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Review Article | DOI: https://doi.org/10.31579/2690-4861/794
1University of Bahri, general Precticner, Sudan.
2University of Gezira, medical officer, Sudan.
*Corresponding Author: Lamies Fadul Ahmed Elawad, University of Bahri, General Precticner, Sudan.
Citation: Ahmed Elawad LF, Ibrahim Teben AF, Elamin Eltayeb ME, (2025), Importance of Genetic and Epigenetic Factors in Preeclampsia and their Protentional Translation Improving Antenatal Care, International Journal of Clinical Case Reports and Reviews, 27(2); DOI:10.31579/2690-4861/794
Copyright: © 2025, Lamies Fadul Ahmed Elawad. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 09 June 2025 | Accepted: 19 June 2025 | Published: 30 June 2025
Keywords: preeclampsia; genetic; epigenetic; antenatal care
Preeclampsia is a pregnancy-specific disorder affecting 5-7% of cases, It is a substantial factor in maternal and fetal morbidity and mortality globally. This diverse condition has multiple underlying mechanisms, making its prevention challenging. Although the pathological process has become clearer over the last two decades, the cause of preeclampsia remains unknown. Preeclampsia, characterized by hypertension developing after 20 weeks of gestation, results in high mothers and babies’ death rates globally. Crucial barriers to early screening and targeted preventive approaches include gaps in understanding the varied molecular pathways of preeclampsia and the absence of adequate, certain diagnostic ways. Although transcriptional analysis of placentas can categorize patients, incorporating epigenetic data could shed light on the gene regulatory mechanisms underlying different preeclampsia pathologies and identify potential biomarkers with clinical utility.
The potential for early preeclampsia diagnosis using miRNAs as predictors and their clinical application remain uncertain and require further study. It is still unclear whether the likelihood of early-onset preeclampsia correlates with the Intensity of clinical assessments and perhaps histopathology of the placenta. Moreover, the gene regulatory landscape underlying preeclampsia is not well understood. Further research is needed to determine whether preeclampsia can be sufficiently differentiated from other normal and abnormal outcomes.
Research has shown that the scale of placental-derived cell-free DNA increases with preeclampsia; however, the rise in maternal sources of cell-free DNA is also considerable. The exact origin of maternal cell-free DNA and its relationship to the disease phenotype needs further investigation, and there is a lack of consistency among studies identifying altered placental DNA methylation in preeclampsia, with most findings lacking replication. Additionally, there was minimal overlap in the miRNAs identified across different studies. This study aimed to delve into current knowledge regarding the contributions of genetic and epigenetic factors to PE and their implications for antenatal care.
Preeclampsia (PE) is considered a gestation-specific syndrome, affecting 5-7% of pregnancies causing maternal and neonatal morbidity and mortality all over the world. The etiology of (PE) still unknown; although research has cast light on its pathological mechanisms [1] (PE) continues to pose significant short-term and long-term health risks for both mothers and their children [1]. This condition places considerable financial stress on the healthcare system. Thus, early prediction and identification are essential for enhancing patient outcomes and treatment strategies.
Regardless of advanced understanding the pathophysiology of (PE), sensitive and specific biomarkers for its early prediction and detection are still deficient, and further researches are necessary to identify the molecular markers linked to (PE) [2]. On top of that, there is a limited overlap in the identified microRNAs (miRNAs) between studies. Moreover, how the mechanisms behind (PE) and genetic variation collaborate with other elements that impact on the rate of this condition remain unclear. [3,4]
Recently, researches has been concerned with identifying novel biomarkers using extracellular RNAs (exRNAs), such as microRNAs (miRNAs) in maternal blood circulation, which could enable noninvasive investigation of placental function. Some studies have explored expression profiles of trimester-specific plasma exosome miRNAs [1] in (Boyano et al. (2023), researchers have developed a novel predictive model using placental DNA methylation patterns to identify early onset preeclampsia (EOPE) [5]
Another promising tool is Genome-wide association studies (GWAS) which have showed liability of genes for (PE) in specific populations also researchers analyze cell-free RNA (cfRNA) transcriptomic patterns in pregnant mothers to identify the genes associated with (PE)[6,7] Furthermore, many investigations have been conducted on the effects of placental long non-coding RNA H19 polymorphisms and promoter methylation on H19 expression in association with (PE) susceptibility [8]also they conduct a comparison of the genomic methylation patterns of fetal endothelial colony-forming cells (ECFC) from uncomplicated and preeclamptic pregnancies have been performed [9]and we have to consider the huge efforts in examination of placental microRNAs (miRNAs) in pregnancies with early onset intrauterine growth restriction and(PE)which have been conducted[3]These studies examine meticulously the current understanding of the genetic and epigenetic contributions to PE and their implications for prenatal care.
