Sex Dependence Research Articles

Genes That Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts.

Aortic valve stenosis is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain underexplored. Hydrogel biomaterials were designed to recapitulate key aspects of the valve tissue microenvironment and to serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to profibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA sequencing was used to define pathways involved in driving sex-dependent activation. Interventions with small molecule inhibitors and siRNA transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker α-smooth muscle actin compared with male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal α-smooth muscle actin stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than in male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase signaling as a potential driver of this sex-dependent myofibroblast activation. Furthermore, we found that genes that escape X-chromosome inactivation such as BMX and STS (encoding for Bmx nonreceptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation through Rho-associated protein kinase signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation through Rho-associated protein kinase signaling. Together, in vivo and in vitro results confirm sex dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent aortic valve stenosis progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of aortic valve stenosis and to help guide sex-based precision therapies.

Vaccination against human papillomavirus in Brazilian schoolchildren: National Survey of School Health, 2019.

to analyze the prevalence of schoolchildren vaccinated against human papillomavirus (HPV) and the reasons related to non-vaccination. cross-sectional study, with data from the 2019 National Survey of School Health. The sample consisted of 160,721 students aged 13 to 17 years. The prevalence and confidence intervals (95%CI) of vaccinated adolescents were estimated according to location, sex, and administrative dependence of the school. The differences between the strata were evaluated with the Chi-square test. Adjusted prevalence ratios (aPR) and 95%CI were estimated with the Poisson regression model. most of the students were vaccinated (62.9%), and the prevalence of girls (76.1%) was higher than that of boys (49.1%). The most prevalent reason for not vaccinating was "did not know they had to take" (46.8%), with the highest aPR in public schoolchildren in Brazil (1.6; 95%CI 1.5;1.7), from the Northeast region (1.2; 95%CI 1.1;1.2), and in students from private schools in the Northeast regions (1.1; 95%CI 1.1;1.2) and North (1.3; 95%CI 1.2;1.4). one out of every two Brazilian schoolchildren was vaccinated against HPV. Misinformation was a recurring reason for non-vaccination. The North and Northeast regions had the highest prevalence of non-vaccinated people, observed mainly in adolescents from public schools. (1) 63% of Brazilian schoolchildren reported having been vaccinated against human papillomavirus (HPV).(2) In Brazil, in 2019, the prevalence of immunized girls was higher than that of boys.(3) Misinformation and fear are reasons for hesitating vaccination.(4) Social and health inequalities may reflect upon HPV vaccination.(5) Achieving the goal of 80% in HPV vaccination coverage is a challenge in Brazil.

Weekly patterns of suicide and the influence of alcohol consumption in an urban sample.

The weekly fluctuation in suicide rates is influenced by several factors including sex, psychiatric illness and alcohol dependence. The purpose of this study is to explore the impact of current alcohol use on suicid. Data on sex, date of death, results of blood and/or urine alcohol tests and history of alcohol dependence in suicide victims over the 1997-2002 period were retrieved from a forensic database in two cities in Chuvash Republic. Over the six-year study period, 1,379 suicides were committed, 59% of them under the influence of alcohol. The peak incidence for men and women regardless of previous alcohol consumption was on Wednesdays and Mondays, respectively. The overall suicide rate was highest on Mondays and lowest on Thursdays. Both sexes were less likely to commit suicide during holidays than on weekends or workdays while intoxicated with alcohol. In this urban sample, the distribution of suicide across weekdays only partly followed the international pattern. The peak incidence of suicide showed sex difference, with the highest incidence for women on Mondays and for men on Wednesdays. The higher suicide rate on workdays might be accounted for by work-related stress, while the lower rate on weekends could be explained that people usually drink alcohol in the comforting company of family or friends, which reduces psychological tension and suicidal ideation. The majority of men consumed alcohol before committing suicide, regardless of the day of the week, while this observation was true for women only on Fridays and Sundays. Alcohol consumption greatly contributes to suicidal behavior in Chuvash Republic.

