Endocrine-disrupting chemical concentrations in follicular fluid and follicular reproductive hormone levels.

PURPOSE: To determine correlations between chemicals in follicular fluid (FF) and follicular reproductive hormone levels. METHODS: The analysis was part of a larger cohort study to determine associations between exposure to EDCs and in vitro fertilization (IVF) outcomes. FF was aspirated from a single leading follicle per participant. Demographics and data on exposure to EDCs were self-reported by the participants using a questionnaire. The concentrations of estradiol (E2), progesterone (PG), anti-Mullerian hormone (AMH), and inhibin B, as well as that of 12 phthalate metabolites and 12 phenolic chemicals were measured in each FF sample. Multivariate linear regression model was used to identify the drivers of hormone levels based on participant's age, BMI, smoking status, and chemical exposure for the monitored chemicals detected in more than 50% of the samples. Benjamini-Hochberg false discovery rate (FDR) correction was applied on the resulting p values (q value). RESULTS: FF samples were obtained from 72 women (mean age 30.9 years). Most of the phthalates and phenolic substances monitored (21/24, 88%) were identified in FF. Ten compounds (7 phthalate metabolites, 3 phenols) were found in more than 50% of samples. In addition, there were positive associations between E2 levels and mono-n-butyl phthalate (MnBP) (beta = 0.01) and mono-isobutyl phthalate (MiBP) (beta = 0.03) levels (q value < 0.05). CONCLUSION: Higher concentrations of several phthalate metabolites, present among others in personal care products, were associated with increased E2 levels in FF. The results emphasize the need to further investigate the mechanisms of action of such EDCs on hormonal cyclicity and fertility in women.

Evaluating distance stereoacuity in children 4-17 years of age with a novel digital application.

Distance stereoacuity measurement enables the evaluation and management of binocular vision disorders. Here, we compare the results obtained using standard tests for distance stereoacuity measurement with the novel STab test. We tested 87 children (4-17 years of age) using different tests for the quantification of stereopsis at distance: Distance Randot Stereotest (DRS), M&S random dots (M&S), and STab. A strong correlation was demonstrated between M&S-DRS (0.8), M&S-STab (0.81), DRS-STab (0.85) (all P < 0.0001). The limit of agreement between M&S and DRS was 0.45; between M&S and STab, 0.47; and between DRS and STab, 0.38. Our results suggest that all three methods can be used interchangeably.

Association between parental smoking and child exposure to environmental tobacco smoke in Israel.

BACKGROUND: Environmental tobacco smoke (ETS) exposure in children can cause delayed lung development and lifelong cardiovascular damage. The aim of this study was to measure ETS exposure in children in Israel in 2020-2021 using urinary cotinine (UC) measurements and to assess correlates of ETS exposure, including parental smoking. METHODS: In the framework of the National Human Biomonitoring Program, spot urine samples and questionnaire data were collected from 166 children aged 4-12 years, during the years 2020-2021. We collected urine samples in 233 adults, 69 of whom were parents of children included in the study. Parents of participating children were asked about parental smoking, child's exposure to ETS and smoking policy at home. Cotinine and creatinine were measured in urine. Creatinine-adjusted and unadjusted urine cotinine (UC) geometric means were calculated. Associations between potential correlates and UC concentrations were analyzed in univariate and multivariate analyses. For 69 child-parent pairs, correlation between child and parental UC was analyzed. RESULTS: Based on urinary cotinine measurement, 65.2% of children of smokers are exposed to ETS, compared to 20.7% of children in non-smoking families. Greater numbers of smokers living in the home (beta = 1.27, p < 0.01), and low maternal education (beta = - 2.32, p < 0.01) were associated with higher levels of UC in a multivariate analysis. Spearman correlations showed a positive moderate correlation between UC in 69 child-parent pairs (r = 0.52, p < 0.01). CONCLUSIONS: In order to reduce child exposure to ETS, smoking parents should be urgently targeted for smoking cessation and smoke-free home interventions. Further interventions are needed to protect all children from ETS.