Clinical manifestations (PE):
The clinical presentation of (PE) varies, reflecting its multisystemic nature. Although hypertension and proteinuria are distinctive features, the absence of one or both does not exclude (PE) [10]. Atypical symptoms, for instance, severe edema, may also occur. All in all, this disorder can affect multiple organ systems and lead to a range of signs and symptoms [11,12].
Hypertension is a key diagnostic criterion typically defined as systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg. Severe (PE) is indicated by a systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 110 mmHg (13–15)
Proteinuria was defined as the presence of ≥ 300 mg of protein in a 24-hour urine sample(16)The International Society for the Study of Hypertension in Pregnancy (ISSHP) defines PE as de novo hypertension accompanied by ≥1 of the new-onset conditions, including proteinuria (≥1+, 30 mg/dL; urine Protein/Creatinine Ratio (PCR) ≥ 30 mg/mmol (0.3 mg/mg))[7]
Although edema has been recognized as a symptom of (PE), it may not always be present [11]
(PE) can lead to dysfunction in various organs and systems. For example, renal disorders, liver function abnormalities, and CNS symptoms are common complications, Neurological complications include persistent headaches and visual disturbances [17]. Thrombocytopenia, which is a reduction in platelet count, may occur. [18]
HELLP Syndrome, which is a complex of hemolysis, increased liver enzymes, and decreased platelet counts, may take place and is considered a severe complication of (PE) [19]
The feared complication is the progression of Eclampsia, which occurs in severe cases and is characterized by seizures. (11)
Diagnostic Criteria
The diagnosis of (PE) connected with an estimation of blood pressure and proteinuria after the 20th week of gestation. According to the American College of Obstetricians and Gynecologists (ACOG), preeclampsia is diagnosed based on the following criteria (14)
Hypertension: Systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm
Proteinuria: Presence of ≥ 300 mg protein in a 24-hour urine sample
However, the current understanding recognizes that (PE) can be also diagnosed in lack the presence of proteinuria. In this circumstance, one or more of the following conditions have to be fulfilled (14)
Kidney disorder
Hepatic dysfunction
CNS disorder
Hemodynamic dysfunctions
Uteroplacental complications
Intrauterine fetal growth restriction
Pathophysiology of (PE)
(PE) It is often described as a disease characterized by abnormal placentation. One of the most relevant theories suggests that PE is a Many-sided disease that involves several genetic and environmental factors despite its clinical manifestation’s symptoms appearing later in pregnancy (17,20). The root behind it starts from early placental development.
In normal gestation, the syncytiotrophoblasts invade and remodel the spiral arteries in the myometrium, leading to an elevation in placental blood flow. In contrast, these processes fail and disturb placentation in (PE). Owing to inappropriate blood flow in the placenta, oxygen supply will be affected, resulting in hypoxia and hyperoxia, which activate oxidative stress, inflammation, and necrosis (21)
Importance of placenta
The placenta is one of the major driving forces behind PE pathogenesis. It occurs due to the failure of extravillous trophoblasts to fully invade the maternal decidua and remodel spiral arteries. In a healthy pregnancy, this remodeling is finished by the second trimester, creating decreased resistance. Since an increase in the vessels' blood flow is needed to enhance fetal growth,
defective placentation leads to decreased maternal blood flow to the intervillous zone, compromising the exchange of gases and nutrients. (6,20) This ischemia results in increased placental xanthine oxidase/dehydrogenase system expression and activity, increased generation of reactive oxygen species, impaired antioxidant mechanisms, and increased apoptosis (6,20,21)
Endothelial Dysfunction
The second player in (PE) pathogenesis is endothelial dysfunction. Increased synthesis of vasoactive mediators produces vasoconstriction and insufficient blood circulation in the placental vessels. Prior clinical symptoms appear, uteroplacental blood flow diminishes, and uterine vessel resistance increases, producing placental ischemia (22)
Placental ischemic events give rise to the release of placental factors that contribute to systemic vascular endothelial dysfunction, resulting in increased systemic vascular resistance and high blood pressure. The syndrome is perhaps started by placental elements that enter maternal blood flow and lead to endothelial dysfunction, yielding to high blood pressure and protein in the urine (12)
Risk Factors (PE).
