OBJECTIVE Assess characteristics of clinical pneumonia after introduction of pneumococcal conjugate vaccine (PCV), by HIV exposure status, in children hospitalised in a governmental hospital in Malawi. METHODS AND FINDINGS We evaluated 1139 children ≤5 years old hospitalised with clinical pneumonia: 101 HIV-exposed, uninfected (HEU) and 1038 HIV-unexposed, uninfected (HUU). Median age was 11 months (IQR 6-20), 59% were male, median mid-upper arm circumference (MUAC) was 14 cm (IQR 13-15) and mean weight-for-height z score was -0.7 (±2.5). The highest Respiratory Index of Severity in Children (RISC) scores were allocated to 10.4% of the overall cohort. Only 45.7% had fever, and 37.2% had at least one danger sign at presentation. The most common clinical features were crackles (54.7%), nasal flaring (53.5%) and lower chest wall indrawing (53.2%). Compared with HUU, HEU children were significantly younger (9 months vs 11 months), with lower mean birth weight (2.8 kg vs 3.0 kg) and MUAC (13.6 cm vs 14.0 cm), had higher prevalence of vomiting (32.7% vs 22.0%), tachypnoea (68.4% vs 49.8%) and highest RISC scores (20.0% vs 9.4%). Five children died (0.4%). However, clinical outcomes were similar for both groups. CONCLUSIONS In this post-PCV setting where prevalence of HIV and malnutrition is high, children hospitalised fulfilling the WHO Integrated Management of Childhood Illness criteria for clinical pneumonia present with heterogeneous features. These vary by HIV exposure status but this does not influence either the frequency of danger signs or mortality. The poor performance of available severity scores in this population and the absence of more specific diagnostics hinder appropriate antimicrobial stewardship and the rational application of other interventions.
OBJECTIVE: Assess characteristics of clinical pneumonia after introduction of pneumococcal conjugate vaccine (PCV), by HIV exposure status, in children hospitalised in a governmental hospital in Malawi. METHODS AND FINDINGS: We evaluated 1139 children ≤5 years old hospitalised with clinical pneumonia: 101 HIV-exposed, uninfected (HEU) and 1038 HIV-unexposed, uninfected (HUU). Median age was 11 months (IQR 6–20), 59% were male, median mid-upper arm circumference (MUAC) was 14 cm (IQR 13–15) and mean weight-for-height z score was −0.7 (±2.5). The highest Respiratory Index of Severity in Children (RISC) scores were allocated to 10.4% of the overall cohort. Only 45.7% had fever, and 37.2% had at least one danger sign at presentation. The most common clinical features were crackles (54.7%), nasal flaring (53.5%) and lower chest wall indrawing (53.2%). Compared with HUU, HEU children were significantly younger (9 months vs 11 months), with lower mean birth weight (2.8 kg vs 3.0 kg) and MUAC (13.6 cm vs 14.0 cm), had higher prevalence of vomiting (32.7% vs 22.0%), tachypnoea (68.4% vs 49.8%) and highest RISC scores (20.0% vs 9.4%). Five children died (0.4%). However, clinical outcomes were similar for both groups. CONCLUSIONS: In this post-PCV setting where prevalence of HIV and malnutrition is high, children hospitalised fulfilling the WHO Integrated Management of Childhood Illness criteria for clinical pneumonia present with heterogeneous features. These vary by HIV exposure status but this does not influence either the frequency of danger signs or mortality. The poor performance of available severity scores in this population and the absence of more specific diagnostics hinder appropriate antimicrobial stewardship and the rational application of other interventions.