The effect of heatwaves on the number of visits to national parks and reserves.

BACKGROUND: Climate change is leading to an increase in the frequency and intensity of heatwaves in many regions of the world. Climate change is also related to air pollution. Both heatwaves and air pollution have adverse health effects, and can also affect social behaviors, including tourism and touristic activities. The aim of this study was to examine the association between heatwaves, air pollution and visits to national parks and reserves in Israel. METHODS: Data on 68,518 visits in 51 national parks and reserves in Israel in the years 2016-2019 was crossed with temperature and air pollution data (represented by particulate matter PM10) and analyzed using statistical tests. RESULTS: Number of visits, as a function of temperature followed a unimodal distribution, in which more visits were reported on mild temperature days (in comparison to hot or cold days). In addition, the number of visits in sites with beaches was linearly correlated with temperature. Negative associations were found between number of visits and heatwaves, and between number of visits and exceedances in PM10 levels. CONCLUSIONS: Heatwaves were shown to have a negative effect on the number of visits in national parks and reserves in Israel. The negative association between exceedances in air pollution and number of visits may be mediated by the positive correlation between air pollution exceedance events and heatwaves.

Antimicrobial resistance in food-producing animals: towards implementing a one health based national action plan in Israel.

BACKGROUND: Development of antimicrobial resistance poses a major threat to human and animal health worldwide. Antimicrobials are frequently used in animal husbandry, making food-producing animals a widespread and important source of antimicrobial resistance. Indeed, recent evidence demonstrates that antimicrobial resistance in food-producing animals poses a threat to the health of humans, animals and the environment. To address this threat, national action plans have been implemented based on a 'One Health' approach, which integrates actions across human and animal health sectors to combat antimicrobial resistance. Although under development, Israel has yet to publish a national action plan against antimicrobial resistance, despite alarming findings of resistant bacteria in food-producing animals in the country. Here we review several national action plans against antimicrobial resistance around the world in order to suggest approaches to develop a national action plan in Israel. MAIN BODY: We investigated worldwide national action plans against antimicrobial resistance based on a 'One Health' approach. We also conducted interviews with representatives of relevant Israeli ministries to understand antimicrobial resistance policy and regulatory frameworks in Israel. Finally, we present recommendations for Israel towards implementing a 'One Health' national action plan against antimicrobial resistance. Many countries have developed such plans, however, only a few are currently funded. Furthermore, many countries, especially in Europe, have taken action to reduce the use of antimicrobials and the spread of antimicrobial resistance in food-producing animals by banning the use of antimicrobials to promote growth, reporting data on the use and sales of antimicrobials in food-producing animals, operating centralized antimicrobial resistance surveillance systems and preventing the use of antimicrobials important to human medicine to treat food-producing animals. CONCLUSIONS: Without a comprehensive and funded national action plan, the risks of antimicrobial resistance to the public health in Israel will escalate. Thus, several actions should be considered: (1) Reporting data on the use of antimicrobials in humans and animals. (2) Operating a centralized surveillance system for antimicrobial resistance in humans, animals and the environment. (3) Improving awareness regarding antimicrobial resistance in the general public and in health practitioners from both human and animal sectors. (4) Composing a list of critically important antimicrobials to human medicine that's use should be avoided in food-producing animals. (5) Enforcing best practices of antimicrobial use at the farm-level. (6) Reducing incidence of infection through farm biosecurity. (7) Supporting research and development of new antimicrobial treatments, vaccines and diagnostic tools.

Deep convolution neural network for screening carotid calcification in dental panoramic radiographs.