Several preexisting maternal circumstances and pregnancy-specific characteristics have been identified as risk factors for (PE), consisting of:
Maternal Age and BMI: Increasing maternal age and higher BMI places pregnant ladies at higher risk of developing (PE) (23) Preexisting Conditions, i.e. women with preexisting hypertension and diabetes, cardiogenic disease, or renal disease before becoming pregnant have an increased risk of developing (PE) (24,25)
Primiparity: First-time gestation is associated with a higher risk of preeclampsia (21)
Family History: A family history of (PE) and perhaps preeclampsia in a prior pregnancy is a significant risk factor (17)
Multiple gestations and in vitro fertilization Women carrying twins or other multiples are at higher risk (17)
Other Potential Factors
Genetic and Epigenetic Factors
Genetic factors significantly contribute to susceptibility to (PE). (26). Women with an affected first relative are at increased risk, suggesting a genetic component from maternal, fetal, and/or paternal genes. Moreover, polymorphisms in genes that control vascular tone, such as the renin-angiotensin system and endothelial nitric oxide synthetase, can significantly increase the risk of (PE) (22)
Polygenic risk scores (PRSs) exert a significant influence on predicting (PE), with blood pressure being the most significant contributing parameter. one study demonstrated that women with a high blood pressure polygenic risk score (BP-PRS) are more likely to develop (PE) and display higher BP readings throughout pregnancy (27)
Environmental elements can also participate in the risk of PE. External influences affecting pregnancy, like stress and cigarette smoke, are correlated with a higher risk of progressing in to (PE). (5,28)
We have to bear in mind that autoimmune diseases are one of the maternal risk factors for (PE) (29). An exacerbation of inflammatory response related to pregnancy. This results in dysregulation of the immune response in early pregnancy, which might be linked to histone modification. (30)
A genome-wide association study (GWAS) found that (PE) was linked with many autoimmune phenotypes, including celiac disease, type 1 diabetes, and hypothyroidism. The GWAS also showed an association with rheumatoid arthritis in female participants. (29) . Systemic lupus erythematosus is also considered as a risk factor connected with clinical risk factors for (PE) in addition reduced SH2B3 function has been correlated to autoimmune diseases. Lastly, the history of autoimmune disease. (29)
Early diagnosis of (PE) before its clinical manifestation is essential for assessing the risk and practicality of the conservation of the pregnancy. Identifying risk factors before pregnancy allows for timely assessment of the likelihood of developing (PE) and implementation of preventive measures. We have to note that (PE) has a sudden onset, making early predictions very tricky.
Discussion
(PE) is a complex gestation-specific high blood pressure disease, in which several genes associated with angiogenesis, inflammation, oxidative stress, and the renin system exert a significant influence on (PE). In this narrative review article, we assessed the genetic components that are essential for elucidating pathophysiology, identifying potential biomarkers, and developing targeted therapies for (PE) (31).
