Karpova, Nataliia Sergeevna

Karpova N., Dmitrenko O., Nurbekov M.

Hypertensive disorders of pregnancy (HDP) are a great danger. A previous GWAS found a relationship between rs259983 of the ZNF831 gene and HDP, such as for chronic hypertension (CHTN) and preeclampsia (PE). We conducted the case-control study to determine the association between rs259983 of the ZNF831 gene and HDP in women with Gestational Diabetes Mellitus (GDM). For target genotyping, we developed primers and TaqMan probes. In analyzing the population, we did not manage to find a relationship between PE and rs259983 of the ZNF831 gene. Additional study of women with PE and PE superimposed on CHTN (SIPE) establishes an association between rs259983 of the ZNF831 gene only with SIPE. Carriers of CC genotypes have been discovered to have a 5.05 times higher risk of SIPE development in women with GDM.

О.П. Д., Н.С. К., А.А. П.

Целью работы было проведение биоинформатического анализа полиморфизмов генов, которые ассоциированы со старением и возраст-ассоциированными заболеваниями. Материалы и методы. Анализ генов проводился с использованием информации, полученной из базы данных полногеномных ассоциативных исследований GWAS Catalog. Для анализа белок-белковых взаимодействий (protein-protein interactions, PPI) использовалась база данных String-DB (версия 12.0). Результаты. Выявлено 7676 уникальных генов, полиморфизмы которых связаны с развитием возраст-ассоциированных заболеваний. Выявлена ассоциация молекулярных функций ряда генов (HLA-DQB1, HLA-DQA1, HLA-DRB1, FTO, APOE, APOC1 и MAPT) и их белковых продуктов со старением и возраст-ассоциированными заболеваниями. The aim of the study was to perform a bioinformatic analysis of gene’s polymorphisms, associated with ageing and ageassociated diseases. Materials and methods. Analysis of genes was performed with the use of information, obtained from the database of genomewide association studies GWAS Catalog. String-DB database (v. 12.0) was used for analysis of protein-protein interactions (PPI). Results. 7676 unique genes have been identified, the polymorphisms of which are associated with the development of ageassociated diseases. The association of molecular functions of a number of genes (HLA-DQB1, HLA-DQA1, HLA-DRB1, FTO, APOE, APOC1 and MAPT) and their protein products with aging and age-associated diseases has been revealed.

Dmitrenko O.P., Abramova O.I., Karpova N.S., Nurbekov M.K., Arshinova E.S.

One of the most significant factors for age-related macular degeneration (AMD) development is considered to be aging, the processes of which are closely associated with telomere shortening. The different forms, indicators of aggressiveness, and intensities of AMD can be observed in the same age group, confirming the need to find a biomarker for early diagnosis and be capable of monitoring the progression of the pathological process. Therefore, we investigated whether the relative telomere length (RTL) has any connection with the risk of development of disease and its progression. RTL was measured using RT-PCR in 166 people, including 96 patients with AMD. RTL was significantly lower in patients with AMD. Women were more likely to develop AMD than men (odds ratio (OR) = 9.53 × 106 vs. OR = 1.04 × 108, respectively). The decrease in RTL in patients reliably correlated with the progression of AMD, and the smallest RTL was observed in late-stage patients. RTL < 0.8 is a significant risk factor for disease progression. The results of our research showed that RTL may be considered as a potential biomarker and a promising predictor of disease progression in patients with early AMD.

Karpova N.S., Dmitrenko O.P., Budykina T.S.

One of the main causes of maternal and neonatal morbidity and mortality is pre-eclampsia. It is characterized by a high sFlt1/PlGF ratio, according to prior research. Pregestational diseases in mothers may increase the risk of developing pre-eclampsia. Only a few studies have looked at the connection between maternal comorbidities before conception and the sFlt1/PlGF ratio. The most recent information regarding the association between maternal pregestational diseases and the ratio of sFlt1/PlGF is described in this review. The paper also examines current research suggesting that changes in pregnancy hormones and metabolites are related to a high sFlt1/PlGF ratio. Certain maternal disorders have been found to dramatically raise sFlt-1 and sFlt1/PlGF levels, according to an analysis of the literature. There is still debate about the data on the association between the sFlt1/PlGF ratio and maternal disorders such as HIV, acute coronary syndromes, cardiovascular function in the mother between 19 and 23 weeks of pregnancy, thyroid hormones, diabetes, and cancer. Additional research is needed to confirm these findings.

Е.С. А., О.П. Д., Н.С. К.

Преэклампсия (ПЭ) является наиболее распространенным осложнением, возникающим во время беременности, и представляет серьезную медико-социальную проблему, поскольку увеличивает частоту нежелательных исходов беременности как для матери, так для плода. В настоящее время своевременная диагностика и прогнозирование ПЭ является актуальной задачей. Существует широкий спектр потенциальных клинических, биохимических и биофизических биомаркёров прогнозирования развития этой патологии, однако ни один из них не был признан эффективным или надежным. Учитывая, что ПЭ является многофакторным заболеванием, значительный вклад в которое вносят генетические факторы, многими исследователями ведется поиск молекулярно-генетических паттернов, вовлеченных в патогенетические пути возникновения преэклампсии. В данном обзоре рассматриваются известные на сегодняшний день молекулярно-генетические биомаркёры, связанные с ПЭ. Preeclampsia (PE) is one of the most common complications of pregnancy. This condition elevates the frequency of undesirable pregnancy outcomes for both the mother and the fetus and represents a serious medical and social problem. For these reasons, it is crucial to timely diagnose and predict the PE course. Although there are multiple potential clinical, biochemical and biophysical biomarkers for predicting the development of PE, none of them has been found effective or reliable so far. As preeclampsia is a multifactorial disease, genetic factors also significantly contribute to its emergence and progression. Thus, potential molecular genetic patterns involved in the PE pathogenetic pathways are being searched for. This review focuses on currently known molecular genetic biomarkers related with PE.

Karpova N., Dmitrenko O., Arshinova E.

Karpova N., Dmitrenko O., Arshinova E., Nurbekov M.

Briefly, 25-hydroxyvitamin D (25(OH)D) plays an essential role in embryogenesis and the course of intra- and postnatal periods and is crucially involved in the functioning of the mother–placenta–fetus system. The low quantity of 25(OH)D during pregnancy can lead to an elevated risk for preeclampsia occurrence. Despite the numerous studies on the association of 25(OH)D deficiency and preeclampsia development, the current research on this theme is contradictory. In this review, we summarize and analyze study data on the effects of 25(OH)D deficiency and supplementation on pregnancy, labor, and fetal and neonatal outcomes.

Karpova N., Dmitrenko O., Arshinova E., Nurbekov M.

Vitamin D plays an essential role in embryogenesis and the course of intra- and postnatal periods and is crucially involved in the functioning of the mother-placenta-fetus system. Low quantity of Vitamin D during pregnancy can lead to the elevated risk for preeclampsia occurence. Despite the numerous studies on the association of Vitamin D deficiency and preeclampsia development, the current research on this theme is contradictory. In this review we summarize and analyze study data on the effects of vitamin D deficiency and supplementation on pregnancy, labor, fetal and neonatal outcomes.

Karpova N

Moshetova L.K., Dmitrenko O.P., Abramova O.I., Karpova N.S., Turkina K.I., Saburina I.N.

