Summary Background The global burden of disease attributable to respiratory syncytial virus (RSV) remains unknown. We aimed to estimate the global incidence of and mortality from episodes of acute ...lower respiratory infection (ALRI) due to RSV in children younger than 5 years in 2005. Methods We estimated the incidence of RSV-associated ALRI in children younger than 5 years, stratified by age, using data from a systematic review of studies published between January, 1995, and June, 2009, and ten unpublished population-based studies. We estimated possible boundaries for RSV-associated ALRI mortality by combining case fatality ratios with incidence estimates from hospital-based reports from published and unpublished studies and identifying studies with population-based data for RSV seasonality and monthly ALRI mortality. Findings In 2005, an estimated 33·8 (95% CI 19·3–46·2) million new episodes of RSV-associated ALRI occurred worldwide in children younger than 5 years (22% of ALRI episodes), with at least 3·4 (2·8–4·3) million episodes representing severe RSV-associated ALRI necessitating hospital admission. We estimated that 66 000–199 000 children younger than 5 years died from RSV-associated ALRI in 2005, with 99% of these deaths occurring in developing countries. Incidence and mortality can vary substantially from year to year in any one setting. Interpretation Globally, RSV is the most common cause of childhood ALRI and a major cause of admission to hospital as a result of severe ALRI. Mortality data suggest that RSV is an important cause of death in childhood from ALRI, after pneumococcal pneumonia and Haemophilus influenzae type b. The development of novel prevention and treatment strategies should be accelerated as a priority. Funding WHO; Bill & Melinda Gates Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Previous estimates of the global burden of disease for children have not included much information from China, leading to a large gap in data. We identified the main causes of ...deaths in neonates (<1 month), postneonatal infants (1–11 months), and children (<5 years) in China using information that was available to the public. Methods The Child Health Epidemiology Reference Group in collaboration with colleagues from Peking University systematically searched Chinese databases that were available to the public. Information was obtained from the Chinese Ministry of Health and Bureau of Statistics websites, Chinese National Knowledge Infrastructure database, and Chinese Health Statistics yearbooks for 1990–2008. We also obtained information from 206 high-quality community-based longitudinal studies of different causes of deaths in children (<5 years) that were written in the Chinese language. A statistical model was developed to estimate the total number of deaths in children according to provinces, age groups, and main causes. Findings During 1990–2008, the mortality rates in neonates, postneonatal infants, and children were reduced by 70% (from 34·0 to 10·2 per 1000 livebirths), 72% (from 53·5 to 14·9 per 1000 livebirths), and 71% (from 64·6 to 18·5 per 1000 livebirths), respectively, meeting the targets set in the Millennium Development Goal 4. The leading causes of deaths in 2008 were pneumonia, birth asphyxia, and preterm birth complications, each accounting for 15–17% of all deaths. Congenital abnormalities and accidents increased in importance during this period, contributing to 11% and 10% of child deaths, respectively. Sudden infant death syndrome contributed to 5% of deaths in children. Interpretation Publically available Chinese databases contain much important information that has been underused in the estimation of global and regional burden of disease. On the basis of trends, preterm birth complications are expected to become the leading cause of child mortality in China, whereas deaths from congenital abnormalities, accidents, and sudden infant death syndrome are predicted to continue increasing in importance in the long term. Funding Bill & Melinda Gates Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The risks of long term sequelae from childhood pneumonia have not been systematically assessed. The aims of this study were to: (i) estimate the risks of respiratory sequelae after pneumonia in ...children under five years; (ii) estimate the distribution of the different types of respiratory sequelae; and (iii) compare sequelae risk by hospitalisation status and pathogen.
We systematically reviewed published papers from 1970 to 2011. Standard global burden of disease categories (restrictive lung disease, obstructive lung disease, bronchiectasis) were labelled as major sequelae. 'Minor' sequelae (chronic bronchitis, asthma, other abnormal pulmonary function, other respiratory disease), and multiple impairments were also included. Thirteen papers were selected for inclusion. Synthesis was by random effects meta-analysis and meta-regression.
Risk of at least one major sequelae was 5.5% (95% confidence interval 95% CI 2.8-8.3%) in non hospitalised children and 13.6% 6.2-21.1%) in hospitalised children. Adenovirus pneumonia was associated with the highest sequelae risk (54.8% 39.2-70.5%) but children hospitalised with no pathogen isolated also had high risk (17.6% 10.9-24.3%). The most common type of major sequela was restrictive lung disease (5.4% 2.5-10.2%) . Potential confounders such as loss to follow up and median age at infection were not associated with sequelae risk in the final models.
