Publications by authors named "Harry Campbell"

538 Publications

The impact of childhood malnutrition on mortality from pneumonia: a systematic review and network meta-analysis.

BMJ Glob Health 2021 Nov;6(11)

The University of Edinburgh Usher Institute, Edinburgh, UK.

Introduction: Childhood malnutrition is widespread in low-income and middle-income countries (LMICs) and increases the frequency and severity of infections such as pneumonia. We aimed to identify studies investigating pneumonia deaths in malnourished children and estimate mortality risk by malnutrition severity.

Methods: We conducted a systematic review of MEDLINE, EMBASE and Global Health databases to identify relevant studies. We used a network meta-analysis to derive ORs of death from pneumonia for moderately and severely underweight children using low weight-for-age, the most reported measure of malnutrition. We compared meta-estimates of studies conducted before and after 2000 to assess changes in mortality risk over time. We estimated the prevalence of underweight hospitalised children from hospital-based cohort studies and calculated the population attributable fraction of in-hospital pneumonia deaths from being underweight using our results.

Results: Our network meta-analysis included 33 544 underweight children from 23 studies. The estimated OR of death from pneumonia was 2.0 (95% CI 1.6 to 2.6) and 4.6 (95% CI 3.7 to 5.9) for children moderately and severely underweight, respectively. The OR of death from pneumonia for those severely underweight was 5.3 (95% CI 3.9 to 7.4) pre-2000 and remained high post-2000 at 4.1 (95% CI 3.0 to 6.0). Prevalence of underweight children hospitalised with pneumonia varied (median 40.2%, range 19.6-66.3) but was high across many LMIC settings. We estimated a median 18.3% (range 10.8-34.6) and 40.9% (range 14.7-69.9) of in-hospital pneumonia deaths were attributable to being moderately and severely underweight, respectively.

Conclusions: The risk of death from childhood pneumonia dramatically increases with malnutrition severity. This risk has remained high in recent years with an estimated over half of in-hospital pneumonia deaths attributable to child malnutrition. Prevention and treatment of all child malnutrition must be prioritised to maintain progress on reducing pneumonia deaths.
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http://dx.doi.org/10.1136/bmjgh-2021-007411DOI Listing
November 2021

Research priorities to address the global burden of chronic obstructive pulmonary disease (COPD) in the next decade.

J Glob Health 2021 9;11:15003. Epub 2021 Oct 9.

Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California, USA.

Background: The global prevalence of chronic obstructive pulmonary disease (COPD) has increased markedly in recent decades. Given the scarcity of resources available to address global health challenges and respiratory medicine being relatively under-invested in, it is important to define research priorities for COPD globally. In this paper, we aim to identify a ranked set of COPD research priorities that need to be addressed in the next 10 years to substantially reduce the global impact of COPD.

Methods: We adapted the Child Health and Nutrition Research Initiative (CHNRI) methodology to identify global COPD research priorities.

Results: 62 experts contributed 230 research ideas, which were scored by 34 researchers according to six pre-defined criteria: answerability, effectiveness, feasibility, deliverability, burden reduction, and equity. The top-ranked research priority was the need for new effective strategies to support smoking cessation. Of the top 20 overall research priorities, six were focused on feasible and cost-effective pulmonary rehabilitation delivery and access, particularly in primary/community care and low-resource settings. Three of the top 10 overall priorities called for research on improved screening and accurate diagnostic methods for COPD in low-resource primary care settings. Further ideas that drew support involved a better understanding of risk factors for COPD, development of effective training programmes for health workers and physicians in low resource settings, and evaluation of novel interventions to encourage physical activity.

Conclusions: The experts agreed that the most pressing feasible research questions to address in the next decade for COPD reduction were on prevention, diagnosis and rehabilitation of COPD, especially in low resource settings. The largest gains should be expected in low- and middle-income countries (LMIC) settings, as the large majority of COPD deaths occur in those settings. Research priorities identified by this systematic international process should inform and motivate policymakers, funders, and researchers to support and conduct research to reduce the global burden of COPD.
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http://dx.doi.org/10.7189/jogh.11.15003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542376PMC
November 2021

External validation of the RISC, RISC-Malawi, and PERCH clinical prediction rules to identify risk of death in children hospitalized with pneumonia.

J Glob Health 2021 9;11:04062. Epub 2021 Oct 9.

Centre d'Infectiologie Charles Mérieux, Antanarivo, Madagascar.

Background: Existing scores to identify children at risk of hospitalized pneumonia-related mortality lack broad external validation. Our objective was to externally validate three such risk scores.

Methods: We applied the Respiratory Index of Severity in Children (RISC) for HIV-negative children, the RISC-Malawi, and the Pneumonia Etiology Research for Child Health (PERCH) scores to hospitalized children in the Pneumonia REsearch Partnerships to Assess WHO REcommendations (PREPARE) data set. The PREPARE data set includes pooled data from 41 studies on pediatric pneumonia from across the world. We calculated test characteristics and the area under the curve (AUC) for each of these clinical prediction rules.

Results: The RISC score for HIV-negative children was applied to 3574 children 0-24 months and demonstrated poor discriminatory ability (AUC = 0.66, 95% confidence interval (CI) = 0.58-0.73) in the identification of children at risk of hospitalized pneumonia-related mortality. The RISC-Malawi score had fair discriminatory value (AUC = 0.75, 95% CI = 0.74-0.77) among 17 864 children 2-59 months. The PERCH score was applied to 732 children 1-59 months and also demonstrated poor discriminatory value (AUC = 0.55, 95% CI = 0.37-0.73).

Conclusions: In a large external application of the RISC, RISC-Malawi, and PERCH scores, a substantial number of children were misclassified for their risk of hospitalized pneumonia-related mortality. Although pneumonia risk scores have performed well among the cohorts in which they were derived, their performance diminished when externally applied. A generalizable risk assessment tool with higher sensitivity and specificity to identify children at risk of hospitalized pneumonia-related mortality may be needed. Such a generalizable risk assessment tool would need context-specific validation prior to implementation in that setting.
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http://dx.doi.org/10.7189/jogh.11.04062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542381PMC
November 2021

Are changes in practice a cause of the rising burden of bronchiolitis for paediatric intensive care units?

Lancet Respir Med 2021 Oct;9(10):1094-1096

Paediatric Intensive Care Unit, Emma Children's Hospital, Amsterdam University Medical Centers, location AMC, Amsterdam 1105AZ, Netherlands. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(21)00367-2DOI Listing
October 2021

Nasopharyngeal pneumococcal carriage in South Asian infants: Results of observational cohort studies in vaccinated and unvaccinated populations.