One of the most important factors predisposing to the development of age-related macular degeneration (AMD) is aging. Telomeres are important for aging by maintaining genome stability. Aim: to identify the association between relative telomere length of buccal epithelial cells and SIRT1 rs12778366 genetic variation and late AMD. Patients and Methods: 100 patients (200 eyes) were enrolled, i.e., 50 patients with AMD (AREDS category 4) and 50 patients without AMD. Genomic DNA isolated from buccal epithelial cells by phenol-chloroform extraction was used. Genotyping of SIRT1 rs12778366 polymorphic locus was performed by TaqMan® real-time PCR. Telomere length was measured by real-time PCR as described earlier [Cawthon, 2002] using specific primers. Relative telomere length was assessed by the relative telomere to single-copy gene (T/S) ratio. Results: the rate of allele C was 25% in the study group and 14% in the control group (p=0.049). The rate of heterozygotic TC genotype was twice higher in the study group compared to the control group (p=0.045). In heterozygotic carriers of the allele C of the SIRT1 rs12778366 gene, the risk of AMD is 2.048- and 2.425-times higher in сodominant and dominant inheritance pattern, respectively. In patients with late AMD, there are more short telomeres (64% vs. 48% in the control group, р=0.0002). Conclusions: further studies of a polymorphic SIRT1 gene locus in the association with telomere length in a larger sample are required. In the future, these molecular markers can be applied to predict the individual course of AMD and to implement preventive measures. Keywords: age-related macular degeneration, relative telomere length, rs12778366, SIRT1 gene, age-related diseases, buccal epithelium, genetic testing. For citation: Moshetova L.K., Dmitrenko O.P., Abramova O.I. et al. Association between relative telomere length and a genetic variant of SIRT gene and age-related macular degeneration. Russian Journal of Clinical Ophthalmology. 2021;21(3):143–146 (in Russ.). DOI: 10.32364/2311- 7729-2021-21-3-143-146.

Dmitrenko O.P., Karpova N.S., Nurbekov M.K., Papysheva O.V.

Preeclampsia (PE) and gestational diabetes mellitus (GDM) are the most common complications of pregnancy, which result in adverse outcomes for the mother and the fetus. GDM is regarded as a separate independent risk factor for PE development, as evidenced by a higher preeclampsia rate in gestational diabetes mellitus than in the general population. The role the endothelial cell dysfunction plays is considered to be the most reasonable one in the origin of these diseases. The activity of plasma and tissue angiotensin converting enzyme (ACE) is believed to be genetically controlled. The available data suggests that increased ACE activity due to deletion (D)/insertion (I) in the 16th intron of ACE gene, which is called ACE gene I/D polymorphism, is associated with preeclampsia and varies depending on the studied population and the geography. We did not find any literature data that estimates the influence of ACE gene I/D polymorphism on PE rate in pregnant women with GDM. Therefore, the present study aimed to investigate a relationship between ACE gene I/D polymorphism and preeclampsia development in the case of GDM in the Russian population. The study used the genomic DNA derived by phenol-chloroform extraction method from venous blood samples in 137 pregnant women, including samples of 74 women with GDM accompanied with PE and the blood samples of 63 women with GDM w/o preeclampsia. Genotyping of insertion/deletion in the I/D region (16 intron of АСЕ gene) was conducted by real-time PCR using the TaqMan competing probe technology. The particular features in the frequency array of alleles and genotypes of the ACE gen I/D polymorphism under review, as associated with preeclampsia development risk in pregnant women with GDM, were identified. The acquired data testify to the need to further study of ACE gene I/D region polymorphism association in a large patient sample taking into account the PE and GDM risk factors estimated in the clinical practice.

Moshetova L.K., Abramova O.I., Turkina K.I., Dmitrenko O.P., Karpova N.S.

Yang M., Chang F., Wu M., Chen C., Cheng T., Kang L.

Vastrad B., Vastrad C.M.

AbstractRecurrent implantation failure (RIF) is a cases in which women have had three fruitless in vitro fertilization (IVF) bid with positive quality embryos. The RIF originates from uterine endometrium microbiota has been implicated in reproductive failure, and poor prognosis and lacks effective treatment. Efforts have been made to elucidate the molecular pathogenesis of RIF. To identify key genes and signaling pathways in RIF, the next genetation sequencing data GSE243550 was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between RIF and normal controls samples were identified using t-tests in the limma R bioconductor package. Using the DEGs, we further performed a series of gene ontology (GO) and REACTOME pathway enrichment analyses. Protein-protein interaction network was derived using the IMex interactome database and visualized using Cytoscape software. The most significant modules from the PPI network were selected for GO and pathway enrichment analysis. A miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed depending on key hub genes and visualized using Cytoscape software. A receiver operating characteristic curve (ROC) analysis was plotted to diagnose RIF. In total, 958 DEGs were identified, of which 479 were up regulated genes and 479 were down regulated genes. GO and REACTOME pathway enrichment analysis results revealed that the upregulated genes were mainly enriched in multicellular organismal process, membrane, small molecule binding and extracellular matrix organization, whereas downregulated genes were mainly enriched in organonitrogen compound metabolic process, intracellular anatomical structure, catalytic activity and translation. Through analyzing the PPI network, we screened hub genes APP, HSP90AA1, CAND1, CUL1, HSP90AB1, SIRT7, SRC, CDKN1A, ISG15 and RPS16 by the Cytoscape software. The regulatory network analysis revealed that microRNAs (miRNAs) include hsa-miR-574-3p and hsa-mir-208a-3p, and transcription factors (TFs) include SREBF1 and RELA might be involved in the development of RIF. Receiver operating characteristic curve analysis demonstrated that the hub genes screened for RIF were of good diagnostic significance. Overall, these results thus highlight a range of novel signaling pathways and genes that are linked to the incidence and progression of RIF, providing a list of important diagnostic and prognostic molecular markers that have the potential to aid in the clinical diagnosis and treatment of RIF.

Deodhare K.G., Pathak N.

The growing incidence of obesity and the rising trend of increased age during pregnancy have led to a high number of pregnant women with chronic kidney disease (CKD). Chronic hypertension is commonly associated with CKD and is not only the result of renal damage but is also the cause of declining renal function. Pregnancy and its unique physiological adaptations are affected by a decrease in the filtration capacity of the kidneys. Preeclampsia is a disorder of the vascular endothelium and is exacerbated by endothelial dysfunction resulting from CKD. Blood pressure targets must be strictly maintained owing to overlapping disease pathogenesis and to minimize cardiovascular damage. Moreover, preexisting renal dysfunction poses a challenge in identifying superimposed preeclampsia, which alters the management strategies in pregnancy. Fetal outcomes in patients with CKD are considerably affected by the presence of hypertension. This review is expected to aid in developing a focused and individualized treatment plan for hypertension in pregnant women with CKD to improve pregnancy outcomes and preserve postpartum renal function.

Duan L., Ma Y., Reisch B., Hadrovic E., Mach P., Kimmig R., Jahn M., Köninger A., Iannaccone A., Gellhaus A.

