Publications by authors named "Catherine Cosgrove"

44 Publications

Prevalence of HIV/hepatitis B and HIV/hepatitis C coinfection among people of East, South, Central and West African ancestry in the United Kingdom.

AIDS 2021 Apr 28. Epub 2021 Apr 28.

King's College Hospital NHS Foundation Trust King's College London Guy's and St Thomas' NHS Foundation Trust St George's University Hospitals NHS Foundation Trust Mortimer Market Centre, Central and NorthWest London NHS Foundation Trust Institute for Global Health, University College London Royal Free London NHS Foundation Trust, London Pennine Acute Hospitals NHS Foundation Trust, Manchester Lewisham and Greenwich NHS Trust, London, United Kingdom.

Regional variability in the prevalence of hepatitis B (HBV) and C (HCV) is reported in sub-Saharan Africa, although data for people with HIV are sparse. We determined the prevalence of HBV/HCV in 2,473 people of African ancestry with HIV in the UK. Overall, 6.2% were co-infected with HBV and 1.3% with HCV. Central (aOR 2.40 [95%CI 1.23-4.67] and West (2.10 [1.29-3.41]) African ancestry was associated with HBV and Central (6.98 [2.00-24.43]) African ancestry with HCV.
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http://dx.doi.org/10.1097/QAD.0000000000002929DOI Listing
April 2021

Phase I Trial Evaluating the Safety and Immunogenicity of Candidate TB Vaccine MVA85A, Delivered by Aerosol to Healthy -Infected Adults.

Vaccines (Basel) 2021 Apr 16;9(4). Epub 2021 Apr 16.

The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.

The immunogenicity of the candidate tuberculosis (TB) vaccine MVA85A may be enhanced by aerosol delivery. Intradermal administration was shown to be safe in adults with latent TB infection (LTBI), but data are lacking for aerosol-delivered candidate TB vaccines in this population. We carried out a Phase I trial to evaluate the safety and immunogenicity of MVA85A delivered by aerosol in UK adults with LTBI (NCT02532036). Two volunteers were recruited, and the vaccine was well-tolerated with no safety concerns. Aerosolised vaccination with MVA85A induced mycobacterium- and vector-specific IFN-γ in blood and mycobacterium-specific Th1 cytokines in bronchoalveolar lavage. We identified several important barriers that could hamper recruitment into clinical trials in this patient population. The trial did not show any safety concerns in the aerosol delivery of a candidate viral-vectored TB vaccine to two UK adults with ( infection. It also systemically and mucosally demonstrated inducible immune responses following aerosol vaccination. A further trial in a country with higher incidence of LTBI would confirm these findings.
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http://dx.doi.org/10.3390/vaccines9040396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073411PMC
April 2021

Should prospective renal transplant recipients be screened for ?

Clin Kidney J 2021 Feb 15;14(2):725-727. Epub 2020 Jun 15.

Department of Nephrology and Transplantation, St George's University Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1093/ckj/sfaa047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886550PMC
February 2021

Presentations and outcomes of central nervous system TB in a UK cohort: The high burden of neurological morbidity.

J Infect 2021 01 31;82(1):90-97. Epub 2020 Oct 31.

Infection Care Group, St George's University Hospitals NHS Foundation Trust, London, UK; Institute for Infection & Immunity, St George's, University of London, London SW17 0RE, UK. Electronic address:

Objectives: Most data for Central Nervous System Tuberculosis (CNS-TB) derive from high-incidence, resource-limited countries. We sought to determine the presentation, management and outcomes of CNS-TB in a low-incidence setting with accessible healthcare.

Methods: We undertook a retrospective, observational study of CNS-TB in adults at a single tertiary-referral London hospital (2001-2017). Cases were categorised as either TB meningitis (TBM) or TB mass lesions without meningitis (TBML), applying novel criteria for definite, probable, and possible TBML.

