256 results on '"Gordon SB"'
Search Results
2. In depth analysis of patients with severe SARS-CoV-2 in sub-Saharan Africa demonstrates distinct clinical and immunological profiles
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Morton, B, primary, Barnes, KG, additional, Anscombe, C, additional, Jere, K, additional, Kamng’ona, R, additional, Brown, C, additional, Nyirenda, J, additional, Phiri, T, additional, Banda, N, additional, Van Der Veer, C, additional, Mndolo, KS, additional, Mponda, K, additional, Rylance, J, additional, Phiri, C, additional, Mallewa, J, additional, Nyirenda, M, additional, Katha, G, additional, Kambiya, P, additional, Jafali, J, additional, Mwandumba, HC, additional, Gordon, SB, additional, Cornick, J, additional, and Jambo, KC, additional
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- 2021
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3. Progression of whole blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in patients with severe influenza
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Dunning, J, Blankley, S, Hoang, LT, Cox, M, Graham, CM, James, PL, Bloom, CI, Chaussabel, D, Banchereau, J, Brett, SJ, Moffatt, MF, Habibi, MS, Johnston, SL, Hansel, TT, Levin, M, Thwaites, RS, Warner, JO, Cookson, WO, Gazzard, BG, Hay, A, McCauley, J, Aylin, P, Ashby, D, Barclay, WS, Elderfield, RA, Nadel, S, Herberg, JA, Drumright, LN, Garcia-Alvarez, L, Holmes, AH, Kon, OM, Aston, SJ, Gordon, SB, Hussell, T, Thompson, C, Zambon, MC, Baillie, KJ, Hume, DA, Simmonds, P, Hayward, A, Smyth, RL, McNamara, PS, Semple, MG, Nguyen-Van-Tam, JS, Ho, LP, McMichael, AJ, Kellam, P, Adamson, WE, Carman, WF, Griffiths, MJ, O'Garra, A, Openshaw, PJM, Wellcome Trust, National Institute for Health Research, Medical Research Council (MRC), and Asthma UK
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0301 basic medicine ,Male ,Neutrophils ,Disease ,DISEASE ,Procalcitonin ,Transcriptome ,Pathogenesis ,0302 clinical medicine ,MARKERS ,Interferon ,Immunology and Allergy ,Medicine ,MOSAIC Investigators ,Young adult ,UNITED-KINGDOM ,Middle Aged ,3. Good health ,1107 Immunology ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Life Sciences & Biomedicine ,medicine.drug ,Adult ,Adolescent ,Immunology ,CIRCULATION ,BIOLOGY ,VIRUS-INFECTION ,Lung injury ,Antiviral Agents ,Article ,03 medical and health sciences ,Young Adult ,Influenza, Human ,Humans ,RNA, Messenger ,PROCALCITONIN ,METAANALYSIS ,Aged ,Science & Technology ,business.industry ,Human genetics ,030104 developmental biology ,Interferons ,business ,LUNG INJURY ,Biomarkers - Abstract
© 2018 The Author(s). Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death ('bacterial') pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this 'bacterial' signature but was able to enhance its development while attenuating the early 'viral' signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.
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- 2018
4. Recovery from pneumonia requires efferocytosis which is impaired in smokers and those with low body mass index and enhanced by statins
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Wootton, DG, Diggle, PJ, Court, J, Eneje, O, Keogan, L, Macfarlane, L, Wilks, S, Woodhead, M, and Gordon, SB
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Adult ,Tobacco and the lung ,Neutrophils ,Smoking ,Apoptosis ,Pneumonia ,Comorbidity ,Middle Aged ,Neutrophil Biology ,Flow Cytometry ,Bronchoalveolar Lavage ,Research Letters ,Body Mass Index ,Community-Acquired Infections ,Macrophage Biology ,England ,Phagocytosis ,Bronchoscopy ,Macrophages, Alveolar ,Humans ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Aged - Abstract
© 2016 BMJ Publishing Group Ltd & British Thoracic Society.Background Efferocytosis (the phagocytosis of apoptotic self cells) is a key mechanism in the resolution of inflammatory processes such as community-acquired pneumonia (CAP). Efferocytosis therefore represents a modifiable target for therapy aimed at enhancing intrinsic recovery mechanisms. It is currently not known which patients recovering from CAP would mostly benefit from a strategy aimed at enhancing efferocytosis. Methods We recruited a cohort of patients with CAP admitted to a hospital in Liverpool. One month into recovery, subjects were invited for research bronchoscopy and bronchoalveolar lavage. An ex vivo efferocytosis assay was performed by challenging alveolar macrophages with autologous, apoptotic neutrophils. The percentage of alveolar macrophages that had undergone efferocytosis was determined by flow cytometry. We conducted a multivariable regression using a linear mixed effects model to determine which clinical parameters were most closely associated with efferocytosis. Results We observed high rates of comorbidity among this CAP cohort. Efferocytosis was measured in 22 subjects. We assessed multiple combinations of clinical parameters for association with efferocytosis and found the best-fitting model included an interaction between smoking status and prior statin use-smoking being associated with decreased efferocytosis and statin use with increased efferocytosis. These effects were modified by an association between efferocytosis and body mass index (BMI), such that as BMI increased so did efferocytosis. Conclusions This is the first study to measure efferocytosis in patients recovering from CAP. The results suggest that smokers with low BMI have impaired efferocytosis and may benefit from a statin to boost recovery.
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- 2016
5. A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi
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Gordon, SB, Rylance, J, Luck, A, Jambo, K, Ferreira, DM, Manda-Taylor, L, Bejon, P, Ngwira, B, Littler, K, Seager, Z, Gibani, M, Gmeiner, M, Roestenberg, M, Mlombe, Y, and Wellcome Trust CHIM workshop participants
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Economic growth ,medicine.medical_specialty ,wc_680 ,workshop report ,030231 tropical medicine ,Alternative medicine ,Medicine (miscellaneous) ,Library science ,Developing country ,wa_395 ,Methods for Diagnostic & Therapeutic Studies ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Controlled human infection model ,vaccine ,Medicine ,030212 general & internal medicine ,Wellcome Trust CHIM workshop participants ,Capacity development ,wa_30 ,CHIM ,business.industry ,Corporate governance ,Health Systems & Services Research ,Articles ,w_20.5 ,3. Good health ,wa_540 ,Host country ,Low and middle income countries ,wz_112 ,Open Letter ,business - Abstract
Controlled human infection model (CHIM) studies have pivotal importance in vaccine development, being useful for proof of concept, pathogenesis, down-selection and immunogenicity studies. To date, however, they have seldom been carried out in low and middle income countries (LMIC), which is where the greatest burden of vaccine preventable illness is found. This workshop discussed the benefits and barriers to CHIM studies in Malawi. Benefits include improved vaccine effectiveness and host country capacity development in clinical, laboratory and governance domains. Barriers include acceptability, safety and regulatory issues. The report suggests a framework by which ethical, laboratory, scientific and governance issues may be addressed by investigators considering or planning CHIM in LMIC.
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- 2017
6. Oral typhoid vaccination with Ty21a generates Ty21a-responsive and heterologous influenza-responsive CD4+ and CD8+ T-cells at the human intestinal mucosa
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Pennington, SH, Thompson, AL, Wright, AK, Ferreira, DM, Jambo, KC, Wright, AD, Faragher, B, Gilmour, JW, Gordon, SB, and Gordon, MA
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Ty21a ,Salmonella ,heterologous immunity ,humoral immunity ,T cells ,immunoglobulins ,cellular immunity ,11 Medical And Health Sciences ,06 Biological Sciences ,Microbiology ,cytokines ,typhoid - Published
- 2016
7. IFITM3 restricts the morbidity and mortality associated with influenza
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Everitt AR1, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB, GenISIS Investigators, MOSAIC Investigators, Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P. Johnston SL, Kon OM, Everitt AR1, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB, MOSAIC Investigators, Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P. Johnston SL, and Kon OM
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- 2012
8. S70 Experimental Human Pneumococcal Colonisation is an asymptomatic event in healthy adults
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Trimble, A, primary, Collins, AM, additional, Hancock, CA, additional, Gordon, SB, additional, Ferreira, DM, additional, and Wright, AD, additional
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- 2015
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9. Non-typhoidal salmonella (NTS) bacteraemia in Malawian adults: a severe, recrudescent, HIV-associated illness
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Gordon, MA, primary, Banda, HT, additional, Gondwe, M, additional, Gordon, SB, additional, Walsh, AL, additional, Phiri, A, additional, Gilks, CF, additional, Hart, CA, additional, and Molyneux, ME, additional
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- 2004
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10. Hidden risks for pneumonia in Malawi
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Fullerton, DG, primary and Gordon, SB, additional
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- 2004
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11. Patient outcome in adults with pneumococcal meningitis or bacteraemia admitted to QECH
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Gordon, SB, primary
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- 2004
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12. Bronchoalveolar CD4+ T cell responses to respiratory antigens are impaired in HIV-infected adults.
