Identification of ALK in Thinness.

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.

Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and Estonian infants. Therefore, their lipopolysaccharide (LPS) exposures arose primarily from Bacteroides rather than from Escherichia coli, which is a potent innate immune activator. We show that Bacteroides LPS is structurally distinct from E. coli LPS and inhibits innate immune signaling and endotoxin tolerance; furthermore, unlike LPS from E. coli, B. dorei LPS does not decrease incidence of autoimmune diabetes in non-obese diabetic mice. Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education.

FinnGen provides genetic insights from a well-phenotyped isolated population.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Improving GWAS discovery and genomic prediction accuracy in biobank data.

Genetically informed, deep-phenotyped biobanks are an important research resource and it is imperative that the most powerful, versatile, and efficient analysis approaches are used. Here, we apply our recently developed Bayesian grouped mixture of regressions model (GMRM) in the UK and Estonian Biobanks and obtain the highest genomic prediction accuracy reported to date across 21 heritable traits. When compared to other approaches, GMRM accuracy was greater than annotation prediction models run in the LDAK or LDPred-funct software by 15% (SE 7%) and 14% (SE 2%), respectively, and was 18% (SE 3%) greater than a baseline BayesR model without single-nucleotide polymorphism (SNP) markers grouped into minor allele frequency-linkage disequilibrium (MAF-LD) annotation categories. For height, the prediction accuracy R2 was 47% in a UK Biobank holdout sample, which was 76% of the estimated [Formula: see text]. We then extend our GMRM prediction model to provide mixed-linear model association (MLMA) SNP marker estimates for genome-wide association (GWAS) discovery, which increased the independent loci detected to 16,162 in unrelated UK Biobank individuals, compared to 10,550 from BoltLMM and 10,095 from Regenie, a 62 and 65% increase, respectively. The average [Formula: see text] value of the leading markers increased by 15.24 (SE 0.41) for every 1% increase in prediction accuracy gained over a baseline BayesR model across the traits. Thus, we show that modeling genetic associations accounting for MAF and LD differences among SNP markers, and incorporating prior knowledge of genomic function, is important for both genomic prediction and discovery in large-scale individual-level studies.

Patterns of genetic connectedness between modern and medieval Estonian genomes reveal the origins of a major ancestry component of the Finnish population.

The Finnish population is a unique example of a genetic isolate affected by a recent founder event. Previous studies have suggested that the ancestors of Finnic-speaking Finns and Estonians reached the circum-Baltic region by the 1st millennium BC. However, high linguistic similarity points to a more recent split of their languages. To study genetic connectedness between Finns and Estonians directly, we first assessed the efficacy of imputation of low-coverage ancient genomes by sequencing a medieval Estonian genome to high depth (23×) and evaluated the performance of its down-sampled replicas. We find that ancient genomes imputed from >0.1× coverage can be reliably used in principal-component analyses without projection. By searching for long shared allele intervals (LSAIs; similar to identity-by-descent segments) in unphased data for >143,000 present-day Estonians, 99 Finns, and 14 imputed ancient genomes from Estonia, we find unexpectedly high levels of individual connectedness between Estonians and Finns for the last eight centuries in contrast to their clear differentiation by allele frequencies. High levels of sharing of these segments between Estonians and Finns predate the demographic expansion and late settlement process of Finland. One plausible source of this extensive sharing is the 8th-10th centuries AD migration event from North Estonia to Finland that has been proposed to explain uniquely shared linguistic features between the Finnish language and the northern dialect of Estonian and shared Christianity-related loanwords from Slavic. These results suggest that LSAI detection provides a computationally tractable way to detect fine-scale structure in large cohorts.

Isolation and characterization of a phage collection against Pseudomonas putida.