Ischemic stroke, a leading global cause of death and disability, is commonly caused by carotid arteries atherosclerosis. Carotid artery calcification (CAC) is a well-known marker of atherosclerosis. Such calcifications are classically detected by ultrasound screening. In recent years it was shown that these calcifications can also be inferred from routine panoramic dental radiographs. In this work, we focused on panoramic dental radiographs taken from 500 patients, manually labelling each of the patients' sides (each radiograph was treated as two sides), which were used to develop an artificial intelligence (AI)-based algorithm to automatically detect carotid calcifications. The algorithm uses deep learning convolutional neural networks (CNN), with transfer learning (TL) approach that achieved true labels for each corner, and reached a sensitivity (recall) of 0.82 and a specificity of 0.97 for individual arteries, and a recall of 0.87 and specificity of 0.97 for individual patients. Applying and integrating the algorithm in healthcare units and dental clinics has the potential of reducing stroke events and their mortality and morbidity consequences.

Influence of exposure to pesticides on telomere length and pregnancy outcome: Diethylphosphates but not Dimethylphosphates are associated with accelerated telomere attrition in a Palestinian cohort.

Exposure to environmental pesticides during pregnancy is associated with adverse health outcomes such as low birth weight and impaired neuro-development. In this study, we assessed maternal leukocyte telomere lengths (TL) in Palestinian pregnant women and compared the data with urinary organophosphate concentrations, demographic, lifestyle and dietary factors, birth weight, body length, gestational age, and head circumference. Women with high urine levels of creatinine adjusted diethylphosphate(DE)derived pesticide metabolites DEP, DETP or DEDTP had shorter telomeres (p = 0.05). Women living in proximity to agricultural fields had shorter telomeres compared to women not living in proximity to agricultural fields (p = 0.011). Regular consumption of organic food was associated with shorter telomeres (p = 0.01), whereas the consumption of other vegetables such as artichokes was rather associated with longer telomeres. By contrast, urine levels of dimethylphosphate(DM)-derived pesticide metabolites DMTP and DMDTP were associated with lower birth weight (p = 0.05) but not with shrter telomeres. In conclusion organophosphate pesticides and living in proximity to agriculture are associated with shorter TL, likely due to higher consumption of contaminated fruits and vegetables and/or the transport of pesticides to non-treatment sites. DE and DM substituted pesticides seem to have different effects on telomeres and development.

Harmonized human biomonitoring in European children, teenagers and adults: EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014-2021).

As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures.

A Tiered Approach for Assessing Individual and Combined Risk of Pyrethroids Using Human Biomonitoring Data.

Pyrethroids are a major insecticide class, suitable for biomonitoring in humans. Due to similarities in structure and metabolic pathways, urinary metabolites are common to various active substances. A tiered approach is proposed for risk assessment. Tier I was a conservative screening for overall pyrethroid exposure, based on phenoxybenzoic acid metabolites. Subsequently, probabilistic approaches and more specific metabolites were used for refining the risk estimates. Exposure was based on 95th percentiles from HBM4EU aligned studies (2014-2021) covering children in Belgium, Cyprus, France, Israel, Slovenia, and The Netherlands and adults in France, Germany, Israel, and Switzerland. In all children populations, the 95th percentiles for 3-phenoxybenzoic acid (3-PBA) exceeded the screening value. The probabilistic refinement quantified the risk level of the most exposed population (Belgium) at 2% or between 1-0.1% depending on the assumptions. In the substance specific assessments, the 95th percentiles of urinary concentrations in the aligned studies were well below the respective human biomonitoring guidance values (HBM-GVs). Both information sets were combined for refining the combined risk. Overall, the HBM data suggest a low health concern, at population level, related to pyrethroid exposure for the populations covered by the studies, even though a potential risk for highly exposed children cannot be completely excluded. The proposed tiered approach, including a screening step and several refinement options, seems to be a promising tool of scientific and regulatory value in future.

Improving the Risk Assessment of Pesticides through the Integration of Human Biomonitoring and Food Monitoring Data: A Case Study for Chlorpyrifos.