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Jambo KC, Sepako E, Fullerton DG, Mzinza D, Glennie S, Wright AK, Heyderman RS, Gordon SB, Jambo, Kondwani C, Sepako, Enoch, Fullerton, Duncan G, Mzinza, David, Glennie, Sarah, Wright, Adam K, Heyderman, Robert S, and Gordon, Stephen B
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Rationale: HIV-infected adults are at an increased risk of lower respiratory tract infections. HIV infection impairs systemic acquired immunity, but there is limited information in humans on HIV-related cell-mediated immune defects in the lung.Objective: To investigate antigen-specific CD4(+) T cell responses to influenza virus, Streptococcus pneumoniae and Mycobacterium tuberculosis antigens in bronchoalveolar lavage (BAL) and peripheral blood between HIV-infected individuals and HIV-uninfected Malawian adults.Methods: We obtained BAL fluid and blood from HIV-infected individuals (n=21) and HIV-uninfected adults (n=24). We determined the proportion of T cell subsets including naive, memory and regulatory T cells using flow cytometry, and used intracellular cytokine staining to identify CD4(+) T cells recognising influenza virus-, S pneumoniae- and M tuberculosis-antigens.Main Results: CD4(+) T cells in BAL were predominantly of effector memory phenotype compared to blood, irrespective of HIV status (p<0.001). There was immune compartmentalisation with a higher frequency of antigen-specific CD4(+) T cells against influenza virus, S pneumoniae and M tuberculosis retained in BAL compared to blood in HIV-uninfected adults (p<0.001 in each case). Influenza virus- and M tuberculosis-specific CD4(+) T cell responses in BAL were impaired in HIV-infected individuals: proportions of total antigen-specific CD4(+) T cells and of polyfunctional IFN-γ and TNF-α-secreting cells were lower in HIV-infected individuals than in HIV-uninfected adults (p<0.05 in each case).Conclusions: BAL antigen-specific CD4(+) T cell responses against important viral and bacterial respiratory pathogens are impaired in HIV-infected adults. This might contribute to the susceptibility of HIV-infected adults to lower respiratory tract infections such as pneumonia and tuberculosis. [ABSTRACT FROM AUTHOR]- Published
- 2011
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13. Proteomic analysis of cerebrospinal fluid in pneumococcal meningitis reveals potential biomarkers associated with survival.
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Goonetilleke UR, Scarborough M, Ward SA, Gordon SB, Goonetilleke, Upali R, Scarborough, Matthew, Ward, Stephen A, and Gordon, Stephen B
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Background: Patients with pneumococcal meningitis often die or have severe neurological damage despite optimal antibiotic therapy. New or improved therapy is required. The delivery of new interventions will require an improved understanding of the disease pathogenesis. Our objective was to learn more about the pathophysiology of severe meningitis through the interpretation of differences in the proteomic profile of cerebrospinal fluid (CSF) from patients with meningitis.Methods: Two-dimensional polyacrylamide gel electrophoresis of CSF from normal subjects (controls, n = 10) and patients with pneumococcal meningitis (n = 20) was analyzed. Spot differences were compared and identified between controls, nonsurvivors (n = 9), and survivors (n = 11).Results: Protein concentration in CSF of patients with meningitis was 4-fold higher than in CSF of control subjects (7.0 mg/mL vs 0.23 mg/mL; P < .01). A mean of 2466 discrete protein spots was present in CSF of patients with meningitis. Thirty-four protein spots were differentially expressed in CSF of nonsurvivors, compared with survivors. None of these protein spots were observed in CSF of control subjects.Conclusions: Proteomic screening of CSF yields potential biomarkers capable of differentiating control subjects from nonsurvivors and survivors of meningitis. Proteins involved in the inflammatory process and central metabolism were represented in the differentially expressed protein repertoire. [ABSTRACT FROM AUTHOR]- Published
- 2010
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14. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa.
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Scarborough M, Gordon SB, Whitty CJM, French N, Njalale Y, Chitani A, Peto TEA, Lalloo DG, Zijlstra EE, Scarborough, Matthew, Gordon, Stephen B, Whitty, Christopher J M, French, Neil, Njalale, Yasin, Chitani, Alex, Peto, Timothy E A, Lalloo, David G, and Zijlstra, Eduard E
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Background: In sub-Saharan Africa, bacterial meningitis is common and is associated with a high mortality. Adjuvant therapy with corticosteroids reduces mortality among adults in the developed world, but it has not been adequately tested in developing countries or in the context of advanced human immunodeficiency virus (HIV) infection.Methods: We conducted a randomized, double-blind, placebo-controlled trial of dexamethasone (16 mg twice daily for 4 days) and an open-label trial of intramuscular versus intravenous ceftriaxone (2 g twice daily for 10 days) in adults with an admission diagnosis of bacterial meningitis in Blantyre, Malawi. The primary outcome was death at 40 days after randomization.Results: A total of 465 patients, 90% of whom were HIV-positive, were randomly assigned to receive dexamethasone (233 patients) or placebo (232 patients) plus intramuscular ceftriaxone (230 patients) or intravenous ceftriaxone (235 patients). There was no significant difference in mortality at 40 days in the corticosteroid group (129 of 231 patients) as compared with the placebo group (120 of 228 patients) by intention-to-treat analysis (odds ratio, 1.14; 95% confidence interval [CI], 0.79 to 1.64) or when the analysis was restricted to patients with proven pneumococcal meningitis (68 of 129 patients receiving corticosteroids vs. 72 of 143 patients receiving placebo) (odds ratio, 1.10; 95% CI, 0.68 to 1.77). There were no significant differences between groups in the outcomes of disability and death combined, hearing impairment, and adverse events. There was no difference in mortality with intravenous ceftriaxone (121 of 230 patients) as compared with intramuscular ceftriaxone (128 of 229 patients) (odds ratio, 0.88; 95% CI, 0.61 to 1.27).Conclusions: Adjuvant therapy with dexamethasone for bacterial meningitis in adults from an area with a high prevalence of HIV did not reduce mortality or morbidity. In this setting, intramuscular administration was not inferior to intravenous administration of ceftriaxone for bacterial meningitis. (Current Controlled Trials number, ISRCTN31371499 [controlled-trials.com].). [ABSTRACT FROM AUTHOR]- Published
- 2007
15. Using the BTS CAP audit to evaluate local data.
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Singh B, Wootton DG, Brown J, Chakrabarti B, Cooke RP, Gordon SB, University Hospital Aintree Pneumonia Group, Singh, B, Wootton, D G, Brown, J, Chakrabarti, B, Cooke, R P D, and Gordon, S B
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- 2012
16. Release of renin by rat kidney slices
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De Vito, E, primary, Gordon, SB, additional, Cabrera, RR, additional, and Fasciolo, JC, additional
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- 1970
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17. Presence of MBL in airways: is it a disease severity marker or an additional host defence mechanism?
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Jambo KC and Gordon SB
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- 2009
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18. Blood culture collection technique and pneumococcal surveillance in Malawi during the four year period 2003-2006: an observational study.
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Mtunthama N, Gordon SB, Kusimbwe T, Zijlstra EE, Molyneux ME, French N, Mtunthama, Neema, Gordon, Stephen B, Kusimbwe, Temwa, Zijlstra, Eduard E, Molyneux, Malcolm E, and French, Neil
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Background: Blood culture surveillance will be used for assessing the public health effectiveness of pneumococcal conjugate vaccines in Africa. Between 2003 and 2006 we assessed blood culture outcome and performance in adult patients in the central public hospital in Blantyre, Malawi, before and after the introduction of a dedicated nurse led blood culture team.Methods: A prospective observational study.Results: Following the introduction of a specialised blood culture team in 2005, the proportion of contaminated cultures decreased (19.6% in 2003 to 5.0% in 2006), blood volume cultured increased and pneumococcal recovery increased significantly from 2.8% of all blood cultures to 6.1%. With each extra 1 ml of blood cultured the odds of recovering a pneumococcus increased by 18%.Conclusion: Standardisation and assessment of blood culture performance (blood volume and contamination rate) should be incorporated into pneumococcal disease surveillance activities where routine blood culture practice is constrained by limited resources. [ABSTRACT FROM AUTHOR]- Published
- 2008
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19. New vaccines against pneumonia: Investigating protein-specific immune responses to Streptococcus pneumoniae using Experimental Human Pneumococcal Carriage
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Owugha, JT, Ferreira, DM, and Gordon, SB
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Infections caused by Streptococcus pneumoniae are a major cause of morbidity and mortality globally: S. pneumoniae is the primary bacterial agent of pneumonia, the leading cause of death in children under 5 years of age and a major cause of invasive disease in the elderly. Currently licensed vaccination strategies target pneumococcal capsular polysaccharides of which there are 94 known types (serotypes). Antibodies against vaccine serotypes effectively protect against invasive pneumococcal disease, but less so against mucosal infections including pneumonia. New vaccine development efforts aim to overcome these hurdles by targeting conserved and immunogenic pneumococcal proteins. The Pneumococcal Surface Protein A (PspA) is a leading candidate due to its expression across all known clinically relevant pneumococcal strains, and ability to protect against infection across serotypes. However, PspA sequence heterogeneity necessitates identification of cross-protective protein constructs. In this doctoral research project, I investigated pneumococcal protein-specific humoral and CD4+ T-lymphocyte immune responses to S. pneumoniae utilising the platform of Experimental Human Pneumococcal Carriage (EHPC). With an emphasis on PspA, immune responses to nasopharyngeal carriage - the prerequisite to pneumococcal disease and proxy for infection - were evaluated. I present the first evidence of CD4+ T-cell responses specific to an individual pneumococcal purified protein in the blood of healthy adults both before and after carriage. PspA-specific CD4+ T-cell responses to S. pneumoniae in bronchoalveolar lavage of healthy adults after EHPC were detected at lower levels than in blood, indicating non-immunodominance of PspA as a T-cell antigen in the lung, and compartmentalisation of immune response. I also describe from preliminary data, a potential role of PspA in protection from pneumococcal carriage re- acquisition, and optimise an assay for the identification of linear pneumococcal protein epitopes with potential for inclusion in a multiple epitope protein. Unveiling protein-specific immune responses to S.pneumoniae using controlled and reproducible EHPC, may aid in our understanding of immunity towards selection of protein vaccine candidates for protection against human pneumococcal infection and disease.
