Rare Diseases: Needs and Impact for Patients and Families: A Cross-Sectional Study in the Valencian Region, Spain.

Families with rare diseases (RDs) have unmet needs that are often overlooked by health professionals. Describing these needs and the impact of the disease could improve their medical care. A total of 163 surveys were obtained from patients visiting primary care centres in the Valencian Region (Spain), during 2015-2017, with a confirmed or suspected diagnosis of RD. Of the 84.7% with a confirmed diagnosis, 50.4% had a diagnostic delay exceeding one year, and it was more prevalent among adults (62.2%). Families with paediatric patients were in a worse economic situation, with lower incomes and higher monthly disease-related expenses (€300 on average). These expenses were incurred by 66.5% of families and were mainly for medication (40.3%). Among them, 58.5% reported not being able to afford adjuvant therapies. The disease had an impact on 73.1% of families, especially on their routine and emotional state. Expenses, needs, and impacts were more frequent among families of patients with a history of hospitalisation or deterioration. Patients with delayed diagnosis had a higher consumption of drugs prior to diagnosis. People affected by RDs in the Valencian Region need therapies to improve their autonomy and emotional state. Health professionals should be aware of these needs.

Maternal factors associated with smoking during gestation and consequences in newborns: Results of an 18-year study.

BACKGROUND: Tobacco use is one of the most important causes of obstetric and perinatal pathologies. Its frequency during pregnancy is high and could be related to various socioeconomic and cultural characteristics of the mothers. AIM: The aim of this study is to determine the trend and prevalence of smoking in pregnant mothers in our area over the years and the socio-cultural or obstetric factors associated with smoking as well as the repercussions on the newborns related to its consumption. METHODS: Retrospective study of 18,959 mothers of healthy newborns in the maternity ward of the regional hospital during the years 2002-2019. The variable under study was maternal smoking during pregnancy compared with various maternal, obstetric, and perinatal factors. RESULTS: A mean percentage of 20.4% of the mothers smoked, with significantly decreasing percentages over the years. There was a significant association between smoking and mothers' age, origin, level of education, the occurrence of previous abortions, parity, type of breastfeeding at discharge, type of delivery, low birth weight, and need for neonatal resuscitation. CONCLUSIONS: This defines a profile of pregnant smokers on whom it is important to act: young, Spanish, with a low level of education, multiparous, and with previous miscarriages. Its repercussions are also evident with a lower birth weight in newborns. Knowledge of these factors will make it possible to design more effective intervention strategies to reduce smoking during pregnancy. RELEVANCE FOR PATIENTS: Any effort that reduces smoking habits can improve the health status of mothers and newborns and the first step is to know who are risk pregnants.

Cytomegalovirus specific polyfunctional T-cell responses expressing CD107a predict control of CMV infection after liver transplantation.

Cytomegalovirus (CMV) viral load after liver transplantation (LT) is controlled by cell mediated immune responses (CMI). Quantification of CMV-specific T-cells may identify patients who control CMV spontaneously and avoid expensive and potentially toxic antiviral therapies. Prospective post-LT clinical, virological and immunological monitoring was carried out up to 1-year post-LT in a cohort of adult recipients. The CMV-specific T-cell response was characterized using flow cytometry intracellular cytokine staining in 49 LT recipients-R (79.6% R+, 20.4% R-). CMV infection occurred in 24 patients (18 D+/R+ and 6 D+/R-). Only patients with undetectable polyfunctional CMV-specific CD4+ T-cells developed CMV infection. Predictive models showed that polyfunctional CMV-specific CD4+ T-cells pre-existing before LT are protective for CMV reactivation posttransplantation. Quantitation of CD4+ T-cell responses to CMV may be a useful marker for spontaneous control of viral replication to tailor antiviral prophylaxis after LT.

Health Risk Assessment of Exposure to 15 Essential and Toxic Elements in Spanish Women of Reproductive Age: A Case Study.

