Polygenic risk scores for cervical HPV infection, neoplasia and cancer show potential for personalised screening: comparison of two methods.

The era of precision medicine requires the achievement of accurate risk assessment. Polygenic risk scores (PRSs) have strong potential for increasing the benefits of nationwide cancer screening programs. The current pool of evidence on the role of a PRS as a risk stratification model in actual practice and implementation is limited. To better understand the impact of possible method-induced variance, we constructed and validated two PRSs for cervical cancer (CC) using the Estonian Biobank female population (691 CC cases and 13,820 controls) and evaluated their utility in predicting incident cervical neoplasia (CIN), cancer, and human papillomavirus (HPV) infection using two methods (LDPred and BayesRR-RC). This study demonstrated that two genetic risk scores were significantly associated with CIN, CC, and HPV infection incidence. Independent of the method, we demonstrated that women with elevated PRS values reached the observed cumulative risk levels of CIN or CC much earlier. Our results indicated that the PRS-based discrimination rules could differ substantially when the PRSs contain similar predictive information. In summary, our analysis indicated that PRSs represent a personalized genetic component that could be an additional tool for cervical cancer risk stratification, and earlier detection of abnormalities provides invaluable information for those at high risk.

Haematological changes from conception to childbirth: An indicator of major pregnancy complications.

BACKGROUND: About 800 women die every day worldwide from pregnancy-related complications, including excessive blood loss, infections and high-blood pressure (World Health Organization, 2019). To improve screening for high-risk pregnancies, we set out to identify patterns of maternal hematological changes associated with future pregnancy complications. METHODS: Using mixed effects models, we established changes in 14 complete blood count (CBC) parameters for 1710 healthy pregnancies and compared them to measurements from 98 pregnancy-induced hypertension, 106 gestational diabetes and 339 postpartum hemorrhage cases. RESULTS: Results show interindividual variations, but good individual repeatability in CBC values during physiological pregnancies, allowing the identification of specific alterations in women with obstetric complications. For example, in women with uncomplicated pregnancies, haemoglobin count decreases of 0.12 g/L (95% CI -0.16, -0.09) significantly per gestation week (p value <.001). Interestingly, this decrease is three times more pronounced in women who will develop pregnancy-induced hypertension, with an additional decrease of 0.39 g/L (95% CI -0.51, -0.26). We also confirm that obstetric complications and white CBC predict the likelihood of giving birth earlier during pregnancy. CONCLUSION: We provide a comprehensive description of the associations between haematological changes through pregnancy and three major obstetric complications to support strategies for prevention, early-diagnosis and maternal care.

Enteral nutrition and dynamics of citrulline and intestinal fatty acid-binding protein in adult ICU patients.

BACKGROUND AND AIMS: Plasma citrulline and intestinal fatty acid binding protein (I-FABP) are biomarkers reflecting enterocyte function and intestinal mucosal injury. The aim was to describe daily dynamics of citrulline and I-FABP concentrations in association with enteral nutrition (EN) in adult ICU patients. We hypothesized that success or failure of EN is reflected by differences in citrulline and I-FABP levels at admission, as well as in daily dynamics over the first week. METHODS: The present study was a planned sub-study of the iSOFA study (ClinicalTrials.gov Identifier: NCT02613000). With delayed informed consent we included adult (18 years or older) patients admitted for unlimited care to 5 ICUs in Europe. Citrulline and I-FABP were assessed and nutritional data recorded daily during the first week of the patients' ICU stay. RESULTS: The study included 224 patients with 693 plasma samples analyzed for citrulline and 695 for I-FABP. The median ICU stay was 2 (IQR 1-4) days and 35 patients (15.6 %) stayed in the ICU for ≥ 7 days. The majority of patients (184/224; 82.1 %) received EN or oral nutrition (ON) during their ICU stay, in 164 patients (73.2 %) nutrition was started within 48 h of admission (early enteral or oral nutrition, EEN/ON). Median biomarker concentrations on admission were: citrulline 24.5 (IQR 18.1-31.7) µmol/L and I-FABP 2763 (1326-4805) pg/mL. Reference range for citrulline was 17-46 µmol/L and for I-FABP 377-2049 pg/mL. Patients with EEN/ON demonstrated an increase in citrulline concentrations over the first week in ICU unlike those not receiving EEN/ON (P = 0.049 for the mean log-citrulline values over time between groups) as well as higher average citrulline concentrations. Success of EEN/ON (80 % of caloric target achieved by day 4) was associated with citrulline values increasing from day 4, whereas a slight decrease was observed with unsuccessful EEN/ON. However, these dynamics over time were not statistically significantly different (P = 0.654). Patients with EEN/ON unexpectedly had I-FABP values higher than those without (average values for all days P = 0.004). Median I-FABP values on day 3 were higher with successful EEN/ON (646 (IQR 313-1116) vs 278 (IQR 190-701) pg/mL, P = 0.022). CONCLUSIONS: EEN/ON was associated with higher values and different dynamics of citrulline over the first week in ICU. No clear difference of measured biomarkers was seen when patients were compared according to success of EEN/ON. Our study does not allow suggesting certain thresholds of citrulline nor I-FABP that could be used for bedside decision-making with regard to EN. This study was a planned sub-study of the iSOFA study (ClinicalTrials.gov Identifier: NCT02613000).