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- 2017
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20. Community-acquired pneumonia in Malawian adults: Aetiology and predictors of mortality
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Aston, SJ, Gordon, SB, Heydernan, RS, and Mwandumba, HC
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Background Community-acquired pneumonia (CAP) is one of the commonest causes of adult hospitalisation in sub-Saharan Africa, but recent data describing its epidemiology, microbial aetiology and outcome are limited. Focusing particularly on Malawi, the overall aim of this thesis was to describe the aetiology and outcome of CAP in sub-Saharan African to determine the key predictors of mortality. Methods Firstly, a systematic review of studies of CAP in adults in sub-Saharan Africa was performed to describe CAP aetiology, estimate the mortality rate and identify risk factors associated with death. Secondly, a prospective observational study of adults hospitalised with clinically diagnosed CAP to Queen Elizabeth Central Hospital, Blantyre, Malawi was completed to describe microbial aetiology using modern diagnostic modalities, determine outcome and identify prognostics factors. Thirdly, having identified in preliminary analyses of the prospective cohort that hypoxaemia was an independent risk factor for mortality, a study of the effectiveness of supplemental oxygen delivery by oxygen concentrator to correct hypoxaemia in adults with suspected CAP was performed. Results In both the systematic review and the prospective cohort the predominant burden of hospitalised CAP was in young (average age 38 and 35, respectively) and HIV-positive (52% and 78%) patients with limited chronic cardiovascular and pulmonary comorbidity. Streptococcus pneumoniae (27% and 21%) and Mycobacterium tuberculosis (19% and 23%) were the most commonly identified causes. The overall mortality rate for hospitalised patients in the systematic review was 9.5%, but data describing prognostic factors were limited. In the prospective cohort (n=459), death by day 30 occurred in 14.6% and was associated with: male sex (aOR 2.57); pre-presentation symptom duration (aOR 1.11 per day increase); inability to stand (aOR 4.28); heart rate (aOR 1.02 per beat/minute rise); oxygen saturations (aOR 0.95 per % rise); white cell count (aOR 0.91 per 109/L rise); haemoglobin (aOR 0.90 per g/dL rise). A newly derived four parameter mortality risk prediction tool based on male sex, oxygen saturations
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- 2017
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21. An Augmented Passive Immunotherapy for Patients Admitted to Critical Care With Severe Sepsis
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Morton, BJ, Gordon, SB, Blakey, J, and Welters, I
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- 2016
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22. P4 therapy for the treatment of severe bacterial infections
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Gore, S, Kadioglu, A, and Gordon, SB
23. The human immune response to oral vaccination with live-attenuated Salmonella Typhi (Ty21a)
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Pennington, SH, Gordon, MA, Ferreira, DM, Gordon, SB, and Kadioglu, A
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complex mixtures - Abstract
Typhoid fever continues to represent a significant threat to global health and currently licensed vaccines confer incomplete protection. In 1975, an oral typhoid vaccine was developed through the chemical mutagenesis of pathogenic Salmonella enterica serovar Typhi strain Ty2. This vaccine, which is designated Ty21a, has been used for many years to combat disease; it is well-tolerated with a cumulative efficacy of approximately 58% up to 2 years following its administration. A great deal of data have been collected concerning peripheral cellular and humoral immune responses to this vaccine; however, only surrogate measures of mucosal immunity exist. The data presented within this thesis demonstrate the value of direct mucosal sampling and provide fresh insight into aspects of human immunity which have not previously been explored. The data presented describe the strength, diversity and duration of mucosal and peripheral cellular immune responses to Ty21a. In addition, the data demonstrate the wider impact of Ty21a on responses to non-related pathogens. Data presented here support the use of direct mucosal sampling to study host-pathogen interaction and the development of S. Typhi based vectors.
24. RSV and rhinovirus increase pneumococcal carriage acquisition and density, whereas nasal inflammation is associated with bacterial shedding.
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Mitsi E, Nikolaou E, Goncalves A, Blizard A, Hill H, Farrar M, Hyder-Wright A, Akeju O, Hamilton J, Howard A, Elterish F, Solorzano C, Robinson R, Reiné J, Collins AM, Gordon SB, Moxon RE, Weiser JN, Bogaert D, and Ferreira DM
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Epidemiological studies report the impact of co-infection with pneumococcus and respiratory viruses upon disease rates and outcomes, but their effect on pneumococcal carriage acquisition and bacterial load is scarcely described. Here, we assess this by combining natural viral infection with controlled human pneumococcal infection in 581 healthy adults screened for upper respiratory tract viral infection before intranasal pneumococcal challenge. Across all adults, respiratory syncytial virus (RSV) and rhinovirus asymptomatic infection confer a substantial increase in secondary infection with pneumococcus. RSV also has a major impact on pneumococcal density up to 9 days post challenge. We also study rates and kinetics of bacterial shedding through the nose and oral route in a subset. High levels of pneumococcal colonization density and nasal inflammation are strongly correlated with increased odds of nasal shedding as opposed to cough shedding. Protection against respiratory viral infections and control of pneumococcal density may contribute to preventing pneumococcal disease and reducing bacterial spread., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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25. Review of Current Tuberculosis Human Infection Studies for Use in Accelerating Tuberculosis Vaccine Development: A Meeting Report.
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Balasingam S, Dheda K, Fortune S, Gordon SB, Hoft D, Kublin JG, Loynachan CN, McShane H, Morton B, Nambiar S, Sharma NR, Robertson B, Schrager LK, and Weller CL
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- Humans, Vaccine Development, BCG Vaccine immunology, BCG Vaccine administration & dosage, Mycobacterium tuberculosis immunology, Animals, Tuberculosis prevention & control, Tuberculosis immunology, Tuberculosis Vaccines immunology, Tuberculosis Vaccines administration & dosage
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Tools to evaluate and accelerate tuberculosis (TB) vaccine development are needed to advance global TB control strategies. Validated human infection studies for TB have the potential to facilitate breakthroughs in understanding disease pathogenesis, identify correlates of protection, develop diagnostic tools, and accelerate and de-risk vaccine and drug development. However, key challenges remain for realizing the clinical utility of these models, which require further discussion and alignment among key stakeholders. In March 2023, the Wellcome Trust and the International AIDS Vaccine Initiative convened international experts involved in developing both TB and bacillus Calmette-Guérin (BCG) human infection studies (including mucosal and intradermal challenge routes) to discuss the status of each of the models and the key enablers to move the field forward. This report provides a summary of the presentations and discussion from the meeting. Discussions identified key issues, including demonstrating model validity, to provide confidence for vaccine developers, which may be addressed through demonstration of known vaccine effects (eg, BCG vaccination in specific populations), and by comparing results from field efficacy and human infection studies. The workshop underscored the importance of establishing safe and acceptable studies in high-burden settings, and the need to validate >1 model to allow for different scientific questions to be addressed as well as to provide confidence to vaccine developers and regulators around use of human infection study data in vaccine development and licensure pathways., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. C. L. W., S. B., N. R. S., and C. N. L. are employees of Wellcome Trust. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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26. Pneumococcal carriage and disease in adults in England 2011-2019: the importance of adults as a reservoir for pneumococcus in communities.
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El Safadi D, Hitchins L, Howard A, Aley P, Bowman J, Bertran M, Collins A, Colin-Jones R, Elterish F, Fry NK, Gordon SB, Gould K, Hinds J, Horn E, Hyder-Wright A, Kandasamy R, Ladhani S, Litt D, Mitsi E, Murphy A, Pollard AJ, Plested E, Pojar S, Ratcliffe H, Robertson MC, Robinson H, Snape MD, Solórzano C, Voysey M, Begier E, Catusse J, Lahuerta M, Theilacker C, Gessner BD, Tiley KS, and Ferreira DM
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Background: Pneumococcal carriage in children has been extensively studied, but carriage in healthy adults and its relationship to invasive pneumococcal disease (IPD) is less understood., Methods: Nasal wash samples from adults without close contact with young children (Liverpool, UK), 2011-2019, were cultured, and culture-negative samples tested by PCR. Pneumococcal carriage in adults 18-44 years was compared with carriage among PCV-vaccinated children 13-48 months (nasopharyngeal swabs, Thames Valley, UK) and IPD data for England for the same ages for 2014-2019. Age-group specific serotype invasiveness was calculated and used with national IPD data to estimate carriage serotype distributions for adults aged 65+ years., Results: In total 98 isolates (97 carriers) were identified from 1,631 adults aged 18+ years (age and sex standardized carriage prevalence 6.4%), with only three identified solely by PCR. Despite different carriage and IPD serotype distributions between adults and children, serotype invasiveness was highly correlated (R=0.9). Serotypes 3, 37 and 8 represented a higher proportion of adult carriage than expected from direct low-level transmission from children to adults. The predicted carriage serotype distributions for 65+ years aligned more closely with the carriage serotype distribution for young adults than young children., Conclusions: The nasal wash technique is highly sensitive; additional benefit of PCR is limited. Comparison of carriage serotype distributions suggests some serotypes may be circulating preferentially within these specific young adults. Our data suggest that for some serotypes carried by adults 65+ years, other adults may be an important reservoir for transmission. Age groups such as older children should also be considered., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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27. Natural carriage of Streptococcus pneumoniae is associated with increased experimental pneumococcal carriage but reduced conjugate vaccine efficacy in a human challenge model.
