Early removal of the etonogestrel contraceptive implant in Spanish women: a prospective cohort study.

Purpose: To know the discontinuation rate and characterize predictors and reasons of contraceptive implant removal within 12 months of insertion in our community setting. Methods: This prospective cohort study included women receiving the etonogestrel contraceptive implant at sexual and reproductive health centers between September 2019 and September 2020. The variables collected were implanted insertion timing, reproductive and demographic characteristics, medical conditions, sexual activity and counseling. Our primary outcome was implant discontinuation. Kaplan-Meier survival curves were used to show the cumulative discontinuation rate of implants contraceptive within the first year of insertion. We also identified factors that increased the risk of implant removal using the log-rank test and the Cox regression model. Reasons for discontinuation were documented. Results: 199 women were followed up. Implant discontinuation was documented in 17.1% of implant users prior to 12 months. Factors that increase the risk of implant removal are living with a partner, being aged 25-34 years and not receiving comprehensive and structured counseling from the midwife. The main reason for removal was unsatisfactory bleeding (97.1%), but this was combined with other reasons such as cessation of sexual intercourse (58.8%), worsening mood (58.8%), weight gain (55.9%) or decreased libido (50.0%). Conclusion: The rate of discontinuous implant uses in the first year is relevant in relation to cost-effectiveness, there is room for improvement that should not be overlooked. Comprehensive and structured midwife-led counseling can reduce early implant abandonment removal. The development in different countries of the role of midwives in the management of contraceptives can contribute to the economic benefit of health services and the satisfaction of women.

New analytical method for the determination of endocrine disruptors in human faeces using gas chromatography coupled to tandem mass spectrometry.

Endocrine-disrupting chemicals are environmental pollutants that can enter our bodies and cause diverse pathologies. Some bisphenols and parabens have been shown to be capable of modifying proper functioning of the endocrine system. Among other dysfunctions, endocrine-disrupting chemicals can cause changes in intestinal microbiota. Faeces are a convenient matrix that can be useful for identifying the quantity of endocrine disruptors that reach the intestine and the extent to which the organism is exposed to these pollutants. The present work developed a new analytical method to determine 17 compounds belonging to the paraben and bisphenol families found in human faeces. The extraction method was optimized using an ultrasound-assisted extraction technique followed by a clean-up step based on the QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) technique. Optimization was performed using the design of experiments technique. In validation analysis, the method was proven to be linear over a wide range. R-squared outcomes were between 95 and 99%. Selectiveness and sensitivity outcomes were acceptable, with detection limits being between 1 and 10 ng g-1 in all cases, whilst quantification limits were between 3 and 25 ng g-1 in all instances, with the exception of bisphenol AF. The method was deemed accurate, with recovery values being close to 100% and relative standard deviations being lower than 15% in all cases. Applicability was examined by analysing 13 samples collected from volunteers (male and female). All samples were contaminated with at least one of the analytes studied. The most commonly found compounds were methylparaben and bisphenol A, which were detected in almost all samples and quantitatively determined in 11 and 12 samples, respectively. Of the 17 compounds analysed, 11 were found in at least one sample. Outcomes demonstrate that faeces can be a good matrix for the determination of exposure to contaminants of interest here.

Risk assessment of food contact materials.

Bisphenol A (BPA) is authorised for use as a chemical compound for the production of plastic food contact materials (FCMs) under Regulation (EU) No 10/2011. But according to requirements of the Regulation (EU) No 2018/213, BPA has been banned in the manufacture of polycarbonate drinking cups or feeding bottles intended for infants and young children. Food has been identified as the main source of human exposure to BPA, followed by dermal absorption, air and dust inhalation, revealing ubiquitous and continuous contact with BPA. Considering that BPA is able to enter the food chain through the migration from food packaging into foodstuffs, assessment of dietary exposure is necessary for accurate estimations and identification of potential exposure from food sources. In 2015, EFSA set a temporary tolerable daily intake (TDI) for BPA of 4 µg/kg body weight (bw) per day and concluded that no health concern from BPA exposure for any age group was to be expected. In 2023, EFSA has re-evaluated BPA safety and the new TDI was reduced by a factor of 20,000 resulting in a TDI of 0.2 ng/kg bw per day. In this case, the CEP Panel concluded that there is a health concern from dietary exposure to BPA. Amongst others, the BfR identified several points of criticism which, in the opinion of the BfR, call into question the risk assessment carried out by EFSA. The BfR derived a TDI of 200 ng/kg bw per day and suggests taking this into account for risk assessment. In the proposed EU-FORA programme, the fellow had the opportunity to gain experience in the exposure assessment and then integrate the data together with the BfR hazard assessment to perform a comprehensive risk assessment. As second objective of the work programme, the fellow was in charge of performing a toxicokinetic analysis in an attempt to correlate external exposure with urinary BPA levels.