Therapeutic plasma exchange (TPE) is a widely used treatment for numerous diseases including pregnancy-related conditions. Our prior study on 20 early-onset preeclampsia patients undergoing TPE revealed a significant extension in pregnancy duration and reduced serum levels of sFlt-1, sFlt-1/PlGF, and sEndoglin. Here, we investigated the impact of TPE on serum sB7-H4, an immunological checkpoint molecule, and placental proteins (Flt-1, Eng, B7-H4, iNOS, TNF-α) in TPE-treated early-onset preeclampsia patients (N = 12, 23 + 2–28 + 5 weeks), conventionally treated counterparts (N = 12, 23 + 5–30 weeks), and gestational age-matched controls (N = 8, 22 + 4–31 + 6 weeks). Immunoblotting, ELISA, and co-immunohistochemistry were used for biomarker analysis, including placental inflammation factors (iNOS, TNF-α). The results showed that TPE extended pregnancy by a median of 6.5 days in this cohort of early-onset preeclampsia. Serum sB7-H4, sFlt-1, and sEndoglin levels decreased, along with reduced expression of their membrane-bound proteins in placental tissue upon TPE treatment. Moreover, TPE-treated patients displayed reduced placental inflammation compared to preeclampsia patients receiving standard-of-care treatment. In conclusion, TPE may improve pregnancy outcomes in early-onset preeclampsia by lowering circulating levels of sB7-H4, sFlt-1, and sEndoglin, as well as reducing placental inflammation. This translational approach holds promise for enhancing placental function and extending gestation in high-risk pregnancies including very preterm PE or HELLP cases.

Kim T., Choodinatha H.K., Kim K.S., Shin K., Kim H.J., Park J.Y., Hong J.W., Lee L.P.

AbstractPreeclampsia is a hypertensive disorder of pregnancy that can lead to stillbirth and preterm birth if not treated promptly. Currently, the diagnosis of preeclampsia relies on clinical symptoms such as hypertension and proteinuria, along with invasive blood tests. Here, we investigate the role of soluble proteins and exosomes in noninvasive diagnosing preeclampsia non-invasively using maternal urine and urine-derived exosomes. We quantified the levels of particles and the presence of TSG101 and CD63 in urine and urinary exosomes via the biologically intact exosome separation technology (BEST) platform. Then, we obtained higher levels of soluble proteins such as fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) from urine as it was than urinary exosomes. Compared to commercial blood tests, the sensitivity of the sFlt-1/PlGF ratio was found to be 4.0 times higher in urine tests and 1.5 times higher in tests utilizing urine-derived exosomes. Our findings offer promising possibilities for the early and non-invasive identification of high-risk individuals at risk of preeclampsia, allowing for comprehensive preventive management.

Vastrad B., Vastrad C.

Abstract Background Endometriosis is a common cause of endometrial-type mucosa outside the uterine cavity with symptoms such as painful periods, chronic pelvic pain, pain with intercourse and infertility. However, the early diagnosis of endometriosis is still restricted. The purpose of this investigation is to identify and validate the key biomarkers of endometriosis. Methods Next-generation sequencing dataset GSE243039 was obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) between endometriosis and normal control samples were identified. After screening of DEGs, gene ontology (GO) and REACTOME pathway enrichment analyses were performed. Furthermore, a protein–protein interaction (PPI) network was constructed and modules were analyzed using the Human Integrated Protein–Protein Interaction rEference database and Cytoscape software, and hub genes were identified. Subsequently, a network between miRNAs and hub genes, and network between TFs and hub genes were constructed using the miRNet and NetworkAnalyst tool, and possible key miRNAs and TFs were predicted. Finally, receiver operating characteristic curve analysis was used to validate the hub genes. Results A total of 958 DEGs, including 479 upregulated genes and 479 downregulated genes, were screened between endometriosis and normal control samples. GO and REACTOME pathway enrichment analyses of the 958 DEGs showed that they were mainly involved in multicellular organismal process, developmental process, signaling by GPCR and muscle contraction. Further analysis of the PPI network and modules identified 10 hub genes, including vcam1, snca, prkcb, adrb2, foxq1, mdfi, actbl2, prkd1, dapk1 and actc1. Possible target miRNAs, including hsa-mir-3143 and hsa-mir-2110, and target TFs, including tcf3 (transcription factor 3) and clock (clock circadian regulator), were predicted by constructing a miRNA-hub gene regulatory network and TF-hub gene regulatory network. Conclusions This investigation used bioinformatics techniques to explore the potential and novel biomarkers. These biomarkers might provide new ideas and methods for the early diagnosis, treatment and monitoring of endometriosis.

Lundgaard M.H., Sinding M.M., Sørensen A.N., Torp N.M., Handberg A., Andersen S., Andersen S.L.

ABSTRACTObjectiveA link between maternal thyroid function and the placental biomarkers, soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF), has been brought forward. This study aimed to describe their association in early pregnancy.DesignRetrospective cohort study.ParticipantsEight hundred and fifty‐eight pregnant women from the North Denmark Region, 2013, with blood samples drawn in early pregnancy.MeasurementsThyroid‐stimulating hormone (TSH), free thyroxine (fT4), thyroid‐peroxidase antibodies (TPO‐Ab), thyroglobulin antibodies (Tg‐Ab) (ADVIA Centaur XPT, Siemens Healthineers), sFlt‐1 and PlGF (Kryptor Compact, ThermoFisher Scientific) were measured. The association between maternal TSH and fT4 and percentile (pc) levels of sFlt‐1 and PlGF (< 25th pc, 25–75th pc, > 75th pc) was evaluated using regression analysis and reported as adjusted beta coefficient (aβ). The frequency of maternal thyroid autoantibodies (TPO‐Ab > 60 U/mL or Tg‐Ab > 33 U/mL) by pc levels of sFlt‐1 and PlGF was compared using chi‐squared test.ResultsHigher levels (> 75th pc) of sFlt‐1 associated with lower TSH (aβ 0.62, 95% CI: 0.51–0.76) and higher fT4 (aβ 1.03, 95% CI: 1.01–1.05). Higher levels of PlGF associated with lower TSH (aβ 0.82, 95% CI: 0.69–0.98), but not with levels of fT4 (aβ 1.00, 95% CI: 0.97–1.02). No association with maternal thyroid autoantibodies was found (TPO‐Ab: sFlt‐1: p‐value 0.5 and PlGF: p‐value 0.1; Tg‐Ab: sFlt‐1: p‐value 0.7 and PlGF: p‐value 0.1).ConclusionsIn a large cohort of Danish pregnant women, higher levels of sFlt‐1 and PlGF associated with maternal thyroid function in early pregnancy, while there was no association with maternal thyroid autoantibodies.

Zambella E., Peruffo B., Guarano A., Inversetti A., Di Simone N.

Preeclampsia is a multifactorial gestational syndrome characterized by increased blood pressure during pregnancy associated with multiorgan involvement. The impact of this disease on maternal and neonatal health is significant, as it can lead to various fetal comorbidities and contribute to the development of maternal comorbidities later in life. Consistent evidence has shown that the microbiota acts as a regulator of the immune system, and it may, therefore, influence the development of preeclampsia by modulating immune factors. This narrative review aims to investigate the role of the immune system in the pathogenesis of preeclampsia and to summarize the most recent literature on the possible link between preeclampsia and alterations in the intestinal microbiota. To this end, we conducted a literature search, aiming to perform a narrative review, on PubMed and Embase from January 1990 to March 2024, focusing on the latest studies that highlight the main differences in microbial composition between patients with and without preeclampsia, as well as the effects of microbial metabolites on the immune system. From the review of 28 studies assessing the intestinal microbiota in preeclamptic women, preeclampsia could be associated with a state of dysbiosis. Moreover, these patients showed higher plasmatic levels of endotoxin, pro-inflammatory cytokines, and T helper 17 cells; however, the findings on specific microbes and metabolites that could cause immune imbalances in preeclampsia are still preliminary.