The environmental bacterium, Pseudomonas putida, possesses a broad spectrum of metabolic pathways. This makes it highly promising for use in biotechnological production as a cell factory, as well as in bioremediation strategies to degrade various aromatic pollutants. For P. putida to flourish in its environment, it must withstand the continuous threats posed by bacteriophages. Interestingly, until now, only a handful of phages have been isolated for the commonly used laboratory strain, P. putida KT2440, and no phage defence mechanisms have been characterized. In this study, we present a new Collection of Environmental P. putida Phages from Estonia, or CEPEST. This collection comprises 67 double-stranded DNA phages, which belong to 22 phage species and 9 phage genera. Our findings reveal that most phages in the CEPEST collection are more infectious at lower temperatures, have a narrow host range, and require an intact lipopolysaccharide for P. putida infection. Furthermore, we show that cryptic prophages present in the P. putida chromosome provide strong protection against the infection of many phages. However, the chromosomal toxin-antitoxin systems do not play a role in the phage defence of P. putida. This research provides valuable insights into the interactions between P. putida and bacteriophages, which could have significant implications for biotechnological and environmental applications.

Using electronic health records to evaluate the adherence to cervical cancer prevention guidelines: A cross-sectional study.

OBJECTIVE: The fight against cervical cancer requires effective screening together with optimal and on-time treatment along the care continuum. We examined the impact of cervical cancer testing and treatment guidelines on testing practices, and follow-up adherence to guidelines. METHODS: Data from Estonian electronic health records and healthcare provision claims for 50,702 women was used. The annual rates of PAP tests, HPV tests and colposcopies during two guideline periods (2nd version 2012-2014 vs 3rd version 2016-2019) were compared. To assess the adherence to guidelines, the subjects were classified as adherent, over- or undertested based on the timing of the appropriate follow-up test. RESULTS: The number of PAP tests decreased and HPV tests increased during the 3rd guideline period (p < 0.01). During the 3rd guideline period, among 21-29-year-old women, the adherence to guidelines ranged from 38.7% (44.4…50.1) for ASC-US to 73.4% (62.6…84.3) for HSIL and among 30-59-year-old from 49.0% (45.9…52.2) for ASC-US to 65.7% (58.8…72.7) for ASCH. The highest rate of undertested women was for ASC-US (21-29y: 25.7%; 30-59y: 21.9%). The rates of over-tested women remained below 12% for all cervical pathologies observed. There were 55.2% (95% CI 49.7…60.8) of 21-24-year-olds and 57.1% (95% CI 53.6…60.6) of 25-29-year-old women who received HPV test not adherent to guidelines. CONCLUSIONS: Our findings highlighted some shortcomings in guideline adherence, especially among women under 30. The insights gained from this study help to improve the quality of care and, thus, reduce cervical cancer incidence and mortality.

Evidence for cryptic molting behavior in the trilobite Toxochasmops vormsiensis from the Upper Ordovician Katian Kõrgessaare Formation, Estonia.

Documentation of cryptic trilobite behavior has presented important insights into the paleoecology of this fully extinct arthropod group. One such example is the preservation of trilobites inside the remains of larger animals. To date, evidence for trilobites within cephalopods, gastropods, hyoliths, and other trilobites has been presented. Importantly, most of these interactions show trilobite molts, suggesting that trilobites used larger animals for protection during molting. To expand the record of molted trilobites within cephalopods, we present a unique case of a Toxochasmops vormsiensis trilobite within the body chamber of a Gorbyoceras textumaraneum nautiloid from the Upper Ordovician Kõrgessaare Formation of Estonia. By examining this material, we present new insights into the ecology of pterygometopid trilobites, highlighting how these forms used large cephalopods as areas to successfully molt.

Experiences from patients in mental healthcare accessing their electronic health records: results from a cross-national survey in Estonia, Finland, Norway, and Sweden.