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Galafa B, Chikaonda T, Kudowa E, Sichone S, Sibale L, Thole F, Mkandawire C, Dula D, Nsomba E, Tembo G, Chaponda M, Chirwa AE, Nkhoma V, Ngoliwa C, Kamng'ona R, Toto N, Makhaza L, Muyaya A, Howard A, Nyazika TK, Ndaferankhande J, Chimgoneko L, Banda NPK, Chiwala G, Rylance J, Ferreira D, Jambo KC, Morton B, Henrion MYR, and Gordon SB
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Background: In Malawi, the national pneumococcal conjugate vaccine (PCV13) demonstrated less herd immunity than the USA, likely due to higher natural pneumococcal carriage rates. We assessed PCV13 efficacy against experimental pneumococcal carriage in healthy Malawian adults. We explored how natural carriage (pneumococcal carriage of any other serotype apart from 6B) influenced experimental carriage rates and vaccine efficacy., Methods: Healthy adults aged 18-40 were randomly assigned PCV13 (n=98) or saline (n=106), followed by intranasal SPN 6B inoculation at 20,000 (n=40), 80,000 (n=74), or 160,000 (n=90) CFU/100µl, 28 days post-vaccination. We evaluated natural and experimental pneumococcal carriage before and after vaccination on days 2, 7, and 14 post-inoculation using culture and multiplex qPCR targeting lytA/cpsA genes and compared carriage rates by vaccination status., Results: Of 204 participants, 19.6% (40) exhibited experimental carriage, detected by culture and 25.5% (52) by qPCR. Vaccinated individuals had lower experimental carriage rates (10.2%, n=10/98) compared to the placebo group (28.3%, n=30/106). This difference in vaccine efficacy was more pronounced in participants without natural carriage (PCV13=8% n=6/75 vs. placebo=25.9%, n=21/81) compared to those with natural carriage (PCV13=14.8%, n=4/27 vs. placebo=26.5%, n=9/34). Using a log-binomial model, vaccine effectiveness (VE) was 62%, whether assessed by culture or qPCR. Natural carriers had a lower VE of 52% compared to participants with no natural carriage (VE=69%)., Conclusion: We have shown that PCV13 VE estimate (62%) is robust whether carriage is assessed by culture or qPCR. PCV13 had lower VE in natural carriers compared to those without natural carriage at the inoculation visit., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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28. Inflammation of the nasal mucosa is associated with susceptibility to experimental pneumococcal challenge in older adults.
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Urban BC, Gonçalves ANA, Loukov D, Passos FM, Reiné J, Gonzalez-Dias P, Solórzano C, Mitsi E, Nikolaou E, O'Connor D, Collins AM, Adler H, Pollard A, Rylance J, Gordon SB, Jochems SP, Nakaya HI, and Ferreira DM
- Abstract
Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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29. A feasibility study of controlled human infection with intradermal Bacillus Calmette-Guérin (BCG) injection: Pilot BCG controlled human infection model.
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Carter E, Morton B, ElSafadi D, Jambo K, Kenny-Nyazika T, Hyder-Wright A, Chiwala G, Chikaonda T, Chirwa AE, Gonzalez Sanchez J, Yip V, Biagini G, Pennington SH, Saunderson P, Farrar M, Myerscough C, Collins AM, Gordon SB, and Ferreira DM
- Abstract
Tuberculosis (TB) caused 1.5 million deaths in 2020, making it the leading infectious killer after COVID-19. Bacille Calmette-Guerin (BCG) is the only licensed vaccine against TB but has sub-optimal efficacy against pulmonary TB and reduced effectiveness in regions close to the equator with high burden. Efforts to find novel vaccines are hampered due to the need for large-scale, prolonged, and costly clinical trials. Controlled human infection models (CHIMs) for TB may be used to accelerate vaccine development by ensuring only the most promising vaccine candidates are selected for phase 3 trials, but it is not currently possible to give participants Mycobacterium tuberculosis as a challenge agent. This study aims to replicate and refine an established BCG CHIM at the Liverpool School of Tropical Medicine. Participants will receive an intradermal injection with licensed BCG vaccine (Statens Serum Institut strain). In phase A, participants will undergo punch biopsy two weeks after administration, paired with minimally invasive methods of skin sampling (skin swab, microbiopsy, skin scrape). BCG detection by classical culture and molecular methods will be compared between these techniques and gold standard punch biopsy. Techniques meeting our pre-defined sensitivity and specificity criteria will be applied in Phase B to longitudinally assess intradermal BCG growth two, seven and fourteen days after administration. We will also measure compartmental immune responses in skin, blood and respiratory mucosa in Phase B. This feasibility study will transfer and refine an existing and safe model of BCG controlled human infection. Longitudinal BCG quantification has the potential to increase model sensitivity to detect vaccine and therapeutic responses. If successful, we aim to transfer the model to Malawi in future studies, a setting with endemic TB disease, to accelerate development of vaccines and therapeutics relevant for underserved populations who stand to benefit the most. Registration: ISRCTN: ISRCTN94098600 and ClinicalTrials.gov: NCT05820594., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Carter E et al.)
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- 2024
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30. Poor association between 13-valent pneumococcal conjugate vaccine-induced serum and mucosal antibody responses with experimental Streptococcus pneumoniae serotype 6B colonisation.
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Tembo G, Mayuni M, Kamng'ona R, Chimgoneko L, Chiwala G, Sichone S, Galafa B, Thole F, Mkandawire C, Chirwa AE, Nsomba E, Nkhoma V, Ngoliwa C, Toto N, Makhaza L, Muyaya A, Kudowa E, Henrion MYR, Dula D, Morton B, Chikaonda T, Gordon SB, and Jambo KC
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- Adult, Humans, Infant, Vaccines, Conjugate, Serogroup, Antibody Formation, Immunoglobulin G, Immunoglobulin A analysis, Pneumococcal Vaccines, Antibodies, Bacterial, Streptococcus pneumoniae, Pneumococcal Infections
- Abstract
Background: Pneumococcal carriage is the primary reservoir for transmissionand a prerequisite for invasive pneumococcal disease. Pneumococcal Conjugate Vaccine 13 (PCV13) showed a 62% efficacy in protection against experimental Streptococcus pneumoniae serotype 6B (Spn6B) carriage in a controlled human infection model (CHIM) of healthy Malawian adults. We, therefore, measured humoral responses to experimental challenge and PCV-13 vaccination and determined the association with protection against pneumococcal carriage., Methods: We vaccinated 204 young, healthy Malawian adults with PCV13 or placebo and nasally inoculated them with Spn6B at least four weeks post-vaccination to establish carriage. We collected peripheral blood and nasal lining fluid at baseline, 4 weeks post-vaccination (7 days pre-inoculation), 2, 7, 14 and > 1 year post-inoculation. We measured the concentration of anti-serotype 6B Capsular Polysaccharide (CPS) Immunoglobulin G (IgG) and IgA antibodies in serum and nasal lining fluid using the World Health Organization (WHO) standardised enzyme-linked immunosorbent assay (ELISA)., Results: PCV13-vaccinated adults had higher serum IgG and nasal IgG/IgA anti-Spn6B CPS-specific binding antibodies than placebo recipients 4 to 6 weeks post-vaccination, which persisted for at least a year after vaccination. Nasal challenge with Spn6B did not significantly alter serum or nasal anti-CPS IgG binding antibody titers with or without experimental pneumococcal carriage. Pre-challenge titers of PCV13-induced serum IgG and nasal IgG/IgA anti-Spn6B CPS binding antibodies did not significantly differ between those that got experimentally colonised by Spn6B compared to those that did not., Conclusion: This study demonstrates that despite high PCV13 efficacy against experimental Spn6B carriage in young, healthy Malawian adults, robust vaccine-induced systemic and mucosal anti-Spn6B CPS binding antibodies did not directly relate to protection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier India Pvt Ltd. All rights reserved.)
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- 2024
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31. Causes, outcomes and diagnosis of acute breathlessness hospital admissions in Malawi: protocol for a multicentre prospective cohort study.
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Spencer SA, Malowa F, McCarty D, Joekes E, Phulusa J, Chinoko B, Kaimba S, Keyala L, Mandala P, Mkandawire M, Mlongoti M, Mnesa B, Mukatipa A, Mijumbi R, Nyirenda M, Sawe HR, Henrion M, Augustine DX, Oxborough D, Worrall E, Limbani F, Dark P, Gordon SB, Rylance J, and Morton B
- Abstract
Background: Hospital admission due to breathlessness carries a significant burden to patients and healthcare systems, particularly impacting people in low-income countries. Prompt appropriate treatment is vital to improve outcomes, but this relies on accurate diagnostic tests which are of limited availability in resource-constrained settings. We will provide an accurate description of acute breathlessness presentations in a multicentre prospective cohort study in Malawi, a low resource setting in Southern Africa, and explore approaches to strengthen diagnostic capacity., Objectives: Primary objective: Delineate between causes of breathlessness among adults admitted to hospital in Malawi and report disease prevalence. Secondary objectives : Determine patient outcomes, including mortality and hospital readmission 90 days after admission; determine the diagnostic accuracy of biomarkers to differentiate between heart failure and respiratory infections (such as pneumonia) including brain natriuretic peptides, procalcitonin and C-reactive protein., Methods: This is a prospective longitudinal cohort study of adults (≥18 years) admitted to hospital with breathlessness across two hospitals: 1) Queen Elizabeth Central Hospital, Blantyre, Malawi; 2) Chiradzulu District Hospital, Chiradzulu, Malawi. Patients will be consecutively recruited within 24 hours of emergency presentation and followed-up until 90 days from hospital admission. We will conduct enhanced diagnostic tests with robust quality assurance and quality control to determine estimates of disease pathology. Diagnostic case definitions were selected following a systematic literature search., Discussion: This study will provide detailed epidemiological description of adult hospital admissions due to breathlessness in low-income settings, which is currently poorly understood. We will delineate between causes using established case definitions and conduct nested diagnostic evaluation. The results have the potential to facilitate development of interventions targeted to strengthen diagnostic capacity, enable prompt and appropriate treatment, and ultimately improve both patient care and outcomes., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Spencer SA et al.)
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- 2024
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32. Medical management of pneumoperitoneum, gastric pneumatosis, and hepatic venous gas secondary to 3% hydrogen peroxide toxicity in a dog.