J Glob Health 2021 4;11:04054. Epub 2021 Sep 4.

KEM Hospital Research Centre, Pune, Maharashtra, India.

Background: Nasopharyngeal pneumococcal carriage (NPC) is a prerequisite for invasive pneumococcal disease and reduced carriage of vaccine serotypes is a marker for the protection offered by the pneumococcal conjugate vaccine (PCV). The present study reports NPC during the first year of life in a vaccinated (with PCV10) cohort in Bangladesh and an unvaccinated cohort in India.

Methods: A total of 450 and 459 infants were recruited from India and Bangladesh respectively within 0-7 days after birth. Nasopharyngeal swabs were collected at baseline, 18 and 36 weeks after birth. The swabs were processed for pneumococcal culture and identification of serotypes by the Quellung test and polymerase chain reaction (PCR). An identical protocol was applied at both sites.

Results: Prevalence of NPC was 48% in the Indian and 54.8% in the Bangladeshi cohort at 18 weeks. It increased to 53% and 64.8% respectively at 36 weeks. The average prevalence of vaccine serotypes was higher in the Indian cohort (17.8% vs 9.8% for PCV-10 and 26.1% vs17.6% for PCV-13) with 6A, 6B, 19F, 23F, and 19A as the common serotypes. On the other hand, the prevalence of non-vaccine serotypes was higher (43.6% vs 27.1% for non-PCV13) in the Bangladeshi cohort with 34, 15B, 17F, and 35B as the common serotypes. Overcrowding was associated with increased risk of pneumococcal carriage. The present PCV-13 vaccine would cover 28%-30% and 47%-48% serotypes in the Bangladeshi and Indian cohorts respectively.

Conclusions: South Asian infants get colonised with pneumococci early in infancy; predominantly vaccine serotypes in PCV naïve population (India) and non-vaccine serotypes in the vaccinated population (Bangladesh). These local findings are important to inform the public health policy and the development of higher valent pneumococcal vaccines.
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http://dx.doi.org/10.7189/jogh.11.04054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442578PMC
September 2021

Hypoxaemia prevalence and its adverse clinical outcomes among children hospitalised with WHO-defined severe pneumonia in Bangladesh.

J Glob Health 2021 11;11:04053. Epub 2021 Sep 11.

The Usher Institute, Edinburgh Medical School: Molecular, Genetic and Population Health Sciences, The University of Edinburgh, Edinburgh, UK.

Background: With an estimated 1 million cases per year, pneumonia accounts for 15% of all under-five deaths globally, and hypoxaemia is one of the strongest predictors of mortality. Most of these deaths are preventable and occur in low- and middle-income countries. Bangladesh is among the six high burden countries with an estimated 4 million pneumonia episodes annually. There is a gap in updated evidence on the prevalence of hypoxaemia among children with severe pneumonia in high burden countries, including Bangladesh.

Methods: We conducted a secondary analysis of data obtained from icddr,b-Dhaka Hospital, a secondary level referral hospital located in Dhaka, Bangladesh. We included 2646 children aged 2-59 months admitted with WHO-defined severe pneumonia during 2014-17. The primary outcome of interest was hypoxaemia, defined as SpO < 90% on admission. The secondary outcome of interest was adverse clinical outcomes defined as deaths during hospital stay or referral to higher-level facilities due to clinical deterioration.

Results: On admission, the prevalence of hypoxaemia among children hospitalised with severe pneumonia was 40%. The odds of hypoxaemia were higher among females (adjusted Odds ratio AOR = 1.44; 95% confidence interval CI = 1.22-1.71) and those with a history of cough or difficulty in breathing for 0-48 hours before admission (AOR = 1.61; 95% CI = 1.28-2.02). Among all children with severe pneumonia, 6% died during the hospital stay, and 9% were referred to higher-level facilities due to clinical deterioration. Hypoxaemia was the strongest predictor of mortality (AOR = 11.08; 95% CI = 7.28-16.87) and referral (AOR = 5.94; 95% CI = 4.31-17) among other factors such as age, sex, history of fever and cough or difficulty in breathing, and severe acute malnutrition. Among those who survived, the median duration of hospital stay was 7 (IQR = 4-11) days in the hypoxaemic group and 6 (IQR = 4-9) days in the non-hypoxaemic group, and the difference was significant at  < 0.001.

Conclusions: The high burden of hypoxaemia and its clinical outcomes call for urgent attention to promote oxygen security in low resource settings like Bangladesh. The availability of pulse oximetry for rapid identification and an effective oxygen delivery system for immediate correction should be ensured for averting many preventable deaths.
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http://dx.doi.org/10.7189/jogh.11.04053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442579PMC
September 2021

Child mortality in Bangladesh - why, when, where and how? A national survey-based analysis.

J Glob Health 2021 11;11:04052. Epub 2021 Sep 11.

International Centre for Diarrhoeal Disease Research, Bangladesh.

Background: Updated information on the cause of childhood mortality is essential for developing policies and designing programmes targeting the major burden of disease. There is a paucity of evidence regarding the current estimates of the cause of death in Bangladesh, which is essential for reinvigorating the current policies and reshaping existing strategies to avert preventable deaths. This paper aims to address this critical evidence gap and report the cause, timing and place of death among children under-five years of age using a nationally representative sample.

Methods: The present study was undertaken to provide updated estimates of causes of death among children under-five years of age using data from the 2017-18 round of the Bangladesh Demographic and Health Survey (BDHS). The verbal autopsy (VA) questionnaire of the 2017-18 BDHS was adapted from the standardised WHO 2016 instruments. Specially trained physicians reviewed the responses of the VA questionnaire and assigned the cause of death based on the online-2016-version of the International Classification of Diseases (ICD-10). We included 456 deaths among children under-five years of age in our analysis. Descriptive statistics were used to present the causes, timing and places of death with uncertainty ranges (UR).