This case study investigates the exposure of 119 Spanish women of reproductive age to 5 essential (Co, Cu, Mn, V, Zn) and 10 toxic (Ba, Be, Cs, Ni, Pb, Pt, Sb, Th, Al, U) elements and assesses their risk. The essential elements (Co, Cu, Mn, V, and Zn) showed average concentrations (GM: geometric mean) of 0.8, 35, 0.5, 0.2, and 347 µg/L, respectively. Five of the toxic elements (Ba, Cs, Ni, Al, U) exhibited detection frequencies of 100%. The GM concentrations of the novel toxic elements were 12 µg/L (Al), 0.01 µg/L (Pt), 0.02 µg/L (U), 0.12 µg/L (Th), 0.009 µg/L (Be) and 4 µg/L (Cs). The urine analysis was combined with a survey to assess any variations between subgroups and potential predictors of exposure to elements in the female population. Significant differences were obtained between the rural and urban areas studied for the toxic element Cs, with higher levels found in mothers living in urban areas. In relation to diet, statistically significantly higher levels of essential (Cu) and toxic (Ba) elements were detected in women with a high consumption of fish, while mothers who consumed a large quantity of legumes presented higher levels of the toxic element Ni (p = 0.0134). In a risk-assessment context, hazard quotients (HQs) greater than 1 were only observed for the essential elements Zn and Cu in P95. No deficiency was found regarding the only essential element for which a biomonitoring equivalent for nutritional deficit is available (Zn). For the less-studied toxic elements (Al, Pt, U, Th, Be, and Cs), HQs were lower than 1, and thus, the health risk due to exposure to these elements is expected to be low for the female population under study.

Biomonitoring of Phthalates, Bisphenols and Parabens in Children: Exposure, Predictors and Risk Assessment.

Exposure to emerging contaminants, such as phthalates, bisphenols and parabens in children has been associated with possible neurodevelopment and endocrine alterations. In the present study, the biomonitoring of biomarkers in children (5-12 years old) from the Valencia Region (Spain) have been implemented using urines from the BIOVAL program. More than 75% of the children studied (n = 562) were internally exposed (>LOQ) to bisphenols and parabens, and the whole population assessed (n = 557) were exposed to at least one phthalate. The geometric means (GM) of the concentrations of bisphenol A, methyl paraben and propyl paraben were 0.9, 1.4 and 0.39 ng/mL, respectively. Regarding phthalates, monoethyl phthalate GM was 55.0 ng/mL and diethyl hexyl phthalate (as the sum of five metabolites) GM was 60.6 ng/mL. Despite the studied population being widely exposed, the detection frequencies and concentrations were in general lower than in previous studies involving children in Spain and in other countries in recent years. Furthermore, the risk assessment study concluded that the internal exposure to phthalates, bisphenols and parabens is lower than the guidance values established, and, therefore, a health risk derived from the exposure to these compounds in the studied population is not expected.

Geographical Variability in Mortality in Urban Areas: A Joint Analysis of 16 Causes of Death.

The geographical distribution of mortality has frequently been studied. Nevertheless, those studies often consider isolated causes of death. In this work, we aim to study the geographical distribution of mortality in urban areas, in particular, in 26 Spanish cities. We perform an overall study of 16 causes of death, considering that their geographical patterns could be dependent and estimating the dependence between the causes of death. We study the deaths in these 26 cities during the period 1996-2015 at the census tract level. A multivariate disease mapping model is used in order to solve the potential small area estimation problems that these data could show. We find that most of the geographical patterns found show positive correlations. This suggests the existence of a transversal geographical pattern, common to most causes of deaths, which determines those patterns to a higher/lower extent depending on each disease. The causes of death that exhibit that underlying pattern in a more prominent manner are chronic obstructive pulmonary disease (COPD), lung cancer, and cirrhosis for men and cardiovascular diseases and dementias for women. Such findings are quite consistent for most of the cities in the study. The high positive correlation found between geographical patterns reflects the existence of both high and low-risk areas in urban settings, in general terms for nearly all the causes of death. Moreover, the high-risk areas found often coincide with neighborhoods known for their high deprivation. Our results suggest that dependence among causes of death is a key aspect to be taken into account when mapping mortality, at least in urban contexts.

Exposure and Risk Assessment of Hg, Cd, As, Tl, Se, and Mo in Women of Reproductive Age Using Urinary Biomonitoring.