INTRODUCTION In Sub-Saharan Africa, the rising rates of cerebrovascular and cardiovascular diseases (CBD/CVD) are intersecting with an ageing HIV-infected population. The widespread use of antiretroviral therapy (ART) may confer an additive risk and may not completely suppress the risk associated with HIV infection. High-quality prospective studies are needed to determine if HIV-infected patients in Africa are at increased risk of CBD/CVD and to identify factors associated with this risk. This study will test the hypothesis that immune activation and dysfunction, driven by HIV and reactivation of latent herpesvirus infections, lead to increased CBD/CVD risk in Malawian adults aged ≥35 years. METHODS AND ANALYSIS We will conduct a single-centre, 36-month, prospective cohort study in 800 HIV-infected patients initiating ART and 190 HIV-uninfected controls in Blantyre, Malawi. Patients and controls will be recruited from government ART clinics and the community, respectively, and will be frequency-matched by 5-year age band and sex. At baseline and follow-up visits, we will measure carotid intima-media thickness and pulse wave velocity as surrogate markers of vasculopathy, and will be used to estimate CBD/CVD risk. Our primary exposures of interest are cytomegalovirus and varicella zoster reactivation, changes in HIV plasma viral load, and markers of systemic inflammation and endothelial function. Multivariable regression models will be developed to assess the study's primary hypothesis. The occurrence of clinical CBD/CVD will be assessed as secondary study endpoints. ETHICS AND DISSEMINATION The University of Malawi College of Medicine and Liverpool School of Tropical Medicine research ethics committees approved this work. Our goal is to understand the pathogenesis of CBD/CVD among HIV cohorts on ART, in Sub-Saharan Africa, and provide data to inform future interventional clinical trials. This study runs between May 2017 and August 2020. Results of the main trial will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER ISRCTN42862937.
Introduction Streptococcus pneumoniae (the pneumococcus) is commonly carried as a commensal bacterium in the nasopharynx but can cause life-threatening disease. Transmission occurs by human respiratory droplets and interruption of this process provides herd immunity. A 2017 WHO Consultation on Optimisation of pneumococcal conjugate vaccines (PCV) Impact highlighted a substantial research gap in investigating why the impact of PCV vaccines in low-income countries has been lower than expected. Malawi introduced the 13-valent PCV (PCV13) into the national Expanded Programme of Immunisations in 2011, using a 3+0 (3 primary +0 booster doses) schedule. With evidence of greater impact of a 2+1 (2 primary +1 booster dose) schedule in other settings, including South Africa, Malawi's National Immunisations Technical Advisory Group is seeking evidence of adequate superiority of a 2+1 schedule to inform vaccine policy. Methods A pragmatic health centre-based evaluation comparing impact of a PCV13 schedule change from 3+0 to 2+1 in Blantyre district, Malawi. Twenty government health centres will be randomly selected, with ten implementing a 2+1 and 10 to continue with the 3+0 schedule. Health centres implementing 3+0 will serve as the direct comparator in evaluating 2+1 providing superior direct and indirect protection against pneumococcal carriage. Pneumococcal carriage surveys will evaluate carriage prevalence among children 15–24 months, randomised at household level, and schoolgoers 5–10 years of age, randomly selected from school registers. Carriage surveys will be conducted 18 and 33 months following 2+1 implementation. Analysis The primary endpoint is powered to detect an effect size of 50% reduction in vaccine serotype (VT) carriage among vaccinated children 15–24 months old, expecting a 14% and 7% VT carriage prevalence in the 3+0 and 2+1 arms, respectively. Ethics and dissemination The study has been approved by the Malawi College of Medicine Research Ethics Committee (COMREC; Ref: P05.19.2680), the University College London Research Ethics Committee (Ref: 8603.002) and the University of Liverpool Research Ethics Committee (Ref: 5439). The results from this study will be actively disseminated through manuscript publications and conference presentations. Trial registration number NCT04078997.