Cost of screening and timely treatment versus the comprehensive management of the severe visual impairment due to retinopathy of premature. / Costo del tamizaje y tratamiento oportuno versus el manejo integral de la discapacidad visual severa por retinopatía del prematuro.

Retinopathy of prematurity (ROP) is one of the leading causes of preventable blindness worldwide. In Guatemala, a large number of premature infants are born in hospitals outside the capital city and present for evaluation at advanced stages of the disease. OBJECTIVE: To compare the cost of screening and timely treatment versus the total cost of comprehensive management of patients with visual impairment secondary to ROP. PATIENTS AND METHOD: The cost of the disease was calculated in patients who consulted due to low vision or blindness secondary to ROP. Direct costs were calculated based on those directly related to the management of the disease: medical care, rehabilitation, education, technical support, transportation, personal assistance, adaptations, and home equipment, compared with the costs of screening and timely treatment. RESULTS: The total cost of managing a child with severe visual impairment due to ROP is USD 214,666.37 and the cost of screening and timely treatment is USD 1,223.12, meaning an additional cost of USD 213,443.24 in patients who were not screened and treated on time. CONCLUSION: The cost of screening and timely treatment represents only 0.57% of the total cost of lifelong management of a child with severe visual impairment.

The Role of Endocrine Disrupting Chemicals in Gestation and Pregnancy Outcomes.

Endocrine disrupting chemicals (EDCs) are exogenous substances widely disseminated both in the environment and in daily-life products which can interfere with the regulation and function of the endocrine system. These substances have gradually entered the food chain, being frequently found in human blood and urine samples. This becomes a particularly serious issue when they reach vulnerable populations such as pregnant women, whose hormones are more unstable and vulnerable to EDCs. The proper formation and activity of the placenta, and therefore embryonic development, may get seriously affected by the presence of these chemicals, augmenting the risk of several pregnancy complications, including intrauterine growth restriction, preterm birth, preeclampsia, and gestational diabetes mellitus, among others. Additionally, some of them also exert a detrimental impact on fertility, thus hindering the reproductive process from the beginning. In several cases, EDCs even induce cross-generational effects, inherited by future generations through epigenetic mechanisms. These are the reasons why a proper understanding of the reproductive and gestational alterations derived from these substances is needed, along with efforts to establish regulations and preventive measures in order to avoid exposition (especially during this particular stage of life).

Levels of Bisphenol A and its analogs in nails, saliva, and urine of children: a case control study.

Introduction: A growing number of studies link the increase in overweight/obesity worldwide to exposure to certain environmental chemical pollutants that display obesogenic activity (obesogens). Since exposure to obesogens during the first stages of life has been shown to have a more intense and pronounced effect at lower doses, it is imperative to study their possible effects in childhood. The objective here was to study the association of Bisphenol A (BPA) and 11 BPA analogs in children, using three biological matrices (nails, saliva and urine), and overweight and obesity (n = 160). Methods: In this case-control study, 59 overweight/obese children and 101 controls were included. The measuring of Bisphenols in the matrices was carried out by ultra-high performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UHPLC-MS/MS). Logistic regression was used to study the association between overweight/obesity and Bisphenol exposure. Results: The results suggested that BPF in nails is associated with overweight/ obesity in children (OR:4.87; p = 0.020). In saliva, however, the highest detected concentrations of BPAF presented an inverse association (OR: 0.06; p = 0.010) with overweight/obesity. No associations of statistical significance were detected between exposure to BPA or its other analogs and overweight/obesity in any of the biological matrices.

Results of a Phase II Trial Testing the Resensitization With Trabectedin in Platinum-resistant Ovarian Cancer.