Results: We identified sixty-two cases of TBM (37% definite; 31% probable; 32% possible) alongside 14 TBML cases (36% definite; 29% probable; and 36% possible). Clinical presentation was highly variable. Among CSF parameters, hypoglycorrhachia proved most discriminatory for "definite" TBM. Neurosurgical intervention was required for mass-effect or hydrocephalus in 16%. Mortality was higher in TBM versus TBML (16% vs. 0%) but overall morbidity was significant; 33% of TBM and 29% of TBML survivors suffered persisting neurological disability at 12-months. In TBM, hydrocephalus, infarct, basal enhancement and low CSF white cell count were independently associated with worse neurological outcomes.

Conclusion: Although mortality was lower than previously reported in other settings, morbidity was significant, highlighting the need for improved CNS-TB diagnostics, therapeutics and interventions to mitigate neurological sequelae.
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http://dx.doi.org/10.1016/j.jinf.2020.10.028DOI Listing
January 2021

Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicentre, observer-blind, randomised, controlled trial.

Lancet Infect Dis 2021 02 15;21(2):252-262. Epub 2020 Sep 15.

Sanofi Pasteur, Swiftwater, PA, USA.

Background: In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate.

Methods: We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov, number NCT01887912, and has been terminated.

Findings: Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20-0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16-0·45]), indicating a vaccine efficacy of -5·2% (95% CI -104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group.

Interpretation: In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped.

Funding: Sanofi Pasteur.
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http://dx.doi.org/10.1016/S1473-3099(20)30331-5DOI Listing
February 2021

Haemophagocytic lymphohistiocytosis in pregnancy.

Lancet Haematol 2020 Jun;7(6):e498

Department of Haematology, St George's Hospital, London, UK.

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http://dx.doi.org/10.1016/S2352-3026(20)30101-0DOI Listing
June 2020

Ocular toxoplasmosis: phenotype differences between toxoplasma IgM positive and IgM negative patients in a large cohort.

Br J Ophthalmol 2021 02 28;105(2):210-215. Epub 2020 Apr 28.

Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, London, London, UK.

Purpose: To investigate the differences in demographics and clinical characteristics of patients diagnosed with ocular toxoplasmosis according to their IgM status.

Methods: Retrospective case note analysis was carried out on patients who tested positive for serum -specific IgM antibodies (IgM+) as well as a comparator group who tested negative for serum IgM (IgM-), but positive for serum IgG. Patient demographics and clinical features were compared between the two groups to evaluate for any significant differences.

Results: One hundred and six patients were included in the study between March 2011 and June 2018, consisting of 37 in the IgM +group and 69 in the IgM- group. Patients in the IgM +group were significantly older (51.1 vs 34.1 years, p<0.0001), more likely to present with central macular lesions (32% vs 12%, p=0.012), and more likely to develop rhegmatogenous retinal detachment (11% vs 1%, p=0.049). In contrast, patients in the IgM- group were more likely present with pain (20% vs 3%, 0.017) and exhibit more severe inflammation of the anterior chamber and vitreous (p<0.05). Overall, retinal lesions were more likely to be superotemporal (55%) and superonasal (31%). Furthermore, age was associated with larger (p=0.003) and more peripheral lesions (p=0.007).

Conclusions: This study demonstrated significant differences in clinical characteristics of ocular toxoplasmosis according to serum IgM status. IgM+ patients were older, less likely to report pain, had lower levels of intraocular inflammation, but were more likely to have macular involvement. We also found age to be correlated with larger and more peripheral lesions.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315522DOI Listing
February 2021

Success of 4CMenB in preventing meningococcal disease: evidence from real-world experience.

Arch Dis Child 2020 08 6;105(8):784-790. Epub 2020 Feb 6.

Paediatric Infectious Diseases Research Group, St. George's University of London, London, UK