The risk assessment of pesticide residues in food is a key priority in the area of food safety. Most jurisdictions have implemented pre-marketing authorization processes, which are supported by prospective risk assessments. These prospective assessments estimate the expected residue levels in food combining results from residue trials, resembling the pesticide use patterns, with food consumption patterns, according to internationally agreed procedures. In addition, jurisdictions such as the European Union (EU) have implemented large monitoring programs, measuring actual pesticide residue levels in food, and are supporting large-scale human biomonitoring programs for confirming the actual exposure levels and potential risk for consumers. The organophosphate insecticide chlorpyrifos offers an interesting case study, as in the last decade, its acceptable daily intake (ADI) has been reduced several times following risk assessments by the European Food Safety Authority (EFSA). This process has been linked to significant reductions in the use authorized in the EU, reducing consumers' exposure progressively, until the final ban in 2020, accompanied by setting all EU maximum residue levels (MRL) in food at the default value of 0.01 mg/kg. We present a comparison of estimates of the consumer's internal exposure to chlorpyrifos based on the urinary marker 3,5,6-trichloro-2-pyridinol (TCPy), using two sources of monitoring data: monitoring of the food chain from the EU program and biomonitoring of European citizens from the HB4EU project, supported by a literature search. Both methods confirmed a drastic reduction in exposure levels from 2016 onwards. The margin of exposure approach is then used for conducting retrospective risk assessments at different time points, considering the evolution of our understanding of chlorpyrifos toxicity, as well as of exposure levels in EU consumers following the regulatory decisions. Concerns are presented using a color code, and have been identified for almost all studies, particularly for the highest exposed group, but at different levels, reaching the maximum level, red code, for children in Cyprus and Israel. The assessment uncertainties are highlighted and integrated in the identification of levels of concern.

Results of the national biomonitoring program show persistent iodine deficiency in Israel.

BACKGROUND: Adequate iodine intake is essential for human health, for normal thyroid function, and for attainment of full intellectual potential in children. In light of Israel's lack of a mandatory salt fortification policy, heavy reliance on desalination and low iodine intake from dairy products and seafood, there is concern in Israel that the population is iodine deficient. Indeed, the first Israeli National Iodine Survey in 2016 found a median urinary iodine concentration (UIC) of 83 µg/L among school age children, falling below the WHO's adequacy range of 100-299 µg/L for children. METHODS: In the framework of the National Human Biomonitoring Program in Israel, spot urine samples and questionnaire data were collected from 166 healthy children aged 4-12 years in 2020-2021. Urinary iodine concentrations were measured at the Ministry of Health National Biomonitoring Laboratory, using mass spectrometry. An international comparison of median urinary iodine concentrations (UIC) was performed taking into consideration the levels of desalinated water per capita, and fortification policies. RESULTS: The overall median (interquartile range [IQR]) UIC was 80.1 µg/L (44.7-130.8 µg/L) indicating that the population's iodine status has not improved in the five years that have passed since inadequacy was first identified. When comparing 13 countries with population size above 150,000, whose desalinated water per capita was at least 1 m3, Israel and Lebanon were the only countries with median UIC below the WHO adequacy range. CONCLUSIONS: There is an urgent need for mandatory salt fortification in Israel. Based on our international comparison, we conclude that the potential impact of desalination on iodine intake can be compensated for using the implementation of salt fortification policy. This study highlights the critical need for public health surveillance of nutritional and environmental exposures using human biomonitoring, with emphasis on vulnerable populations such as pregnant women and children.

Lead in children's jewelry: the impact of regulation.

BACKGROUND: In 2016 we identified a regulatory gap in Israel reflecting a lack of restrictions on lead in children's jewelry. We conducted surveys that found high levels of lead in children's jewelry. Following the findings, a new standard restricting lead content was introduced in 2018. OBJECTIVE: The goal of this study is to assess whether the new standard had an impact on lead concentrations in children's jewelry on the market 4 months after entry into force, and to examine factors that influenced the standard's effectiveness. METHODS: Thirty-five items of children's jewelry were sampled from stores in Israel in 2018. Lead content of 130 subsamples of these items was tested with X-ray Fluorescence Spectrometry (XRF). We compared these findings to those before the introduction of the standard. We also conducted five structured interviews with professionals from government ministries, industry and expert bodies to examine factors influencing the standard's enactment and implementation. RESULTS: 17% of jewelry samples exceeded the ASTM lead standard in 2018 compared with 50% in 2016. The mean of the jewelry subsamples analyzed in 2018 was 936 (±1700) compared to 1420 (±5740) ppm in 2016. Scientific and regulatory consensus among those setting the new standard led to its swift enactment. However, enforcement challenges may reduce the standard's impact. SIGNIFICANCE: A new standard on lead in children's jewelry was followed by a decline in lead concentrations, but some products with lead exceedances remained available on the market. Public health campaigns, standards and compliance monitoring, and higher penalties will all help to reach the goal of protecting public health.