Xu C., Chen X., Chen Y., Wen Z., Cheng F.

The reference intervals (RIs) is defined as the central 95 % range of reference values from healthy individuals. The establishment of appropriate medical RIs for specific populations is crucial for accurate diagnosis and treatment of disease. However, the RIs for 25-hydroxyvitamin D (25(OH)D) in Chinese pediatric individuals are currently not available. This retrospective study aimed to establish pediatric RIs for serum 25-hydroxyvitamin D (25(OH)D) in the Nanjing area of China.

Khalatyan A.S., Shishparenok A.N., Avetisov K.S., Gladilina Y.A., Blinova V.G., Zhdanov D.D.

Background: Age plays a primary role in the development of age-related macular degeneration (AMD). Telomere length (TL) is one of the most relevant biomarkers of aging. In our study, we aimed to determine the association of TL with T lymphocytes, B lymphocytes, NK cells or monocytes with different forms of AMD. Methods: Our study included 62 patients with AMD: geographic atrophy (GA), neovascular AMD (NVAMD) with and without macular atrophy and 22 healthy controls. Each leukocyte subtype was isolated from peripheral blood by immunomagnetic separation, and the DNA was purified. The TL in the genomic DNA was determined using qPCR by amplifying the telomere region with specific oligonucleotide primers and normalizing to the control gene. Statistical analysis was performed using R version 4.5.1. Results: We observed a statistically significant increase in TL in the T cells between the control and NVAMD groups but not for the GA group. The B cells and monocytes showed a significant decrease in TL in all AMD groups. The TL in the NK cells did not decrease in any of the AMD groups. Conclusions: The TL in the monocytes had the strongest association with AMD. It reflects a person’s “telomeric status” and may become a diagnostic hallmark of these degenerative processes.

Nguyen-Thanh T., Nguyen-Vu P., Le-Thi Q., Phan-Thi T., Ha T.

The objective of this meta-analysis was to evaluate the association between maternal and fetal genetic variants and the risk of preeclampsia, a pregnancy-related condition that affects women. Despite the unclear role of these genetic factors in the development of preeclampsia, this analysis aimed to provide insights into the potential contributing factors. An electronic search of online databases was conducted to identify relevant studies. Stata SE software was used for the meta-analysis. A random-effects model was used to establish the association between the genetic variants and preeclampsia risk. Egger’s test was utilized to evaluate publication bias. Ten observational studies were selected from databases that met the inclusion criteria and included seven genes and twenty polymorphisms to analyze preeclampsia susceptibility influenced by the genetic background of both the mother and fetus. Our meta-analysis revealed that both the maternal and fetal polymorphisms, FLT1 rs4769613, were significantly associated with the risk of preeclampsia. However, the association between the maternal ACE rs4646994 polymorphism and preeclampsia risk was not statistically significant. Nevertheless, a significant association was observed between the fetal ACE rs4646994 polymorphism and preeclampsia in a dominant genetic model. In this study, the associations between maternal and fetal polymorphisms in ERAP2, VEGF, VDR, REN, and MMP were not statistically significant. According to the available evidence, maternal and fetal polymorphisms can impact the likelihood of developing preeclampsia. Additional research is required to fully understand the underlying mechanisms connecting maternal and fetal polymorphisms to preeclampsia, and to formulate recommendations for screening pregnant women based on these genetic variations.

Javandoust Gharehbagh F., Soltani-Zangbar M.S., Yousefzadeh Y.

Maternal immunologic mechanisms for tolerance are essential for a successful pregnancy because they prevent maladaptive immune responses to the placenta and semi-allogeneic fetus and promote fetal growth. Preeclampsia is a major global cause of fetal mortality and morbidity. It is characterized by new-onset hypertension and proteinuria that occurs at twenty weeks of pregnancy or later. Preeclampsia is defined by a rise in cytokines that are pro-inflammatory and antiangiogenic components in the fetoplacental unit and the vascular endothelium of pregnant women, as well as an excessive and increasing stimulation of the immune system. Crucially, inflammation can result in low birth weight and inadequate placental perfusion in neonates. Preeclampsia, which is ultimately connected to inflammatory responses, can be impacted by several immunological mechanisms. Our goal in this work was to compile the most recent research on the pathoimmunology of preeclampsia, including studies on angiogenic variables and, in particular, immunological components.

Dwivedi S., Singh V., Sen A., Yadav D., Agrawal R., Kishore S., Misra S., Sharma P.

Vitamin D, a versatile secosteroid hormone, continues to captivate scientific interest due to its multifaceted influence on human health. This comprehensive review, part 1 of a series, provides an up-to-date exploration of the molecular mechanisms governing Vitamin D’s impact on various aspects of health. Focusing on its pivotal role in the central nervous system (CNS), neurodevelopmental disorders, and neurodegenerative diseases, the review also delves into its intriguing correslations with oral, prostate, breast, and colon cancers. Beyond these domains, Vitamin D’s reach extends to viral infections and reproductive health, affecting fertility in both males and females and playing a crucial role throughout pregnancy. The article offers an in-depth examination of the complex molecular pathways and signaling cascades through which Vitamin D exerts its physiological effects. Importantly, it provides a detailed overview of Vitamin D’s involvement in a spectrum of diseases, laying the foundation for the upcoming second part of the article. This forthcoming article (part II) will expand on the role of Vitamin D in additional diseases, contributing to a more comprehensive understanding of its therapeutic potential. In summary, this article serves as a valuable resource for researchers and healthcare professionals, offering insights into the diverse roles of Vitamin D and setting the stage for further exploration in part II.

Vastrad B.M., Vastrad C.M.

AbstractEndometriosis is a common cause of endometrial-type mucosa outside the uterine cavity with symptoms such as painful periods, chronic pelvic pain, pain with intercourse and infertility. However, the early diagnosis of endometriosis is still restricted. The purpose of this investigation is to identify and validate the key biomarkers of endometriosis. Next generation sequencing (NGS) dataset GSE243039 was obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between endometriosis and normal control samples were identified. After screening of DEGs, gene ontology (GO) and REACTOME pathway enrichment analyses were performed. Furthermore, a protein-protein interaction (PPI) network was constructed and modules were analysed using the Human Integrated Protein-Protein Interaction rEference (HIPIE) database and Cytoscape software, and hub genes were identified. Subsequantely, a network between miRNAs and hub genes, and network between TFss and hub genes were constructed using the miRNet and NetworkAnalyst tool, and possible key miRNAs and TFs were predicted. Finally, receiver operating characteristic curve (ROC) analysis was used to validate the hub genes. A total of 958 DEGs, including 479 up regulated genes and 479 down regulated genes, were screened between endometriosis and normal control samples. GO and REACTOME pathway enrichment analyses of the 958 DEGs showed that they were mainly involved in multicellular organismal process, developmental process, signaling by GPCR and muscle contraction. Further analysis of the PPI network and modules identified 10 hub genes, including VCAM1, SNCA, PRKCB, ADRB2, FOXQ1, MDFI, ACTBL2, PRKD1, DAPK1 and ACTC1. Possible target miRNAs, including hsa-mir-3143 and hsa-mir-2110, and target TFs, including TCF3 and CLOCK, were predicted by constructing a miRNA-hub gene regulatory network and TF-hub gene regulatory network. This investigation used bioinformatics techniques to explore the potential and novel biomarkers. These biomarkers might provide new ideas and methods for the early diagnosis, treatment, and monitoring of endometriosis.