The present study analyzed the exposure and risk assessment of 4 toxic (Hg, Cd, As, Tl) and 2 essential (Se, Mo) elements in 119 Spanish women of reproductive age. The focus was on the elements for which risk-based benchmark, biomonitoring equivalents, or health-related human biomonitoring values have already been established. All elements presented frequencies of detection of 100% (greater than the limit of detection), except for Cd (99%). The 95th percentile concentrations were, for the toxic metals, 358.37 µg/L (total As), 1.10 µg/L (Cd), 0.41 µg/L (Tl), and 3.03 µg/L (total Hg) and, for the essential elements, 68.95 µg/L (total Se) and 154.67 (Mo). We examined sociodemographic factors and dietary habits of women as predictors of urinary metal concentrations. Arsenic was positively associated with fish, shellfish, and canned fish consumption, whereas Mo was found to be associated with the consumption of cereals and pastry products. Maternal urine levels of As were negatively correlated with gestational age. In a risk-assessment context, hazard quotients (HQs) using the 95th percentile ranged from 0.08 (Tl) to 15.1 (urinary speciated As), with Cd presenting an HQ of 1.1 (95th percentile). None of the essential metals presented concentrations higher than their upper intake level; however, 3% of the mothers showed lower levels of Se than the estimated average requirement (EAR) biomonitoring equivalent, and 20% of the mothers were found to have lower levels of Mo than the EAR biomonitoring equivalent, suggesting a nutritionally inadequate diet. Environ Toxicol Chem 2021;40:1477-1490. © 2021 SETAC.

Exposure and cumulative risk assessment to non-persistent pesticides in Spanish children using biomonitoring.

The main objective of the present research is to evaluate the exposure to pesticides in children (n = 568) from the Valencian Region (Spain). Six non-specific and 20 specific metabolites of organophosphate pesticides (OPs), herbicides (Herb), and pyrethroids (Pyr) were analyzed in urine samples. The biomarkers with the highest detection frequencies (>70%) were diethyl phosphate, p-nitrophenol, 3-phenoxybenzoic acid, and 3,5,6-trichloro-2-pyridinol, whose geometric mean concentrations (ng·ml-n1) were 1.53, 1.03, 1.51 and 1.19, respectively. Robust regression models showed that the province of residence and the recent consumption of vegetables, legumes and cereals were some of the most important predictors of pesticide exposure. Pesticide risk assessment is estimated using two different strategies: one based on the pesticides' mode of action (MoA); and the other based on cumulative assessment groups (CAGs), proposed by EFSA. The estimated daily intakes (EDIs) ranged from 0.08 (chlorpyrifos) to 1.62 µg·kg bw-1 (λ-cyhalothrin). The MoA approach resulted in hazard quotients ranging from 0.01 (chlorpyrifos) to 0.65 (λ-cyhalothrin), and a hazard index for OPs lower than 1. Similarly, the risk assessment based on CAGs led to total margins of exposure (MOETs) far from 100. In conclusion, both risk assessment strategies does not reveal any evidence of a potential health risk due to pesticide exposure in Spanish children.

Biomonitoring of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in human milk: Exposure and risk assessment for lactating mothers and breastfed children from Spain.

The main objective of the present research was to evaluate the levels of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (dl-PCBs) in the human milk of Spanish lactating women who participated in the BETTERMILK project so that exposure and risk could be assessed for these mothers and their breastfed children. The total ∑PCDD/Fs + dl-PCBs TEQ2005 concentrations in the upper-bound (UB) ranged from 1.29 to 13.48 pgTEQ2005 g-1 lipid. The estimated geometric mean level for the sum of PCDD/F and dl-PCBs was 4.10 and 4.42 pgTEQ2005 g-1 lipid, lower-bound (LB) and UB respectively and were below the reference level reported by EFSA, which is associated with adverse effects in boys of 9 years and related to lactating mothers' exposure values of the tolerable weekly intake (TWI) of around 2 pgTEQ2005 kg-1 bw per week. Nevertheless, it was exceeded when the 95th percentile (8.31 pgTEQ2005 g-1 lipid, as UB) was considered. Results from a multiple regression analysis showed that age has a significant impact on milk ∑PCDD/Fs + dl-PCBs levels, with higher concentrations observed in the milk from older mothers.

Biomonitoring of bisphenols A, F, S and parabens in urine of breastfeeding mothers: Exposure and risk assessment.