All children with pneumonia diagnosed by a health professional should be considered at risk of long term sequelae. Evaluation of childhood pneumonia interventions should include potential impact on long term respiratory sequelae.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence.
We searched PubMed and Scopus up to ...06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded.
We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer.
Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Vitamin D deficiency is highly prevalent across the globe. Existing studies suggest that a low vitamin D level is associated with more than 130 outcomes. Exploring the causal role ...of vitamin D in health outcomes could support or question vitamin D supplementation.
Methods
We carried out a systematic literature review of previous Mendelian-randomization studies on vitamin D. We then implemented a Mendelian Randomization–Phenome Wide Association Study (MR-PheWAS) analysis on data from 339 256 individuals of White British origin from UK Biobank. We first ran a PheWAS analysis to test the associations between a 25(OH)D polygenic risk score and 920 disease outcomes, and then nine phenotypes (i.e. systolic blood pressure, diastolic blood pressure, risk of hypertension, T2D, ischaemic heart disease, body mass index, depression, non-vertebral fracture and all-cause mortality) that met the pre-defined inclusion criteria for further analysis were examined by multiple MR analytical approaches to explore causality.
Results
The PheWAS analysis did not identify any health outcome associated with the 25(OH)D polygenic risk score. Although a selection of nine outcomes were reported in previous Mendelian-randomization studies or umbrella reviews to be associated with vitamin D, our MR analysis, with substantial study power (>80% power to detect an association with an odds ratio >1.2 for per standard deviation increase of log-transformed 25OHD), was unable to support an interpretation of causal association.
Conclusions
We investigated the putative causal effects of vitamin D on multiple health outcomes in a White population. We did not support a causal effect on any of the disease outcomes tested. However, we cannot exclude small causal effects or effects on outcomes that we did not have enough power to explore due to the small number of cases.
C-reactive protein (CRP) has been studied extensively for association with a large number of non-infectious diseases and outcomes. We aimed to evaluate the breadth and validity of associations ...between CRP and non-infectious, chronic health outcomes and biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses and a systematic review of Mendelian randomization (MR) studies. PubMed, Scopus, and Cochrane Database of Systematic Reviews were systematically searched from inception up to March 2019. Meta-analyses of observational studies and MR studies examining associations between CRP and health outcomes were identified, excluding studies on the diagnostic value of CRP for infections. We found 113 meta-analytic comparisons of observational studies and 196 MR analyses, covering a wide range of outcomes. The overwhelming majority of the meta-analyses of observational studies reported a nominally statistically significant result (95/113, 84.1%); however, the majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for a causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is remarkably limited.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Age-related macular degeneration (AMD) is the third most common cause of blindness, and the fourth leading cause of visual impairment worldwide, but little is known about the burden of this disease ...in the most populous country-China. This study provides the first comprehensive estimates of the prevalence and burden of AMD in China from 1990 to 2015, with projections till 2050.
In this study, a systematic review and meta-analysis was conducted to estimate the prevalence of AMD in China. China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedicine Literature Database (CBM-SinoMed), PubMed, Embase and Medline were searched before September 2016. Multilevel mixed-effect meta-regression was performed to define the prevalence rates of AMD and its subtypes. UN population data were used to estimate and project the number of people affected from 1990 to 2050. Based on different demographic and geographic features, the national burden of AMD in 2000 and 2010 was distributed to different regions in China.
Our search returned 2016 citations, of which 25 met the inclusion criteria. The prevalence of any AMD ranged from 2.44% (95% CI = 1.85-3.22) in people aged 45-49 years to 18.98% (95% CI = 15.05-23.66) in people aged 85-89 years. Prevalence of early AMD ranged from 1.79% (95% CI = 1.05-3.02) to 10.05% (95% CI = 6.17-15.97), and, in the case of late AMD, from 0.38% (95% CI = 0.16-0.97) to 3.88% (95% CI = 1.68-9.13). In late AMD, the prevalence of geographic atrophy (GA) was 0.15% (95% CI = 0.05-0.47) in people aged 45-49 years and 1.09% (95% CI = 0.35-3.36) in those aged 85-89 years, and the prevalence of neovascular AMD (NVAMD) ranged between 0.24% (95% CI = 0.11-0.50) and 2.79% (95% CI = 1.33-5.77). The number of people with any AMD was 12.01 million (95% CI = 9.29-15.46) in 1990 and 26.65 million (95% CI = 20.62-34.27) in 2015. Within the same period, the number of people with early AMD increased from 9.44 million (95% CI = 7.74-11.15) to 20.91 million (95% CI = 17.16-24.68), and those with late AMD rose from 2.58 million (95% CI = 1.56-4.30) to 5.74 million (95% CI = 3.46-9.59). In late AMD, the number of people living with GA ranged from 0.87 million (95% CI = 0.40-1.83) in 1990 to 1.93 million (95% CI = 0.89-4.08) in 2015, and NVAMD from 1.71 million (95% CI = 1.16-2.47) to 3.81 million (95% CI = 2.57-5.51). The projected number of people with any AMD in 2020 is 31.23 million (95% CI = 24.18-40.14), increasing to 55.19 million (95% CI = 43.04-70.30) in 2050. Between different regions, the South Central owed the most AMD cases (5.50 million in 2000 and 7.52 million in 2010), whereas the North-West China the least (0.66 million in 2000 and 0.95 million in 2010).