Hazardous chemicals in outdoor and indoor surfaces: artificial turf and laminate flooring.

BACKGROUND: Synthetic materials, increasingly used for indoor and outdoor surfaces including homes and playgrounds, may contain toxic chemicals. Infants have a higher potential of exposure to chemicals in these materials, which may pose a risk to their health. OBJECTIVE: To understand potential risks related to outdoor surface coverings, based on a review of the literature and regulations, and to assess levels of hazardous chemicals in surface coverings in Israel. METHODS: We reviewed the literature and regulations on artificial turf. We tested 46 samples of surfaces for trace metals in synthetic playground surfaces; trace metals, phthalates, and di(2-ethylhexyl) terephthalate (DEHT) in synthetic grass, and phthalates, DEHT and formaldehyde in laminate flooring. RESULTS: Twelve studies reporting high levels of polycyclic aromatic hydrocarbons (PAH), and varying levels of trace metals in synthetic playground surfaces were identified, as well as five international regulations on lead with maximum acceptable concentrations in the range 40-500 mg/kg. Surface tests showed that 20 out of 30 samples of synthetic playground surfaces exceeded relevant standards for trace metals, of which five had cadmium levels ≥30 mg/kg and four had chromium levels ≥510 mg/kg. In synthetic grass, three out of eight samples exceeded relevant standards, with lead levels ≥1200 mg/kg. In Laminate flooring (n = 8) formaldehyde levels were in the range of 0.7-1.2 mg/m2 formaldehyde, and five samples contained ~5% DEHT. SIGNIFICANCE: The literature on chemicals in surfaces is limited, but indicates some exceedance of regulatory limits. Trace metals in synthetic playground surfaces and synthetic grass, not regulated in Israel, exceeded relevant international standards in 72% of samples. Laminate flooring, regulated for formaldehyde, did not exceed the 3.5 mg/m2 standard, but contained DEHT, a replacement for ortho-substituted phthalates. The results of this preliminary study show that flooring surfaces may be a source of children's exposure to toxic chemicals. IMPACT STATEMENT: Synthetic surfaces are increasingly being used in, for example, children's playgrounds and sports fields. Exceedances of regulatory limits from other jurisdictions, of heavy metal levels in most outdoor surfaces sampled in Israel indicates the potential for children's exposure. Domestic regulations should be implemented to reduce the risk to children from exposure to these surfaces.

MRI guided focused ultrasound (MRgFUS) treatment for uterine fibroids among women with and without abdominal scars.

INTRODUCTION: MRI guided focused ultrasound (MRgFUS) is a noninvasive technique for treating uterine fibroids. The presence of abdominal scars can limit the number of women eligible for the procedure, due to absorbance of beam energy. The goals of this study were to assess the number of women that fit the procedure and to compare outcomes among women with or without abdominal scars. MATERIAL AND METHODS: A prospective cohort study of all women that were interested in MRgFUS in a single University-Affiliated Hospital between November 2012 and December 2019. Rates of women that were referred to further screening, fulfilled selection criteria and underwent the procedure were compared between patients with or without abdominal scars. We evaluated the treatment parameters of the two groups and used linear regression model predict non-perfused volume (NPV) at the end of the process. RESULTS: Out of 701 patients, 21.8% were suitable for MRgFUS. Women with scars had significant lower NPV compared with women without scars (60% versus 82.4%, p = 0.021). No serious adverse events were reported in both groups. Linear regression models showed that fibroids' volume, stopping the treatment due to severe pain and the presence of abdominal scars had a statistically significantly negative effect on NPV (betas: -11.51, -6.96, and -6.29, p-values: <0.001, 0.003, and 0.007 respectively), while number of sonication had a statistically significantly positive effect on NPV (beta = 5.98, p = 0.011). CONCLUSION: Regardless of strict inclusion criteria, MRgFUS treatment is less efficient among women with abdominal scars, although still feasible for those who are interested in noninvasive option.