Developmental Trajectories of Anhedonia in Preclinical Models.

This chapter discusses how the complex concept of anhedonia can be operationalized and studied in preclinical models. It provides information about the development of anhedonia in the context of early-life adversity, and the power of preclinical models to tease out the diverse molecular, epigenetic, and network mechanisms that are responsible for anhedonia-like behaviors.Specifically, we first discuss the term anhedonia, reviewing the conceptual components underlying reward-related behaviors and distinguish anhedonia pertaining to deficits in motivational versus consummatory behaviors. We then describe the repertoire of experimental approaches employed to study anhedonia-like behaviors in preclinical models, and the progressive refinement over the past decade of both experimental instruments (e.g., chemogenetics, optogenetics) and conceptual constructs (salience, valence, conflict). We follow with an overview of the state of current knowledge of brain circuits, nodes, and projections that execute distinct aspects of hedonic-like behaviors, as well as neurotransmitters, modulators, and receptors involved in the generation of anhedonia-like behaviors. Finally, we discuss the special case of anhedonia that arises following early-life adversity as an eloquent example enabling the study of causality, mechanisms, and sex dependence of anhedonia.Together, this chapter highlights the power, potential, and limitations of using preclinical models to advance our understanding of the origin and mechanisms of anhedonia and to discover potential targets for its prevention and mitigation.

Possible Age and Sex Dependency of Costal Cartilage Calcification Degree Investigated by Computed Tomography: First Costal Cartilage Calcification is of Significance

Possible Age and Sex Dependency of Costal Cartilage Calcification Degree Investigated by Computed Tomography: First Costal Cartilage Calcification is of Significance

Examining a brief measure and observed cutoff scores to identify reward and relief drinking profiles: Psychometric properties and pharmacotherapy response

BackgroundPrecision medicine approaches attempt to reduce variability in alcohol use disorder (AUD) outcomes by identifying patient characteristics that predict response to a particular treatment. Recent work has examined the extent to which individuals with AUD may seek alcohol to enhance positive experiences (reward drinking) or relieve negative states (relief drinking) and shown that a high reward/low relief phenotype predicts naltrexone treatment response. Yet, limitations of reward/relief drinking measures may hamper efforts to translate findings to clinical practice. We sought to refine a brief measure of reward/relief drinking and develop cutoff scores to identify reward/relief subgroups that predict pharmacotherapy response. MethodsThe Inventory of Drinking Situations (IDS), used in previous studies to measure reward/relief drinking, was administered to 426 participants (77% male; average age = 45.3) in a clinical trial examining naltrexone and acamprosate. ResultsItem response theory and tests of differential item functioning across sex, age, and alcohol dependence severity were used to create a 10-item measure, titled the Reward and Relief IDS (RR-IDS). Cutoff scores on the RR-IDS for the reward/relief drinking subgroups were identified using latent profile and area under the curve analyses. The cutoff scores demonstrated good construct validity. Individuals in the high reward/low relief subgroup who received naltrexone or acamprosate had a decreased likelihood of heavy drinking (large effect sizes) versus those who received placebo. ConclusionsThe RR-IDS is a practical measure for identifying reward/relief subgroups and predicting pharmacotherapy response. Pending replication of these findings, the RR-IDS could be a critical precision medicine tool for prescribing AUD medications.