Results: Pneumonia is the major killer (19%), accounting for approximately 24 268 (UR = 21 626-26 695) under-five deaths per-year. It is followed by birth asphyxia (16%), prematurity and low-birth-weight (11%), serious infections including sepsis (8%) causing 20 882 (UR = 18 608-22 970), 14 956 (UR = 13 327-16,452), and 10 723 (UR = 9555-11,795) deaths per-year, respectively. Drowning (8%) caused 10 441 (UR = 9304-11 485) deaths and congenital anomaly (7%) resulted in d 8748 (UR = 7795-9623) deaths per-year. Around 29% of all deaths occurred on the first day, 52% within the first week, and 66% within the first month of life. Around 70% of birth asphyxia, prematurity, and low birth weight-related deaths happen on the day of birth. Approximately 43% of pneumonia-related deaths occur in age 1-11 months, and around 51% of drowning-related deaths happen in age 12-23 months.

Conclusions: Pneumonia with other serious infections, birth asphyxia, prematurity and low-birth-weight are responsible for more than half of all deaths among children under-five years of age. Strengthening the existing maternal, neonatal and child health programmes may be helpful in averting the majority of these preventable deaths. A multisectoral approach is required for the prevention of childhood deaths, especially drowning-related fatalities. Special measures need to be taken to prevent and control emerging public health challenges like birth defects and congenital anomalies.
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http://dx.doi.org/10.7189/jogh.11.04052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442576PMC
September 2021

Time-Varying Association Between Severe Respiratory Syncytial Virus Infections and Subsequent Severe Asthma and Wheeze and Influences of Age at the Infection.

J Infect Dis 2021 Sep 15. Epub 2021 Sep 15.

Centre for Global Health, Usher Institute, Edinburgh Medical School, University of Edinburgh, Scotland, UK.

Background: Early-life severe respiratory syncytial virus (RSV) infection has been associated with subsequent risk of asthma and recurrent wheeze. However, changes in the association over time and the interaction effect of the age at first RSV infection are less well understood. We aimed to assess the time-varying association between RSV and subsequent asthma and wheeze admission and explore how the association was affected by the age at RSV infection.

Methods: We retrospectively followed up a cohort of 23 365 children for a median of 6.9 years using Scottish health databases. Children who were born between 2001 and 2013 and had RSV-associated respiratory tract infection (RTI) admissions under 2 years were in the exposed group; those with unintentional accident admissions under 2 years comprised the control group. The Cox proportional-hazards model was used to report adjusted hazard ratios (HRs) of RSV admissions on subsequent asthma and wheeze admissions. We did subgroup analyses by follow-up years. We also explored how this association was affected by the age at first RSV admission.

Results: The association was strongest in the first 2 years of follow-up and decreased over time. The association persisted for 6 years in children whose first RSV-RTI admission occurred at 6-23 months of age, with an adjusted HR of 3.9 (95% confidence interval [CI], 3.1-4.9) for the first 2 years, 2.3 (95% CI, 1.6-3.2) for 2 to <4 years, and 1.9 (95% CI, 1.2-2.9) for 4 to <6 years of follow-up. In contrast, the association was only significant for the first 2 years after first RSV-RTI admissions occurring at 0-5 months.

Conclusions: We found a more persistent association for subsequent asthma and wheeze in children whose first severe RSV infection occurred at 6-23 months compared to those whose first severe RSV infection occurred at 0-6 months. This provides new evidence for further assessment of the association and RSV intervention programs.
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http://dx.doi.org/10.1093/infdis/jiab308DOI Listing
September 2021

An observational and Mendelian randomisation study on vitamin D and COVID-19 risk in UK Biobank.

Sci Rep 2021 09 14;11(1):18262. Epub 2021 Sep 14.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland, UK.

A growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55-1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55-0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42-0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66-0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.
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http://dx.doi.org/10.1038/s41598-021-97679-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440633PMC
September 2021

The association of community mobility with the time-varying reproduction number (R) of SARS-CoV-2: a modelling study across 330 local UK authorities.

Lancet Digit Health 2021 10 31;3(10):e676-e683. Epub 2021 Aug 31.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Community mobility data have been used to assess adherence to non-pharmaceutical interventions and its impact on SARS-CoV-2 transmission. We assessed the association between location-specific community mobility and the reproduction number (R) of SARS-CoV-2 across UK local authorities.

Methods: In this modelling study, we linked data on community mobility from Google with data on R from 330 UK local authorities, for the period June 1, 2020, to Feb 13, 2021. Six mobility metrics are available in the Google community mobility dataset: visits to retail and recreation places, visits to grocery and pharmacy stores, visits to transit stations, visits to parks, visits to workplaces, and length of stay in residential places. For each local authority, we modelled the weekly change in R (the R ratio) per a rescaled weekly percentage change in each location-specific mobility metric relative to a pre-pandemic baseline period (Jan 3-Feb 6, 2020), with results synthesised across local authorities using a random-effects meta-analysis.

Findings: On a weekly basis, increased visits to retail and recreation places were associated with a substantial increase in R (R ratio 1·053 [99·2% CI 1·041-1·065] per 15% weekly increase compared with baseline visits) as were increased visits to workplaces (R ratio 1·060 [1·046-1·074] per 10% increase compared with baseline visits). By comparison, increased visits to grocery and pharmacy stores were associated with a small but still statistically significant increase in R (R ratio 1·011 [1·005-1·017] per 5% weekly increase compared with baseline visits). Increased visits to parks were associated with a decreased R (R ratio 0·972 [0·965-0·980]), as were longer stays at residential areas (R ratio 0·952 [0·928-0·976]). Increased visits to transit stations were not associated with R nationally, but were associated with a substantial increase in R in cities. An increasing trend was observed for the first 6 weeks of 2021 in the effect of visits to retail and recreation places and workplaces on R.

Interpretation: Increased visits to retail and recreation places, workplaces, and transit stations in cities are important drivers of increased SARS-CoV-2 transmission; the increasing trend in the effects of these drivers in the first 6 weeks of 2021 was possibly associated with the emerging alpha (B.1.1.7) variant. These findings provide important evidence for the management of current and future mobility restrictions.

Funding: Wellcome Trust and Data-Driven Innovation initiative.
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http://dx.doi.org/10.1016/S2589-7500(21)00144-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452268PMC
October 2021

Bidirectional Mendelian randomisation analysis of the relationship between circulating vitamin D concentration and colorectal cancer risk.

Int J Cancer 2022 Jan 6;150(2):303-307. Epub 2021 Sep 6.

Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, UK.