Genetic factors in PE:
Angiogenesis-Related Genes
Angiogenesis by definition, is the formation of new blood vessels, and it is fundamental for establishing and maintaining a normal placenta. The impairment of angiogenesis is a hallmark of (PE). Several genes and microRNAs (miRNAs) that regulate angiogenesis have been identified in many studies (17)
MicroRNAs (miRNAs): These are involved in regulating trophoblast invasion and immune activation in the placentas. They play numerous fundamental roles in regulating cell growth. Certain miRNAs, such as miR-181a-5p, contribute to trophoblast dysfunction in PE. Also, miR-431 affected trophoblast migration and invasion by targeting ZEB1 (21)
Vascular Endothelial Growth Factor (VEGF) is important for the promotion of angiogenesis. Studies have found that the downregulation of miR-10 causes more expression of both sFlt-1 and Flt-1 and markedly impairs the angiogenic behavior of human endothelial cells. Both sFlt-1 and Flt-1 bind to VEGF, and placental growth factor (PlGF) promotes angiogenesis (17). Ephrin-B2 and EPHB4 genes are targeted by upregulated angiogenesis-associated microRNAs, such as miR-17, -20a, and -20b in preeclamptic placentas (17)
Inflammation-Related Genes
Many studies show the importance of inflammatory-related genes in (PE). An overactivated inflammatory response can generate immune imbalance and vascular endothelial damage, triggering the development of (PE) (31)
miRNA-499 (miR-499) acts as an inflammation suppressor by targeting genes involved in inflammatory responses and regulating hypoxic-ischemic conditions (31)
Interleukin-10 (IL-10): This is linked with preeclampsia in a Tunisian population, suggesting its role in the inflammatory pathways of the disorder (31)
INHBA, OPRK1, and TPBG: These elements of inflammation-associated genes can be used as potential genetic biomarkers for (PE) prediction and treatment (31) RELA-miR-548K/miR-1206-TPBG this perhaps a potential RNA controlling course that governs the progression of early (PE) (31)
Oxidative Stress-Related Genes
Oxidative stress, known as the disproportion between the generation of free radicals and antioxidant defenses, gives rise to the development of (PE). For example, Polymorphisms in genes such as GPx-1 (rs1050450) and MnSOD (rs4880) have been studied for their association with (PE) susceptibility (31)
OPRK1, also recognized as KOR, is associated with ROS generation of Reactive Oxygen Species. Animal experiments have shown that a-opioid receptor agonists do not stimulate any generation to mitigate the impact of hyperlipidemic destruction on endothelial function (32)
Renin-Angiotensin System (RAS)-Related Genes
RAS is a fundamental regulator of blood pressure and fluid balance. Dysregulation of the RAS has been implicated in (PE). Components of the renin-angiotensin system pathway, which harbors genes that were previously reported to be protective or disease-causing for (PE) for example the genetic variations in genes like AGTR1, AGTR2, ERAP1, ERAP2, LNPEP, CYP17A1, and CYP21A2. (26,33)
Variations in these genes can alter receptor function, enzyme activity, and hormone synthesis, affecting blood pressure regulation and potentially leading to (PE) note that Natriuretic peptides work against the RAS, offering potential protective effects (29). eNOSgene regulation of normal blood pressure depends on IP3R1-mediated eNOS (12).
Genome-Wide Association Studies (GWAS)
GWAS generally is scanning the genomes of many individuals to distinguish genetic variants, such as single nucleotide polymorphisms (SNPs) linked to a precise trait or disease. GWAS have been useful tool for identifying the genetic loci associated with (PE) susceptibility; however, it also has limitations. We must recognize the importance of both strengths and limitations of interpreting results and designing future research strategies (2).
A GWAS in the Chinese Han population identified rs13210237 and rs13176432 as potential (PE)-susceptible genetic factors; rs13210237 is linked to HSF2 and GJA1, whereas rs13176432 is linked to TRIM36 (15). Pathway analysis indicated enrichment in the adenylyl cyclase-inhibiting G protein-coupled receptor signaling pathway
Another study, which is a many-ancestry GWAS meta-analysis, distinguished 18 independent genomic locations related to preeclampsia and perhaps gestational hypertension (29), which stresses the roles of angiogenesis, natriuretic peptide signaling, renal glomerular function, and immune dysregulation in the pathogenesis of these conditions. It also demonstrates that the placental genetic variant rs4769613 upstream FLT1 is linked with (PE) development (6). The C allele of rs4769613 is a preeclampsia-specific risk factor participates in the early recognition of high-risk women (34)
Other Specific Genes and SNPs GWAS are as follows:
The C allele of rs2021783 in CYP21A2 indicates an increased risk of preeclampsia
The TT genotype for rs1004467 and GG genotype for rs3824755 were identified as risk Factors for mild (PE) (28)
Genetic variants of ERAP1 and ERAP2 are associated with eclampsia and preeclampsia, respectively (33). The rs1640299 and rs720014 polymorphisms in DGCR8 are associated with an increased risk of late-onset preeclampsia (LOPE) (35)
A genetic likelihood to high blood pressure is linked with (PE) in women who are genetically liable to hypertension and have a high risk of (PE). The blood pressure polygenic risk score (BP-PRS) is strongly associated with (PE) and gestational hypertension (13)
Strengths of GWAS
GWAS offers several advantages for studying genetics (PE). GWAS examines the entire genome, allowing the discovery of novel genes and pathways that may not have been previously suspected (15). Furthermore, it does not require prior knowledge of specific candidate genes, making it possible to uncover unexpected genetic associations.