BACKGROUND: Patients' online record access (ORA) enables patients to read and use their health data through online digital solutions. One such solution, patient-accessible electronic health records (PAEHRs) have been implemented in Estonia, Finland, Norway, and Sweden. While accumulated research has pointed to many potential benefits of ORA, its application in mental healthcare (MHC) continues to be contested. The present study aimed to describe MHC users' overall experiences with national PAEHR services. METHODS: The study analysed the MHC-part of the NORDeHEALTH 2022 Patient Survey, a large-scale multi-country survey. The survey consisted of 45 questions, including demographic variables and questions related to users' experiences with ORA. We focused on the questions concerning positive experiences (benefits), negative experiences (errors, omissions, offence), and breaches of security and privacy. Participants were included in this analysis if they reported receiving mental healthcare within the past two years. Descriptive statistics were used to summarise data, and percentages were calculated on available data. RESULTS: 6,157 respondents were included. In line with previous research, almost half (45%) reported very positive experiences with ORA. A majority in each country also reported improved trust (at least 69%) and communication (at least 71%) with healthcare providers. One-third (29.5%) reported very negative experiences with ORA. In total, half of the respondents (47.9%) found errors and a third (35.5%) found omissions in their medical documentation. One-third (34.8%) of all respondents also reported being offended by the content. When errors or omissions were identified, about half (46.5%) reported that they took no action. There seems to be differences in how patients experience errors, omissions, and missing information between the countries. A small proportion reported instances where family or others demanded access to their records (3.1%), and about one in ten (10.7%) noted that unauthorised individuals had seen their health information. CONCLUSIONS: Overall, MHC patients reported more positive experiences than negative, but a large portion of respondents reported problems with the content of the PAEHR. Further research on best practice in implementation of ORA in MHC is therefore needed, to ensure that all patients may reap the benefits while limiting potential negative consequences.

SARS-CoV-2 infection during pregnancy and perinatal outcomes in Estonia in 2020 and 2021: A register-based study.

INTRODUCTION: Data from different countries show partly controversial impact of SARS-CoV-2 infection on pregnancy outcomes. A nationwide register-based study was conducted in Estonia to assess the impact of SARS-CoV-2 infection at any time during pregnancy on stillbirth, perinatal mortality, Apgar score at 5 minutes, cesarean section rates, rates of preterm birth and preeclampsia. MATERIAL AND METHODS: Data on all newborns and their mothers were obtained from the Estonian Medical Birth Registry, and data on SARS-CoV-2 testing dates, test results and vaccination dates against SARS-CoV-2 from the Estonian Health Information System. Altogether, 26 211 births in 2020 and 2021 in Estonia were included. All analyses were performed per newborn. Odds ratios with 95% confidence intervals (CI) were analyzed for all outcomes, adjusted for mother's place of residence, body mass index, age of mother at delivery and hypertension and for all the aforementioned variables together with mother's vaccination status using data from 2021 when vaccinations against SARS-CoV-2 became available. For studying the effect of a positive SARS-CoV-2 test during pregnancy on preeclampsia, hypertension was omitted from the models to avoid overadjustment. RESULTS: SARS-CoV-2 infection during pregnancy was associated with an increased risk of stillbirth (adjusted odds ratio [aOR] 2.81; 95% CI 1.37-5.74) and perinatal mortality (aOR 2.34; 95% CI 1.20-4.56) but not with a lower Apgar score at 5 minutes, higher risk of cesarean section, preeclampsia or preterm birth. Vaccination slightly decreased the impact of SARS-CoV-2 infection during pregnancy on perinatal mortality. CONCLUSIONS: A positive SARS-CoV-2 test during pregnancy was associated with higher rates of stillbirth and perinatal mortality in Estonia but was not associated with change in preeclampsia, cesarean section or preterm birth rates.

Impact of health spending on hospitalization rates in Baltic countries: a comparative analysis.

INTRODUCTION: This study examines the association between healthcare indicators and hospitalization rates in three high-income European countries, namely Estonia, Latvia, and Lithuania, from 2015 to 2020. METHOD: We used a sex-stratified generalized additive model (GAM) to investigate the impact of select healthcare indicators on hospitalization rates, adjusted by general economic status-i.e., gross domestic product (GDP) per capita. RESULTS: Our findings indicate a consistent decline in hospitalization rates over time for all three countries. The proportion of health expenditure spent on hospitals, the number of physicians and nurses, and hospital beds were not statistically significantly associated with hospitalization rates. However, changes in the number of employed medical doctors per 10,000 population were statistically significantly associated with changes of hospitalization rates in the same direction, with the effect being stronger for males. Additionally, higher GDP per capita was associated with increased hospitalization rates for both males and females in all three countries and in all models. CONCLUSIONS: The relationship between healthcare spending and declining hospitalization rates was not statistically significant, suggesting that the healthcare systems may be shifting towards primary care, outpatient care, and on prevention efforts.