Zhao S., Zhou J., Chen R., Zhou W., Geng H., Huang Y., Shi S., Yuan L., Wang Z., Wang D.

This study aimed to investigate the expression of fibroblast growth factor 23 (FGF23) in pregnant women with preeclampsia and elucidate its role in promoting placental angiogenesis through the ERK1/2-EGR-1 signaling pathway. Serum FGF23 levels were measured by ELISA in healthy pregnant women and patients with preeclampsia during the first, second, and third trimesters of pregnancy. Wound healing, Transwell, and tube formation assays were performed to investigate the effects of FGF23 on cell migration, invasion and tube formation. The expression of vascular endothelial growth factor A (VEGF-A) and its upstream signaling molecules, p-ERK, and EGR-1, in placental tissues was detected by RT-qPCR and western blotting. Additionally, the effect of FGF23 on VEGF-A, p-ERK, and EGR-1 expression was further explored in vitro. Serum FGF23 levels increased with gestational age. During the third trimester, the control group exhibited a more pronounced increase in FGF23 levels than the preeclampsia group. Administering exogenous FGF23 promoted trophoblast cell migration, invasion and enhanced tube formation in vascular endothelial cells. The expression levels of VEGF-A, p-ERK, and EGR-1 in the placental tissues were significantly lower in the preeclampsia group than in the control group. In vitro experiments confirmed that FGF23 up-regulated VEGF-A expression through the p-ERK/EGR-1 signaling pathway. The serum level of FGF23 decreased in pregnant women with preeclampsia, inhibiting the ERK1/2-EGR-1 pathway and resulting in decreased expression of VEGF-A, thereby inhibiting placental angiogenesis. This could be a potential mechanism involved in the progression of preeclampsia.

Dong R., Ying G.

ABSTRACTObjective To evaluate the recent practice of design and statistical analysis of ophthalmic randomized clinical trials (RCTs). Design Review of 96 ophthalmic RCTs. Method Two authors reviewed primary result papers published January 2020 through December 2021 in Ophthalmology, JAMA Ophthalmology, American Journal of Ophthalmology, and British Journal of Ophthalmology. Data were extracted and analyzed for the characteristics of design (one-eye design, two-eye design, paired-eye design, subject design), sample size and power, and statistical analysis for inter-eye correlation adjustment, missing data, and correction for multiplicity. Main Outcome Measures Characteristics of trial design and statistical analysis. Results Among 96 RCTs, 50 (52%) used one-eye design, 21 (22%) two-eye design, 10 (10%) paired-eye design, and 15 (16%) subject design. In 31 trials of two-eye design or paired-eye design, 18 (58%) trials had suboptimal analysis of data from both eyes by analyzing data from one eye (n=10), taking the average of two eyes (n=2), analyzing two eyes separately (n=1), ignoring inter-eye correlation (n=3), or not specifying how two-eye data were analyzed (n=2), and 13 trials (42%) properly adjusted the inter-eye correlation by using the mixed effects model (n=6), paired t-test (n=5), generalized estimating equations (n=1) or marginal Cox regression model (n=1). Among 96 trials, 75 (78%) provided both sample size and statistical power estimation, but only 16 (17%) trials described statistical test for sample size or power estimation. Missing data in primary outcome occurred in 86 (90%) trials with a median missing data rate of 8%, 32 (37%) trials applied statistical methods for missing data, including last value carried forward (n=10), multiple imputation (n=14) or other approaches (n=8). Among 25 trials with more than two arms, 16 (64%) corrected for multiplicity using Bonferroni procedure (n=8), Hochberg procedure (n=2), Gatekeeping procedure (n=2), or hierarchical procedure (n=4). Among 16 trials with multiple primary outcomes, 4 (25%) corrected for multiplicity by Bonferroni procedure. Conclusion There are opportunities for improvement in the design and statistical analyses of ophthalmic trials, particularly in the aspects of adjustment for inter-eye correlation, missing data and multiplicity. Continuing education in ophthalmology and vision research community may improve the quality of ophthalmic trials.

Hunt M.S., Chee Y.E., Saraf S.S., Chew E.Y., Lee C.S., Lee A.Y., Manookin M.B.

Investigate associations of natural environmental exposures with exudative and nonexudative age-related macular degeneration (AMD) across the United States.Database study.Patients aged ≥ 55 years who were active in the IRIS Registry from 2016 to 2018 were analyzed. Patients were categorized as nonexudative, inactive exudative, and active exudative AMD by International Classification of Diseases 10th Revision and Current Procedural Terminology (CPT) codes. Patients without provider-level ZIP codes matching any ZIP code tabulation area were excluded.Environmental data were obtained from public sources including the US Geological Survey, National Renewable Energy Laboratory, National Oceanic and Atmospheric Administration, and Environmental Protection Agency. Multiple variable, mixed effects logistic regression models with random intercepts per ZIP code tabulation area quantified the association of each environmental variable with any AMD versus non-AMD patients, any exudative AMD versus nonexudative AMD, and active exudative AMD versus inactive exudative and nonexudative AMD using 3 separate models, while adjusting for age, sex, race, insurance type, smoking history, and phakic status.Odds ratios for environmental factors.A total of 9 884 527 patients were included. Elevation, latitude, solar irradiance measured in global horizontal irradiance (GHI) and direct normal irradiance (DNI), temperature and precipitation variables, and pollution variables were included in our models. Statistically significant associations with active exudative AMD were GHI (odds ratio [OR], 3.848; 95% confidence interval [CI] with Bonferroni correction, 1.316-11.250), DNI (OR, 0.581; 95% CI, 0.370-0.913), latitude (OR, 1.110; 95% CI, 1.046-1.178), ozone (OR, 1.014; 95% CI, 1.004-1.025), and nitrogen dioxide (OR, 1.005; 95% CI, 1.000-1.010). The only significant environmental associations with any AMD were inches of snow in the winter (OR, 1.005; 95% CI, 1.001-1.009) and ozone (OR, 1.011; 95% CI, 1.003-1.019).The strongest environmental associations differed between AMD subgroups. The solar variables GHI, DNI, and latitude were significantly associated with active exudative AMD. Two pollutant variables, ozone and nitrogen dioxide, also showed positive associations with AMD. Further studies are warranted to investigate the clinical relevance of these associations. Our curated environmental dataset has been made publicly available at https://github.com/uw-biomedical-ml/AMD_environmental_dataset.

Huang W., Wu T., Jin T., Zhang Y., Wang J., Qi J., Li Y., Jiang H., Zhang J., Jiang Z., Chen L., Ying Z.

Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease affecting women of childbearing age. We aimed to conduct a meta-analysis of published observational studies to systematically evaluate the association between RA and adverse pregnancy outcomes. Medline (PubMed), EMBASE, and Web of Science were searched for keywords from the date of inception to December 28, 2021, to identify relevant studies reporting adverse maternal and/or fetal outcomes in RA pregnancies. Data from individual studies were pooled using random-effects models and presented as odds ratios (ORs) with 95% confidence intervals (CIs). Eighteen studies with a total number of over 50 million participants were eligible for inclusion. This current analysis showed that in pregnant women with RA, there was a significantly increased risk of adverse maternal outcomes, including caesarean section (OR, 1.39; 95% CI 1.24–1.55), pre-eclampsia (OR, 1.48; 95% CI 1.19–1.83), gestational hypertension (OR, 1.34; 95% CI 1.07–1.68) and spontaneous abortion (OR, 1.16; 95% CI 1.04–1.29). Similarly, maternal RA during pregnancy was also associated with a significantly increased risk of adverse fetal outcomes, including preterm birth (OR, 1.58; 95% CI 1.44–1.74), small for gestational age (OR, 1.49; 95% CI 1.22–1.82), low birth weight (OR, 1.45; 95% CI 1.30–1.63), congenital anomalies (OR, 1.36; 95% CI 1.01–1.83) and stillborn (OR, 1.38; 95% CI 1.09–1.74). Maternal RA is significantly associated with an increased risk of adverse maternal and fetal outcomes. Close monitoring of the clinical status of RA patients before and during pregnancy is essential in clinical practice.

Giardini V., Ornaghi S., Gambacorti-Passerini C., Casati M., Carrer A., Acampora E., Vasarri M.V., Arienti F., Vergani P.

COVID-19 and preeclampsia (preE) share the ANG-II mediated endothelial dysfunction, resulting from a significant dysregulation of RAS and an imbalanced proportion of anti-angiogenic and pro-angiogenic soluble plasmatic factors. Of note, an increased incidence of preE has been reported among COVID-19-infected mothers compared to the general pregnant population. The two most promising angiogenic markers are the soluble fms-like tyrosine kinase receptor-1 (sFlt-1), the major antiangiogenic factor, and the placental growth factor (PlGF), a powerful angiogenic factor. Since these markers have proven useful in the prediction, diagnosis, and severity of preE, this study aimed to evaluate their maternal serum levels in pregnancies complicated by SARS-CoV-2 infection and to assess their potential use to guide the management of these women. A retrospective analysis of SARS-CoV-2-positive pregnant women was performed. The serum levels of sFlt-1 and PlGF were collected at the diagnosis of SARS-CoV-2 infection at the hospital, before the beginning of steroid/hydroxychloroquine and/or antithrombotic therapy. The sFlt-1/PlGF ratio was stratified using cut-off values clinically utilized in the diagnosis and prediction of preE (low < 38, intermediate 38–85/110* and high >85/110*, * if before or after the 34th week of gestation). A total of 57 women were included, of whom 20 (35%) had signs and symptoms of COVID-19 at hospital presentation and 37 (65%) were asymptomatic. None were vaccinated. The mean gestational age at diagnosis of SARS-CoV-2 infection was 32 weeks in symptomatic patients and 37 weeks and 5 days in asymptomatic ones (p = 0.089). sFlt-1 serum levels were higher in SARS-CoV-2 positive asymptomatic patients compared to women with COVID-19 related symptoms (4899 ± 4357 pg/mL vs. 3187 ± 2426 pg/mL, p = 0.005). sFlt-1/PlGF at admission was <38 in 18 of the 20 symptomatic women (90%) compared to 22 (59%) of the asymptomatic patients (p = 0.018). Of note, two of the three women admitted to the intensive care unit had a very low ratio (<2). In turn, rates of patients with sFlt-1/PlGF at admission > 85/110 were not significantly different between the two groups: 11% in asymptomatic patients (4/37) vs. none of the symptomatic patients (p = 0.286), and all of them presented a placental dysfunction, like preE (n = 1) and FGR (n = 3). Of note, there were no stillbirths or maternal or neonatal deaths among symptomatic patients; also, no cases of preE, FGR, or small for gestational age neonates were diagnosed. In conclusion, our data suggest that SARS-CoV-2 infection during pregnancy could influence the angiogenic balance. A significant pathological alteration of the sFlt-1/PlGF ratio cannot be identified during the symptomatic phase; however, if left untreated, SARS-CoV-2 infection could potentially trigger placental dysfunction.

Kluivers A.C., Biesbroek A., Visser W., Saleh L., Russcher H., Danser J.A., Neuman R.I.

In patients with pre-eclampsia (PE) and fetal growth restriction (FGR), soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased, while free placental growth factor (PlGF) is decreased, either due to sFlt-1 binding or decreased PlGF production.To distinguish increased sFlt-1 binding and decreased PlGF production, we calculated total PlGF from measured sFlt-1 and free PlGF in a prospective cohort study involving 407 pregnancies with suspected or confirmed PE, making a distinction between both early- and late-onset PE (gestational age

Ruan L., Zhang S., Chen X., Liang W., Xie Q.

Breast cancer is one of the most common cancers in women, which can metastasize to other organs and has a high mortality rate. Previous studies have shown that angiogenic factors can contribute to tumor growth, development, and metastasis by altering the tumor microenvironment (TME). These angiogenic factors include a wide range of molecules, and in contrast, anti-angiogenic factors also inhibit angiogenesis and inhibit tumor growth. Evidence suggests that an imbalance between angiogenic and anti-angiogenic factors leads to angiogenesis, facilitating the migration of tumor cells from the source tissue in the breast to other organs such as the lung, liver, bone, and brain. By supplying blood through these neomicrovascular vessels, the nutrients and oxygen needed to grow tumor cells are provided. Due to the significant anti-tumor role of anti-angiogenesis factors, cancer researchers have always considered these molecules, and it is believed that anti-angiogenesis factors can be employed in cancer treatment approaches. This review discusses the role of anti-angiogenesis agents in breast cancer pathogenesis and reviews therapeutic approaches based on anti-angiogenesis factors.

Ratnik K., Rull K., Aasmets O., Kikas T., Hanson E., Kisand K., Fischer K., Laan M.

Preeclampsia (PE) is a common pregnancy-linked disease, causing preterm births, complicated deliveries, and health consequences for mothers and offspring. We have previously developed 6PLEX, a multiplex assay that measures PE-related maternal serum biomarkers ADAM12, sENG, leptin, PlGF, sFlt-1, and PTX3 in a single test tube. This study investigated the potential of 6PLEX to develop novel PE prediction models for early pregnancy. We analyzed 132 serum samples drawn at 70–275 gestational days (g days) from 53 pregnant women (PE, n = 22; controls, n = 31). PE prediction models were developed using a machine learning strategy based on the stepwise selection of the most significant models and incorporating parameters with optimal resampling. Alternative models included also placental FLT1 rs4769613 T/C genotypes, a high-confidence risk factor for PE. The best performing PE prediction model using samples collected at 70–98 g days comprised of PTX3, sFlt-1, and ADAM12, the subject's parity and gestational age at sampling (AUC 0.94 [95%CI 0.84–0.99]). All cases, that developed PE several months later (onset 257.4 ± 15.2 g days), were correctly identified. The model's specificity was 80% [95%CI 65–100] and the overall accuracy was 88% [95%CI 73–95]. Incorporating additionally the placental FLT1 rs4769613 T/C genotype data increased the prediction accuracy to 93.5% [AUC = 0.97 (95%CI 0.89–1.00)]. However, 6PLEX measurements of samples collected at 100–182 g days were insufficiently informative to develop reliable PE prediction models for mid-pregnancy (accuracy &lt;75%). In summary, the developed model opens new horizons for first-trimester PE screening, combining the easily standardizable 6PLEX assay with routinely collected antenatal care data and resulting in high sensitivity and specificity.