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Gordon SB and Nadolski AC
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- Dogs, Female, Animals, Hydrogen Peroxide, Aftercare, Patient Discharge, Gastric Mucosa, Pneumoperitoneum chemically induced, Pneumoperitoneum diagnostic imaging, Pneumoperitoneum veterinary, Thoracic Injuries veterinary, Dog Diseases chemically induced, Dog Diseases therapy
- Abstract
Objective: To describe the medical management and outcome of a dog suffering severe hydrogen peroxide toxicity., Case Summary: A 3-year-old neutered female Bichon Frise was presented to an emergency and referral practice after ingestion of 10-20 mL/kg 3% hydrogen peroxide. On presentation, the dog was obtunded, was tachypneic, and had severe gastric tympany. Abdominal radiographs revealed pneumoperitoneum, gastric pneumatosis, and hepatic venous gas. The dog was managed conservatively with supportive care and oxygen therapy. Repeat radiographs 6 hours later showed complete resolution of all gas inclusions. While hospitalized, the dog developed severe hematemesis, and abdominal ultrasound revealed severe gastric wall thickening. Subsequent endoscopy confirmed severe gastric mucosal necrosis without evidence of deeper ulceration and relatively mild petechiation of the esophagus. The dog was ultimately discharged after 5 days of hospitalization and continued to do well at home. Recheck ultrasound 5 weeks postdischarge showed normal gastric wall appearance., New or Unique Information Provided: To the authors' knowledge, this is the first reported case of pneumoperitoneum secondary to hydrogen peroxide toxicity and the first description of the clinical course of severe toxicity in dogs., (© Veterinary Emergency and Critical Care Society 2024.)
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- 2024
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33. Serotype 3 Experimental Human Pneumococcal Challenge (EHPC) study protocol: dose ranging and reproducibility in a healthy volunteer population (challenge 3).
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Hazenberg P, Robinson RE, Farrar M, Solorzano C, Hyder-Wright A, Liatsikos K, Brunning J, Fleet H, Bettam A, Howard A, Kenny-Nyazika T, Urban B, Mitsi E, El Safadi D, Davies K, Lesosky M, Gordon SB, Ferreira DM, and Collins AM
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- Adult, Humans, Healthy Volunteers, Serogroup, Reproducibility of Results, Streptococcus pneumoniae, Pneumococcal Vaccines, Adaptive Immunity
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Introduction: Since the introduction of pneumococcal conjugate vaccines, pneumococcal disease rates have declined for many vaccine-type serotypes. However, serotype 3 (SPN3) continues to cause significant disease and is identified in colonisation epidemiological studies as one of the top circulating serotypes in adults in the UK. Consequently, new vaccines that provide greater protection against SPN3 colonisation/carriage are urgently needed. The Experimental Human Pneumococcal Challenge (EHPC) model is a unique method of determining pneumococcal colonisation rates, understanding acquired immunity, and testing vaccines in a cost-effective manner. To enhance the development of effective pneumococcal vaccines against SPN3, we aim to develop a new relevant and safe SPN3 EHPC model with high attack rates which could be used to test vaccines using small sample size., Methods and Analysis: This is a human challenge study to establish a new SPN3 EHPC model, consisting of two parts. In the dose-ranging/safety study, cohorts of 10 healthy participants will be challenged with escalating doses of SPN3. If first challenge does not lead into colonisation, participants will receive a second challenge 2 weeks after. Experimental nasopharyngeal (NP) colonisation will be determined using nasal wash sampling. Using the dose that results in ≥50% of participants being colonised, with a high safety profile, we will complete the cohort with another 33 participants to check for reproducibility of the colonisation rate. The primary outcome of this study is to determine the optimal SPN3 dose and inoculation regime to establish the highest rates of NP colonisation in healthy adults. Secondary outcomes include determining density and duration of experimental SPN3 NP colonisation and characterising mucosal and systemic immune responses to SPN3 challenge., Ethics and Dissemination: This study is approved by the NHS Research and Ethics Committee (reference 22/NW/0051). Findings will be published in peer-reviewed journals and reports will be made available to participants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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34. Experimental pneumococcal carriage in people living with HIV in Malawi: the first controlled human infection model in a key at-risk population.
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Doherty K, Dula D, Chirwa A, Nsomba E, Nkhoma VS, Toto N, Chikaonda T, Kamng'ona R, Phiri J, Reiné J, Ndaferankhande J, Makhaza L, Banda P, Jambo K, Ferreira DM, and Gordon SB
- Abstract
Background: As well as suffering a high burden of pneumococcal disease people living with HIV (PLHIV) may contribute to community transmission in sub-Saharan African (sSA) settings. Pneumococcal vaccination is not currently offered to PLHIV in sSA but may prevent disease and reduce transmission. More evidence of vaccine effectiveness against carriage in PLHIV is needed. An Experimental Human Pneumococcal Carriage model (EHPC) has been safely and acceptably used in healthy adults in Malawi to evaluate pneumococcal vaccines against carriage and to identify immune correlates of protection from carriage. This study will establish the same model in PLHIV and will be the first controlled human infection model (CHIM) in this key population. Methods: Healthy participants with and without HIV will be inoculated intranasally with Streptococcus pneumoniae serotype 6B. Sequential cohorts will be challenged with increasing doses to determine the optimal safe challenge dose to establish experimental carriage. Nasal fluid, nasal mucosal, and blood samples will be taken before inoculation and on days 2, 7, 14, and 21 following inoculation to measure pneumococcal carriage density and identify immune correlates of protection from carriage. The vast majority of natural pneumococcal carriage events in PLHIV do not result in invasive disease and no invasive disease is expected in this study. However, robust participant safety monitoring is designed to identify signs of invasive disease early should they develop, and to implement treatment immediately. Participants will complete a Likert-style questionnaire at study-end to establish acceptability. Interpretations: We expect the EHPC model to be safely and acceptably implemented in PLHIV. The CHIM can then be used to accelerate pneumococcal vaccine evaluations in this population, and an evidence-based pneumococcal vaccination policy for PLHIV in sSA., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Doherty K et al.)
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- 2024
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35. A Randomized Controlled Clinical Trial of Nasal Immunization with Live Virulence Attenuated Streptococcus pneumoniae Strains Using Human Infection Challenge.
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Hill H, Mitsi E, Nikolaou E, Blizard A, Pojar S, Howard A, Hyder-Wright A, Devin J, Reiné J, Robinson R, Solórzano C, Jochems SP, Kenny-Nyazika T, Ramos-Sevillano E, Weight CM, Myerscough C, McLenaghan D, Morton B, Gibbons E, Farrar M, Randles V, Burhan H, Chen T, Shandling AD, Campo JJ, Heyderman RS, Gordon SB, Brown JS, Collins AM, and Ferreira DM
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- Adult, Humans, Virulence, Nose, Immunization, Antibodies, Bacterial, Immunoglobulin G, Pneumococcal Vaccines therapeutic use, Streptococcus pneumoniae, Pneumococcal Infections prevention & control
- Abstract
Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 ( Δfhs/piaA ) or SpnA3 ( ΔproABC/piaA ) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293).
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- 2023
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36. Effect of 13-valent pneumococcal conjugate vaccine on experimental carriage of Streptococcus pneumoniae serotype 6B in Blantyre, Malawi: a randomised controlled trial and controlled human infection study.
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Dula D, Morton B, Chikaonda T, Chirwa AE, Nsomba E, Nkhoma V, Ngoliwa C, Sichone S, Galafa B, Tembo G, Chaponda M, Toto N, Kamng'ona R, Makhaza L, Muyaya A, Thole F, Kudowa E, Howard A, Kenny-Nyazika T, Ndaferankhande J, Mkandawire C, Chiwala G, Chimgoneko L, Banda NPK, Rylance J, Ferreira D, Jambo K, Henrion MYR, and Gordon SB
- Subjects
- Adult, Child, Humans, Malawi epidemiology, Vaccines, Conjugate, Serogroup, Streptococcus pneumoniae, Pneumococcal Vaccines therapeutic use
- Abstract
Background: The effect of childhood pneumococcal conjugate vaccine implementation in Malawi is threatened by absence of herd effect. There is persistent vaccine-type pneumococcal carriage in both vaccinated children and the wider community. We aimed to use a human infection study to measure 13-valent pneumococcal conjugate vaccine (PCV13) efficacy against pneumococcal carriage., Methods: We did a double-blind, parallel-arm, randomised controlled trial investigating the efficacy of PCV13 or placebo against experimental pneumococcal carriage of Streptococcus pneumoniae serotype 6B (strain BHN418) among healthy adults (aged 18-40 years) from Blantyre, Malawi. We randomly assigned participants (1:1) to receive PCV13 or placebo. PCV13 and placebo doses were prepared by an unmasked pharmacist to maintain research team and participant masking with identification only by a randomisation identification number and barcode. 4 weeks after receiving either PCV13 or placebo, participants were challenged with 20 000 colony forming units (CFUs) per naris, 80 000 CFUs per naris, or 160 000 CFUs per naris by intranasal inoculation. The primary endpoint was experimental pneumococcal carriage, established by culture of nasal wash at 2, 7, and 14 days. Vaccine efficacy was estimated per protocol by means of a log-binomial model adjusting for inoculation dose. The trial is registered with the Pan African Clinical Trials Registry, PACTR202008503507113, and is now closed., Findings: Recruitment commenced on April 27, 2021 and the final visit was completed on Sept 12, 2022. 204 participants completed the study protocol (98 PCV13, 106 placebo). There were lower carriage rates in the vaccine group at all three inoculation doses (0 of 21 vs two [11%] of 19 at 20 000 CFUs per naris; six [18%] of 33 vs 12 [29%] of 41 at 80 000 CFUs per naris, and four [9%] of 44 vs 16 [35%] of 46 at 160 000 CFUs per naris). The overall carriage rate was lower in the vaccine group compared with the placebo group (ten [10%] of 98 vs 30 [28%] of 106; Fisher's p value=0·0013) and the vaccine efficacy against carriage was estimated at 62·4% (95% CI 27·7-80·4). There were no severe adverse events related to vaccination or inoculation of pneumococci., Interpretation: This is, to our knowledge, the first human challenge study to test the efficacy of a pneumococcal vaccine against pneumococcal carriage in Africa, which can now be used to establish vaccine-induced correlates of protection and compare alternative strategies to prevent pneumococcal carriage. This powerful tool could lead to new means to enhance reduction in pneumococcal carriage after vaccination., Funding: Wellcome Trust., Competing Interests: Declaration of interests DF declares grant funding from Pfizer to her institution for separate projects and consulting fees from Pfizer, MSD, and Sanofi. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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37. Use of hospital services by patients with chronic conditions in sub-Saharan Africa: a systematic review and meta-analysis.