Diversity of Sarcocystis parasites in southeastern Baltic Sea catchment ecosystems.

Currently, research on apicomplexan Sarcocystis parasites is mainly carried out by analyzing animal carcasses. However, environmental studies would not only allow faster detection of possible sources of infection but also avoid the use of animals for investigations. Therefore, in the current study, we aimed to identify tested Sarcocystis species in sediment collected from water bodies located in the southeastern Baltic countries. A total of 99 sediment samples were collected during the summer from different types of water bodies in Estonia, Latvia, Lithuania, and Poland. Species-specific nested PCR targeting cox1 gene was used for the detection of selected Sarcocystis species (S. cruzi, S. bovifelis, S. hirsuta, S. arieticanis, S. tenella, S. capracanis, S. miescheriana, and S. bertrami) infecting livestock. The results showed a statistically lower (p < 0.05) occurrence of Sarcocystis parasites in Estonia (50%) compared to three countries, where the detection rate of Sarcocystis spp. DNA was remarkably higher, ranging from 88 to 100%. Among Sarcocystis species tested, S. cruzi (83.8%) and S. arieticanis (55.6%) using cattle and sheep as their intermediate hosts were most commonly identified. The detection rates of some of the analyzed Sarcocystis species were significantly different in southeastern Baltic countries. It is discussed that the detection rates of certain Sarcocystis species depend not only on the number of animals per 1 km2 but also on various ecological factors and farming practices that differ in the amount of contact domestic animals have with predators and the potential for animals to become infected through natural water or food sources.

The Variability of Phytophthora infestans Isolates Collected from Estonian Islands in the Baltic Sea.

Knowledge of a pathogen's genetic variability and population structure is of great importance to effective disease management. In this study, 193 isolates of Phytophthora infestans collected from three Estonian islands were characterized over 3 years using simple sequence repeat (SSR) marker data complemented by information on their mating type and resistance to metalaxyl. In combination with SSR marker data from samples in the neighboring Pskov region of Northwest Russia, the impact of regional and landscape structure on the level of genetic exchange was also examined. Among the 111 P. infestans isolates from Estonian islands, 49 alleles were detected among 12 SSR loci, and 59 SSR multilocus genotypes were found, of which 64% were unique. The genetic variation was higher among years than that among islands, as revealed by the analysis of molecular variance. The frequency of metalaxyl-resistant isolates increased from 9% in 2012 to 30% in 2014, and metalaxyl resistance was most frequent among A1 isolates. The test for isolation by distance among the studied regions was not significant, and coupled with the absence of genetic differentiation, the result revealed gene flow and the absence of local adaptation. The data are consistent with a sexual population in which diversity is driven by an annual germination of soilborne oospores. The absence of shared genotypes over the years has important implications when it comes to the management of diseases. Such population diversity can make it difficult to predict the nature of the outbreak in the coming year as the genetic makeup is different for each year.

Reliability and validity of the Estonian version of the Clinical Institute of Withdrawal Assessment for Alcohol scale.

AIMS: Our aim was to adapt the Clinical Institute of Withdrawal Assessment for Alcohol scale (CIWA-Ar) into Estonian and test its reliability and validity. METHODS: A total of 72 patients with alcohol withdrawal syndrome participated in the study. In order to assess the interrater reliability, at first assessment the CIWA-Ar was simultaneously completed by two nurses. In order to assess the sensitivity of the CIWA-Ar to the changes in the severity of the withdrawal syndrome, as well as its correlations to several indices characterizing the subjects' current condition, the CIWA-Ar, the Clinical Global Impression Severity subscale (CGI-S), the visual analogue scales for the assessment of the general feeling of malaise, anxiety and depression were filled in and the vital signs were measured at inclusion, in 4 h and after the withdrawal syndrome had been resolved. RESULTS: The intraclass correlation coefficient (ICC) for the Estonian version of the CIWA-Ar total score, used as an indicator of interrater reliability, was excellent. The CIWA-Ar had significant correlations with the psychiatrists' CGI-S ratings of the severity of the patient's condition at all assessment points. Significant correlations were also found between CIWA-Ar and patients' self-ratings, the highest correlations found with self-rated anxiety and general feeling of malaise. CIWA-Ar total score did not correlate with simultaneously measured heart rate, systolic and diastolic blood pressure at the first assessment. At the second assessment, heart rate had a significant correlation with the CIWA-Ar total score. CONCLUSION: Our study provides confirmation that the CIWA-Ar tool is well applicable in the Estonian language and culture setting.