Verisokina N.E., Kuryaninova V.A., Petrosyan M.A., Zakharova I.N., Zaplatnikov A.L., Zubkov V.V., Klimov L.Y., Dmitrieva D.V., Beketova N.Y., Momotova A.A.

Introduction. Inadequate vitamin D supply worldwide is a public health problem. Low vitamin D levels during pregnancy can lead to abnormal placentation, placental insufficiency and abnormal fetal development, which contributes to poor health after birth.Objective of the study is to analyze the vitamin D status of premature infants born in the south of Russia.Materials and methods. A total of 141 premature infants were examined. Extremely low birth weight was found in 19 (13.4%) newborns, very low birth weight in 35 (24.8%), and low birth weight in 75 (53.2%).Results and discussion. Premature infants had vitamin D deficiency in the majority of cases (51%), with a median of 16.9 [11.7; 22.9] ng/mL. Correlation analysis demonstrated a positive association between 25(OH)D levels and body weight in very low birth weight infants (r = 0.34, p = 0.043). Serum vitamin D concentrations were 1.6 times lower in infants whose mothers did not receive multivitamins than in those whose mothers received multivitamins, 13.8 [9.7; 20.9] and 21.6 [16.9; 28.6] ng/mL, respectively (p = 0.001). Infants with an Apgar score of 7-10 had higher vitamin D levels, 17.8 [11.9; 22.7] ng/mL, than infants with severe asphyxia, 13.8 [9.9; 16.8] ng/mL (p = 0.036). Premature infants with congenital infection had lower 25(OH)D levels than infants without an infectious process, 15.6 [10.8; 22.9] and 18.4 [14.2; 22.7] ng/mL, respectively. Children with an infectious process that subsequently ended in death had lower 25(OH)D levels than children without an infectious process (p = 0.001). Children with cerebral ischemia had lower 25(OH)D concentrations than children without cerebral ischemia (p = 0.001).Conclusions. Premature infants born in the south of Russia have vitamin D deficiency in more than half of the cases. Administration of preparations containing cholecalciferol reduces the proportion of newborns with severe vitamin D deficiency, but does not ensure optimal serum levels. Initially low levels of 25(OH)D can be considered as an unfavorable prognostic sign against the background of the development of congenital infection.

Padayachee S., Govender N., Naicker T.

A dysregulation of angiogenic mediators has been implicated in HIV infection. Inconsistent data exists on highly active antiretroviral therapy (HAART) usage in pregnancy and its association with PE development. In view of the high prevalence of HIV infection and PE in SA, this study was aimed at determining PlGF and sFlt-1 levels in HIV-infected normotensive and preeclamptic pregnancies treated with HAART. Both PlGF and sFlt-1 were quantified in serum from HIV positive [normotensive (N+) and preeclamptic (P+)]; and HIV negative [normotensive (N-) and preeclamptic (P-)] pregnancies, using a Milliplex Multiplex immunoassay. sFlt-1 was significantly upregulated in P+ vs the N+ groups. PlGF was significantly downregulated in PE vs normotensive groups, regardless of HIV status. sFlt-1/PlGF ratio was significantly increased in PE- vs the N- groups. We report an amplification of sFlt-1 in lieu of PlGF down-regulation in HIV-infected pregnancies receiving HAART . 

Levkovitz O., Lagerev E., Bauer-Rusak S., Litmanovitz I., Grinblatt E., Sirota G.L., Shalit S., Arnon S.

Vitamin D plays a key role in regulating calcium and phosphate metabolism. However, whether maternal vitamin D levels affect fetal bone strength is unclear. This study assessed correlations between maternal 25(OH)D status and neonatal bone strength 25(OH)D levels, these were measured in the maternal and infant cord blood of 81 mother–infant dyads. Bone strength was measured using a quantitative ultrasound (QUS) of tibial bone speed of sound (SOS). Maternal vitamin D intake, medical history and lifestyle were evaluated from questionnaires. Maternal 25(OH)D levels were deficient (<25 nmol/L) in 24.7%, insufficient (25–50 nmol/L) in 37% and sufficient (>50 nmol/L) in 38.3%. The maternal and cord blood 25(OH)D levels correlated (r = 0.85, p < 0.001). Cord blood levels (57.9 ± 33.5 nmol/L) were higher than the maternal blood levels (46.3 ± 23.2: p < 0.001). The mean SOS was 3042 ± 130 m/s. The neonatal SOS and 25(OH)D levels were not correlated. The mean bone SOS levels were comparable in the three maternal and cord blood 25(OH)D groups. No correlation was found between the maternal 25(OH)D levels and the neonatal anthropometrics. Although the 25(OH)D levels were higher in Jewish mothers than they were in Muslim mothers (51.1 ± 22.6 nmol/L vs. 24 ± 14.7 nmol/L, respectively: p = 0.002) and in those who took supplemental vitamin D, the bone SOS levels were comparable. In conclusion, maternal vitamin D levels correlate with cord levels but do not affect bone strength or growth parameters.

Karge A., Desing L., Haller B., Ortiz J.U., Lobmaier S.M., Kuschel B., Graupner O.

Obese women are at high risk of developing pre-eclampsia (PE). As an altered angiogenic profile is characteristic for PE, measurement of soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PIGF) ratio in the maternal serum can be helpful for PE diagnosis, as well as for adverse perinatal outcome (APO) prediction. There is growing evidence that obesity might influence the level of sFlt-1/PIGF and, therefore, the aim of the study was the evaluation of sFlt-1/PIGF as an APO predictor in obese women with PE. Pre-eclamptic women who had an sFlt-1/PIGF measurement at the time of diagnosis were retrospectively included. Women were classified according to their pre-pregnancy body mass index (BMI) as normal weight (BMI < 25 kg/m2), overweight (BMI > 25–29.9 kg/m2) or obese (BMI ≥ 30 kg/m2). APO was defined as the occurrence of one of the following outcomes: Small for gestational age, defined as a birthweight < 3rd centile, neonatal mortality, neonatal seizures, admission to neonatal unit required (NICU) or respiratory support. A total of 141 women were included. Of them, 28 (20%) patients were obese. ROC (receiver operating characteristic) analysis revealed a high predictive value for sFlt-1/PIGF and APO across the whole study cohort (AUC = 0.880, 95% CI: 0.826–0.936; p < 0.001). However, the subgroup of obese women showed a significantly lower level of sFlt-1 and, therefore, the performance of sFlt-1/PIGF as APO predictor was poorer compared to normal or overweight PE women (AUC = 0.754, 95% CI: 0.552–0.956, p = 0.025). In contrast to normal or overweight women, a ratio of sFlt-1/PIGF < 38 could not rule out APO in women with obesity.

Freimane K.Z., Kerrigan L., Eastwood K., Watson C.J.