GWAS generally emphasize large sample sizes, increasing the statistical power to detect genetic associations. Meta-analyses generate data from multiple GWAS can further boost statistical power and effectively identify common genetic variants that contribute to disease risk development (15,34)
Many studies have identified common SNPs associated with (PE) susceptibility (6), extracted from GWAS can be used to calculate polygenic risk scores (PRSs) to estimate an individual's risk of (PE). BP-PRSs have shown promise in predicting hypertensive disorders during pregnancy (36)
Limitations of GWAS
Despite their strengths, GWAS have several limitations that need to be considered
GWAS identifies genetic variants associated with a disease but does not prove causation. Further functional studies are needed to determine whether the identified variants directly contribute to PE pathogenesis (34). It primarily focuses on common genetic variants, meaning that rare variants with large effects on (PE) risk may be missed. We have to bear in mind the genetic architecture of preeclampsia may vary across different populations, leading to inconsistent findings across research. Studies on specific populations, such as the Han Chinese population, may identify unique genetic factors (15).
GWAS often demonstrates only a little percentage of the heritability of complex diseases such as (PE). The "missing heritability" may be due to rare variants, gene-environment interactions, epigenetic factors, or other genetic mechanisms not detected by GWAS (34)
Many SNPs recognized by GWAS are in non-coding areas of the DNA, making it challenging to determine their functional importance; hence, further research is required to understand how these SNPs affect gene expression and protein function (6)
The sample sizes in preeclampsia GWAS are often smaller than those in GWAS for other common diseases, limiting the statistical power. Larger multicenter studies and meta-analyses are needed to increase power and identify additional genetic associations (29)
PE is clinically heterogeneous, with different subtypes (e.g., early onset vs. late onset), potentially having distinct genetic bases. GWAS
that do not account for this heterogeneity may miss subtype-specific genetic associations. It is important to mention that the majority of GWAS have been established in populations of European backgrounds, limiting the generalizability of findings to other ethnic groups. In addition, environmental elements such as diet, smoking, and obesity can impact the risk of (PE) and interact with genetic factors. WAS may not fully capture these gene-environment interactions (28). Finally, GTEx samples had a limited database and were segregated from a cohort of male (67.1%) and female (32.9%) tissue donors, none of whom were pregnant (GTEx database, V8 Donor Info) (6)
Familial aggregation and heritability
Familial aggregation and heritability have a major impact on (PE). Studies have suggested that a substantial proportion of the tendency to (PE) can be assigned to maternal genetics. Familial aggregation indicates that (PE) occurs more frequently in some families than in the general population.
Mother and baby genetic factors are worth a large proportion of familial aggregation (PE). Heritability estimates suggest that a considerable percentage of (PE) predispositions are due to maternal genetics.