Bioaccumulation of organochlorine pesticides in Antarctic krill (Euphausia superba): Profile, influencing factors, and mechanisms

Accumulation of organochlorine pesticides (OCPs) in Antarctic krill (Euphausia superba), a keystone species in the Southern Ocean, is potentially harmful to the Antarctic ecosystem and human health. In the current study, we collected E. superba specimens (including muscle and carapace tissues) from Bransfield Strait in northern Antarctic Peninsula and South Georgia to analyze the profile, influencing factors and mechanisms of OCPs bioaccumulation in them. Results indicated that the biological traits (δ13C, δ15N and lipid contents) of krill were significantly affected by habitat. There may exist growth dilution of OCPs in Antarctic krill and no fresh OCPs input in Antarctica, except for endosulfan I. Based on lipid-normalized concentrations, no significant differences were observed between the two regions at most sampling sites. However, OCP levels showed tissue and sex dependence. Boosted regression trees (BRTs) and partial least squares structural equation models (PLS-SEMs) were built to better investigate the main factors affecting the bioaccumulation of OCPs. Lipid content, negatively correlated with OCP levels, was the main factor. In vitro silicon modeling indicated that CYP3A4 metabolism capacity in krill contributed to the OCP residues except for endosulfan I. The results of this study expand current knowledge of OCPs in Antarctic marine biota, as well as their influencing factors and potential mechanisms.

Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis.

BackgroundThis is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance.Methods and ResultsThe Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred.ConclusionsThis nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.

Normal tissue complication probability modeling to guide individual treatment planning in pediatric cranial proton and photon radiotherapy.

Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT). Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio. IMPT plans resulted in lower NTCP compared to IMRT across all models (p<0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (>20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p<0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p<0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p<0.0001). Due to the scarcity of pediatric NTCP data available, sensitivity analyses were performed using plausible ranges based on published adult data. In the clinical scenario where, if female pediatric patients were 20% more radiosensitive (lower TD50 value), they could be up to twice as likely to experience side-effects of brainstem necrosis and cochlea tinnitus compared to males, highlighting the need for considering the sex in NTCP models. Based on our sensitivity analyses, age and sex of a pediatric patient could significantly affect the resultant NTCP from cranial radiotherapy, especially at higher α/β values.

The Relationship between the Presence of White Nails and Mortality among Rural, Older, Admitted Patients: A Prospective Cohort Study.

White nails are a sign of various physical deteriorations, including poor nutrition, organ damage, and aging. During a physical examination, white nails can be a helpful health indicator in older patients with vague and multiple symptoms. In this prospective cohort study of patients admitted to the Department of General Medicine in a rural community hospital, we investigated the relationship between white nails and patient mortality. Patient data, including age, sex, condition, and bloodwork results, were collected. Trained family physicians confirmed the presence of white nails. Logistic regression analysis was performed to determine the relationship between white nails and death during hospitalization. Of 711 study participants, 74 died during hospitalization. White nails, male sex, and caregiver dependence were associated with high in-hospital mortality (odds ratio (OR) = 3.47, p < 0.001; OR 2.05, p = 0.01; OR 1.92, p = 0.049, respectively). High albumin concentration was associated with low in-hospital mortality (OR = 0.44, p < 0.001). White nails, along with serum albumin concentration, male sex, and caregiver dependence, are associated with mortality. The identification of white nails can predict the deterioration of patients. Various professionals should learn to identify the presence of white nails to facilitate the care of elderly patients.

A Cross-Sectional Observation on Maximal Eccentric Hamstring Strength in 7- to 15-Year-Old Competitive Alpine Skiers.