Background: Pre-eclampsia is a serious consideration for women with type 1 diabetes mellitus (T1DM) planning pregnancy. Risk stratification strategies, such as biomarkers measured in the first trimester of pregnancy, could help identify high-risk women. The literature on T1DM-specific pre-eclampsia biomarkers is expanding. We aimed to provide a narrative review of recently published evidence to identify the most promising biomarker candidates that could be targeted for clinical implementation in existing PE models.Methods: A search using MeSH terms was carried out of Medline, EMBASE, Maternity and Infant Care, Web of Science, and Scopus for relevant papers published since 2015 inclusive and in English. The time limit was applied from the publication of the preceding systematic review in this field. Included studies had pre-eclampsia as a primary outcome, measured one or more serum, plasma or urine biomarkers at any time during pregnancy, and had a distinct group of women with T1DM who developed pre-eclampsia. Studies with pre-eclampsia as a composite outcome were not considered. No restrictions on study types were applied. A narrative synthesis approach was adopted for analysis.Results: A total of 510 records were screened yielding 18 eligible studies relating to 32 different biomarkers. Higher first-trimester levels of HbA1c and urinary albumin were associated with an increased risk of pre-eclampsia development in women with T1DM. Urinary neutrophil gelatinase-associated lipocalin and adipokines were novel biomarkers showing moderate predictive ability before 15 gestational weeks. Two T1DM-specific pre-eclampsia prediction models were proposed, measuring adipokines or urinary neutrophil gelatinase-associated lipocalin together with easily attainable maternal clinical characteristics. Contradicting previous literature, pre-eclampsia risk in women with T1DM was correlated with vitamin D levels and atherogenic lipid profile in the context of haptoglobin phenotype 2-2. Pregnancy-associated plasma protein-A and soluble endoglin did not predict pre-eclampsia in women with T1DM, and soluble Fms-like tyrosine kinase 1 only predicted pre-eclampsia from the third trimester.Conclusion: Maternally derived biomarkers reflecting glycemic control, insulin resistance and renal dysfunction performed better as PE predictors among women with T1DM than those derived from the placenta. These biomarkers could be trialed in current PE prediction algorithms to tailor them for women with T1DM.

Koller A., Brandl C., Lamina C., Zimmermann M.E., Summerer M., Stark K.J., Würzner R., Heid I.M., Kronenberg F.

Relative telomere length (RTL) is a biomarker for physiological aging. Premature shortening of telomeres is associated with oxidative stress, which is one possible pathway that might contribute to age-related macular degeneration (AMD). We therefore aimed to investigate the association between RTL and AMD in a well-characterized group of elderly individuals.We measured RTL in participants of the AugUR study using a multiplex quantitative PCR-based assay determining the ratio between the telomere product and a single-copy gene product (T/S ratio). AMD was assessed by manual grading of color fundus images using the Three Continent AMD Consortium Severity Scale.Among the 2262 individuals 70 to 95 years old (627 with AMD and 1635 without AMD), RTL was significantly shorter in individuals with AMD compared to AMD-free participants. In age- and sex-adjusted logistic regression analyses, we observed an 8% higher odds for AMD per 0.1 unit shorter RTL (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.02-1.14; P = 0.005). The estimates remained stable when adjusted for smoking, high-density lipoprotein cholesterol, cardiovascular disease, diabetes, and hypertension. Interestingly, this association was only present in women (OR = 1.14; 95% CI, 1.06-1.23; P < 0.001), but not in men (OR = 1.01; 95% CI, 0.93-1.10; P = 0.76). A significant sex-by-RTL interaction on AMD was detected (P = 0.043).Our results show an association of RTL with AMD that was restricted to women. This is in line with altered reactive oxygen species levels and higher telomerase activity in women and provides an indication for a sex-differential pathway for oxidative stress and AMD.

Abascal-Saiz A., Duque-Alcorta M., Fioravantti V., Antolín E., Fuente-Luelmo E., Haro M., Ramos-Álvarez M.P., Perdomo G., Bartha J.L.

Antiangiogenic factors are currently used for the prediction of preeclampsia. The present study aimed to evaluate the relationship between antiangiogenic factors and lipid and carbohydrate metabolism in maternal plasma and placenta. We analyzed 56 pregnant women, 30 healthy and 26 with preeclampsia (including early and late onset). We compared antiangiogenic factors soluble Fms-like Tyrosine Kinase-1 (sfLt-1), placental growth factor (PlGF), and soluble endoglin (sEng)), lipid and carbohydrate metabolism in maternal plasma, and lipid metabolism in the placenta from assays of fatty acid oxidation, fatty acid esterification, and triglyceride levels in all groups. Antiangiogenic factors sFlt-1, sFlt-1/PlGF ratio, and sEng showed a positive correlation with triglyceride, free fatty acid, and C-peptide maternal serum levels. However, there was no relationship between angiogenic factors and placental lipid metabolism parameters. Free fatty acids were predictive of elevated sFlt-1 and sEng, while C-peptide was predictive of an elevated sFlt1/PlGF ratio. The findings in this study generate a model to predict elevated antiangiogenic factor values and the relationship between them with different products of lipid and carbohydrate metabolism in maternal serum and placenta in preeclampsia.

Tkachuk A.S., Vasukova E.A., Anopova A.D., Karonova T.L., Pustozerov E.A., Teplova Y.A., Eriskovskaya A.I., Isakov A.O., Vasilieva E.Y., Kokina M.A., Zazerskaya I.Y., Pervunina T.M., Grineva E.N., Popova P.V.

Several meta-analyses found an association between low maternal serum 25-hydroxyvitamin D (25(OH)D) level and gestational diabetes mellitus (GDM). However, some of them reported significant heterogeneity. We examined the association of serum 25(OH)D concentration measured in the first and in the second halves of pregnancy with the development of GDM in Russian women surveyed in the periods of 2012–2014 and 2018–2021. We conducted a case–control study (including 318 pregnant women) nested on two previous studies. In 2012–2014, a total of 214 women (83 GDM and 131 controls) were enrolled before 15 weeks of gestation and maternal serum 25(OH)D concentrations were measured twice: at 8th–14th week of gestation and simultaneously with two-hour 75 g oral glucose tolerance test (OGTT) at 24th–32nd week of gestation. In the period of 2018–2021, 104 women (56 GDM and 48 controls) were included after OGTT and 25(OH)D concentrations were measured at 24th–32nd week of gestation. Median 25(OH)D levels were 20.0 [15.1–25.7] vs. 20.5 [14.5–27.5] ng/mL (p = 0.565) in GDM and control group in the first half of pregnancy and 25.3 [19.8–33.0] vs. 26.7 [20.8–36.8] ng/mL (p = 0.471) in the second half of pregnancy, respectively. The prevalence rates for vitamin D deficiency (25(OH)D levels < 20 ng/mL) were 49.4% and 45.8% (p = 0.608) in the first half of pregnancy and 26.2% vs. 22.1% (p = 0.516) in the second half of pregnancy in women who developed GDM and in women without GDM, respectively. The frequency of vitamin D supplements intake during pregnancy increased in 2018–2021 compared to 2012–2014 (p = 0.001). However, the third trimester 25(OH)D levels and prevalence of vitamin D deficiency (25.5 vs. 23.1, p = 0.744) did not differ in women examined in the periods of 2012–2014 and 2018–2021. To conclude, there was no association between gestational diabetes risk and maternal 25(OH)D measured both in the first and in the second halves of pregnancy. The increased prevalence of vitamin D supplements intake during pregnancy by 2018–2021 did not lead to higher levels of 25(OH)D.