Epidemiological evidence is consistent with a protective effect of vitamin D against colorectal cancer (CRC), but the observed strong associations are open to confounders and potential reverse causation. Previous Mendelian randomisation (MR) studies were limited by poor genetic instruments and inadequate statistical power. Moreover, whether genetically higher CRC risk can influence vitamin D level, namely the reverse causation, still remains unknown. Herein, we report the first bidirectional MR study. We employed 110 newly identified genetic variants as proxies for vitamin D to obtain unconfounded effect estimates on CRC risk in 26 397 CRC cases and 41 481 controls of European ancestry. To test for reserve causation, we estimated effects of 115 CRC-risk variants on vitamin D level among 417 580 participants from the UK Biobank. The causal association was estimated using the random-effect inverse-variance weighted (IVW) method. We found no significant causal effect of vitamin D on CRC risk [IVW estimate odds ratio: 0.97, 95% confidence interval (CI) = 0.88-1.07, P = .565]. Similarly, no significant reverse causal association was identified between genetically increased CRC risk and vitamin D levels (IVW estimate β: -0.002, 95% CI = -0.008 to 0.004, P = .543). Stratified analysis by tumour sites did not identify significant causal associations in either direction between vitamin D and colon or rectal cancer. Despite the improved statistical power of this study, we found no evidence of causal association of either direction between circulating vitamin D and CRC risk. Significant associations reported by observational studies may be primarily driven by unidentified confounders.
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http://dx.doi.org/10.1002/ijc.33779DOI Listing
January 2022

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

Using evidence, expert opinion and epidemiological model to understand pathways to survival and mortality: The Pathways to Survival (PATHS) Tool.

J Glob Health 2021 12;11:15001. Epub 2021 Jun 12.

Health Nutrition and Population, The World Bank, Washington, DC, USA.

Background: The reasons why episodes of illness can lead to fatal outcomes in affected persons in low resource settings are numerous and complex. A tool that allows policy makers to better understand those complexities could be useful to improve success of programmes that are implemented globally to reduce mortality.

Methods: We developed a "Pathways to Survival" (PATHS) tool: an epidemiological model using decision trees, available evidence and expert opinion. PATHS visualises the "architecture" of mortality in the population by following the entire population cohort over a certain period of time. It explains how initially healthy persons progress through health systems to lethal outcomes at the end of the specified time period. We developed an illustrative example based on the 136 million newborns and an estimated 907 000 deaths from newborn sepsis in the year 2008. This allowed us to develop an epidemiological model that described pathways to deaths from neonatal sepsis globally in 2010.

Results: The model described the "status quo' situation in 2010 with 907 000 deaths to allow an assessment of the potential impact and feasibility of different interventions and programmes at various level of health systems in reducing this cause of mortality. A useful model should incorporate both a 'horizontal' and a 'vertical' component. The 'horizontal' would track the progress of all neonates globally through time, ie, their first 28 days of life, and separate them into different 'pathways' every time a change in their risk of dying from neonatal infection occurs because of their specific contextual circumstances. The 'vertical' would track their position within the health systems of their countries and separate them into different categories based on the ability of health system to intervene and reduce their risk of dying. Based on those requirements, PATHS tool was developed which is based on decision trees where different "branches" of the trees are associated with varying case-fatality rates.

Conclusions: The application of the PATHS tool on the example of newborn sepsis revealed that novel diagnostic tests could save many lives, so we should continue to invest in them to improve their validity, deliverability and affordability. However, PATHS showed that investments in better diagnostics have limited impact unless they are coupled with improvements of the context. Programs for parental education improve compliance and care seeking. Promoting legislation change to empower community health workers (CHWs) to actively engage in prevention, diagnosis and care also makes a difference, as well as programs for training CHWs to use diagnostic tests and administer treatments correctly. Care-seeking behaviour can also be improved through programs of conditional cash transfers. Finally, PATHS demonstrated that improving access to primary and secondary health care for everyone is the most powerful contextual change.
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http://dx.doi.org/10.7189/jogh.11.15001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310575PMC
August 2021

Increasing burden of viral bronchiolitis in the pediatric intensive care unit; an observational study.

J Crit Care 2021 Jul 22. Epub 2021 Jul 22.

Pediatric Intensive Care Unit, Emma Children's Hospital, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands.

Purpose: Viral bronchiolitis is a major cause of pediatric intensive care unit (PICU) admission. Insight in the trends of bronchiolitis-associated PICU admissions is limited, but imperative for future PICU resource and capacity planning.

Materials And Methods: We retrospectively studied trends in PICU admissions for bronchiolitis in six European sites, including three full national registries, between 2000 and 2019 and calculated population-based estimates per 100,000 children where appropriate. Information concerning risk factors for severe disease and use of invasive mechanical ventilation was also collected when available.

Results: In total, there were 15,606 PICU admissions for bronchiolitis. We observed an increase in the annual number, rate and estimates per 100,000 children of PICU admissions for bronchiolitis at all sites over the last two decades, while the proportion of patients at high risk for severe disease remained relatively stable.

Conclusions: The international increased burden of bronchiolitis for the PICU is concerning, and warrants further international attention and investigation.
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http://dx.doi.org/10.1016/j.jcrc.2021.07.009DOI Listing
July 2021

Methodology in phenome-wide association studies: a systematic review.

J Med Genet 2021 11 16;58(11):720-728. Epub 2021 Jul 16.

School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Phenome-wide association study (PheWAS) has been increasingly used to identify novel genetic associations across a wide spectrum of phenotypes. This systematic review aims to summarise the PheWAS methodology, discuss the advantages and challenges of PheWAS, and provide potential implications for future PheWAS studies. Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica Database (EMBASE) databases were searched to identify all published PheWAS studies up until 24 April 2021. The PheWAS methodology incorporating how to perform PheWAS analysis and which software/tool could be used, were summarised based on the extracted information. A total of 1035 studies were identified and 195 eligible articles were finally included. Among them, 137 (77.0%) contained 10 000 or more study participants, 164 (92.1%) defined the phenome based on electronic medical records data, 140 (78.7%) used genetic variants as predictors, and 73 (41.0%) conducted replication analysis to validate PheWAS findings and almost all of them (94.5%) received consistent results. The methodology applied in these PheWAS studies was dissected into several critical steps, including quality control of the phenome, selecting predictors, phenotyping, statistical analysis, interpretation and visualisation of PheWAS results, and the workflow for performing a PheWAS was established with detailed instructions on each step. This study provides a comprehensive overview of PheWAS methodology to help practitioners achieve a better understanding of the PheWAS design, to detect understudied or overstudied outcomes, and to direct their research by applying the most appropriate software and online tools for their study data structure.
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http://dx.doi.org/10.1136/jmedgenet-2021-107696DOI Listing
November 2021

Global hospital admissions and in-hospital mortality associated with all-cause and virus-specific acute lower respiratory infections in children and adolescents aged 5-19 years between 1995 and 2019: a systematic review and modelling study.