Simple SummaryCompetitive alpine skiing is a sport with frequent occurrence of severe knee injuries, and it is well known that the hamstring muscles play an important role in preventing these injuries. The aim of this study was to assess the maximal strength capacity for braking, the downward movement during Nordic Hamstring Exercises, the so called maximal eccentric hamstring strength, in 7- to 15-year-old skiers. Absolute strength values were greater in skiers under 15 years old (U15) skiers than in those under 10 years old (U10), as well as in U15 males compared to their female counterparts. There were no sex differences in U10 skiers. Absolute strength values were generally dependent on age and biological developmental stage, but this dependence was considerably attenuated when body weight was considered. This should be kept in mind when testing athletes around the growth spurt.Severe knee injuries are common in alpine skiing and the hamstring muscles are known to counteract the anterior tibial displacement that typically accompanies major injury mechanisms. This study aimed to assess the Maximal Eccentric Hamstring Strength (MEHS) of youth competitive alpine skiers during Nordic Hamstring Exercise (NHE) in terms of dependence of sex, age and biological maturation. A total of 246 7- to 15-year-old skiers were tested with respect to their MEHS using an NHE-based measurement device (Vald Performance, Newstead, Australia). Significantly greater absolute MEHS was observed in skiers of the under 15 years (U15) category compared to skiers under 10 years old (U10) (227.9 ± 61.1 N vs. 142.6 ± 28.9 N; p < 0.001), also when grouped by sex. Absolute MEHS was revealed to be lower in U15 females compared to males (213.5 ± 49.0 N vs. 241.9 ± 68.4 N; p = 0.001); in U10 skiers there was no sex difference. For all age groups and sexes, absolute MEHS values were significantly correlated with age and biological maturation (p < 0.001). However, when normalized to body weight such associations disappeared, which is why this is strongly recommended when testing around their growth spurt. Overall, this study established sport-specific normative reference data that may be of interest to researchers and sport practitioners alike.

Age and sex dependency of thoracic aortopathy in a mouse model of Marfan syndrome.

Thoracic aortic aneurysm is one of the manifestations of Marfan syndrome (MFS) that is known to affect men more severely than women. However, the incidence of MFS is similar between men and women. The aim of this study is to show that during pathological aortic dilation, sex-dependent severity of thoracic aortopathy in a mouse model of MFS translates into sex-dependent alterations in cells and matrix of the ascending aorta, consequently affecting aortic biomechanics. Fibrillin-1 C1041G/+ (Het) mice were used as a mouse model of MFS. Ultrasound measurements from 3 to 12 mo showed increased aortic diameter in Het aorta, with larger percentage increase in diameter for males compared with females. Immunohistochemistry showed decreased contractile smooth muscle cells in Het aortic wall compared with healthy aorta, which was accompanied by decreased contractility measured by wire myography. Elastin autofluorescence, second-harmonic generation microscopy of collagen fibers, and passive biomechanical assessments using myography showed more severe damage to elastin fibers, increased medial fibrosis, and increased stiffness of the aortic wall in MFS males but not females. Male and female Het mice showed increased expression of Sca-1-positive adventitial progenitor cells versus controls at young ages. In agreement with clinical data, Het mice demonstrate sex-dependent severity of thoracic aortopathy. It was also shown that aging exacerbates the disease state especially for males. Our findings suggest that female mice are protected from progression of aortic dilation at early ages, leading to a lag in aneurysm growth.NEW & NOTEWORTHY Male Fbn1C1041G/+ mice show more severe thoracic aortic changes compared with females, especially at 12 mo of age. Up to 6 mo of age, Sca-1+ smooth muscle progenitor cells are more abundant in the adventitia of both male and female Fbn1 Het mice compared with wild types (WTs). Male and female Het mice show similar patterns of expression of Sca-1+ cells at early ages.

Clinical Efficacy of Ruxolitinib in Patients with Myelofibrosis: A Nationwide Population-Based Study in Korea.

Previous studies have reported the survival benefit after ruxolitinib treatment in patients with myelofibrosis (MF). However, population-based data of its efficacy are limited. We analyzed the effects of ruxolitinib in MF patients with data from the Korean National Health Insurance Database. In total, 1199 patients diagnosed with MF from January 2011 to December 2017 were identified, of which 731 were included in this study. Patients who received ruxolitinib (n = 224) were matched with those who did not receive the drug (n = 507) using the 1:1 greedy algorithm. Propensity scores were formulated using five variables: age, sex, previous history of arterial/venous thrombosis, and red blood cell (RBC) or platelet (PLT) transfusion dependence at the time of diagnosis. Cox regression analysis for overall survival (OS) revealed that ruxolitinib treatment (hazard ratio (HR), 0.67; p = 0.017) was significantly related to superior survival. In the multivariable analysis for OS, older age (HR, 1.07; p < 0.001), male sex (HR, 1.94; p = 0.021), and RBC (HR, 3.72; p < 0.001) or PLT (HR, 9.58; p = 0.001) transfusion dependence were significantly associated with poor survival, although type of MF did not significantly affect survival. Considering evidence supporting these results remains weak, further studies on the efficacy of ruxolitinib in other populations are needed.