The dynamic optotype (Dyop): a novel visual acuity test for use in children.

PURPOSE: To evaluate the "dynamic optotype" (Dyop), a simple visual acuity test based on a dynamic target that requires minimal knowledge of symbols and letters. METHODS: A total of 160 consecutive, systemically healthy children, 4-17 years of age were prospectively recruited from the Pediatric Ophthalmology Unit of Meir Medical Center. Children were tested with the Dyop visual acuity test and the Early Treatment Diabetic Retinopathy Study (ETDRS) Lea numbers chart. The results of both tests were compared. The eye with the poorest acuity was tested with the new Dyop eye chart and the Lea numbers chart. The order of the testing was reversed between children. The logMAR visual acuity scores for each eye chart were compared. RESULTS: We found a strong linear correlation (r = 0.88) between visual acuity measures. The mean difference in visual acuity was -0.01 (95% CI, -0.02 to 0.01). The 95% limits of agreement were ±1.2 lines. The logMAR equivalent mean difference was about less than 1 letter. The Dyop test underestimated visual acuity relative to the Lea numbers chart. CONCLUSIONS: The results of this study support the Dyop eye chart as a valid measure of visual acuity in children 4-17 years of age, with visual acuity ranging from 20/16 to 20/200.

Prediction of vaccine hesitancy based on social media traffic among Israeli parents using machine learning strategies.

INTRODUCTION: Vaccines have contributed to substantial reductions of morbidity and mortality from vaccine-preventable diseases, mainly in children. However, vaccine hesitancy was listed by the World Health Organization (WHO) in 2019 as one of the top ten threats to world health. AIM: To employ machine-learning strategies to assess how on-line content regarding vaccination affects vaccine hesitancy. METHODS: We collected social media posts and responses from vaccination discussion groups and forums on leading social platforms, including Facebook and Tapuz (A user content website that contains blogs and forums). We investigated 65,603 records of children aged 0-6 years who are insured in Maccabi's Health Maintenance Organization (HMO). We applied three machine learning algorithms (Logistic regression, Random forest and Neural networks) to predict vaccination among Israeli children, based on demographic and social media traffic. RESULTS: Higher hesitancy was associated with more social media traffic, for most of the vaccinations. The addition of the social media traffic features improved the performances of most of the models. However, for Rota virus, Hepatitis A and hepatitis B, the performances of all algorithms (with and without the social media features) were close to random (accuracy up to 0.63 and F1 up to 0.65). We found a negative association between on-line discussions and vaccination. CONCLUSIONS: There is an association between social media traffic and vaccine hesitancy. Policy makers are encouraged to perceive social media as a main channel of communication during health crises. Health officials and experts are encouraged to take part in social media discussions, and be equipped to readily provide the information, support and advice that the public is looking for, in order to optimize vaccination actions and to improve public health.

Optimizing prediction of response to antidepressant medications using machine learning and integrated genetic, clinical, and demographic data.

