mother and infant. Pregnant women with HIV-infection are at high risk of preterm birth (PTB <37 weeks), with 2–4-fold the risk of uninfected women. There is accumulating evidence that certain combinations are associated with higher rates of PTB that others or no antiretroviral treatment. Understanding the pathogenesis of PTB in this group of women will be essential to target preventative strategies in the face of increasing HIV prevalence and rapidly expanding mother-to-child-transmission prevention programmes.

Journal article

Charlton TG, Franklin JM, Douglas M, Short CE, Mills I, Smith R, Clarke A, Smith J, Tookey PA, Cortina-Borja M, Taylor GPet al., 2014, The impact of HIV infection and antiretroviral therapy on the predicted risk of Down syndrome, Prenatal Diagnosis, Vol: 34, Pages: 121-127, ISSN: 0197-3851

ObjectiveThe aim of this study was to assess predicted Down syndrome risk, based on three serum analytes (triple test), with HIV infection status and antiretroviral therapy regimen.MethodsScreening results in 72 HIV‐positive women were compared with results from age‐matched and race‐matched HIV‐negative controls. Mean concentrations of each analyte were compared by serostatus and antiretroviral therapy. Observed Down syndrome incidence in the offspring of HIV‐positive women was calculated from national HIV surveillance data.ResultsOverall, women with HIV had a significantly higher probability of receiving a ‘high‐risk’ result than uninfected controls (p = 0.002). Compared with matched uninfected controls, women with HIV infection had significantly higher human chorionic gonadotrophin, lower unconjugated estriol, and higher overall predicted risk of their infant having Down syndrome (1/6250 vs. 1/50 000 p = < 0.001). National surveillance data show no evidence of higher than expected incidence of Down syndrome in the offspring of HIV‐positive women.ConclusionsHIV infection impacts the serum analytes used to assay for Down syndrome risk resulting in a high rate of ‘high risk’ results. However, there is no population‐based association between maternal HIV infection and Down syndrome. Care should be taken when interpreting high‐risk serum screening results in HIV‐positive women to avoid unnecessary invasive diagnostic procedures. © 2013 John Wiley & Sons, Ltd.

Journal article

Short C-ES, Shaw SG, Fisher MJ, Walker-Bone K, Gilleece YCet al., 2014, Prevalence of and risk factors for osteoporosis and fracture among a male HIV-infected population in the UK., International Journal of STD and AIDS, Vol: 25, Pages: 113-121, ISSN: 0956-4624

Rates of osteoporosis and fracture may be increased in HIV but there are few UK data. Our aim was to examine the prevalence of and risk factors for osteoporosis and fractures among a homogeneous cohort of well-characterized HIV-infected men. In total, 168 men were recruited, median age 45 years, 37 combination antiretroviral therapy (cART) naïve, 46 with <3 years cART exposure and 85 cART-exposed longer term (median >10 years). All participants provided information on bone health and underwent DEXA scanning. Osteopenia was found in 58% of subjects and osteoporosis in 12%; 14% reported fractures since HIV diagnosis. Number of fractures since HIV diagnosis was significantly increased among those with osteoporosis (OR 3.5, 95% CI 1.2-10.4, p = 0.018). Duration of infection greater than 13 years was significantly associated with osteoporosis. Duration of cART was associated in univariate but not multivariate analyses. Strategies to prevent osteoporosis and fractures in HIV will require attention to viral and lifestyle factors and not just cART.

Journal article

Short C-E, Foster R, Douglas M, Iveson H, de Ruiter A, Fidler S, Taylor Get al., 2013, Elevated leukocyte adhesion marker VCAM-1 in HIV-1-infected in women initiating PI-based ART during pregnancy compared to women conceiving on PI-based ART and women initiating triple-NRTI ART, HIV MEDICINE, Vol: 14, Pages: 6-6, ISSN: 1464-2662

Journal article

Olubaniyi AO, Short C-E, Remedios D, Kapembwa Met al., 2013, An unexpected cause of digital gangrene: HIV associated peripheral arterial thrombosis., British Journal of General Practice, Vol: 63, Pages: 162-163, ISSN: 0960-1643

Journal article

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