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Spencer SA, Rylance J, Quint JK, Gordon SB, Dark P, and Morton B
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- Adult, Humans, Africa South of the Sahara epidemiology, Hospitals, Prospective Studies, Chronic Disease, Patients, Delivery of Health Care
- Abstract
Objective: To estimate the prevalence of individual chronic conditions and multimorbidity among adults admitted to hospital in countries in sub-Saharan Africa., Methods: We systematically searched MEDLINE®, Embase®, Global Index Medicus, Global Health and SciELO for publications reporting on patient cohorts recruited between 1 January 2010 and 12 May 2023. We included articles reporting prevalence of pre-specified chronic diseases within unselected acute care services (emergency departments or medical inpatient settings). No language restrictions were applied. We generated prevalence estimates using random-effects meta-analysis alongside 95% confidence intervals, 95% prediction intervals and I
2 statistics for heterogeneity. To explore associations with age, sex, country-level income status, geographical region and risk of bias, we conducted pre-specified meta-regression, sub-group and sensitivity analyses., Findings: Of 6976 identified studies, 61 met the inclusion criteria, comprising data from 20 countries and 376 676 people. None directly reported multimorbidity, but instead reported prevalence for individual conditions. Among medical admissions, the highest prevalence was human immunodeficiency virus infection (36.4%; 95% CI: 31.3-41.8); hypertension (24.4%; 95% CI: 16.7-34.2); diabetes (11.9%; 95% CI: 9.9-14.3); heart failure (8.2%; 95% CI: 5.6-11.9); chronic kidney disease (7.7%; 95% CI: 3.9-14.7); and stroke (6.8%; 95% CI: 4.7-9.6)., Conclusion: Among patients seeking hospital care in sub-Saharan Africa, multimorbidity remains poorly described despite high burdens of individual chronic diseases. Prospective public health studies of multimorbidity burden are needed to generate integrated and context-specific health system interventions that act to maximize patient survival and well-being., ((c) 2023 The authors; licensee World Health Organization.)- Published
- 2023
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38. A health systems approach to critical care delivery in low-resource settings: a narrative review.
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Spencer SA, Adipa FE, Baker T, Crawford AM, Dark P, Dula D, Gordon SB, Hamilton DO, Huluka DK, Khalid K, Lakoh S, Limbani F, Rylance J, Sawe HR, Simiyu I, Waweru-Siika W, Worrall E, and Morton B
- Subjects
- Humans, Critical Care, Systems Analysis, Health Resources, Delivery of Health Care, Health Workforce
- Abstract
There is a high burden of critical illness in low-income countries (LICs), adding pressure to already strained health systems. Over the next decade, the need for critical care is expected to grow due to ageing populations with increasing medical complexity; limited access to primary care; climate change; natural disasters; and conflict. In 2019, the 72nd World Health Assembly emphasised that an essential part of universal health coverage is improved access to effective emergency and critical care and to "ensure the timely and effective delivery of life-saving health care services to those in need". In this narrative review, we examine critical care capacity building in LICs from a health systems perspective. We conducted a systematic literature search, using the World Heath Organisation (WHO) health systems framework to structure findings within six core components or "building blocks": (1) service delivery; (2) health workforce; (3) health information systems; (4) access to essential medicines and equipment; (5) financing; and (6) leadership and governance. We provide recommendations using this framework, derived from the literature identified in our review. These recommendations are useful for policy makers, health service researchers and healthcare workers to inform critical care capacity building in low-resource settings., (© 2023. The Author(s).)
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- 2023
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39. Practical considerations for a TB controlled human infection model (TB-CHIM); the case for TB-CHIM in Africa, a systematic review of the literature and report of 2 workshop discussions in UK and Malawi.
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Gordon SB, Sichone S, Chirwa AE, Hazenberg P, Kafuko Z, Ferreira DM, Flynn J, Fortune S, Balasingam S, Biagini GA, McShane H, Mwandumba HC, Jambo K, Dedha K, Raj Sharma N, Robertson BD, Walker NF, and Morton B
- Abstract
Background: Tuberculosis (TB) remains a major challenge in many domains including diagnosis, pathogenesis, prevention, treatment, drug resistance and long-term protection of the public health by vaccination. A controlled human infection model (CHIM) could potentially facilitate breakthroughs in each of these domains but has so far been considered impossible owing to technical and safety concerns. Methods: A systematic review of mycobacterial human challenge studies was carried out to evaluate progress to date, best possible ways forward and challenges to be overcome. We searched MEDLINE (1946 to current) and CINAHL (1984 to current) databases; and Google Scholar to search citations in selected manuscripts. The final search was conducted 3
rd February 2022. Inclusion criteria: adults ≥18 years old; administration of live mycobacteria; and interventional trials or cohort studies with immune and/or microbiological endpoints. Exclusion criteria: animal studies; studies with no primary data; no administration of live mycobacteria; retrospective cohort studies; case-series; and case-reports. Relevant tools (Cochrane Collaboration for RCTs and Newcastle-Ottawa Scale for non-randomised studies) were used to assess risk of bias and present a narrative synthesis of our findings. Results: The search identified 1,388 titles for review; of these 90 were reviewed for inclusion; and 27 were included. Of these, 15 were randomised controlled trials and 12 were prospective cohort studies. We focussed on administration route, challenge agent and dose administered for data extraction. Overall, BCG studies including fluorescent BCG show the most immediate utility, and genetically modified Mycobacteria tuberculosis is the most tantalising prospect of discovery breakthrough. Conclusions: The TB-CHIM development group met in 2019 and 2022 to consider the results of the systematic review, to hear presentations from many of the senior authors whose work had been reviewed and to consider best ways forward. This paper reports both the systematic review and the deliberations. Registration: PROSPERO ( CRD42022302785; 21 January 2022)., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Gordon SB et al.)- Published
- 2023
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40. Comprehensive review of safety in Experimental Human Pneumococcal Challenge.
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Robinson RE, Myerscough C, He N, Hill H, Shepherd WA, Gonzalez-Dias P, Liatsikos K, Latham S, Fyles F, Doherty K, Hazenberg P, Shiham F, Mclenghan D, Adler H, Randles V, Zaidi S, Hyder-Wright A, Mitsi E, Burhan H, Morton B, Rylance J, Lesosky M, Gordon SB, Collins AM, and Ferreira DM
- Subjects
- Adult, Humans, Young Adult, Pneumococcal Vaccines adverse effects, Nasopharynx, Anti-Bacterial Agents adverse effects, Streptococcus pneumoniae, Pneumococcal Infections prevention & control
- Abstract
Introduction: Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies., Methods: A single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation., Results: In 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = <0.001). The majority were mild (pneumococcal group = 72.7% [120/165 reported symptoms], non-pneumococcal = 86.7% [124/143 reported symptoms]). 1.6% (23/1416) required antibiotics for safety., Discussion: No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated., Conclusion: Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Robinson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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41. Clinical predictors of bacteraemia in neonates with suspected early-onset sepsis in Malawi: a prospective cohort study.
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de Baat T, Lester R, Ghambi L, Twabi HH, Nielsen M, Gordon SB, van Weissenbruch MM, Feasey NA, Dube Q, Kawaza K, and Iroh Tam PY
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- Infant, Newborn, Humans, Female, Pregnancy, Infant, Prospective Studies, Malawi epidemiology, Anti-Bacterial Agents therapeutic use, Sepsis diagnosis, Sepsis epidemiology, Sepsis drug therapy, Bacteremia diagnosis, Bacteremia drug therapy, Bacteremia epidemiology, Neonatal Sepsis diagnosis, Neonatal Sepsis drug therapy, Neonatal Sepsis epidemiology
- Abstract
Objectives: We studied neonates with suspected early-onset sepsis (EOS, sepsis developing in the first 72 hours after delivery) in Malawi to (1) describe clinical characteristics and microbiological findings, (2) identify which patient characteristics may be associated with pathogen positivity on blood culture, and (3) describe mortality and its potential determinants., Design: Prospective observational study (May 2018-June 2019)., Setting: Neonatal ward in Queen Elizabeth Central Hospital, the largest government hospital in Malawi., Patients: All neonates with suspected EOS in whom a blood culture was obtained., Results: Out of 4308 neonatal admissions, 1244 (28.9%) had suspected EOS. We included 1149 neonates, of which 109 blood cultures had significant growth (9.5%). The most commonly isolated pathogens were Staphylococcus aureus , Klebsiella pneumoniae , Enterobacter cloacae , Escherichia coli and Acinetobacter baumanii . Many of the Gram negatives were extended-spectrum beta lactamase-producing Enterobacteriaceae, and these were 40-100% resistant to first-line and second-line antimicrobials. Gestational age (GA) of <32 weeks was associated with pathogen-positive blood cultures (<28 weeks: adjusted OR (AOR) 2.72, 95% CI 1.04 to 7.13; 28-32 weeks: AOR 2.26, 95% CI 1.21 to 4.21; p=0.005). Mortality was 17.6% (202/1149) and associated with low birth weight (<1000 g: AOR 47.57, 95% CI 12.59 to 179.81; 1000-1500 g: AOR 11.31, 95% CI 6.97 to 18.36; 1500-2500 g: AOR 2.20, 95% CI 1.42 to 3.39; p<0.001), low Apgar scores at 5 min (0-3: AOR 18.60, 95% CI 8.81 to 39.27; 4-6: AOR 4.41, 95% CI 2.81 to 6.93; p<0.001), positive maternal venereal disease research laboratory status (AOR 2.53, 95% CI 1.25 to 5.12; p=0.001) and congenital anomalies (AOR 7.37, 95% CI 3.61 to 15.05; p<0.001). Prolonged rupture of membranes was inversely associated with mortality (AOR 0.43, 95% CI 0.19 to 0.98; p 0.007)., Conclusion: In Malawi, EOS was suspected in nearly a third of neonatal admissions and had a high mortality. Ten per cent were culture-confirmed and predicted by low GA. To reduce the impact of suspected neonatal sepsis in least developed countries, improved maternal and antenatal care and development of rapid point of care methods to more accurately guide antimicrobial use could simultaneously improve outcome and reduce antimicrobial resistance., Competing Interests: Competing interests: PI has received investigator-initiated research grant support from Bill & Melinda Gates Foundation. MN has received grant support from Roche. The remaining authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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42. Oxygen saturation targets for adults with acute hypoxemia in low and lower-middle income countries: a scoping review with analysis of contextual factors.