Meningococcal disease remains one of the most feared infectious diseases worldwide because of its sudden onset, rapid progression and high case fatality rates, while survivors are often left with severe long-term sequelae. Young children have the highest incidence of invasive meningococcal disease (IMD), and nearly all cases in the UK, as in most of Europe and many other industrialised countries, are due to group B meningococci (MenB). The licensure of a broad-coverage, recombinant protein-based MenB vaccine (4CMenB) in 2013 was, therefore, heralded a major breakthrough in the fight against IMD. This vaccine was, however, licensed on immunogenicity and reactogenicity studies only, raising uncertainties about field effectiveness, long-term safety and antibody persistence. In 2015, the UK became the first country to implement 4CMenB into the national infant immunisation schedule and, since then, several countries have followed suit. Seven years after licensure, a wealth of real-world data has emerged to confirm 4CMenB effectiveness, along with large-scale safety data, duration of protection in different age groups, successful strategies to reduce vaccine reactogenicity, impact on carriage in adolescents and the potential for 4CMenB to protect against other meningococcal serogroups and against gonorrhoea. A number of questions, however, remain unanswered, including the investigation and management of vaccine-associated fever in infants, as well as disease severity and assessment of breakthrough cases in immunised children. Increasing use of 4CMenB will provide answers in due course. We now have vaccines against all the major serogroups causing IMD worldwide. Next-generation and combination vaccines against multiple serogroups look very promising.
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http://dx.doi.org/10.1136/archdischild-2019-318047DOI Listing
August 2020

Persistent eosinophilia among 21 historic cases of Strongyloides stercoralis infection: a case for routine follow-up and repeat treatment.

Trans R Soc Trop Med Hyg 2020 02;114(2):137-139

Infection Department, St George's University Hospitals NHS Foundation Trust, Blackshaw Road, London, SW17 0QT ,UK.

Background: Strongyloidasis affects more than 100 million people worldwide and causes persisting infection.

Methods: We retrospectively reviewed 21 cases of parasitologically confirmed Strongyloides stercoralis infection at our centre.

Results: We found four individuals who had eosinophilia (>0.5x109/litre) more than 6 mo after treatment.

Conclusions: This may represent ongoing or relapsed infection. Our data support the need for continued follow-up of treated individuals, particularly those with abnormal host defences who are at risk of severe forms of the disease.
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http://dx.doi.org/10.1093/trstmh/trz085DOI Listing
February 2020

Tuberculous arthritis: negative Xpert MTB/RIF assay does not rule out infection!

BMJ Case Rep 2018 Jun 29;2018. Epub 2018 Jun 29.

Radiology, St Mark's Hospital, Harrow, London.

We present a case of a 31-year-old man of Indian origin with no previous medical history who presented with an inflamed knee. Treatment for bacterial infection was unsuccessful, and needle aspiration of the left knee effusion/collection was smear and culture positive for tuberculosis (TB), despite Xpert MTB/RIF being falsely negative. The patient was commenced on quadruple therapy for TB and within 2 months had improved significantly with no clinical evidence of ongoing inflammation.
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http://dx.doi.org/10.1136/bcr-2018-224288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040497PMC
June 2018

Localized cyclical variations in immunoproteins in the female genital tract and the implications on the design and assessment of mucosal infection and therapies.

Am J Reprod Immunol 2018 02 29;79(2). Epub 2017 Dec 29.

Mucosal Infection & Immunity Group, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, UK.

Problem: Fluctuating hormones regulate reproductive processes in the female genital tract. Consequent changes in the local immunological environment are likely to affect cellular interaction with infectious agents and the assessment of therapies that target mucosal infections.

Method Of Study: We compared Softcup and Weck-Cel sampling protocols and assessed the changes in the concentrations of 39 soluble proteins with menstrual cycle progression in the mucosal and peripheral compartments.

Results: We demonstrate that the mucosal immunological profile is distinct from serum with inflammatory and migratory signatures that are localized throughout the cycle. The analytes highlighted in the mucosal compartment were generally highest at the follicular phase with a tendency to fall as the cycle progressed through ovulation to the luteal phase.

Conclusion: Our results underscore the need to consider these localized cyclical differences in studies aimed at assessing the outcome of disease and the efficacy of mucosal vaccines and other therapies.
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http://dx.doi.org/10.1111/aji.12801DOI Listing
February 2018

infection in the flexor sheath of the right index finger in an immunocompetent patient.

BMJ Case Rep 2017 Mar 13;2017. Epub 2017 Mar 13.

Department of Infectious Diseases, St George's Healthcare NHS Trust, London, UK.