BACKGROUND/AIM: In patients with advanced platinum-resistant ovarian cancer we prospectively evaluated whether trabectedin could resensitize the tumor cells to platinum rechallenge. PATIENTS AND METHODS: Upon progression to platinum-based chemotherapy, trabectedin was administered as a 3-hour infusion every three weeks and subsequently crossed over to carboplatin/carboplatin-based combinations. The primary endpoints comprised objective response rate (ORR) and time to progression after trabectedin (TTP Trab). Secondary endpoints included ORR following platinum post-trabectedin, the growth modulation index (GMI) assessed as the ratio of successive TTP to platinum, given after (TTP2) and before (TTP1) trabectedin, quality of life (QoL), and ancillary translational studies. RESULTS: Ten patients with platinum-resistant ovarian cancer from a single institution were treated with trabectedin, one of whom achieved a partial response (PR) reaching the ORR of 10% and six had stable disease (SD) for a disease control rate (DCR) of 70%. After the treatment with platinum post-trabectedin, one patient achieved a PR and two had SD, attaining a rate of resensitization to platinum of 37.5%. The median TTP with trabectedin treatment was 15.0 weeks, while eight patients who received platinum post-trabectedin had the median TTP2 of 19.9 weeks. One patient reached the threshold of GMI >1 (12.5%) as indicator of clinical benefit. QoL of patients was not deteriorated with trabectedin. Predictive biomarkers of response to trabectedin and/or re-exposure to platinum could not be identified. CONCLUSION: Although trabectedin did not achieve a wide resensitization to platinum in this heavily pretreated platinum-resistant population, a significant number of patients attained disease control.

Reducing preoperative anxiety in parents of surgical patients.

Aims and objectives: To investigate preoperative anxiety in parents of paediatric surgical patients, testing whether the provision of information (using video and story books) regarding the surgical process can impact on reducing anxiety. Analyse if any personal factors influence the reduction of anxiety. Background: Attending a surgical theatre generates anxiety, especially in the case of children. The effect of different preoperative intervention procedures in children that attempt to reduce their anxiety level have been studied a great deal. However, although their parents also suffer high levels of anxiety, potential intervention to reduce their levels has not received the same attention. Study design: Randomised Clinical trial. Methods: One hundred and twenty-five parents of children (8-12 y.o.) undergoing surgery in a public hospital were randomly assigned to the control group CG (34 individuals) or one of the 3 experimental groups EG (91). In this Randomised Controlled Study, children and parents of the experimental groups were provided with a story book, a video with additional information of nursing, or both. Prior to the surgical intervention, the State Anxiety, S-A, and Trait Anxiety, T-A, of the parents and children were measured using the STAI and STAIC questionnaires respectively. Data collection was carried out for 12 months starting in October 2016. Results: Parents' S-A in the control group was higher than in the experimental groups. A linear model explains the parents' S-A using as regressors: children S-A, age and T-A of the parents, and children age. Conclusions: Providing information about the surgical process (through stories or videos) to which a child is going to be subjected can reduce the anxiety of the parents. Relevance to clinical practice: Given their close connection to the patient and the potential effects on the children of their psychological situation, healthcare professionals should consider paying greater attention to communicating with the parents.

Presence of Parabens in Different Children Biological Matrices and Its Relationship with Body Mass Index.

Parabens have been accepted almost worldwide as preservatives by the cosmetic, food, and pharmaceutical industries. Since epidemiological evidence of the obesogenic activity of parabens is weak, the aim of this study was to investigate the association between parabens exposure and childhood obesity. Four parabens (methylparaben/MetPB, ethylparaben/EthPB, propylparaben/PropPB, and butylparaben/ButPB) were measured in 160 children's bodies between 6 and 12 years of age. Parabens measurements were performed with ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Logistic regression was used to evaluate risk factors for elevated body weight associated with paraben exposure. No significant relation was detected between children's body weight and the presence of parabens in the samples. This study confirmed the omnipresence of parabens in children's bodies. Our results could be a basis for future research about the effect of parabens on childhood body weight using nails as a biomarker due to the ease of its collection and its non-invasive character.

Association of genetic polymorphisms in detoxifying systems and urinary metal(loid) levels with excess body weight among Spanish children: A proof-of-concept study.