BMJ Glob Health 2021 07;6(7)

Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, Edinburgh, UK

Introduction: The burden of acute lower respiratory infections (ALRI), and common viral ALRI aetiologies among 5-19 years are less well understood. We conducted a systematic review to estimate global burden of all-cause and virus-specific ALRI in 5-19 years.

Methods: We searched eight databases and Google for studies published between 1995 and 2019 and reporting data on burden of all-cause ALRI or ALRI associated with influenza virus, respiratory syncytial virus, human metapneumovirus and human parainfluenza virus. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We developed an analytical framework to report burden by age, country and region when there were sufficient data (all-cause and influenza-associated ALRI hospital admissions). We estimated all-cause ALRI in-hospital deaths and hospital admissions for ALRI associated with respiratory syncytial virus, human metapneumovirus and human parainfluenza virus by region.

Results: Globally, an estimated 5.5 million (UR 4.0-7.8) all-cause ALRI hospital admissions occurred annually between 1995 and 2019 in 5-19 year olds, causing 87 900 (UR 40 300-180 600) in-hospital deaths annually. Influenza virus and respiratory syncytial virus were associated with 1 078 600 (UR 4 56 500-2 650 200) and 231 800 (UR 142 700-3 73 200) ALRI hospital admissions in 5-19 years. Human metapneumovirus and human parainfluenza virus were associated with 105 500 (UR 57 200-181 700) and 124 800 (UR 67 300-228 500) ALRI hospital admissions in 5-14 years. About 55% of all-cause ALRI hospital admissions and 63% of influenza-associated ALRI hospital admissions occurred in those 5-9 years globally. All-cause and influenza-associated ALRI hospital admission rates were highest in upper-middle income countries, Asia-Pacific region and the Latin America and Caribbean region.

Conclusion: Incidence and mortality data for all-cause and virus-specific ALRI in 5-19 year olds are scarce. The lack of data in low-income countries and Eastern Europe and Central Asia, South Asia, and West and Central Africa warrants efforts to improve the development and access to healthcare services, diagnostic capacity, and data reporting.
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http://dx.doi.org/10.1136/bmjgh-2021-006014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281096PMC
July 2021

Managing pneumonia through facility-based integrated management of childhood management (IMCI) services: an analysis of the service availability and readiness among public health facilities in Bangladesh.

BMC Health Serv Res 2021 Jul 7;21(1):667. Epub 2021 Jul 7.

University of Edinburgh, Edinburgh, UK.

Background: With an estimated 24,000 deaths per year, pneumonia is the single largest cause of death among young children in Bangladesh, accounting for 18% of all under-5 deaths. The Government of Bangladesh adopted the WHO recommended Integrated Management of Childhood Illness (IMCI)-strategy in 1998 for outpatient management of pneumonia, which was scaled-up nationally by 2014. This paper reports the service availability and readiness related to IMCI-based pneumonia management in Bangladesh. We conducted a secondary analysis of the Bangladesh Health Facility Survey-2017, which was conducted with a nationally representative sample including all administrative divisions and types of health facilities. We limited our analysis to District Hospitals (DHs), Maternal and Child Welfare Centres (MCWCs), Upazila (sub-district) Health Complexes (UHCs), and Union Health and Family Welfare Centres (UH&FWCs), which are mandated to provide IMCI services. Readiness was reported based on 10 items identified by national experts as 'essential' for pneumonia management.

Results: More than 90% of DHs and UHCs, and three-fourths of UH&FWCs and MCWCs provide IMCI-based pneumonia management services. Less than two-third of the staff had ever received IMCI-based pneumonia training. Only one-third of the facilities had a functional ARI timer or a watch able to record seconds on the day of the visit. Pulse oximetry was available in 27% of the district hospitals, 18% of the UHCs and none of the UH&FWCs. Although more than 80% of the facilities had amoxicillin syrup or dispersible tablets, only 16% had injectable gentamicin. IMCI service registers were not available in nearly one-third of the facilities and monthly reporting forms were not available in around 10% of the facilities. Only 18% of facilities had a high-readiness (score 8-10), whereas 20% had a low-readiness (score 0-4). The readiness was significantly poorer among rural and lower level facilities (p < 0.001). Seventy-two percent of the UHCs had availability of one of any of the four oxygen sources (oxygen concentrators, filled oxygen cylinder with flowmeter, filled oxygen cylinder without flowmeter, and oxygen distribution system) followed by DHs (66%) and MCWCs (59%).

Conclusion: There are substantial gaps in the readiness related to IMCI-based pneumonia management in public health facilities in Bangladesh. Since pneumonia remains a major cause of child death nationally, Bangladesh should make a substantial effort in programme planning, implementation and monitoring to address these critical gaps to ensure better provision of essential care for children suffering from pneumonia.
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http://dx.doi.org/10.1186/s12913-021-06659-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260350PMC
July 2021

Global burden of acute lower respiratory infection associated with human parainfluenza virus in children younger than 5 years for 2018: a systematic review and meta-analysis.

Lancet Glob Health 2021 08 21;9(8):e1077-e1087. Epub 2021 Jun 21.

Vienna Vaccine Safety Initiative, Berlin, Germany; Université Bourgogne-Franche Comté, Besançon, France.

Background: Human parainfluenza virus (hPIV) is a common virus in childhood acute lower respiratory infections (ALRI). However, no estimates have been made to quantify the global burden of hPIV in childhood ALRI. We aimed to estimate the global and regional hPIV-associated and hPIV-attributable ALRI incidence, hospital admissions, and mortality for children younger than 5 years and stratified by 0-5 months, 6-11 months, and 12-59 months of age.