A 53-year-old woman was identified with infection in the flexor sheath of the right index finger. Tissue was debrided at operation, and the patient was successfully treated with appropriate antimicrobials. is a rare cause of non-tubercular mycobacterium infection worldwide, and there are currently no clear guidelines on diagnosis and management. This is the first case reporting infection in the flexor sheath of the right index finger of a non-immunocompromised patient in the UK.
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http://dx.doi.org/10.1136/bcr-2016-217722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353364PMC
March 2017

Abdominal tuberculosis: Diagnosis and demographics, a 10-year retrospective review from a single centre.

World J Clin Cases 2016 Aug;4(8):207-12

Jeremy S Nayagam, Andrew Poullis, Gastroenterology, St George's Hospital, London SW17 0QT, United Kingdom.

Aim: To review all cases of abdominal tuberculosis (ATB) for demographic details, diagnostic work up and evidence of vitamin D deficiency.

Methods: This was a retrospective analysis of all patients diagnosed with ATB from June 2003 to August 2013 at St George's Hospital, London. Demographic data was available from the local tuberculosis database. Further clinical information was collected from electronic patient records, including radiology, endoscopy, microbiology, histology, biochemistry and serology. Patients were classified as either confirmed ATB [if mycobacteria tuberculosis (MTB) was cultured from abdominal site] or presumed ATB (if suggestive findings or high clinical suspicion). Subtypes of ATB were classified as tuberculosis (TB) peritonitis, luminal TB, solid organ TB or from a combination of sites.

Results: There were a total of 65 cases identified in this time period, with a mean of 6.5 cases per year (range 4-9). Mean age 42 years, 49.2% females. Fifty-two point three percent were South Asian, 38.5% African. Forty-nine point two percent had gastrointestinal endoscopy, 30.8% paracentesis and 24.6% surgery in order to obtain samples. Forty-seven point seven percent were defined as confirmed ATB with positive culture of MTB from abdominal sites, the rest were treated as presumed ATB. Twenty-four point six percent had co-existing sputum culture positive for MTB, and 30.8% had an abnormal chest X-ray. Subtypes of ATB: 35.4% had TB peritonitis; 27.7% luminal TB; 3.1% solid organ TB; and 33.8% TB at a combination of abdominal sites. Thirteen point nine percent were human immunodeficiency virus positive, all with CD4 count less than 300 cells/μL. Seventy point five percent had severe vitamin D deficiency, and 25% were vitamin D deficient.

Conclusion: ATB mainly affects young South Asian and African patients, with difficulties in confirming diagnosis despite a range of non-invasive and invasive diagnostic tests.
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http://dx.doi.org/10.12998/wjcc.v4.i8.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983690PMC
August 2016

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Nat Genet 2016 09 1;48(9):1060-5. Epub 2016 Aug 1.

Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
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http://dx.doi.org/10.1038/ng.3627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988037PMC
September 2016

XDR-TB transmission in London: Case management and contact tracing investigation assisted by early whole genome sequencing.

J Infect 2016 09 14;73(3):210-8. Epub 2016 Jun 14.

Institute for Infection and Immunity, St. George's University of London, London, SW17 0RE, United Kingdom; Infection Care Group, St George's Healthcare NHS Trust, London, United Kingdom. Electronic address:

Objectives: We describe the first published cluster of extensively drug resistant Tuberculosis (XDR-TB) in the UK and show how early whole genome sequencing (WGS) of Mtb can assist in case management and contact investigations.

Methods: We describe the contact tracing investigation undertaken after the presentation of an adult with XDR-TB. Active cases were treated with an XDR-TB drug regimen and contacts underwent a programme of follow-up for 2 years. All isolates of Mycobacterium tuberculosis (Mtb) were assessed early using whole genome sequencing (WGS) as well as routine drug susceptibility testing (DST).

Results: Thirty-three contacts were screened. In the first year one confirmed and one probable case were identified through contact tracing. A further possible case was identified through epidemiological links. Two confirmed cases were identified through WGS 2 years later. Twenty-five (80%) contacts without evidence of tuberculosis were adherent to 1 year of follow-up and 14 (45%) were adherent to 2 years of follow-up. WGS of Mtb was used to guide drug choices, rapidly identify transmission events, and alter public health management.