The estimates in this study suggest a substantial burden of AMD in China, with the ageing process in Chinese society, this burden will be increasing in the foreseen future. Primary and secondary prevention and treatment and effective government response are urgently needed. Improved epidemiological studies are also required to better develop eye-care strategies and health services.
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NUK, OILJ, UL, UM, UPUK, VSZLJ
Previous studies have shown that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) lower colorectal cancer (CRC) risk. However, the lowest effective NSAID dose, treatment duration, and ...effects on survival are not defined. In a large population-based case-control study, we have explored the relationship between NSAID dose and duration, CRC risk and overall CRC-specific survival.
The relationship between NSAID use and CRC risk was examined in 2279 cases and 2907 controls. Subjects completed food-frequency and lifestyle questionnaires. NSAID categories were low-dose aspirin (75 mg), non-aspirin NSAIDs (NA-NSAIDs) and any NSAID. Users were defined as taking >4 tablets/week for >1 month. ORs were calculated by logistic regression models and adjusted for potential confounding factors. Effect of NSAID use on all-cause and CRC-specific mortality was estimated using Logrank tests and Cox's hazard models.
In all, 354 cases (15.5%) were taking low-dose aspirin compared to 526 controls (18.1%). Low-dose aspirin use was associated with decreased CRC risk (OR 0.78 95% CI 0.65 to 0.92, p=0.004), evident after 1 year and increasing with duration of use (p(trend)=0.004). NA-NSAID and any NSAID use were also inversely associated with CRC. There was no demonstrable effect of NSAIDS on all-cause (HR 1.11, p=0.22, 0.94-1.33) or CRC-specific survival (HR 1.01, p=0.93, 0.83-1.23).
This is the first study to demonstrate a protective effect against CRC associated with the lowest dose of aspirin (75 mg per day) after only 5 years use in the general population. NSAID use prior to CRC diagnosis does not influence survival from the disease.
Epidemiological studies observed gender differences in COVID-19 outcomes, however, whether sex hormone plays a causal in COVID-19 risk remains unclear. This study aimed to examine associations of sex ...hormone, sex hormones-binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and COVID-19 risk.
Two-sample Mendelian randomization (TSMR) study was performed to explore the causal associations between testosterone, estrogen, SHBG, IGF-1, and the risk of COVID-19 (susceptibility, hospitalization, and severity) using genome-wide association study (GWAS) summary level data from the COVID-19 Host Genetics Initiative (N=1,348,701). Random-effects inverse variance weighted (IVW) MR approach was used as the primary MR method and the weighted median, MR-Egger, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test were conducted as sensitivity analyses.
Higher genetically predicted IGF-1 levels have nominally significant association with reduced risk of COVID-19 susceptibility and hospitalization. For one standard deviation increase in genetically predicted IGF-1 levels, the odds ratio was 0.77 (95% confidence interval CI, 0.61-0.97, p=0.027) for COVID-19 susceptibility, 0.62 (95% CI: 0.25-0.51, p=0.018) for COVID-19 hospitalization, and 0.85 (95% CI: 0.52-1.38, p=0.513) for COVID-19 severity. There was no evidence that testosterone, estrogen, and SHBG are associated with the risk of COVID-19 susceptibility, hospitalization, and severity in either overall or sex-stratified TSMR analysis.
Our study indicated that genetically predicted high IGF-1 levels were associated with decrease the risk of COVID-19 susceptibility and hospitalization, but these associations did not survive the Bonferroni correction of multiple testing. Further studies are needed to validate the findings and explore whether IGF-1 could be a potential intervention target to reduce COVID-19 risk.
We acknowledge support from NSFC (LR22H260001), CRUK (C31250/A22804), SHLF (Hjärt-Lungfonden, 20210351), VR (Vetenskapsrådet, 2019-00977), and SCI (Cancerfonden).
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