INTRODUCTION: Streptococcus pneumoniae (the pneumococcus) is commonly carried as a commensal bacterium in the nasopharynx but can cause life-threatening disease. Transmission occurs by human respiratory droplets and interruption of this process provides herd immunity. A 2017 WHO Consultation on Optimisation of pneumococcal conjugate vaccines (PCV) Impact highlighted a substantial research gap in investigating why the impact of PCV vaccines in low-income countries has been lower than expected. Malawi introduced the 13-valent PCV (PCV13) into the national Expanded Programme of Immunisations in 2011, using a 3+0 (3 primary +0 booster doses) schedule. With evidence of greater impact of a 2+1 (2 primary +1 booster dose) schedule in other settings, including South Africa, Malawi's National Immunisations Technical Advisory Group is seeking evidence of adequate superiority of a 2+1 schedule to inform vaccine policy. METHODS: A pragmatic health centre-based evaluation comparing impact of a PCV13 schedule change from 3+0 to 2+1 in Blantyre district, Malawi. Twenty government health centres will be randomly selected, with ten implementing a 2+1 and 10 to continue with the 3+0 schedule. Health centres implementing 3+0 will serve as the direct comparator in evaluating 2+1 providing superior direct and indirect protection against pneumococcal carriage. Pneumococcal carriage surveys will evaluate carriage prevalence among children 15–24 months, randomised at household level, and schoolgoers 5–10 years of age, randomly selected from school registers. Carriage surveys will be conducted 18 and 33 months following 2+1 implementation. ANALYSIS: The primary endpoint is powered to detect an effect size of 50% reduction in vaccine serotype (VT) carriage among vaccinated children 15–24 months old, expecting a 14% and 7% VT carriage prevalence in the 3+0 and 2+1 arms, respectively. ETHICS AND DISSEMINATION: The study has been approved by the Malawi College of Medicine Research Ethics Committee (COMREC; Ref: P05.19.2680), the University ...
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10−20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10−13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10−10) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data. ; We acknowledge The Cancer Genome Atlas (TCGA) for their contribution of lung cancer genomic data to this study (TCGA Project Number 3230). We also acknowledge support from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. This study was supported by the NIH (U19CA148127, R01CA055769, 5R01CA127219, 5R01CA133996 and 5R01CA121197). The work performed at ICR was supported by Cancer Research UK (C1298/A8780 and C1298/A8362), National Cancer Research Network (NCRN), HEAL, Sanofi-Aventis and National Health Service funding to the Royal Marsden Hospital and Institute of Cancer Research, as well as the National Institute for Health Research Biomedical Research Centre. B.K. was the recipient of a Sir John Fisher Foundation PhD studentship. Work at ICR was also supported by NIH GM103534 and the Institute for Quantitative Biomedical Sciences at Dartmouth to C.I.A. The work performed in Toronto was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The work performed at Heidelberg was supported by Deutsche Krebshilfe (70-2387 and 70-2919) and the German Federal Ministry of Education and Research (EPIC-Heidelberg). The work performed at IARC was supported by the Institut National du Cancer, France, the European Community (LSHG-CT-2005-512113), the Norwegian Cancer Association, the Functional Genomics Programme of Research Council of Norway, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), the NIH (R01-CA111703 and UO1-CA63673), the Fred Hutchinson Cancer Research Center, the US NCI (R01 CA092039), an FP7 grant (REGPOT 245536), the Estonian Government (SF0180142s08), the EU European Regional Development Fund in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure's Roadmap and the University of Tartu (SP1GVARENG) and an IARC Postdoctoral Fellowship (M.N.T.). Work at the NCI was supported by the Intramural Research Program of the NIH, the NCI, US Public Health Service contracts NCI (N01-CN-45165, N01-RC-45035, N01-RC-37004, NO1-CN-25514, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476 and NO1-CN-25404), the American Cancer Society, the NIH Genes, Environment and Health Initiative in part by HG-06-033-NCI-01 and RO1HL091172-01, genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446). Work was also supported by NIH grants (P50 CA70907, R01CA121197, RO1 CA127219, U19 CA148127 and RO1 CA55769) and a Cancer Prevention Research Institute of Texas grant (RP100443). Genotyping was provided by the Center for Inherited Disease Research (CIDR). Work performed at Harvard was supported by the NIH (CA074386, CA092824 and CA090578). The Icelandic study was supported in part by NIH DA17932.