Cervical cancer screening patterns among HIV-positive women in Estonia: a population-based retrospective cohort study.

BACKGROUND: The World Health Organisation (WHO) calls for the elimination of cervical cancer (CC) as a public health issue. To achieve elimination, efforts must be aligned and accelerated. Women living with HIV (WLWH) have excess risk for developing, and dying from, CC over the general population. Estimates of cervical cancer screening programme coverage in Eastern European countries that have experienced HIV epidemics since the early 2000's are scarce. METHOD: This population-based retrospective study uses a healthcare administrative database and follows cohorts of all WLWH in a ratio of 1:3 randomly matched (age, region) HIV negative women from 2009 to 2018. Annual and longitudinal (over the whole study period) coverage for cervical cancer screening (opportunistic, organised, HIV specific) and adjusted odds ratios (AORs) for longitudinal screening coverage predictors were estimated from 2009 to 2018. RESULTS: Among WLWH and HIV-negative women, the mean annual coverage with opportunistic screening was 61.45 and 65.59%; and organised screening was 20.4 and 28.7%, respectively (both: p < 0.00001). 19.01% (95% CI 18.05-19.97) HIV-negative and 13.9% (95% CI 12.35-15.45) WLWH were longitudinally covered with organised cervical cancer screening. Among WLWH, the mean annual HIV-specific cervical cancer screening coverage was 49.4, and 24.3% were longitudinally covered. Longitudinal coverage with HIV-specific cervical cancer screening was inversely associated with age, hepatitis C virus (HCV) co-infection (AOR 0.754, 95% CI 0.619, 0.916), not having insurance (AOR 0.331, 95% CI 0.264, 0.412), drug abuse (AOR 0.459, 95% CI 0.336, 0.618) and higher among those retained in HIV care (AOR 1.972, 95% CI 1.615, 2.410). Among HIV-negative women, longitudinal coverage with organised cervical cancer screening was inversely associated with residence in the region and higher among older women. CONCLUSIONS: Our results highlight unacceptably low coverage of cervical cancer screening of WLWH in Estonia. There is need for dedicated cervical cancer screening efforts for WLWH considering the high cancer risk and rate in the study population.

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults.

BACKGROUND: The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets. METHODS: In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). RESULTS: We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn's disease. CONCLUSIONS: Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.

Treatment of chlamydia and gonorrhoea, compliance with treatment guidelines and factors associatedwith non-compliant prescribing: findings form a cross-sectional study.

OBJECTIVES: Proper antibiotic treatment of STI reduces transmission, antimicrobial resistance and serious disease complications. In this study, we assessed compliance with STI treatment guidelines for genital gonorrhoea and chlamydia infections in Estonia. METHODS: Prescription data from the Estonian Health Insurance Fund on 7556 treatment episodes of 6499 patients treated for gonorrhoea or chlamydia during 2012-2014 were analysed to assess compliance with the guidelines and factors associated with it. RESULTS: Between 1 January 2012 and 31 December 2014, a total of 6074 patients were treated for chlamydia and 425 for gonorrhoea in Estonia. Among all prescriptions, 48.6% were non-compliant with gonorrhoea treatment guidelines and 3.8% for chlamydia. Non-compliant antibiotic treatment for gonorrhoea was associated with patient gender (female (adjusted OR (AOR)) 3.0, 95% CI 1.6 to 5.9), region (east AOR 3.3, 95% CI 1.3 to 8.2; west AOR 6.5, 95% CI 2.2 to 19.7) and prescribing physician specialty (general healthcare doctors: AOR 5.6, 95% CI 2.3 to 13.8; gynaecologists: AOR 5.9, 95% CI 2.8 to 12.4). Non-compliant antibiotic treatment for chlamydia was associated with younger patient age (15-24 AOR 0.5, 95% CI 0.4 to 0.7), region (north AOR 1.9, 95% CI 1.4 to 2.6; west AOR 2.3, 95% CI 1.5 to 3.4) and multiple treatment episodes (AOR 2.7, 95% CI 2.1 to 3.9). Approximately 14% of prescriptions were multiple treatments for the same patient for the same infection over the 3-year period (6.1% for gonorrhoea and 14.5% for chlamydia). CONCLUSION: There are significant differences in terms of compliance with treatment guidelines for gonorrhoea and chlamydia, and several factors associated with non-compliance that can potentially be targeted with interventions. Future research should explore reasons clinicians do not follow guidelines and examine ways to improve practice among doctors and patients and assess factors associated with multiple treatments, particularly multiple treatments for the same STI.