Methods: We did a systematic review of hPIV-associated ALRI burden studies published between Jan 1, 1995, and Dec 31, 2020, found in MEDLINE, Embase, Global Health, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Global Health Library, three Chinese databases, and Google search, and also identified a further 41 high-quality unpublished studies through an international research network. We included studies reporting community incidence of ALRI with laboratory-confirmed hPIV; hospital admission rates of ALRI or ALRI with hypoxaemia in children with laboratory-confirmed hPIV; proportions of patients with ALRI admitted to hospital with laboratory-confirmed hPIV; or in-hospital case-fatality ratios (hCFRs) of ALRI with laboratory-confirmed hPIV. We used a modified Newcastle-Ottawa Scale to assess risk of bias. We analysed incidence, hospital admission rates, and hCFRs of hPIV-associated ALRI using a generalised linear mixed model. Adjustment was made to account for the non-detection of hPIV-4. We estimated hPIV-associated ALRI cases, hospital admissions, and in-hospital deaths using adjusted incidence, hospital admission rates, and hCFRs. We estimated the overall hPIV-associated ALRI mortality (both in-hospital and out-hospital mortality) on the basis of the number of in-hospital deaths and care-seeking for child pneumonia. We estimated hPIV-attributable ALRI burden by accounting for attributable fractions for hPIV in laboratory-confirmed hPIV cases and deaths. Sensitivity analyses were done to validate the estimates of overall hPIV-associated ALRI mortality and hPIV-attributable ALRI mortality. The systematic review protocol was registered on PROSPERO (CRD42019148570).

Findings: 203 studies were identified, including 162 hPIV-associated ALRI burden studies and a further 41 high-quality unpublished studies. Globally in 2018, an estimated 18·8 million (uncertainty range 12·8-28·9) ALRI cases, 725 000 (433 000-1 260 000) ALRI hospital admissions, and 34 400 (16 400-73 800) ALRI deaths were attributable to hPIVs among children younger than 5 years. The age-stratified and region-stratified analyses suggested that about 61% (35% for infants aged 0-5 months and 26% for 6-11 months) of the hospital admissions and 66% (42% for infants aged 0-5 months and 24% for 6-11 months) of the in-hospital deaths were in infants, and 70% of the in-hospital deaths were in low-income and lower-middle-income countries. Between 73% and 100% (varying by outcome) of the data had a low risk in study design; the proportion was 46-65% for the adjustment for health-care use, 59-77% for patient groups excluded, 54-93% for case definition, 42-93% for sampling strategy, and 67-77% for test methods. Heterogeneity in estimates was found between studies for each outcome.

Interpretation: We report the first global burden estimates of hPIV-associated and hPIV-attributable ALRI in young children. Globally, approximately 13% of ALRI cases, 4-14% of ALRI hospital admissions, and 4% of childhood ALRI mortality were attributable to hPIV. These numbers indicate a potentially notable burden of hPIV in ALRI morbidity and mortality in young children. These estimates should encourage and inform investment to accelerate the development of targeted interventions.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(21)00218-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298256PMC
August 2021

Contribution of common risk variants to multiple sclerosis in Orkney and Shetland.

Eur J Hum Genet 2021 Nov 4;29(11):1701-1709. Epub 2021 Jun 4.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.

Orkney and Shetland, the population isolates that make up the Northern Isles of Scotland, are of particular interest to multiple sclerosis (MS) research. While MS prevalence is high in Scotland, Orkney has the highest global prevalence, higher than more northerly Shetland. Many hypotheses for the excess of MS cases in Orkney have been investigated, including vitamin D deficiency and homozygosity: neither was found to cause the high prevalence of MS. It is possible that this excess prevalence may be explained through unique genetics. We used polygenic risk scores (PRS) to look at the contribution of common risk variants to MS. Analyses were conducted using ORCADES (97/2118 cases/controls), VIKING (15/2000 cases/controls) and Generation Scotland (30/8708 cases/controls) data sets. However, no evidence of a difference in MS-associated common variant frequencies was found between the three control populations, aside from HLA-DRB1*15:01 tag SNP rs9271069. This SNP had a significantly higher risk allele frequency in Orkney (0.23, p value = 8 × 10) and Shetland (0.21, p value = 2.3 × 10) than mainland Scotland (0.17). This difference in frequency is estimated to account for 6 (95% CI 3, 8) out of 150 observed excess cases per 100,000 individuals in Shetland and 9 (95% CI 8, 11) of the observed 257 excess cases per 100,000 individuals in Orkney, compared with mainland Scotland. Common variants therefore appear to account for little of the excess burden of MS in the Northern Isles of Scotland.
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http://dx.doi.org/10.1038/s41431-021-00914-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560837PMC
November 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Trends in infant mortality and stillbirth rates in Scotland by socio-economic position, 2000-2018: a longitudinal ecological study.

BMC Public Health 2021 05 27;21(1):995. Epub 2021 May 27.

The Usher Institute, The University of Edinburgh, Edinburgh, UK.

Background: As Scotland strives to become a country where children flourish in their early years, it is faced with the challenge of socio-economic health inequalities, which are at risk of widening amidst austerity policies. The aim of this study was to explore trends in infant mortality rates (IMR) and stillbirth rates by socio-economic position (SEP) in Scotland, between 2000 and 2018, inclusive.

Methods: Data for live births, infant deaths, and stillbirths between 2000 and 2018 were obtained from National Records of Scotland. Annual IMR and stillbirth rates were calculated and visualised for all of Scotland and when stratified by SEP. Negative binomial regression models were used to estimate the association between SEP and infant mortality and stillbirth events, and to assess for break points in trends over time. The slope (SII) and relative (RII) index of inequality compared absolute and relative socio-economic inequalities in IMR and stillbirth rates before and after 2010.

Results: IMR fell from 5.7 to 3.2 deaths per 1000 live births between 2000 and 2018, with no change in trend identified. Stillbirth rates were relatively static between 2000 and 2008 but experienced accelerated reduction from 2009 onwards. When stratified by SEP, inequalities in IMR and stillbirth rates persisted throughout the study and were greatest amongst the sub-group of post-neonates. Although comparison of the SII and RII in IMR and stillbirths before and after 2010 suggested that inequalities remained stable, descriptive trends in mortality rates displayed a 3-year rise in the most deprived quintiles from 2016 onwards.

Conclusion: Whilst Scotland has experienced downward trends in IMR and stillbirth rates between 2000 and 2018, the persistence of socio-economic inequalities and suggestion that mortality rates amongst the most deprived groups may be worsening warrants further action to improve maternal health and strengthen support for families with young children.
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http://dx.doi.org/10.1186/s12889-021-10928-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155799PMC
May 2021

Current COVID-19 treatments: Rapid review of the literature.

J Glob Health 2021 Apr 24;11:10003. Epub 2021 Apr 24.

Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK.