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Herbst A, Goel S, Beane A, Brotherton BJ, Dula D, Ely EW, Gordon SB, Haniffa R, Hedt-Gauthier B, Limbani F, Lipnick MS, Lyon S, Njoki C, Oduor P, Otieno G, Pisani L, Rylance J, Shrime MG, Uwamahoro DL, Vanderburg S, Waweru-Siika W, Twagirumugabe T, and Riviello E
- Abstract
Knowing the target oxygen saturation (SpO
2 ) range that results in the best outcomes for acutely hypoxemic adults is important for clinical care, training, and research in low-income and lower-middle income countries (collectively LMICs). The evidence we have for SpO2 targets emanates from high-income countries (HICs), and therefore may miss important contextual factors for LMIC settings. Furthermore, the evidence from HICs is mixed, amplifying the importance of specific circumstances. For this literature review and analysis, we considered SpO2 targets used in previous trials, international and national society guidelines, and direct trial evidence comparing outcomes using different SpO2 ranges (all from HICs). We also considered contextual factors, including emerging data on pulse oximetry performance in different skin pigmentation ranges, the risk of depleting oxygen resources in LMIC settings, the lack of access to arterial blood gases that necessitates consideration of the subpopulation of hypoxemic patients who are also hypercapnic, and the impact of altitude on median SpO2 values. This process of integrating prior study protocols, society guidelines, available evidence, and contextual factors is potentially useful for the development of other clinical guidelines for LMIC settings. We suggest that a goal SpO2 range of 90-94% is reasonable, using high-performing pulse oximeters. Answering context-specific research questions, such as an optimal SpO2 target range in LMIC contexts, is critical for advancing equity in clinical outcomes globally., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Herbst, Goel, Beane, Brotherton, Dula, Ely, Gordon, Haniffa, Hedt-Gauthier, Limbani, Lipnick, Lyon, Njoki, Oduor, Otieno, Pisani, Rylance, Shrime, Uwamahoro, Vanderburg, Waweru-Siika, Twagirumugabe and Riviello.)- Published
- 2023
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43. A comparison of four epidemic waves of COVID-19 in Malawi; an observational cohort study.
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Anscombe C, Lissauer S, Thole H, Rylance J, Dula D, Menyere M, Kutambe B, van der Veer C, Phiri T, Banda NP, Mndolo KS, Mponda K, Phiri C, Mallewa J, Nyirenda M, Katha G, Mwandumba H, Gordon SB, Jambo KC, Cornick J, Feasey N, Barnes KG, Morton B, and Ashton PM
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- Adult, Humans, SARS-CoV-2, Malawi, Cohort Studies, Data Accuracy, COVID-19
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Background: Compared to the abundance of clinical and genomic information available on patients hospitalised with COVID-19 disease from high-income countries, there is a paucity of data from low-income countries. Our aim was to explore the relationship between viral lineage and patient outcome., Methods: We enrolled a prospective observational cohort of adult patients hospitalised with PCR-confirmed COVID-19 disease between July 2020 and March 2022 from Blantyre, Malawi, covering four waves of SARS-CoV-2 infections. Clinical and diagnostic data were collected using an adapted ISARIC clinical characterization protocol for COVID-19. SARS-CoV-2 isolates were sequenced using the MinION™ in Blantyre., Results: We enrolled 314 patients, good quality sequencing data was available for 55 patients. The sequencing data showed that 8 of 11 participants recruited in wave one had B.1 infections, 6/6 in wave two had Beta, 25/26 in wave three had Delta and 11/12 in wave four had Omicron. Patients infected during the Delta and Omicron waves reported fewer underlying chronic conditions and a shorter time to presentation. Significantly fewer patients required oxygen (22.7% [17/75] vs. 58.6% [140/239], p < 0.001) and steroids (38.7% [29/75] vs. 70.3% [167/239], p < 0.001) in the Omicron wave compared with the other waves. Multivariable logistic-regression demonstrated a trend toward increased mortality in the Delta wave (OR 4.99 [95% CI 1.0-25.0 p = 0.05) compared to the first wave of infection., Conclusions: Our data show that each wave of patients hospitalised with SARS-CoV-2 was infected with a distinct viral variant. The clinical data suggests that patients with severe COVID-19 disease were more likely to die during the Delta wave., (© 2023. The Author(s).)
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- 2023
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44. 'Why would they spend all this money and give us these items for free?': Exploring precarity and power in a cleaner cookstove intervention in rural Malawi.
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Ardrey J, Jehan K, Desmond N, Kumbuyo C, Nyirenda D, Gordon SB, Mortimer K, and Tolhurst R
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We carried out a qualitative study to gain a deeper understanding of the social context of the Cooking and Pneumonia Study (CAPS) and implications for implementation of clean cooking and similar interventions. Such initiatives are recognised as complex, power-laden processes, which has consequences for outcomes and uptake. However, understanding of how precarious livelihoods and unequal power differentials impact on trials of technology is limited and potentially hampers the achievement of the SDGs including SDG 7, Affordable and Clean Energy. An in-depth exploration of experiences and perceptions of cooking and cookstove use within CAPS was completed using qualitative methods and the participatory methodology Photovoice. Ten CAPS participants from each of five villages participated in Photovoice activities and five village representatives were interviewed. Twelve fieldworkers participated in gender specific focus groups and four were interviewed. A thematic content approach was used for data analysis. The analysis showed that economic and power inequity underpinned the complex social relationships within CAPS impacting on trial participation, perceptions of the cookstoves, and on the potential of the intervention to affect health and other benefits. Power can be understood as relational and productive within the research environment. This is illustrated by an analysis of the role of fieldworkers and community representatives who needed to negotiate resistance to trial compliance decisions, including 'satanic' rumours about cookstoves and blood-taking. Transformative approaches that challenge existing power inequities are needed to maximise the success and beneficence of cookstove and other health promoting interventions, and achievement of the SDGs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ardrey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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45. A secondary data analysis of a cluster randomized controlled trial: improved cookstoves associated with reduction in incidence of low birthweight in rural Malawi.
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Best R, Malava J, Dube A, Katundu C, Kalobekamo F, Mortimer K, Gordon SB, Nyirenda M, Crampin A, and McLean E
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- Infant, Humans, Incidence, Birth Weight, Malawi epidemiology, Secondary Data Analysis, Cooking, Air Pollution, Indoor adverse effects
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Background: In northern rural Malawi, the majority of households cook using open fires and there is also a high burden of adverse birth outcomes. The use of open fires or highly polluting cookstoves is associated with low birthweight in babies. There is mixed evidence on whether implementation of cleaner burning cookstoves reduces the number of babies born with low birthweight., Methods: This is a secondary analysis of a cluster randomized control trial in Malawi, conducted over 2014-17. Households were randomized to receive improved cookstoves or to continue current practices. For this analysis, the primary outcome was low birthweight in households under routine demographic surveillance, among births occurring within the trial time frame (N = 4010). A subset of data with stricter exposure definitions respecting the original randomized allocation was also analysed (N = 1050). A causal, forwards modelling approach was used., Results: The main dataset showed evidence of effect of the intervention on low birthweight [adjusted odds ratio (aOR) 0.69; 95% CI 0.48-0.99, n = 2788). The subset analysis lacked power to provide evidence of association between improved cookstoves and low birthweight in the stricter exposure definition (aOR 0.62; 95% CI 0.35-1.09, n = 932)., Conclusions: This study provides some evidence that an improved cookstove intervention in rural Malawi reduced the number of babies born with low birthweight by 30%. This direction of the effect was also seen in the subset analysis. The analysis suggests that the intervention reduced the number of infants born prematurely or with intra-uterine growth restriction, indicating that improved cookstoves could be a useful maternal health intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)
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- 2022
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46. Effect of resistance to third-generation cephalosporins on morbidity and mortality from bloodstream infections in Blantyre, Malawi: a prospective cohort study.