Field Testing the "Avoid the Needle" Intervention for Persons at Risk for Transitioning to Injecting Drug Use in Tallinn, Estonia and New York City, USA.

This study aimed to field tested the "Avoid the Needle" (AtN) intervention to reduce transitions from non-injecting to injecting drug use in two different epidemiological settings. Respondent driven sampling was used to recruit current non-injecting drug users (NIDUs) in Tallinn, Estonia in 2018-19 and in New York City (NYC) in 2019-20. Both persons who had never injected and persons who had previously injected but not in the last 6 months were eligible; a structured interview was administered, a blood sample collected, and the intervention administered by trained interventionists. We recruited 19 non-injectors from Tallinn and 140 from NYC. Participants in Tallinn were younger and had begun using drugs at earlier ages than participants in NYC. The primary drugs used in Tallinn were amphetamine, fentanyl, and opioid analgesics, while in NYC they were heroin, cocaine, speedball, and fentanyl. Six-month follow-up data were obtained from 95% of participants in Tallinn. The study was interrupted by COVID-19 lockdown in NYC, but follow-up data were obtained from 59% of participants. There were minimal transitions to injecting: 1/18 in Tallinn and 0/83 in NYC. There were significant declines in the frequencies of using readily injectable drugs (fentanyl, amphetamine, heroin, cocaine) from baseline to follow-up in both sites (Cochran-Armitage tests for trend, χ2 = 21.3, p < 0.001 for New York City; and χ2 = 3.9, p = 0.048 for Tallinn). Reducing transitions into injecting is a potentially very important method for reducing HIV transmission and other harms of drug use. Further investigation and implementation of AtN type interventions is warranted.

Lifeday coverage of oral anticoagulants and one-year relative survival in patients with atrial fibrillation: a population-based study in Estonia.

BACKGROUND: Routine oral anticoagulation (OAC) is recommended for almost all high-risk patients with atrial fibrillation, yet registries show that OACs are still underused. Our aim was to study the lifeday coverage (LDC) of OAC prescriptions and its relationship with one-year mortality rates of AF patients aged ≥ 65 in Estonia for the years 2019 and 2020. METHODS: Medical data for AF patients aged ≥ 65 years from 2018 and alive as of 01.01.2019 (cohort I) and new AF documentation from 2019 and alive as of 01.01.2020 (cohort II) was obtained from the Health Insurance Fund's electronic database. The data was linked to the nationwide Estonian Medical Prescription Centre's database of prescribed OACs. For LDC analysis, daily doses of guideline-recommended OACs were used. The patients were categorized into three LDC groups: 0%, 1-79%, and ≥ 80%. The data was linked to the Estonian Causes of Death Registry to establish the date of death and mortality rate for the whole Estonian population aged ≥ 65. RESULTS: There were 34,018 patients in cohort I and 9,175 patients with new AF documentation (cohort II), previously not included in cohort I. Of the patients, 77.7% and 68.6% had at least one prescription of OAC in cohorts I and II respectively. 57.4% in cohort I and 44.5% in cohort II had an LDC of ≥ 80%. The relative survival estimates at 1 year for LDC lifeday coverage groups 0%, 1-79%, and ≥ 80% were 91.2%, 98.2%, and 98.5% (cohort I), and 91.9%, 95.2%, and 97.6% (cohort II), respectively. CONCLUSIONS: Despite clear indications for OAC use, LDC is still insufficient and anticoagulation is underused for stroke prevention in Estonia. Further education of the medical community and patients is needed to achieve higher lifeday coverage of prescribed OACs.