Background: As SARS-CoV-2 continues to spread worldwide, it has already resulted in over 110 million cases and 2.5 million deaths. Currently, there are no effective COVID-19 treatments, although numerous studies are under way. SARS-CoV-2, however, is not the first coronavirus to cause serious outbreaks. COVID-19 can be compared with previous human coronavirus diseases, such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), to better understand the development of treatments.

Methods: Databases Medline, Embase and WHO COVID-19 was systematically searched on 9 February 2021 for studies reporting on therapeutic effect of COVID-19 treatments. Clinical trials, case reports, observational studies and systematic reviews in the English language were eligible.

Results: 1416 studies were identified and 40 studies were included in this review. Therapies included are: remdesivir, convalescent plasma, hydroxychloroquine, lopinavir/ ritonavir, interferon, corticosteroids, cytokine storm inhibitors and monoclonal antibodies. Remdesivir, convalescent plasma and interferon seems to provide some clinical benefits such as faster recovery time and reduced mortality, but these effects are not clinically significant. Some corticosteroids are effective in reducing mortality in severe COVID-19 patients. Hydroxychloroquine do not convey any beneficial, and therapies such as cytokine storm inhibitors and monoclonal antibodies were also not effective and require further investigation.

Conclusions: There is no single therapy effective against COVID-19. However, a combination of therapies administered at different stages of infection may provide some benefit. This conclusion is reflected in the limited effects of these treatments in previous human coronaviruses.
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http://dx.doi.org/10.7189/jogh.11.10003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068411PMC
April 2021

Differential genetic influences over colorectal cancer risk and gene expression in large bowel mucosa.

Int J Cancer 2021 09 2;149(5):1100-1108. Epub 2021 Jun 2.

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Site-specific variation in colorectal cancer (CRC) incidence, biology and prognosis are poorly understood. We sought to determine whether common genetic variants influencing CRC risk might exhibit topographical differences on CRC risk through regional differences in effects on gene expression in the large bowel mucosa. We conducted a site-specific genetic association study (10 630 cases, 31 331 controls) to identify whether established risk variants exert differential effects on risk of proximal, compared to distal CRC. We collected normal colorectal mucosa and blood from 481 subjects and assessed mucosal gene expression using Illumina HumanHT-12v4 arrays in relation to germline genotype. Expression quantitative trait loci (eQTLs) were explored by anatomical location of sampling. The rs3087967 genotype (chr11q23.1 risk variant) exhibited significant site-specific effects-risk of distal CRC (odds ratio [OR] = 1.20, P = 8.20 × 10 ) with negligible effects on proximal CRC risk (OR = 1.05, P = .10). Expression of 1261 genes differed between proximal and distal colonic mucosa (top hit PRAC gene, fold-difference = 10, P = 3.48 × 10 ). In eQTL studies, rs3087967 genotype was associated with expression of 8 cis- and 21 trans-genes. Four of these (AKAP14, ADH5P4, ASGR2, RP11-342M1.7) showed differential effects by site, with strongest trans-eQTL signals in proximal colonic mucosa (eg, AKAP14, beta = 0.61, P = 5.02 × 10 ) and opposite signals in distal mucosa (AKAP14, beta = -0.17, P = .04). In summary, genetic variation at the chr11q23.1 risk locus imparts greater risk of distal rather than proximal CRC and exhibits site-specific differences in eQTL effects in normal mucosa. Topographical differences in genomic control over gene expression relevant to CRC risk may underlie site-specific variation in CRC. Results may inform individualised CRC screening programmes.
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http://dx.doi.org/10.1002/ijc.33616DOI Listing
September 2021

RSV genomic diversity and the development of a globally effective RSV intervention.

Vaccine 2021 05 22;39(21):2811-2820. Epub 2021 Apr 22.

Fogarty International Center, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Respiratory syncytial virus (RSV) is the most common cause of serious lower respiratory tract illness in infants and children and causes significant disease in the elderly and immunocompromised. Recently there has been an acceleration in the development of candidate RSV vaccines, monoclonal antibodies and therapeutics. However, the effects of RSV genomic variability on the implementation of vaccines and therapeutics remain poorly understood. To address this knowledge gap, the National Institute of Allergy and Infectious Diseases and the Fogarty International Center held a workshop to summarize what is known about the global burden and transmission of RSV disease, the phylogeographic dynamics and genomics of the virus, and the networks that exist to improve the understanding of RSV disease. Discussion at the workshop focused on the implications of viral evolution and genomic variability for vaccine and therapeutics development in the context of various immunization strategies. This paper summarizes the meeting, highlights research gaps and future priorities, and outlines what has been achieved since the meeting took place. It concludes with an examination of what the RSV community can learn from our understanding of SARS-CoV-2 genomics and what insights over sixty years of RSV research can offer the rapidly evolving field of COVID-19 vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2021.03.096DOI Listing
May 2021

Recommendations for respiratory syncytial virus surveillance at the national level.

Eur Respir J 2021 09 1;58(3). Epub 2021 Oct 1.

Statens Serum Institut, Copenhagen, Denmark.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infections and hospitalisations among young children and is globally responsible for many deaths in young children, especially in infants aged <6 months. Furthermore, RSV is a common cause of severe respiratory disease and hospitalisation among older adults. The development of new candidate vaccines and monoclonal antibodies highlights the need for reliable surveillance of RSV. In the European Union (EU), no up-to-date general recommendations on RSV surveillance are currently available. Based on outcomes of a workshop with 29 European experts in the field of RSV virology, epidemiology and public health, we provide recommendations for developing a feasible and sustainable national surveillance strategy for RSV that will enable harmonisation and data comparison at the European level. We discuss three surveillance components: active sentinel community surveillance, active sentinel hospital surveillance and passive laboratory surveillance, using the EU acute respiratory infection and World Health Organization (WHO) extended severe acute respiratory infection case definitions. Furthermore, we recommend the use of quantitative reverse transcriptase PCR-based assays as the standard detection method for RSV and virus genetic characterisation, if possible, to monitor genetic evolution. These guidelines provide a basis for good quality, feasible and affordable surveillance of RSV. Harmonisation of surveillance standards at the European and global level will contribute to the wider availability of national level RSV surveillance data for regional and global analysis, and for estimation of RSV burden and the impact of future immunisation programmes.
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http://dx.doi.org/10.1183/13993003.03766-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485062PMC
September 2021

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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http://dx.doi.org/10.1101/2021.04.01.21254789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043484PMC
April 2021

Antibiotic use for inpatient newborn care with suspected infection: EN-BIRTH multi-country validation study.