Risk Factors for COVID-19 Morbidity and Mortality in Institutionalised Elderly People.

Background: SARS-CoV-2 has caused a high mortality in institutionalised individuals. There are very few studies on the involvement and the real impact of COVID-19 in nursing homes. This study analysed factors related to morbidity and mortality of COVID-19 in institutionalised elderly people. Methods: This cohort study included 842 individuals from 12 nursing homes in Sant Cugat del Vallès (Spain) from 15 March to 15 May 2020. We evaluated individual factors (demographic, dependence, clinical, and therapeutic) and those related to the nursing homes (size and staff) associated with infection and mortality by SARS-CoV-2. Infection was diagnosed by molecular biology test. Results: Of the 842 residents included in the analysis, 784 underwent a Polymerase Chain Reaction (PCR) test; 74.2% were women, the mean age was 87.1 years, and 11.1% died. The PCR test was positive in 44%. A total of 33.4% of the residents presented symptoms compatible with COVID-19 and of these, 80.9% were PCR-positive for SARS-CoV-2. Infection by SARS-CoV-2 among residents was associated with the rate of staff infected in the homes. Mortality by SARS-CoV-2 was related to male sex and a greater grade of dependence measured with the Barthel index. Conclusions: SARS-Cov-2 infection in institutionalised people is associated with the infection rate in nursing home workers and mortality by SARS-Cov-2 with sex and greater dependency according to the Barthel index. Adequate management of nursing home staff and special attention to measures of infection control, especially of individuals with greater dependence, are keys for successful management of future pandemic situations.

An international comparison of age and sex dependency of COVID-19 deaths in 2020: a descriptive analysis

The number of reported coronavirus disease (COVID-19) deaths per 100,000 persons observed so far in 2020 is described in 15 European countries and the USA as dependent on age groups and sex. It is compared with the corresponding historic all-cause mortality per year depending on age and sex observed in these countries. Some common features exist although substantial differences in age and sex dependency of COVID-19 mortality were noted between countries. An exponential increase with age is a good model to describe and analyze both COVID-19 and all-cause mortality above 40 years old, where almost all COVID-19 deaths occur. Moreover, age dependency is stronger for COVID-19 mortality than for all-cause mortality, and males have an excess risk compared with women, which is less pronounced in the higher age groups. Additionally, concerning calendar time, differences in the age and sex dependency between countries were noted with the common tendency that male excess risk for COVID-19 mortality was smaller in the second half of the year.

Are children exposed to light rare earth elements in urban environments?

BACKGROUND AND AIM: Human biomonitoring can provide invaluable information on exposure of a specific population to chemical pollutants to appropriately manage the threat. The aim was to identify whether children living in Alcalá de Henares, one of the biggest populated cities in the Community of Madrid (Spain), are exposed to rare earth elements (REEs), specifically cerium (Ce) and neodymium (Nd). METHODS: Scalp hair was collected from 120 children (6 to 9-years-old; 50 boys, 70 girls). Ce and Nd were analysed by ICP-MS after appropriate removal of exogenous contamination. Data was processed using different statistical models according to the detection frequency with the support of the ‘NADA’ statistical package. RESULTS:The limits of detection were (in µg/g): Ce (0.0048) and Nd (0.0028). Both REEs were detected in almost all the hair samples monitored (78.8% & 71.7%, respectively), which would suggest a general exposure to these contaminants as they have been poorly detected in scalp hair from other groups of population living in the Comunidad de Madrid. Concentrations are provided as median and interquartile range in µg/g: Ce 0.011 (0.005, 0.017) and Nd 0.004 (0.0028, 0.007). Both REEs did not show sex dependency, but Ce showed statistical significance according to zones of residency (p0.01); the mean concentration of Ce was lower in children’s hair living in areas with a higher density of green areas than in those with higher number of buildings/industrial activities (0.008 vs 0.014 µg/g). CONCLUSIONS:Alcalá’s children population have not been significantly exposed to Ce and Nd, as levels of Ce and Nd in scalp hair were of the same order of magnitude as those reported in the literature in non-exposed children. However, the implementation of interventions to minimise the environmental exposure REEs in Alcalá might be needed, as these can affect the physical growth and development, function of immune system and intelligence in children. KEYWORDS: Cerium, neodymium, human hair, monitoring, Spanish children, exposure.