Outpatient fluoroquinolone use in relation to European Medicines Agency's recommendation: An Estonian nationwide drug utilization study.

PURPOSE: To determine possible changes in prescribing of fluoroquinolones in relation to the European Medicines Agency's (EMA) recommendation in October 2018. METHODS: We conducted a nationwide time-series study on outpatient use of fluoroquinolones during January 2016-June 2021 in Estonia. Joinpoint regression was used to identify change points over time. Several subgroup analyses by prescriber specialty, indication group, risk factors for tendon injury, aortic aneurysm/dissection or heart valve regurgitation/incompetence and the prescribing of other antibiotics were performed. RESULTS: During the study period 236 989 prescriptions of fluoroquinolones were dispensed to 142 659 persons. The number of episodes per month declined from 3780 (2.9/1000 inhabitants) to 2570 (1.9/1000 inhabitants). We identified three change points with four different trend segments: from January 2016 to November 2018 monthly percent change (MPC) -0.4%, from November 2018 to June 2019 MPC -2.5%, from June 2019 to July 2020 MPC 1.7% and from July 2020 to June 2021 MPC -3.3%. Prescribing for indications which were removed or restricted by EMA's recommendation comprised a small proportion of all fluoroquinolone episodes -2.8% and 6.3%, respectively. The risk factors for tendon injury and for cardiac disorders (aortic aneurysm/dissection or heart valve regurgitation/incompetence) were present in 46.4% and 57.8% episodes of fluoroquinolone users, respectively. No changes in the trend of prescribing to users with risk factors was detected. CONCLUSIONS: The EMA's recommendation may have contributed to the greater decline in the use of fluoroquinolones. However, there is still a high proportion of users with predisposing factors for tendon injury and serious cardiac disorders.

Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia.

OBJECTIVE: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per- and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics. METHODS: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in >90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Machine Regression. RESULTS: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, ß = -0.21, 95% CI: -0.38, -0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, ß = -0.22, 95% CI: -0.44, -0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1, ß = -0.16, 95% CI -0.31, -0.02) and the Estonian population (Q2 vs. Q1, ß = -0.27, 95% CI -0.45, -0.08), and for PFOA in the Estonian population (Q4 vs. Q1, ß = -0.31, 95% CI -0.61, -0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals. CONCLUSIONS: Within a large chemical mixture, we observed significant inverse associations levels of DEHP metabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.

Validation of the short forms of the Pelvic Floor Distress Inventory and the Pelvic Floor Impact Questionnaire in Estonian.

INTRODUCTION AND HYPOTHESIS: Pelvic Floor Distress Inventory (PFDI-20) and the Pelvic Floor Impact Questionnaire (PFIQ-7) are reliable instruments for evaluating the quality of life in women with pelvic organ prolapse (POP). They have been translated and validated in many languages. The study was aimed at validating the Estonian translations of the PFDI-20 and PFIQ-7 tools. METHODS: The questionnaires were translated into Estonian using a multistep translation method. A total of 132 women were enrolled: patients with diagnosed POP (n=57) were allocated to test-retest reliability analyses, and those with no POP signs (n=88) completed the questionnaire only once. The total scores of questionnaires and their subscales of both patient and reference groups were compared. Item response rate, floor and ceiling effects, corrected item-total correlations, internal consistency, and convergent and discriminant validity were analyzed. The study was approved by the Ethics Committee of Human Research of the University Clinic of Tartu, Estonia, and informed consent was obtained from each participant. RESULTS: The translated questionnaires demonstrated good internal consistency (Cronbach's α values 0.77-0.93). The item response rate was 99%. Intra-class correlations (ICC) were strong for PFDI-20 and PFIQ-7 and their subscales ranged from 0.86 to 0.96. Construct validity of the tools demonstrated by manyfold higher scores among patients with POP compared with women without POP (p<0.0001). CONCLUSIONS: The Estonian versions of the PFDI-20 and PFIQ-7 tools are reliable and valid instruments for assessing the quality of life in women with POP.