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Lester R, Musicha P, Kawaza K, Langton J, Mango J, Mangochi H, Bakali W, Pearse O, Mallewa J, Denis B, Bilima S, Gordon SB, Lalloo DG, Jewell CP, and Feasey NA
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- Humans, Escherichia coli, Prospective Studies, Malawi epidemiology, Anti-Bacterial Agents pharmacology, Cephalosporins pharmacology, Morbidity, Bacteremia drug therapy, Sepsis drug therapy
- Abstract
Background: The burden of antimicrobial resistance is a major threat to global health; however, prospective clinical outcome data from Africa are scarce. In Malawi, third-generation cephalosporins are the antibiotics of choice in patients admitted to hospital despite a rapid proliferation of resistance to these drugs. We aimed to quantify the effect of resistance to third-generation cephalosporins on mortality and length of hospital stay among patients with bloodstream infections., Methods: We did a prospective cohort study of patients admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Patients of all ages who had positive blood cultures for Enterobacterales were included, with the exception of those from the genus Salmonella, and were followed up for 180 days. We characterised blood culture isolates using whole-genome sequencing and used Cox regression models to estimate the effect of resistance to third-generation cephalosporins on length of hospital stay, in-hospital mortality, and survival., Findings: Between Jan 31, 2018, and Jan 13, 2020, we recruited 326 patients, from whom 220 (68%) of 326 isolates were resistant to third-generation cephalosporins. The case fatality proportion was 45% (99 of 220) in patients with bloodstream infections that were resistant to third-generation cephalosporins, and 34% (36 of 106) in patients with bloodstream infections that were sensitive to third-generation cephalosporins. Resistance to third-generation cephalosporins was associated with an increased probability of in-hospital mortality (hazard ratio [HR] 1·44, 95% CI 1·02-2·04), longer hospital stays (1·5 days, 1·0-2·0) and decreased probability of discharge alive (HR 0·31, 0·22-0·45). Whole-genome sequencing showed a high diversity of sequence types of both Escherichia coli and Klebsiella pneumoniae. Although isolates associated with death were distributed across clades, we identified three E coli clades (ST410, ST617, and ST648) that were isolated from 14 patients who all died., Interpretation: Resistance to third-generation cephalosporins is associated with increased mortality and longer hospital stays in patients with bloodstream infections in Malawi. These data show the urgent need for allocation of resources towards antimicrobial resistance mitigation strategies in Africa., Funding: Wellcome Trust and Wellcome Asia and Africa Programme., Competing Interests: Declaration of interests NAF received a Wellcome Asia and Africa Programme Grant to the Malawi Liverpool Wellcome Research Programme and a Medical Research Council programme grant. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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47. Human Infection Challenge with Serotype 3 Pneumococcus.
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Robinson RE, Mitsi E, Nikolaou E, Pojar S, Chen T, Reiné J, Nyazika TK, Court J, Davies K, Farrar M, Gonzalez-Dias P, Hamilton J, Hill H, Hitchins L, Howard A, Hyder-Wright A, Lesosky M, Liatsikos K, Matope A, McLenaghan D, Myerscough C, Murphy A, Solórzano C, Wang D, Burhan H, Gautam M, Begier E, Theilacker C, Beavon R, Anderson AS, Gessner BD, Gordon SB, Collins AM, and Ferreira DM
- Subjects
- Humans, Child, Infant, Young Adult, Adult, Serogroup, Carrier State, Pneumococcal Vaccines therapeutic use, Nasopharynx microbiology, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents pharmacology, Streptococcus pneumoniae, Pneumococcal Infections prevention & control
- Abstract
Rationale: Streptococcus pneumoniae serotype 3 (SPN3) is a cause of invasive pneumococcal disease and associated with low carriage rates. Following the introduction of pediatric 13-valent pneumococcal conjugate vaccine (PCV13) programs, SPN3 declines are less than other vaccine serotypes and incidence has increased in some populations coincident with a shift in predominant circulating SPN3 clade, from I to II. A human challenge model provides an effective means for assessing the impact of PCV13 on SPN3 in the upper airway. Objectives: To establish SPN3's ability to colonize the nasopharynx using different inoculum clades and doses, and the safety of an SPN3 challenge model. Methods: In a human challenge study involving three well-characterized and antibiotic-sensitive SPN3 isolates (PFESP306 [clade Ia], PFESP231 [no clade], and PFESP505 [clade II]), inoculum doses (10,000, 20,000, 80,000, and 160,000 cfu/100 μl) were escalated until maximal colonization rates were achieved, with concurrent acceptable safety. Measurement and Main Results: Presence and density of experimental SPN3 nasopharyngeal colonization in nasal wash samples, assessed using microbiological culture and molecular methods, on Days 2, 7, and 14 postinoculation. A total of 96 healthy participants (median age 21, interquartile range 19-25) were inoculated ( n = 6-10 per dose group, 10 groups). Colonization rates ranged from 30.0-70.0% varying with dose and isolate. 30.0% (29/96) reported mild symptoms (82.8% [24/29] developed a sore throat); one developed otitis media requiring antibiotics. No serious adverse events occurred. Conclusions: An SPN3 human challenge model is feasible and safe with comparable carriage rates to an established Serotype 6B human challenge model. SPN3 carriage may cause mild upper respiratory symptoms.
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- 2022
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48. Quality of antibody responses by adults and young children to 13-valent pneumococcal conjugate vaccination and Streptococcus pneumoniae colonisation.
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Wolf AS, Mitsi E, Jones S, Jochems SP, Roalfe L, Thindwa D, Meiring JE, Msefula J, Bonomali F, Makhaza Jere T, Mbewe M, Collins AM, Gordon SB, Gordon MA, Ferreira DM, French N, Goldblatt D, Heyderman RS, and Swarthout TD
- Subjects
- Humans, Child, Infant, Adult, Child, Preschool, Antibody Formation, Pneumococcal Vaccines, Vaccines, Conjugate, Vaccination, Immunoglobulin G, Nasopharynx, Streptococcus pneumoniae, Pneumococcal Infections prevention & control
- Abstract
Childhood pneumococcal conjugate vaccine (PCV) protects against invasive pneumococcal disease caused by vaccine-serotype (VT) Streptococcus pneumoniae by generating opsonophagocytic anti-capsular antibodies, but how vaccination protects against and reduces VT carriage is less well understood. Using serological samples from PCV-vaccinated Malawian individuals and a UK human challenge model, we explored whether antibody quality (IgG subclass, opsonophagocytic killing, and avidity) is associated with protection from carriage. Following experimental challenge of adults with S. pneumoniae serotype 6B, 3/21 PCV13-vaccinees were colonised with pneumococcus compared to 12/24 hepatitis A-vaccinated controls; PCV13-vaccination induced serotype-specific IgG, IgG1, and IgG2, and strong opsonophagocytic responses. However, there was no clear relationship between antibody quality and protection from carriage or carriage intensity after vaccination. Similarly, among PCV13-vaccinated Malawian infants there was no relationship between serotype-specific antibody titre or quality and carriage through exposure to circulating serotypes. Although opsonophagocytic responses were low in infants, antibody titre and avidity to circulating serotypes 19F and 6A were maintained or increased with age. These data suggest a complex relationship between antibody-mediated immunity and pneumococcal carriage, and that PCV13-driven antibody quality may mature with age and exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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49. High Intrapulmonary Rifampicin and Isoniazid Concentrations Are Associated With Rapid Sputum Bacillary Clearance in Patients With Pulmonary Tuberculosis.
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McCallum AD, Pertinez HE, Chirambo AP, Sheha I, Chasweka M, Malamba R, Shani D, Chitani A, Mallewa JE, Meghji JZ, Ghany JF, Corbett EL, Gordon SB, Davies GR, Khoo SH, Sloan DJ, and Mwandumba HC
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- Adult, Humans, Isoniazid therapeutic use, Isoniazid pharmacokinetics, Rifampin pharmacokinetics, Sputum microbiology, Antitubercular Agents pharmacokinetics, Pyrazinamide pharmacokinetics, Ethambutol therapeutic use, Tuberculosis, Pulmonary drug therapy, Tuberculosis, Pulmonary microbiology, Bacillus
- Abstract
Background: Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi., Methods: Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0-8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models., Results: Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified., Conclusions: Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes., Competing Interests: Potential conflicts of interest. A. M. reports MLW’s core activities and infrastructure are supported by a 5-year renewable Core grant from Wellcome, Current Core Grant (grant number 2018-2023) is 206545/Z/17/Z. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2022
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50. Hepatitis B Vaccination Impact and the Unmet Need for Antiviral Treatment in Blantyre, Malawi.
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Stockdale AJ, Meiring JE, Shawa IT, Thindwa D, Silungwe NM, Mbewe M, Kachala R, Kreuels B, Patel P, Patel P, Henrion MYR, Bar-Zeev N, Swarthout TD, Heyderman RS, Gordon SB, Maria Geretti A, and Gordon MA
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- Adolescent, Adult, Antiviral Agents therapeutic use, Child, Female, Hepatitis B Surface Antigens, Hepatitis B Vaccines therapeutic use, Hepatitis B virus, Humans, Infant, Malawi epidemiology, Male, Seroepidemiologic Studies, Vaccination, HIV Infections drug therapy, HIV Infections epidemiology, Hepatitis B drug therapy, Hepatitis B epidemiology, Hepatitis B prevention & control
- Abstract
Background: Hepatitis B is the leading cause of cirrhosis and liver cancer in sub-Saharan Africa. To reduce mortality, antiviral treatment programs are needed. We estimated prevalence, vaccine impact, and need for antiviral treatment in Blantyre, Malawi., Methods: We conducted a household study in 2016-2018. We selected individuals from a census using random sampling and estimated age-sex-standardized hepatitis B surface antigen (HBsAg) seroprevalence. Impact of infant hepatitis B vaccination was estimated by binomial log-linear regression comparing individuals born before and after vaccine implementation. In HBsAg-positive adults, eligibility for antiviral therapy was assessed., Results: Of 97386 censused individuals, 6073 (median age 18 years; 56.7% female) were sampled. HBsAg seroprevalence was 5.1% (95% confidence interval [CI], 4.3%-6.1%) among adults and 0.3% (95% CI, .1%-.6%) among children born after vaccine introduction. Estimated vaccine impact was 95.8% (95% CI, 70.3%-99.4%). Of HBsAg-positive adults, 26% were HIV-positive. Among HIV-negative individuals, 3%, 6%, and 9% were eligible for hepatitis B treatment by WHO, European, and American hepatology association criteria, respectively., Conclusions: Infant HBV vaccination has been highly effective in reducing HBsAg prevalence in urban Malawi. Up to 9% of HBsAg-positive HIV-negative adults are eligible, but have an unmet need, for antiviral therapy., Competing Interests: Potential conflicts of interest. N. B.-Z. reports grants from Merck-Sharp-Dohme, Johnson & Johnson, and Serum Institute of India, outside the submitted work. A. M. G. reports grants and personal fees from Roche Pharma Research and Early Development, ViiV Healthcare, and Gilead; personal fees from Janssen; and consulting fees from GSK, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2022
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