Exposure to metal(loid)s during critical developmental windows could result in permanent damage to the target organ system, increasing susceptibility to disease later in life. In view of the fact that metals(loid)s have been shown to work as obesogens, the aim of the present case-control study was to evaluate the modification effect of exposure to metal(loid)s on the association between SNPs in genes involved in metal(loid) detoxification and excess body weight among children. A total of 134 Spanish children aged 6-12 years old were included (88 controls and 46 cases). Seven SNPs (GSTP1 rs1695 and rs1138272; GCLM rs3789453, ATP7B rs1061472, rs732774 and rs1801243; and ABCC2 rs1885301) were genotyped on GSA microchips, and ten metal(loid)s were analysed in urine samples through Inductively coupled plasma mass spectrometry (ICP-MS). Multivariable logistic regressions were conducted to assess the genetic and metal exposures' main association and interaction effects. GSTP1 rs1695 and ATP7B rs1061472 showed significant effects on excess weight increase in those children carrying two copies of the risk G allele and being highly exposed to chromium (ORa = 5.38, p = 0.042, p interaction = 0.028 for rs1695; and ORa = 4.20, p = 0.035, p interaction = 0.012 for rs1061472) and lead (ORa = 7.18, p = 0.027, p interaction = 0.031 for rs1695, and ORa = 3.42, p = 0.062, p interaction = 0.010 for rs1061472). Conversely, GCLM rs3789453 and ATP7B rs1801243 appeared to play a protective role against excess weight in those exposed to copper (ORa = 0.20, p = 0.025, p interaction = 0.074 for rs3789453) and lead (ORa = 0.22, p = 0.092, p interaction = 0.089 for rs1801243). Our findings provide the first proof that interaction effects could exist between genetic variants within GSH and metal transporting systems and exposure to metal(loid)s, on excess body weight among Spanish children.

Effectiveness of a Meningococcal Group B Vaccine (4CMenB) in Children.

BACKGROUND: In September 2015, the four-component, protein-based meningococcal serogroup B vaccine (4CMenB; Bexsero) became available for private purchase in Spain. METHODS: We conducted a nationwide matched case-control study to assess the effectiveness of 4CMenB in preventing invasive meningococcal disease in children. The study included all laboratory-confirmed cases of invasive meningococcal disease in children younger than 60 months of age between October 5, 2015, and October 6, 2019, in Spain. Each case patient was matched with four controls according to date of birth and province. 4CMenB vaccination status of the case patients and controls was compared with the use of multivariate conditional logistic regression. RESULTS: We compared 306 case patients (243 [79.4%] with serogroup B disease) with 1224 controls. A total of 35 case patients (11.4%) and 298 controls (24.3%) had received at least one dose of 4CMenB. The effectiveness of complete vaccination with 4CMenB (defined as receipt of at least 2 doses, administered in accordance with the manufacturer's recommendations) was 76% (95% confidence interval [CI], 57 to 87) against invasive meningococcal disease caused by any serogroup, and partial vaccination was 54% (95% CI, 18 to 74) effective. Complete vaccination resulted in an effectiveness of 71% (95% CI, 45 to 85) against meningococcal serogroup B disease. Vaccine effectiveness with at least one dose of 4CMenB was 64% (95% CI, 41 to 78) against serogroup B disease and 82% (95% CI, 21 to 96) against non-serogroup B disease. With the use of the genetic Meningococcal Antigen Typing System, serogroup B strains that were expected to be covered by 4CMenB were detected in 44 case patients, none of whom had been vaccinated. CONCLUSIONS: Complete vaccination with 4CMenB was found to be effective in preventing invasive disease by serogroup B and non-serogroup B meningococci in children younger than 5 years of age.

Presence of parabens in children's faeces. Optimization and validation of a new analytical method based on the use of ultrasound-assisted extraction and liquid chromatography-tandem mass spectrometry.

Due to their antimicrobial properties, parabens are a family of synthetic chemical compounds widely used as preservative additives in food and cosmetics. For this reason, humans are highly exposed to them. These substances are capable of altering the proper functioning of the endocrine system and are classified as endocrine disrupting chemicals (EDCs). Traditionally, urine has been the typical matrix studied as an excretion route. However, faeces contain valuable information. In the present study, the presence of methyl-, ethyl-, isopropyl-, propyl-, isobutyl-, butyl- and phenylparaben in stool samples from children has been evaluated. A new analytical method has been optimised and validated. The method is based on the use of ultrasound-assisted extraction followed by clean-up of the extracts by dispersive solid phase extraction dSPE). Parabens were analysed by ultrahigh performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The matrix effect was evaluated and a significant effect was observed for all analytes. Therefore, calibration and validation were performed by addition of different concentrations of analytes to faecal blanks. The coefficient of determination (%R2) for calibration curves was higher than 98.9% in all cases. The limits of detection and quantification were between 0.2 and 0.4 and 0.6-1.0 ng g-1 respectively. The recovery for accuracy assessment had values between 89.0% and 112.7% with an RSD of less than 15% in all cases. The method was successfully applied to 14 samples from children volunteers, 100% of which showed contamination by at least one of the analysed compounds.