Major depressive disorder (MDD) is complex and multifactorial, posing a major challenge of tailoring the optimal medication for each patient. Current practice for MDD treatment mainly relies on trial and error, with an estimated 42-53% response rates for antidepressant use. Here, we sought to generate an accurate predictor of response to a panel of antidepressants and optimize treatment selection using a data-driven approach analyzing combinations of genetic, clinical, and demographic factors. We analyzed the response patterns of patients to three antidepressant medications in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and employed state-of-the-art machine learning (ML) tools to generate a predictive algorithm. To validate our results, we assessed the algorithm's capacity to predict individualized antidepressant responses on a separate set of 530 patients in STAR*D, consisting of 271 patients in a validation set and 259 patients in the final test set. This assessment yielded an average balanced accuracy rate of 72.3% (SD 8.1) and 70.1% (SD 6.8) across the different medications in the validation and test set, respectively (p < 0.01 for all models). To further validate our design scheme, we obtained data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) of patients treated with citalopram, and applied the algorithm's citalopram model. This external validation yielded highly similar results for STAR*D and PGRN-AMPS test sets, with a balanced accuracy of 60.5% and 61.3%, respectively (both p's < 0.01). These findings support the feasibility of using ML algorithms applied to large datasets with genetic, clinical, and demographic features to improve accuracy in antidepressant prescription.

Effects of chronic exposure to ambient air pollutants, demographic, and socioeconomic factors on COVID-19 morbidity: The Israeli case study.

BACKGROUND: Recent studies conducted in several OECD countries have shown that chronic exposure to elevated levels of air pollutants (especially PM2.5, PM10 and NOx), might negatively impact COVID-19 morbidity and mortality rates. The aim of this study was to examine the association between chronic exposure to air pollution in Israeli cities and towns, their demographic and socioeconomic status, and COVID-19 morbidity, during the three local morbidity waves. METHODS: We examined the associations between: (a) annual average concentrations of NOx, CO, PM10, PM2.5 and SO2 in 2016-2019, and demographic and socioeconomic parameters, and (b) COVID-19 positive cases in 279 Israeli cities and towns, in the four state-wide morbidity peaks: 1st wave peak: March 31st, 2020; 2nd wave peaks: July 24th and September 27th, 2020, and the 3rd wave peak: January 17th, 2021, which occurred after the beginning of the nationwide vaccination campaign. These associations were calculated using both Spearman correlations and multivariate linear regressions. RESULTS: We found statistically significant positive correlations between the concentrations of most pollutants in 2016-19 and COVID-19 morbidity rate at the first three timepoints but not the 4th (January 17th, 2021). Population density and city/town total population were also positively associated with the COVID-19 morbidity rates at these three timepoints, but not the 4th, in which socioeconomic parameters were more dominant - we found a statistically significant negative correlation between socioeconomic cluster and COVID-19 morbidity. In addition, all multivariate models including PM2.5 concentrations were statistically significant, and PM2.5 concentrations were positively associated with the COVID-19 morbidity rates in all models. CONCLUSIONS: We found a nationwide association between population chronic exposure to five main air pollutants in Israeli cities and towns, and COVID-19 morbidity rates during two of the three morbidity waves experienced in Israel. The widespread morbidity that was related to socioeconomic factors during the 3rd wave, emphasizes the need for special attention to morbidity prevention in socioeconomically vulnerable populations and especially in large household communities. Nevertheless, this ecological study has several limitations, such as the inability to draw conclusions about causality or mechanisms of action. The growing body of evidence, regarding association between exacerbated COVID-19 morbidity and mortality rates and long-term chronic exposure to elevated concentrations of air pollutants should serve as a wake-up call to policy makers regarding the urgent need to reduce air pollution and its harmful effects.

Association between follicular fluid phthalate concentrations and extracellular vesicle microRNAs expression.

