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Short C-E, Quinlan R, Preda V, et 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<
Rosa A, Pye VE, Graham C, et al., 2021, SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity, SCIENCE ADVANCES, Vol: 7, ISSN: 2375-2548
Pereira C, Harris B, Di Giovannantonio M, et 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.
Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, et 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.
Short C-E, Brown R, Quinlan R, et 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.
Rosa A, Pye VE, Graham C, et 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.
Harris BHL, Zuhair M, Di Giovannantonio M, et 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.
Harris BHL, Zuhair M, di Giovannantonio M, et 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.
Short CS, Quinlan R, Bennett P, et 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.
Buell KG, Puri A, Demontis MA, et al., 2016, Effect of pulsed methylprednisolone on pain, in patients with HTLV-1-associated myelopathy, PLOS One, Vol: 11, ISSN: 1932-6203
Short C-ES, Shaw SG, Fisher MJ, et 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
Samuel M, Bradshaw D, Perry M, et 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.
Short C-ES, Douglas M, Smith JH, et 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.
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.
Charlton TG, Franklin JM, Douglas M, et 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.
Short C-ES, Shaw SG, Fisher MJ, et 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.
Short C-E, Foster R, Douglas M, et 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
Olubaniyi AO, Short C-E, Remedios D, et 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
Byrne L, de Alwis O, Toby M, et al., 2012, Managing the pregnancies of HIV elite controllers: what are we doing?, HIV MEDICINE, Vol: 13, Pages: 1-1, ISSN: 1464-2662
Short C-ES, Gilleece YC, Fisher MJ, et al., 2009, Trimetrexate and folinic acid: a valuable salvage option for Pneumocystis jirovecii pneumonia, AIDS, Vol: 23, Pages: 1287-1290, ISSN: 0269-9370
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