Conclusion: WGS of Mtb enabled rapid effective individualized treatment and facilitated public health interventions by early identification of transmission events.
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http://dx.doi.org/10.1016/j.jinf.2016.04.037DOI Listing
September 2016

Comparative Immunogenicity of HIV-1 gp140 Vaccine Delivered by Parenteral, and Mucosal Routes in Female Volunteers; MUCOVAC2, A Randomized Two Centre Study.

PLoS One 2016 9;11(5):e0152038. Epub 2016 May 9.

Mucosal Infection & Immunity Group, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.

Background: Defining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.

Methods: In this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel.

Results: Three IM immunizations of CN54 gp140 at either 20 or 100 μg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization.

Conclusions: These data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming.

Clinical Trials Registration: EudraCT 2010-019103-27 and the UK Clinical Research Network (UKCRN) Number 11679.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152038PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861263PMC
April 2017

Clinical use of whole genome sequencing for Mycobacterium tuberculosis.

BMC Med 2016 Mar 23;14:46. Epub 2016 Mar 23.

Institute of Infection and Immunity, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK.

Drug-resistant tuberculosis (TB) remains a major challenge to global health and to healthcare in the UK. In 2014, a total of 6,520 cases of TB were recorded in England, of which 1.4 % were multidrug-resistant TB (MDR-TB). Extensively drug-resistant TB (XDR-TB) occurs at a much lower rate, but the impact on the patient and hospital is severe. Current diagnostic methods such as drug susceptibility testing and targeted molecular tests are slow to return or examine only a limited number of target regions, respectively. Faster, more comprehensive diagnostics will enable earlier use of the most appropriate drug regimen, thus improving patient outcomes and reducing overall healthcare costs. Whole genome sequencing (WGS) has been shown to provide a rapid and comprehensive view of the genotype of the organism, and thus enable reliable prediction of the drug susceptibility phenotype within a clinically relevant timeframe. In addition, it provides the highest resolution when investigating transmission events in possible outbreak scenarios. However, robust software and database tools need to be developed for the full potential to be realized in this specialized area of medicine.
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http://dx.doi.org/10.1186/s12916-016-0598-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804576PMC
March 2016

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

Hum Mutat 2015 Dec 30;36(12):1197-204. Epub 2015 Sep 30.

Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, United Kingdom.

To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.
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http://dx.doi.org/10.1002/humu.22901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833192PMC
December 2015

Clinical application of whole-genome sequencing to inform treatment for multidrug-resistant tuberculosis cases.

J Clin Microbiol 2015 May 11;53(5):1473-83. Epub 2015 Feb 11.

Institute for Infection and Immunity, St. George's University of London, London, United Kingdom

The treatment of drug-resistant tuberculosis cases is challenging, as drug options are limited, and the existing diagnostics are inadequate. Whole-genome sequencing (WGS) has been used in a clinical setting to investigate six cases of suspected extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) encountered at a London teaching hospital between 2008 and 2014. Sixteen isolates from six suspected XDR-TB cases were sequenced; five cases were analyzed in a clinically relevant time frame, with one case sequenced retrospectively. WGS identified mutations in the M. tuberculosis genes associated with antibiotic resistance that are likely to be responsible for the phenotypic resistance. Thus, an evidence base was developed to inform the clinical decisions made around antibiotic treatment over prolonged periods. All strains in this study belonged to the East Asian (Beijing) lineage, and the strain relatedness was consistent with the expectations from the case histories, confirming one contact transmission event. We demonstrate that WGS data can be produced in a clinically relevant time scale some weeks before drug sensitivity testing (DST) data are available, and they actively help clinical decision-making through the assessment of whether an isolate (i) has a particular resistance mutation where there are absent or contradictory DST results, (ii) has no further resistance markers and therefore is unlikely to be XDR, or (iii) is identical to an isolate of known resistance (i.e., a likely transmission event). A small number of discrepancies between the genotypic predictions and phenotypic DST results are discussed in the wider context of the interpretation and reporting of WGS results.
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http://dx.doi.org/10.1128/JCM.02993-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400773PMC
May 2015

Characterization of a plant-produced recombinant human secretory IgA with broad neutralizing activity against HIV.