BMC Pregnancy Childbirth 2021 Mar 26;21(Suppl 1):229. Epub 2021 Mar 26.

Maternal, Adolescent, Reproductive & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK.

Background: An estimated 30 million neonates require inpatient care annually, many with life-threatening infections. Appropriate antibiotic management is crucial, yet there is no routine measurement of coverage. The Every Newborn Birth Indicators Research Tracking in Hospitals (EN-BIRTH) study aimed to validate maternal and newborn indicators to inform measurement of coverage and quality of care. This paper reports validation of reported antibiotic coverage by exit survey of mothers for hospitalized newborns with clinically-defined infections, including sepsis, meningitis, and pneumonia.

Methods: EN-BIRTH study was conducted in five hospitals in Bangladesh, Nepal, and Tanzania (July 2017-July 2018). Neonates were included based on case definitions to focus on term/near-term, clinically-defined infection syndromes (sepsis, meningitis, and pneumonia), excluding major congenital abnormalities. Clinical management was abstracted from hospital inpatient case notes (verification) which was considered as the gold standard against which to validate accuracy of women's report. Exit surveys were conducted using questions similar to The Demographic and Health Surveys (DHS) approach for coverage of childhood pneumonia treatment. We compared survey-report to case note verified, pooled across the five sites using random effects meta-analysis.

Results: A total of 1015 inpatient neonates admitted in the five hospitals met inclusion criteria with clinically-defined infection syndromes. According to case note verification, 96.7% received an injectable antibiotic, although only 14.5% of them received the recommended course of at least 7 days. Among women surveyed (n = 910), 98.8% (95% CI: 97.8-99.5%) correctly reported their baby was admitted to a neonatal ward. Only 47.1% (30.1-64.5%) reported their baby's diagnosis in terms of sepsis, meningitis, or pneumonia. Around three-quarters of women reported their baby received an injection whilst in hospital, but 12.3% reported the correct antibiotic name. Only 10.6% of the babies had a blood culture and less than 1% had a lumbar puncture.

Conclusions: Women's report during exit survey consistently underestimated the denominator (reporting the baby had an infection), and even more so the numerator (reporting known injectable antibiotics). Admission to the neonatal ward was accurately reported and may have potential as a contact point indicator for use in household surveys, similar to institutional births. Strengthening capacity and use of laboratory diagnostics including blood culture are essential to promote appropriate use of antibiotics. To track quality of neonatal infection management, we recommend using inpatient records to measure specifics, requiring more research on standardised inpatient records.
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http://dx.doi.org/10.1186/s12884-020-03424-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995687PMC
March 2021

The temporal association of introducing and lifting non-pharmaceutical interventions with the time-varying reproduction number (R) of SARS-CoV-2: a modelling study across 131 countries.

Lancet Infect Dis 2021 02 22;21(2):193-202. Epub 2020 Oct 22.

Usher Institute, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Non-pharmaceutical interventions (NPIs) were implemented by many countries to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19. A resurgence in COVID-19 cases has been reported in some countries that lifted some of these NPIs. We aimed to understand the association of introducing and lifting NPIs with the level of transmission of SARS-CoV-2, as measured by the time-varying reproduction number (R), from a broad perspective across 131 countries.

Methods: In this modelling study, we linked data on daily country-level estimates of R from the London School of Hygiene & Tropical Medicine (London, UK) with data on country-specific policies on NPIs from the Oxford COVID-19 Government Response Tracker, available between Jan 1 and July 20, 2020. We defined a phase as a time period when all NPIs remained the same, and we divided the timeline of each country into individual phases based on the status of NPIs. We calculated the R ratio as the ratio between the daily R of each phase and the R from the last day of the previous phase (ie, before the NPI status changed) as a measure of the association between NPI status and transmission of SARS-CoV-2. We then modelled the R ratio using a log-linear regression with introduction and relaxation of each NPI as independent variables for each day of the first 28 days after the change in the corresponding NPI. In an ad-hoc analysis, we estimated the effect of reintroducing multiple NPIs with the greatest effects, and in the observed sequence, to tackle the possible resurgence of SARS-CoV-2.

Findings: 790 phases from 131 countries were included in the analysis. A decreasing trend over time in the R ratio was found following the introduction of school closure, workplace closure, public events ban, requirements to stay at home, and internal movement limits; the reduction in R ranged from 3% to 24% on day 28 following the introduction compared with the last day before introduction, although the reduction was significant only for public events ban (R ratio 0·76, 95% CI 0·58-1·00); for all other NPIs, the upper bound of the 95% CI was above 1. An increasing trend over time in the R ratio was found following the relaxation of school closure, bans on public events, bans on public gatherings of more than ten people, requirements to stay at home, and internal movement limits; the increase in R ranged from 11% to 25% on day 28 following the relaxation compared with the last day before relaxation, although the increase was significant only for school reopening (R ratio 1·24, 95% CI 1·00-1·52) and lifting bans on public gatherings of more than ten people (1·25, 1·03-1·51); for all other NPIs, the lower bound of the 95% CI was below 1. It took a median of 8 days (IQR 6-9) following the introduction of an NPI to observe 60% of the maximum reduction in R and even longer (17 days [14-20]) following relaxation to observe 60% of the maximum increase in R. In response to a possible resurgence of COVID-19, a control strategy of banning public events and public gatherings of more than ten people was estimated to reduce R, with an R ratio of 0·71 (95% CI 0·55-0·93) on day 28, decreasing to 0·62 (0·47-0·82) on day 28 if measures to close workplaces were added, 0·58 (0·41-0·81) if measures to close workplaces and internal movement restrictions were added, and 0·48 (0·32-0·71) if measures to close workplaces, internal movement restrictions, and requirements to stay at home were added.

Interpretation: Individual NPIs, including school closure, workplace closure, public events ban, ban on gatherings of more than ten people, requirements to stay at home, and internal movement limits, are associated with reduced transmission of SARS-CoV-2, but the effect of introducing and lifting these NPIs is delayed by 1-3 weeks, with this delay being longer when lifting NPIs. These findings provide additional evidence that can inform policy-maker decisions on the timing of introducing and lifting different NPIs, although R should be interpreted in the context of its known limitations.

Funding: Wellcome Trust Institutional Strategic Support Fund and Data-Driven Innovation initiative.
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http://dx.doi.org/10.1016/S1473-3099(20)30785-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581351PMC
February 2021
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