Presence of elements associated with e-waste in teenagers living in Alcalá de Henares (Spain)

BACKGROUND AND AIM: Electronic and technological waste (e-waste) is growing fast in parallel with economic and technological development. Inappropriate disposal or processing of e-waste can have severe implications for the environment, with unknown harmful effects in humans. As a result, a human monitoring programme was performed to determine the exposure to elements commonly found in technology, specifically silver (Ag), antimony (Sb), bismuth (Bi) and neodymium (Nd), in Alcalá de Henares (Community of Madrid, Spain). METHODS: Scalp hair was collected from 96 adolescents (13-16 years-old; 28 boys and 68 girls) living in Alcalá, who were recruited following strict selection criteria to minimise the effect of confounding factors. Elements were analysed by ICP-MS in processed samples following appropriate methodologies. Data was processed using statistical methods applied to censored data available in the ‘NADA’ statistical package. RESULTS:The concentrations in scalp hair were as follows [data is presented as median and interquartile range (IQR) in µg/g]: Ag 0.065 (0.030, 0.222), Sb 0.009 (0.006, 0.015) and Bi 0.002 (0.001, 0.005). As Nd was detected only in 3.1% of the monitored samples, only the 97.5th percentile is provided for this element (0.013 µg/g). Only the levels of Ag showed sex dependency (p0.001), being higher in female participants (median values; 0.103 vs. 0.036), which is in agreement with the literature. The presence of these elements were lower relative to those reported in scalp hair from young adults from the Community of Madrid and also Italy, which indicate that Alcalá’s adolescents would have not been generally exposed to e-waste. Our results also might indicate minimal exposure to Nd, as the range found (0.015-0.030 µg/g) was much lower than that reported in exposed Chinese adolescents aged 11-15 (0.09-5.27 µg/g). CONCLUSIONS:Adolescents living in Alcalá de Henares should be regarded as a neglected risk group for e-waste exposure. KEYWORDS: E-waste, human hair, monitoring, Spanish teenagers, exposure.

Sex-Specific Influence of Gestational PM2.5 Exposure on Placental Metabolic Gene Expression within the Rhode Island Child Health Study (RICHS)

BACKGROUND AND AIM: Gestational exposure to ambient PM2.5 contributes to adverse metabolic health outcomes. Given the importance of the placenta in determining fetal growth and its potential to influence metabolic health outcomes in later life, we explored the influence of estimated ambient PM2.5 on placental metabolism in an infant sex-specific manner within the Rhode Island Child Health Study (RICHS). METHODS: Using Gene Ontology annotations, we identified 657 genes related to lipid and/or glucose metabolism. We first used existing RNA-Seq data on gene expression from the placentas of 148 term births to identify those genes whose expression was associated with PM2.5. We then validated the findings from this first stage using RT-PCR in placental samples from an additional 267 term births. Associations between pregnancy average PM2.5 levels and gene expression were quantified using linear regressions, overall and stratified by infant sex. RESULTS:PM2.5 was associated with expression of 32 genes (FDR 0.1) related to lipid or glucose metabolism, 24 of which exhibited sex-specific associations. We selected 5 genes ({ABHD3, ATP11A, PSCA, CLTCL1} and {ST6GALNAC4}) for validation via RT-PCR in a separate sample. PM2.5 was associated with expression of four of these genes ({ABHD3, ATP11A, PSCA} and {ST6GALNAC4}). In sex-stratified analyses, we found that PM2.5 was associated with {ABHD3, ATP11A} and {PSCA} in male infants only, while {ST6GALNAC4} showed no sex dependency. CONCLUSIONS:Placental metabolic gene expression was associated with PM2.5 levels during pregnancy, were over-represented for genes involved in lipid metabolism and demonstrated stronger associations in male infants. [NIH-NIEHS Funding: {P30ES023515, P30ES109776; R24ES028507, 2T32ES007324-16}]. KEYWORDS: PM2.5, placenta, metabolism, sex, pregnancy

