Environmental Risk Factors for Childhood Acute Lymphoblastic Leukemia: An Umbrella Review

Leukemia is the most common type of cancer among children and adolescents worldwide. The aim of this umbrella review was (1) to provide a synthesis of the environmental risk factors for the onset of childhood acute lymphoblastic leukemia (ALL) by exposure window, (2) evaluate their strength of evidence and magnitude of risk, and as an example (3) estimate the prevalence in the German population, which determines the relevance at the population level. Relevant systematic reviews and pooled analyses were identified and retrieved through PubMed, Web of Science databases and lists of references. Only two risk factors (low doses of ionizing radiation in early childhood and general pesticide exposure during maternal preconception/pregnancy) were convincingly associated with childhood ALL. Other risk factors including extremely low frequency electromagnetic field (ELF-MF), living in proximity to nuclear facilities, petroleum, benzene, solvent, and domestic paint exposure during early childhood, all showed some level of evidence of association. Maternal consumption of coffee (high consumption/>2 cups/day) and cola (high consumption) during pregnancy, paternal smoking during the pregnancy of the index child, maternal intake of fertility treatment, high birth weight (≥4000 g) and caesarean delivery were also found to have some level of evidence of association. Maternal folic acid and vitamins intake, breastfeeding (≥6 months) and day-care attendance, were inversely associated with childhood ALL with some evidence. The results of this umbrella review should be interpreted with caution; as the evidence stems almost exclusively from case-control studies, where selection and recall bias are potential concerns, and whether the empirically observed association reflect causal relationships remains an open question. Hence, improved exposure assessment methods including accurate and reliable measurement, probing questions and better interview techniques are required to establish causative risk factors of childhood leukemia, which is needed for the ultimate goal of primary prevention.

Environmental risk factors associated with the presence of Mycobacterium ulcerans in Victoria, Australia

In recent years reported cases of Buruli ulcer (BU), caused by Mycobacterium ulcerans (MU), have increased substantially in Victoria, Australia, with the epidemic also expanding geographically. To develop an understanding of how MU circulates in the environment and transmits to humans we analyzed environmental samples collected from 115 properties of recent BU cases and from 115 postcode-matched control properties, for the presence of MU. Environmental factors associated with increased odds of MU presence at a property included certain native plant species and native vegetation in general, more alkaline soil, lower altitude, the presence of common ringtail possums (Pseudocheirus peregrinus) and overhead powerlines. However, only powerlines and the absence of the native plant Melaleuca lanceolata were associated with BU case properties. Samples positive for MU were more likely to be found at case properties and were associated with detections of MU in ringtail possum feces, supporting the hypothesis that MU is zoonotic, with ringtail possums the strongest reservoir host candidate. However, the disparity in environmental risk factors associated with MU positive properties versus case properties indicates a strong human behavioral component or the influence of other environmental factors in disease acquisition that requires further study.

Concepts in Multifactorial Etiology of Developmental Disorders: Gene-Gene and Gene-Environment Interactions in Holoprosencephaly

Many common developmental disorders are thought to arise from a complex set of genetic and environmental risk factors. These factors interact with each other to affect the strength and duration of key developmental signaling pathways, thereby increasing the possibility that they fail to achieve the thresholds required for normal embryonic patterning. One such disorder, holoprosencephaly (HPE), serves as a useful model system in understanding various forms of multifactorial etiology. Genomic analysis of HPE cases, epidemiology, and mechanistic studies of animal models have illuminated multiple potential ways that risk factors interact to produce adverse developmental outcomes. Among these are: 1) interactions between driver and modifier genes; 2) oligogenic inheritance, wherein each parent provides predisposing variants in one or multiple distinct loci; 3) interactions between genetic susceptibilities and environmental risk factors that may be insufficient on their own; and 4) interactions of multiple genetic variants with multiple non-genetic risk factors. These studies combine to provide concepts that illuminate HPE and are also applicable to additional disorders with complex etiology, including neural tube defects, congenital heart defects, and oro-facial clefting.

Paediatric Acquired Demyelinating Syndromes

Paediatric acquired demyelinating syndromes (ADS) are characterised by neurological deficits persisting for at least 24 hours, involving the optic nerve, spinal cord or brain with a clinical spectrum of diagnoses including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) and MOG-Ab associated disease (MOGAD). Important strides have been made in delineating MS from other ADS subtypes over the past decade, including the discovery of serum aquaporin-4 (AQP4) and Myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). Both genetic (e.g. human leukocyte antigen, HLA-DRB1*1501 allele) and environmental risk factors (e.g. low serum vitamin D levels and prior exposure to Epstein–Barr virus) may contribute to risk of MS in children. Some of these risk factors not only confer increased susceptibility to MS but may also affect the disease course. Paediatric AQP4-Ab NMOSD is a rare disease worldwide but variations in incidence/prevalence have been described among different geographic regions and ethnicities. One-third of children who present with an ADS have MOG-Ab, and approximately half of patients with MOG-Ab have a relapsing disease course. It seems there is no racial or gender predominance in MOGAD, which is in contrast to the female and non-white predominance seen in both MS and NMOSD.‎ In this review, we examine the current literature regarding the epidemiology and demographics of these different ADS entities with a particular focus on the genetic and environmental risk factors for MS in children. While insights into disease pathophysiology in paediatric ADS have led recent therapeutic advances, well designed, collaborative large scale epidemiological studies are likely to provide the critical next step to a personalised approach to these conditions.

Individual and Environmental Risk Factors for COVID- 19 Mortality in Elderly

Several studies have already explored individual and environmental risk factors for COVID-19 morality, however most study populations consisted of the overall population and mainly from China or the US. Our study focused on COVID-19 mortality in the elderly in seven European cities. Long-term exposure to air pollution was estimated through annual pollutant concentrations at the residential address averaged over the last two years of the study period between February and May 2020. We focused on the main outdoor air pollutants PM10, PM2.5, NO2 and O3. Short-term variations in air pollutants and weather parameters (e.g. temperature, UV, relative humidity) were also examined through a 20-day period before the confirmed PCR diagnostic of COVID-19. Individual risk factors such as smoking status, sex, body mass index (BMI), ischemic heart disease, diabetes, hypertension, chronic renal failure, history of cancer, COPD, and lung fibrosis, were taken into account. We found positive associations for diabetes and COVID-19 mortality (OR 2.2 CI 95% :1.1, 4.4). Using a multivariate logistic regression model adjusted for all patient characteristics and city, we fail to reject the null hypothesis of no association between COVID-19 mortality and long-term and short-term increase in PM2.5, PM10, NO2 and O3. Our study suffers from the fact that patient profiles strongly differ between high-polluted and less-polluted cities. Strong differences in COVID-19 mortalities were observed between cities, which could be due to differences in COVID-19 management and treatment, such as accessibility to reanimation and intensive units between cities. Overall, our study highlights the need to improve estimation of individual exposure to air pollution. Indeed, even with the high-efficiency modelisation systems used in our study, we were unable to estimate the effect of air pollution within each city, because variations in air pollution exposure were too small. Individual markers of air pollution exposure such as recently demonstrated with urinary black carbon or passive individual samplers, would be most suitable for future explorations. Concerning weather parameters, although previous studies concluded that increase in temperature and UV index could decrease COVID-19 morality, our data did not allow us to reject the null hypotheses.