Associations of residential greenspace exposure and fetal growth across four areas in Spain

An accumulating body of evidence has associated exposure to greenspace with improved birth outcomes, including higher birth weight and lower risk of low birth weight; however, evidence on such association with in-utero fetal growth is scarce. We explored the influence of maternal exposure to residential greenspace and fetal growth in four INMA (Infancia y Medio Ambiente) Spanish birth cohorts (2003–2008), with 2,465 participants. Residential greenspace was characterised by the Normalised Difference Vegetation Index (NDVI) average across 100 m, 300 m, and 500 m buffers around the residence. Repeated ultrasound measurements of the abdominal circumference (AC), biparietal diameter (BPD), femur length (FL), and estimated fetal weight (EFW) were used. We created customised-generalised least squares models to evaluate associations of residential greenspace exposure on each fetal growth parameter, controlled for the relevant confounders. There were associations between the 500 m buffer and BPD, FL, and AC. We also found associations in the 300 m buffer and FL and AC. The associations in the 100 m buffer were null. Estimates were higher among participants with lower socioeconomic status. Mediation analyses found that air pollution might explain 15–37% of our associations. Mediation by physical activity was not observed. Greenspace exposure may be beneficial for fetal growth.     

Future directions in managing aniridia-associated keratopathy

Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive loss of corneal transparency and thereby loss of vision. Currently, there is no approved therapy to delay or prevent its progression, and clinical management is challenging because of phenotypic variability and high risk of complications after interventions; however, new insights into the molecular pathogenesis of AAK may help improve its management. Here, we review the current understanding about the pathogenesis and management of AAK. We highlight the biological mechanisms involved in AAK development with the aim to develop future treatment options, including surgical, pharmacological, cell therapies, and gene therapies.     

Derivation of occupational exposure limits: Differences in methods and protection levels

Frameworks for deriving occupational exposure limits (OELs) and OEL-analogue values (such as derived-no-effect levels [DNELs]) in various regulatory areas in the EU and at national level in Germany were analysed. Reasons for differences between frameworks and possible means of improving transparency and harmonisation were identified. Differences between assessment factors used for deriving exposure limits proved to be one important reason for diverging numerical values. Distributions for exposure time, interspecies and intraspecies extrapolation were combined by probabilistic methods and compared with default values of assessment factors used in the various OEL frameworks in order to investigate protection levels. In a subchronic inhalation study showing local effects in the respiratory tract, the probability that assessment factors were sufficiently high to protect 99% and 95% of the target population (workers) from adverse effects varied considerably from 9% to 71% and 17% to 87%, respectively, between the frameworks. All steps of the derivation process, including the uncertainty associated with the point of departure (POD), were further analysed with two examples of full probabilistic assessments. It is proposed that benchmark modelling should be the method of choice for deriving PODs and that all OEL frameworks should provide detailed guidance documents and clearly define their protection goals by stating the proportion of the exposed population the OEL aims to cover and the probability with which they intend to provide protection from adverse effects. Harmonisation can be achieved by agreeing on the way to perform the methodological steps for deriving OELs and on common protection goals.     

Clinical Benefit-Risk Profile of Lenalidomide in Patients With Lower-risk Myelodysplastic Syndromes Without del(5q): Results of a Phase III Trial

BackgroundIn the phase III MDS-005 study of patients with lower-risk, non-del(5q) myelodysplastic syndromes, lenalidomide was associated with a higher rate of ≥ 8 weeks red blood cell transfusion independence (RBC-TI) compared with placebo, but also with a higher risk of hematologic adverse events (AEs).Patients and MethodsThis analysis evaluated the ratio of clinical benefit-risk in patients treated with lenalidomide or placebo, and assessed the effect of lenalidomide dose reductions on response. Clinical benefit was a composite endpoint defined as RBC-TI, transfusion reduction ≥ 4 units packed red blood cells, hemoglobin increase ≥ 1.5 g/dL, or cytogenetic response.ResultsThe rate of clinical benefit was higher with lenalidomide than with placebo (31.9% vs. 3.8%). The ratio of response (RBC-TI and clinical benefit) to risk (hematologic AEs) favored lenalidomide over placebo. Patients who underwent ≥ 1 lenalidomide dose reduction had a longer duration of treatment, received a higher cumulative dose, and were more likely to experience clinical benefit versus patients without dose reductions.ConclusionDespite the occurrence of hematologic AEs, the overall benefit-risk profile supported lenalidomide treatment. Appropriate management of hematologic AEs by dose reductions may help patients with myelodysplastic syndromes to remain on treatment and achieve clinical benefit.     

Prenatal exposure to perfluoroalkyl substances,immune-related outcomes,and lung function in children from a Spanish birth cohort study