In the present study we used human biomonitoring to assess the internal exposure and the risk to four parabens and three bisphenols in 103 Spanish breastfeeding mothers participating in the BETTERMIILK project. Urinary methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP) presented detection frequencies ranging from 12% (BP) to 92% (MP), while bisphenol A (BPA), bisphenol F (BPF) and bisphenol S (BPS) were detected in 76% (BPA) and 20% (BPF, BPS) of the mothers. Average paraben concentrations (geometric mean) ranged from 0.021 ng mL-1 (BP) to 17.7 ng mL-1 (MP), whereas bisphenols had geometric means concentrations from 0.042 ng mL-1 (BPF) to 0.927 ng mL-1 (BPA). Except for BPA, the estimated daily intakes (EDI) were calculated in order to interpret urinary levels in a risk assessment context. The obtained EDIs ranged from 0.00042 mg/kg/day for PP to 0.0434 mg/kg/day for MP and EP. A hazard quotient (HQ) was calculated for BPA (0.0049) and parabens (0.001-0.004), showing no risk in the studied population. Sociodemographic characteristics, food consumption, and usage patterns of personal care products (PCPs) were investigated as possible determinants of exposure. Use of makeup and skincare products were associated with higher concentrations of MP and PP, respectively. Regarding dietary habits, MP was also associated with the consumption of packaged and bakery products.

Polybrominated diphenyl ethers in foods from the Region of Valencia: Dietary exposure and risk assessment.

Dietary exposure to polybrominated diphenyl ethers (PBDEs) of the population in the Region of Valencia, Spain, was assessed. A group of 320 composite samples of different fatty foods was collected and analyzed, including the following: vegetable oils, and foods of animal origin such as (a) fish and seafood, (b) eggs, (c) milk and dairy products, and (d) meat and meat products. Two scenarios were assumed for left-censored results: lower-bound (LB) and upper-bound (UB). Vegetable oils, and fish and seafood presented the highest content of PBDEs [mean values of 503 and 464 pg g-1 wet weight (ww) for total PBDEs, respectively, in the UB]. The dominating congeners were BDE47 in the food categories of fish and seafood, meat and meat products, and vegetable oils, and BDE99 in the categories of eggs, and milk and dairy products. The dietary exposure to PBDEs through consumption of the studied foods by the population in the Region of Valencia was estimated for adults (>15 years of age) and young people (6-15 years of age). Average intake levels (UB scenario) were 1.443 and 3.456 ng kg bw-1 day-1 for adults and young people, respectively. In a risk-assessment context, the margin of exposure (MOE) for congener BDE47, -99, -153, and -209 (ranged: 30-3E6) indicate that the current dietary exposure to these substances does not pose a risk to human health.

Biomonitoring of non-persistent pesticides in urine from lactating mothers: Exposure and risk assessment.

The aim of the present study was to assess the exposure to pesticides in urine from Spanish lactating mothers (n = 116). Six nonspecific (dialkyl phosphates) and 20 specific metabolites of organophosphate pesticides (OPs), herbicides and pyrethroids were analyzed. The most frequently detected biomarkers were diethyl phosphate, p-nitrophenol, 3,5,6-trichloro-2-pyridinol and 3-phenoxybenzoic acid, whose geometric means were 1.9 ng·mL-1, 0.8 ng·mL-1, 1.5 ng·mL-1 and 1.4 ng·mL-1, respectively. Herbicide metabolites were the least frequently detected biomarkers with detection frequencies between 0% (2,4,5-Trichlorophenoxyacetic acid) and 22% (2,4-Dichlorophenoxyacetic acid). Multiple regression analyses showed that the closeness to a farming activity, the place of residence and the presence of garden/plants at home were some of the most important contributors to urinary levels of pesticide metabolites. Estimated daily intake (EDI), hazard quotient (HQ) and hazard index (HI) were obtained in order to interpret urinary levels of the most frequently detected pesticide metabolites in a risk assessment context. The highest EDIs were obtained for chlorpyrifos (0.40-1.14 µg·kg bw-1·day-1) and deltamethrin (0.34-4.73 µg·kg bw-1·day-1). The calculated HQ for chlorpyrifos, dimethoate, parathion and deltamethrin ranged from 0.01 to 0.47, and HI for OPs ranged from 0.09 to 0.33 showing that apparently there were low health risks due to the exposure to these pesticides in this group of Spanish breastfeeding women.

Biomonitoring of parabens in human milk and estimated daily intake for breastfed infants.