Bone mineral density modeling via random field: Normality, stationarity, sex and age dependence

Background and ObjectiveCapturing the population variability of bone properties is of paramount importance to biomedical engineering. The aim of the present paper is to describe variability and correlations in bone mineral density with a spatial random field inferred from routine computed tomography data. MethodsRandom fields were simulated by transforming pairwise uncorrelated Gaussian random variables into correlated variables through the spectral decomposition of an age-detrended correlation matrix. The validity of the random field model was demonstrated in the spatiotemporal analysis of bone mineral density. The similarity between the computed tomography samples and those generated via random fields was analyzed with the energy distance metric. ResultsThe random field of bone mineral density was found to be approximately Gaussian/slightly left-skewed/strongly right-skewed at various locations. However, average bone density could be simulated well with the proposed Gaussian random field for which the energy distance, i.e., a measure that quantifies discrepancies between two distribution functions, is convergent with respect to the number of correlation eigenpairs. ConclusionsThe proposed random field model allows the enhancement of computational biomechanical models with variability in bone mineral density, which could increase the usability of the model and provides a step forward in in-silico medicine.

Sex-Specific Pharmacotherapy for Back Pain: A Proof-of-Concept Randomized Trial.

BackgroundPreventing transition to chronic back pain (CBP) is a long-sought strategy that could rescue patients from prolonged suffering. Recent rodent and human brain imaging studies suggest involvement of sexually dimorphic, dopaminergic-motivational, mesolimbic circuits in the transition to chronic pain (tCBP), and hint that the combination of carbidopa/levodopa and naproxen (LDP + NPX) may block tCBP. Here we evaluated, in people with recent-onset back pain, whether a 3-month treatment with LDP + NPX is safe, blocks tCBP, and whether its efficacy is sex-dependent.MethodsA total of 72 participants were enrolled and stratified by risk for tCBP using brain-imaging biomarkers. Low-risk participants entered a no-treatment arm. Others were randomized to placebo + naproxen or LDP + NPX for 3 months.ResultsBoth treatments resulted in more than 50% pain relief for approximately 75% of participants. A strong sex by treatment interaction was observed for daily pain intensity (phone NRS, P = 0.007), replicated on 4-week average pain (Pain/4w, P = 0.00001), and in intent-to-treat analysis (Pain/4w, P = 0.000004). Nucleus accumbens functional connectivity with medial prefrontal cortex, a predefined objective biomarker, showed sex dependence at baseline (P = 0.03) and sex-by-treatment interaction effect 3 months after treatment cessation (P = 0.031). Treatment modified the psychological profile of participants, and disrupted brain modeling-based predicted back pain intensity trajectories. Forty participants were queried 3.3 years from trial start; back pain ratings were similar between end of treatment and at 3.3 years (P = 0.62), indicating persistence of relief for this duration.ConclusionsThese results provide the first evidence for preventing transition to chronic back pain using sex-specific pharmacotherapy. These provocative observations require confirmation in a larger study. ClinicalTrials.gov identifier: NCT01951105.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40122-021-00297-2.