MAbs 2014 ;6(6):1585-97

a The Hotung Molecular Immunology Group; Institute for Infection & Immunity; St George's ; University of London ; London , UK.

Recombinant Secretory IgA (SIgA) complexes have the potential to improve antibody-based passive immunotherapeutic approaches to combat many mucosal pathogens. In this report, we describe the expression, purification and characterization of a human SIgA format of the broadly neutralizing anti-HIV monoclonal antibody (mAb) 2G12, using both transgenic tobacco plants and transient expression in Nicotiana benthamiana as expression hosts (P2G12 SIgA). The resulting heterodecameric complexes accumulated in intracellular compartments in leaf tissue, including the vacuole. SIgA complexes could not be detected in the apoplast. Maximum yields of antibody were 15.2 μg/g leaf fresh mass (LFM) in transgenic tobacco and 25 μg/g LFM after transient expression, and assembly of SIgA complexes was superior in transgenic tobacco. Protein L purified antibody specifically bound HIV gp140 and neutralised tier 2 and tier 3 HIV isolates. Glycoanalysis revealed predominantly high mannose structures present on most N-glycosylation sites, with limited evidence for complex glycosylation or processing to paucimannosidic forms. O-glycan structures were not identified. Functionally, P2G12 SIgA, but not IgG, effectively aggregated HIV virions. Binding of P2G12 SIgA was observed to CD209 / DC-SIGN, but not to CD89 / FcalphaR on a monocyte cell line. Furthermore, P2G12 SIgA demonstrated enhanced stability in mucosal secretions in comparison to P2G12 IgG mAb.
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http://dx.doi.org/10.4161/mabs.36336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622858PMC
September 2015

Rare variants in NR2F2 cause congenital heart defects in humans.

Am J Hum Genet 2014 04;94(4):574-85

School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980509PMC
April 2014

Association between C677T polymorphism of methylene tetrahydrofolate reductase and congenital heart disease: meta-analysis of 7697 cases and 13,125 controls.

Circ Cardiovasc Genet 2013 Aug 22;6(4):347-53. Epub 2013 Jul 22.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Background: Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious.

Methods And Results: We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03-1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91-1.03]) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate.

Conclusions: The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855044PMC
August 2013

Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot.

BMC Genet 2013 Jun 19;14:57. Epub 2013 Jun 19.

Institute of Genetic Medicine, Newcastle University, Newcastle, UK.

Background: Epidemiological studies indicate a substantial excess familial recurrence of non-syndromic Tetralogy of Fallot (TOF), implicating genetic factors that remain largely unknown. The Rho induced kinase 1 gene (ROCK1) is a key component of the planar cell polarity signalling pathway, which plays an important role in normal cardiac development. The aim of this study was to investigate the role of genetic variation in ROCK1 on the risk of TOF.

Results: ROCK1 was sequenced in a discovery cohort of 93 non-syndromic TOF probands to identify rare variants. TagSNPs were selected to capture commoner variation in ROCK1. Novel variants and TagSNPs were genotyped in a discovery cohort of 458 TOF cases and 1331 healthy controls, and positive findings were replicated in a further 209 TOF cases and 1290 healthy controls. Association between genotypes and TOF was assessed using LAMP.A rare SNP (c.807C > T; rs56085230) discovered by sequencing was associated with TOF risk (p = 0.006) in the discovery cohort. The variant was also significantly associated with the risk of TOF in the replication cohort (p = 0.018). In the combined cohorts the odds ratio for TOF was 2.61 (95% CI 1.58-4.30); p < 0.0001. The minor allele frequency of rs56085230 in the cases was 0.02, and in the controls it was 0.007. The variant accounted for 1% of the population attributable risk (PAR) of TOF. We also found significant association with TOF for an uncommon TagSNP in ROCK1, rs288979 (OR 1.64 [95% CI 1.15-2.30]; p = 1.5x10⁻⁵). The minor allele frequency of rs288979 in the controls was 0.043, and the variant accounted for 11% of the PAR of TOF. These association signals were independent of each other, providing additional internal validation of our result.

Conclusions: Low frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF.
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http://dx.doi.org/10.1186/1471-2156-14-57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734041PMC
June 2013

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.