The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling.

Core planar cell polarity (PCP) genes, which are involved in various neurodevelopmental disorders such as neural tube closure, epilepsy, and autism spectrum disorder, have poorly defined molecular signatures in neurons, mostly synapse-centric. Here, we show that the core PCP protein Prickle-like protein 2 (Prickle2) controls neuronal polarity and is a previously unidentified member of the axonal initial segment (AIS) proteome. We found that Prickle2 is present and colocalizes with AnkG480, the AIS master organizer, in the earliest stages of axonal specification and AIS formation. Furthermore, by binding to and regulating AnkG480, Prickle2 modulates its ability to bundle microtubules, a crucial mechanism for establishing neuronal polarity and AIS formation. Prickle2 depletion alters cytoskeleton organization, and Prickle2 levels determine both axon number and AIS maturation. Last, early Prickle2 depletion produces impaired action potential firing.

Effect of exposure to endocrine disrupting chemicals in obesity and neurodevelopment: The genetic and microbiota link.

Current evidence highlights the importance of the genetic component in obesity and neurodevelopmental disorders (attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID)), given that these diseases have reported an elevated heritability. Additionally, environmental stressors, such as endocrine disrupting chemicals (EDCs) have been classified as obesogens, neuroendocrine disruptors, and microbiota disrupting chemicals (MDCs). For this reason, the importance of this work lies in examining two possible biological mechanistic pathways linking obesity and neurodevelopmental/behavioural disorders: EDCs - gene and EDCs - microbiota interactions. First, we summarise the shared mechanisms of action of EDCs and the common genetic profile in the bidirectional link between obesity and neurodevelopment. In relation to interaction models, evidence from the reviewed studies reveals significant interactions between pesticides/heavy metals and gene polymorphisms of detoxifying and neurotransmission systems and metal homeostasis on cognitive development, ASD and ADHD symptomatology. Nonetheless, available literature about obesity is quite limited. Importantly, EDCs have been found to induce gut microbiota changes through gut-brain-microbiota axis conferring susceptibility to obesity and neurodevelopmental disorders. In view of the lack of studies assessing the impact of EDCs - gene interactions and EDCs - mediated dysbiosis jointly in obesity and neurodevelopment, we support considering genetics, EDCs exposure, and microbiota as interactive factors rather than individual contributors to the risk for developing obesity and neurodevelopmental disabilities at the same time.

Improved method for the determination of endocrine-disrupting chemicals in urine of school-age children using microliquid-liquid extraction and UHPLC-MS/MS.

The presence of endocrine-disrupting chemicals in our daily life is increasing every day and, by extension, human exposure and the consequences thereof. Among these substances are bisphenols and parabens. Urine is used to analyze the exposure. The determination of 12 bisphenol homologues and 6 parabens is proposed. A procedure based on a method previously developed by our research group in 2014 is improved. The extraction yield is higher, because the new protocol is 5 times more efficient. Also, a comparison between calibration with pure standards and matrix calibration, to calculate the matrix effect, was also made. A high grade of matrix effect for all analytes was observed. In terms of validation, the limits of detection (LOD) were between 0.03 and 0.3 ng mL-1 and limits of quantification (LOQ) 0.1 to 1.0 ng mL-1, respectively, and the recovery is higher than 86.4% and lower than 113.6%, with a RSD lower than 13.5% in all cases. A methodology for accurate and sensitive quantification of bisphenol homologues together with parabens in human urine using UHPLC-MS/MS was developed. The method was successfully applied to 30 urine samples from children.

Developing and maintaining a nose-to-brain map of odorant identity.

Olfactory sensory neurons (OSNs) in the olfactory epithelium of the nose transduce chemical odorant stimuli into electrical signals. These signals are then sent to the OSNs' target structure in the brain, the main olfactory bulb (OB), which performs the initial stages of sensory processing in olfaction. The projection of OSNs to the OB is highly organized in a chemospatial map, whereby axon terminals from OSNs expressing the same odorant receptor (OR) coalesce into individual spherical structures known as glomeruli. This nose-to-brain map of odorant identity is built from late embryonic development to early postnatal life, through a complex combination of genetically encoded, OR-dependent and activity-dependent mechanisms. It must then be actively maintained throughout adulthood as OSNs experience turnover due to external insult and ongoing neurogenesis. Our review describes and discusses these two distinct and crucial processes in olfaction, focusing on the known mechanisms that first establish and then maintain chemospatial order in the mammalian OSN-to-OB projection.