STUDY QUESTION: Are phthalate metabolite concentrations in follicular fluid (FF) associated with the expression of extracellular vesicle microRNAs (EV-miRNAs)? SUMMARY ANSWER: Phthalate metabolite concentrations are associated with the expression of EV-miRNA and their associated pathways in FFs. WHAT IS KNOWN ALREADY: Phthalate metabolites were recently detected in FF. Urinary phthalate metabolite concentrations alter the expression of EV-miRNAs in FF. STUDY DESIGN, SIZE, DURATION: Prospective study including 105 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed FF concentrations of 12 phthalate metabolites. EV-miRNAs were isolated from aliquots of the same FF, and their expression profiles were measured using a human miRNA panel. Associations between EV-miRNAs that were present in >50% of the samples and phthalate metabolites that were measured in >74% of the FF samples were tested. Genes regulated by EV-miRNAs that were found to be significantly (false discovery rate q-value < 0.1) correlated with FF-phthalates were analyzed for pathways linked with female fertility using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources and Kyoto Encyclopedia of Genes and Genomes (KEGG). MAIN RESULTS AND THE ROLE OF CHANCE: Of 12 phthalate metabolites, 11 were measured in at least one FF sample. Mono (6-COOH-2-methylheptyl) phthalate (MCOMHP), mono-2-ethyl-5-carboxypentyl phthalate (mECPP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP) and mono (7-COOH-2-methyloctyl) phthalate (MCOMOP) were detected in more than 74% of the samples. Of 754 EV-miRNAs tested, 39 were significantly associated either with MEP, MBzP, MCOMOP, MCOMHP and/or with mECPP, after adjusting for multiple testing (P < 0.05). KEGG-based pathway enrichment analysis of the genes regulated by these miRNAs showed that these EV-miRNAs may be involved in pathways related to ovary or oocyte development, maturation and fertilization. LIMITATIONS, REASONS FOR CAUTION: The use of miRNA panel array limits the number of potential relevant miRNAs. Moreover, several of the phthalate metabolites examined may be biased due to internal (enzymatic activity) or external (contamination in medical interventions) causes. WIDER IMPLICATIONS OF THE FINDINGS: Phthalate metabolites may alter follicular EV-miRNAs profile and thus impair pathways that are involved with oocyte development, maturation and fertilization. Our results contribute to understanding of possible mechanism(s) in which endocrine disruptor chemicals interfere with female fertility. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Institutes of Environmental Health Sciences [Grant R21-ES024236]; and Environmental Health Fund, Israel [Grant 1301], no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Effects of chronic exposure to ambient air pollutants on COVID-19 morbidity and mortality - A lesson from OECD countries.

BACKGROUND: Exposure to ambient air pollution is related to 4.2 million premature deaths per year worldwide and is associated with a variety of adverse health outcomes, such as respiratory and cardiovascular morbidity. Furthermore, exposure to air pollution can increase human sensitivity to respiratory pathogens via damage to the respiratory tract or via airborne transmission on the surface of particulate matter, and might be an additional factor influencing COVID-19 morbidity and mortality rates. The aim of this study was to examine the association between populations' exposure to air pollution and the morbidity and mortality rates from COVID-19. METHODS: We examined the association between population-weighted long-term exposure to PM2.5 and NOx, and the morbidity and mortality over time following the detection of the first COVID-19 positive case in 36 OECD countries. Pearson and Spearman correlations between daily COVID-19 morbidity and mortality (Jan-Jun 2020) on the 10th, 20th, 40th, 60th and 80th days since first confirmed case in the country, and demographic, health, economic, and environmental data were calculated. Multivariate linear regression were used to examine the associations between demographic, health, economic and air pollution features and the rate of confirmed cases and deaths on the 60th and 80th days following the first confirmed case. RESULTS: PM2.5 concentrations in 2015-2017 were positively correlated with COVID-19 morbidity and mortality on the 10th, 20th, 40th and 60th days since the first confirmed case in all countries. NOx concentrations in 2015-2017 and country's density (population/Km2) were positively correlated with COVID-19 morbidity and mortality on the 60th day. All multivariate linear regressions consisting PM2.5 concentrations models were statistically significant. Our models also emphasize the importance of the relative number of hospital beds in decreasing the morbidity and mortality of COVID-19. CONCLUSIONS: The adverse health outcomes stemming from long-term exposure to various air pollutants has long been known to the scientific community. According to our results and previously published studies, it appears that long-term exposure to air pollutants concentrations exceeding WHO guidelines, such as PM2.5 and NOx, might exacerbate morbidity and mortality rates from COVID-19. These results should raise a red flag globally among decision makers about the urgent need to reduce air pollution and its harmful effects.