BackgroundPrenatal exposure to perfluoroalkyl substances (PFASs) has been associated with impaired immune and respiratory health during childhood but the evidence is inconsistent and limited for lung function. We studied the association between prenatal PFASs exposure and immune and respiratory health, including lung function, up to age 7 years in the Spanish INMA birth cohort study.MethodsWe assessed four PFASs in maternal plasma samples collected during the 1st trimester of pregnancy (years: 2003–2008): perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorononanoate (PFNA). Mothers reported the occurrence (yes/no) of lower respiratory tract infections, wheezing, asthma, and eczema in the previous 12 months at 1.5 and 4 years of the child (n = 1188) and at 7 years (n = 1071). At ages 4 (n = 503) and 7 (n = 992) years lung function was assessed using spirometry tests.ResultsThe most abundant PFASs were PFOS and PFOA (geometric means: 5.80 and 2.31 ng/mL, respectively). The relative risk of asthma during childhood per each doubling in PFNA concentration was 0.74 (95 CI%: 0.57, 0.96). The relative risk of eczema during childhood per every doubling in PFOS concentration was 0.86 (95 CI%: 0.75, 0.98). Higher PFOA concentrations were associated with lower forced vital capacity and lower forced expiratory volume in 1 s z-scores at 4 years [β (95 CI %): −0.17 (−0.34, −0.01) and −0.13 (−0.29, 0.03), respectively], but not at 7 years.ConclusionThis longitudinal study suggests that different PFASs may affect the developing immune and respiratory systems differently. Prenatal exposure to PFNA and PFOS may be associated with reduced risk of respiratory and immune outcomes, particularly asthma and eczema whereas exposure to PFOA may be associated with reduced lung function in young children. These mixed results need to be replicated in follow-up studies at later ages.     

Firefighters' and instructors’ absorption of PAHs and benzene during training exercises

IntroductionTraining fires may constitute a major portion of some firefighters’ occupational exposures to smoke. However, the magnitude and composition of those exposures are not well understood and may vary by the type of training scenario and fuels.ObjectivesTo understand how structure fire training contributes to firefighters' and instructors’ select chemical exposures, we conducted biological monitoring during exercises involving combustion of pallet and straw and oriented strand board (OSB) or the use of simulated smoke.MethodsUrine was analyzed for metabolites of polycyclic aromatic hydrocarbons (PAHs) and breath was analyzed for volatile organic compounds (VOCs) including benzene.ResultsMedian concentrations of nearly all PAH metabolites in urine increased from pre-to 3-hr post-training for each scenario and were highest for OSB, followed by pallet and straw, and then simulated smoke. For instructors who supervised three trainings per day, median concentrations increased at each collection. A single day of OSB exercises led to a 30-fold increase in 1-hydroxypyrene for instructors, culminating in a median end-of-shift concentration 3.5-fold greater than median levels measured from firefighters in a previous controlled-residential fire study. Breath concentrations of benzene increased 2 to 7-fold immediately after the training exercises (with the exception of simulated smoke training). Exposures were highest for the OSB scenario and instructors accumulated PAHs with repeated daily exercises.ConclusionsDermal absorption likely contributed to the biological levels as the respiratory route was well protected. Training academies should consider exposure risks as well as instructional objectives when selecting training exercises.     

Application of the Draft NIOSH Occupational Exposure Banding Process to Bisphenol A: A case study

Bisphenol A is a commercially important chemical used to make polycarbonate plastic, epoxy resins, and other specialty products. Despite an extensive body of in vitro, animal and human observational studies on the effects of exposure to bisphenol A, no authoritative bodies in the U.S. have adopted or recommended occupational exposure limits for bisphenol A. In 2017, the National Institute for Occupational Safety and Health published a Draft process for assigning health-protective occupational exposure bands, i.e., an airborne concentration range, to chemicals lacking an occupational exposure limit. Occupational exposure banding is a systematic process that uses both quantitative and qualitative toxicity information on selected health effect endpoints to assign an occupational exposure band for a chemical. The Draft process proposes three methodological tiers of increasing complexity for assigning an occupational exposure band. We applied Tier 1 (based on the Globally Harmonized System of Classification and Labelling) and Tier 2 (based on authoritative sources/reviews) to assign an occupational exposure band to bisphenol A. Under both Tier 1 and 2, the occupational exposure band for bisphenol A was “E” (<0.01?mg/m³), an assignment based on eye damage. “E” is the lowest exposure concentration range, reserved for chemicals with high potential toxicity. If eye damage was excluded in assigning an air concentration exposure range, then bisphenol A would band as “D” (>0.01 to 0.1?mg/m³) under Tier 1 (based on reproductive toxicity and respiratory/skin sensitization) and under Tier 2 (based on specific target organ toxicity-repeated exposure). In summary, Tiers 1 and 2 gave the same occupational exposure band for bisphenol A when eye damage was included (“E”) or excluded (“D”) as an endpoint.     

万古霉素药物暴露量阈值与肾毒性的相关性分析

目的探讨万古霉素药物暴露量与肾毒性发生的相关性,并确定其上限阈值。方法前瞻性收集2018年5月-2019年1月接受静脉注射万古霉素治疗的成人住院患者信息。使用贝叶斯最大后验概率法计算药时曲线下面积(AUC)并采用分类和回归树(CART)的方法分析和确定万古霉素初始剂量及与肾毒性相关的稳态AUC阈值。通过受试者工作特征(ROC)曲线评估上述方法所得AUC阈值的预测性能及对万古霉素相关肾毒性的诊断价值,并采用多因素logistic回归分析量化肾毒性发生风险因素。结果共纳入患者155例,其中发生肾毒性患者13例(8.39%)。经CART分析得到AUC0-24、AUC24-48、AUCss0-24对肾毒性预测的最佳阈值点分别为622 mg·h/L、617 mg·h/L、578 mg·h/L。经多因素logistic回归分析,AUC超过最佳阈值点时肾毒性发生率显著提高(P≤0.01),联合使用肾毒性药物与肾毒性发生独立相关,会提高约6倍的肾毒性发生率(P<0.01)。结论万古霉素暴露量超过阈值时会大幅提高肾毒性发生风险,提示AUC监测对预测肾毒性发生有很高的临床价值。