Nat Genet 2013 Jul 26;45(7):822-4. Epub 2013 May 26.

Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻⁷) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻⁵; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹⁰). Genotype accounted for ~9% of the population-attributable risk of ASD.
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http://dx.doi.org/10.1038/ng.2637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793630PMC
July 2013

Genome-wide association study identifies loci on 12q24 and 13q32 associated with tetralogy of Fallot.

Hum Mol Genet 2013 Apr 7;22(7):1473-81. Epub 2013 Jan 7.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10(-7)) and replicated convincingly (P = 3.9 × 10(-5)) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10(-11) in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10(-7)) and replicated convincingly (P = 1.2 × 10(-5)) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10(-11) in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.
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http://dx.doi.org/10.1093/hmg/dds552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596849PMC
April 2013

Functional significance of SRJ domain mutations in CITED2.

PLoS One 2012 17;7(10):e46256. Epub 2012 Oct 17.

Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

CITED2 is a transcriptional co-activator with 3 conserved domains shared with other CITED family members and a unique Serine-Glycine Rich Junction (SRJ) that is highly conserved in placental mammals. Loss of Cited2 in mice results in cardiac and aortic arch malformations, adrenal agenesis, neural tube and placental defects, and partially penetrant defects in left-right patterning. By screening 1126 sporadic congenital heart disease (CHD) cases and 1227 controls, we identified 19 variants, including 5 unique non-synonymous sequence variations (N62S, R92G, T166N, G180-A187del and A187T) in patients. Many of the CHD-specific variants identified in this and previous studies cluster in the SRJ domain. Transient transfection experiments show that T166N mutation impairs TFAP2 co-activation function and ES cell proliferation. We find that CITED2 is phosphorylated by MAPK1 in vitro at T166, and that MAPK1 activation enhances the coactivation function of CITED2 but not of CITED2-T166N. In order to investigate the functional significance in vivo, we generated a T166N mutation of mouse Cited2. We also used PhiC31 integrase-mediated cassette exchange to generate a Cited2 knock-in allele replacing the mouse Cited2 coding sequence with human CITED2 and with a mutant form deleting the entire SRJ domain. Mouse embryos expressing only CITED2-T166N or CITED2-SRJ-deleted alleles surprisingly show no morphological abnormalities, and mice are viable and fertile. These results indicate that the SRJ domain is dispensable for these functions of CITED2 in mice and that mutations clustering in the SRJ region are unlikely to be the sole cause of the malformations observed in patients with sporadic CHD. Our results also suggest that coding sequence mutations observed in case-control studies need validation using in vivo models and that predictions based on structural conservation and in vitro functional assays, or even in vivo global loss of function models, may be insufficient.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046256PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474824PMC
April 2013

Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease.

Am J Hum Genet 2012 Sep 30;91(3):489-501. Epub 2012 Aug 30.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

Previous studies have shown that copy-number variants (CNVs) contribute to the risk of complex developmental phenotypes. However, the contribution of global CNV burden to the risk of sporadic congenital heart disease (CHD) remains incompletely defined. We generated genome-wide CNV data by using Illumina 660W-Quad SNP arrays in 2,256 individuals with CHD, 283 trio CHD-affected families, and 1,538 controls. We found association of rare genic deletions with CHD risk (odds ratio [OR] = 1.8, p = 0.0008). Rare deletions in study participants with CHD had higher gene content (p = 0.001) with higher haploinsufficiency scores (p = 0.03) than they did in controls, and they were enriched with Wnt-signaling genes (p = 1 × 10(-5)). Recurrent 15q11.2 deletions were associated with CHD risk (OR = 8.2, p = 0.02). Rare de novo CNVs were observed in ~5% of CHD trios; 10 out of 11 occurred on the paternally transmitted chromosome (p = 0.01). Some of the rare de novo CNVs spanned genes known to be involved in heart development (e.g., HAND2 and GJA5). Rare genic deletions contribute ~4% of the population-attributable risk of sporadic CHD. Second to previously described CNVs at 1q21.1, deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD. Rare de novo CNVs identified in CHD trios exhibit paternal origin bias.
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http://dx.doi.org/10.1016/j.ajhg.2012.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511986PMC
September 2012