In this study, we assessed the presence of four parabens in human milk of 120 mothers from Valencia (Spain) which took part in a human biomonitoring project (BETTERMILK). The detection frequency ranges of parabens were 41-60% and 61-89% for unconjugated- and total (unconjugated + conjugated)-parabens, respectively. The concentrations ranged from

Biomonitoring of bisphenols A, F, S in human milk and probabilistic risk assessment for breastfed infants.

The present study addresses the presence of bisphenols A (BPA) and its analogs bisphenol F (BPF) and S (BPS) in milk of 120 mothers living in Valencia (Spain) and participating in the BETTERMILK project (year 2015). We also studied the factors that could influence the BPA levels and estimated the exposure and the risk for breast fed infants. The frequency of detection of total (conjugated + unconjugated) and unconjugated-BPA were 83% and 77%, with a geometric mean of 0.29 ng/mL and 0.15 ng/mL, respectively. The frequency of detection was much lower for total-BPF (22%) and total-BPS (1.1%). The place of residence of the mother and the use of personal care products showed significant association with BPA concentrations. The estimated daily intake of total-BPA for breastfed infants amounted to a geometric mean of 0.04 µg/kg bw and a 95th percentile of 1.0 µg/kg bw, below the tolerable daily intake of 4 µg/kg bw-day established by EFSA. To our knowledge, this is the largest biomonitoring study of bisphenols in human milk in Europe.

Biomonitoring of mercury in hair of children living in the Valencian Region (Spain). Exposure and risk assessment.

In this study, we assessed total mercury levels in hair specimens of 661 children, aged 6 to 11, participating in the BIOVAL programme, a human biomonitoring study carried out by the Health Department of the Regional Government of Valencia (Spain). The reference value (95th percentile) determined for this population, within this programme, was 3.25 µg g-1. Hg concentrations ranged between 0.03 µg g-1 and 8.71 µg g-1, with a geometric mean of 0.79 (CI 95%: 0.73-0.85) µg g-1. This mean value was five times higher than the average levels found in children of 17 other European countries (0.145 µg g-1). About 13% of children had hair mercury levels above the FAO/WHO JECFA guideline of 2.3 µg g-1 and 18% of children had levels above the EFSA health-based guidance value of 1.9 µg. Multiple regression analysis revealed that fish consumption, mother's country of birth (Spain or abroad) and the employment situation of parents were the main predictors of mercury in hair.

Some findings on zero-inflated and hurdle poisson models for disease mapping.

Zero excess in the study of geographically referenced mortality data sets has been the focus of considerable attention in the literature, with zero-inflation being the most common procedure to handle this lack of fit. Although hurdle models have also been used in disease mapping studies, their use is more rare. We show in this paper that models using particular treatments of zero excesses are often required for achieving appropriate fits in regular mortality studies since, otherwise, geographical units with low expected counts are oversmoothed. However, as also shown, an indiscriminate treatment of zero excess may be unnecessary and has a problematic implementation. In this regard, we find that naive zero-inflation and hurdle models, without an explicit modeling of the probabilities of zeroes, do not fix zero excesses problems well enough and are clearly unsatisfactory. Results sharply suggest the need for an explicit modeling of the probabilities that should vary across areal units. Unfortunately, these more flexible modeling strategies can easily lead to improper posterior distributions as we prove in several theoretical results. Those procedures have been repeatedly used in the disease mapping literature, and one should bear these issues in mind in order to propose valid models. We finally propose several valid modeling alternatives according to the results mentioned that are suitable for fitting zero excesses. We show that those proposals fix zero excesses problems and correct the mentioned oversmoothing of risks in low populated units depicting geographic patterns more suited to the data.

Biomonitoring of mercury in hair of breastfeeding mothers living in the Valencian Region (Spain). Levels and predictors of exposure.

This study focused on the evaluation of the levels of total mercury in hair among 120 breastfeeding mothers aged 20 to 45 -. The concentrations of Hg ranged from 0.07 to 6.87 µg/g with a geometric mean (GM) of 1.22 µg/g. This GM is six times higher than the average internal exposure of mothers from other 17 European countries (0.225 µg/g). Near 70% of mothers presented levels of Hg above the USA EPA internal exposure guideline of 1 µg/g, and 27% exceeded the EFSA health-based guidance value of 1.9 µg/g. The multivariate regression analysis revealed that age, smoking and fish consumption (sword fish, small fat fish, small lean fish) were the major predictors of mercury in hair.