One study (Honigberg et al., 2023) estimated that 31–35% of (PE) predispositions are attributable to maternal genetics
A family background of chronic hypertension is more frequent in women with eclampsia and HELLP syndrome, indicating having common genetic components between essential hypertension and hypertensive diseases during gestation (37)
Epigenetics factors in (PE)
Investigations of alterations in the manner of methylated DNA in placental tissues and maternal blood in (PE) have found exactly what genes and pathways are affected in (PE) and many prior studies have demonstrated that PE is linked with alteration in DNA methylation in the placental cytology (10). To explain this more clearly, DNA methylation is an epigenetic modification that regulates various cellular activities and genetic phenotypes (10).PE and PE+IUGR placentas illustrate hypomethylation at L1s (long interspersed element-1) in comparison to control placenta. Moreover, L1s consist of approximately 18% of the human genome. Consequently, the hypomethylation of these elements in PE indicates possible global hypomethylation (2)
Besides, these variants of microRNAs (miRNAs) are connected with (PE). miRNA196a2 rs11614913 CT, TT genotypes and the T allele of placental tissues are with low possibility of (PE) however both placental and maternal miR-499 rs3746444 CC genotypes are related to (PE) (21)
Specific methylation pattern
Note that research found that Early onset (PE) is linked to a specific pattern of hypermethylated locations which are mostly found in promoter regions and introns. Also, methylation haplotypes are enriched in CTCF on the X chromosome (38).
Considerable differential methylation in the CMIP gene has been recognized and validated, putting forward its association with PE pathogenesis and it’s found in blood which makes them a potential diagnostic biomarker (39). Moreover, DNA methylation signatures in PE are distinguished from those in uncomplicated pregnancies.
Scientists noticed a low expression level of DNMT3A (DNA methyltransferase 3A) implicated in immunological-associated diseases and abnormal placentation in (PE) (39). ZNF417 hypomethylation in PE with severe features compared with PE without severe features. The total cell-free DNA concentration is higher in (PE) patients than in healthy control women (27)
Histone modifications
Many studies Suggests a great reaching importance of Histone modifications in (PE) the concept behind histone modification is they can alter gene production without modification the DNA pattern. Studies reveal that the expression of placental histone proteins H3K4me3 (trimethylated lysine 4 of histone H3) and H3K9ac (acetylated lysine 9 of histone H3) are reduced in PE. one study demonstrated decreased levels of H3K4me3 in PE-affected placentas compared to controlled ones, with similar findings for H3K9ac (30) Immunohistochemical staining illustrated that H3K4me3 and H3K9ac reduction occurs in the syncytium and decidua. Positivity of cells to these histone changes have been recognized as extra villous trophoblasts (EVTs) (30). A notable reduction in H3K4me3 and H3K9ac levels suggests a loss of accessibility for gene transcription. Since H3K4me3 and H3K9ac typically show active locations at gene promoters and enhancers, their reduction points to low gene activation in PE. Furthermore, the expression of methylated histone H3K4me3 demonstrates a positive correlation with higher maternal age in PE placentas (30)
Also, we have to consider that many studies highlighted the power of H3K9ac in the production of vascular endothelial cadherin, which is fundamental for angiogenesis. Defective remodeling of spiral arteries and vascular dilation are key elements in the pathological mechanisms of PE, resulting in dysfunctional uteroplacental perfusion and systemic inflammation.
Histone modifications are associated with macrophage activation and polarization during mucosal inflammation, leading to derangement of the immune response, which is a distinguished component of PE pathophysiology. (30).
An abnormality of H3K9 trimethylation is observed in the promoter region of vascular endothelial growth factor (VEGF) in PE. modified histone acetylation of H3 and H4 in the promoter region caused by hypoxia affecting the placental growth factor (PlGF). In essence, these changes suggest that histone modifications contribute to PE pathogenesis (30)
MicroRNAs (miRNAs)
MicroRNAs (miRNAs) are small, non-coding RNAs that have a consequential role in multiple biological processes, including those which are connected to (PE) miRNAs are classified as epigenetic regulators because they control gene production without changing the DNA sequence. They govern gene expression post-transcriptionally by attaching to the 3 untranslated regions (UTRs) of target messenger RNAs (mRNAs), leading to mRNA degradation or translational inhibition (40)
There are several biological processes linked to (miRNAs) including cell growth, proliferation, invasion, apoptosis, autophagy, stress response, death, angiogenesis, and differentiation. The most important point is that miRNA) regulate trophoblast invasion and immune activation in the placenta (20).
Specific miRNAs, such as miR-195, are hinting to control PE via their target genes and manipulate processes, for example, placental proliferation, apoptosis, and angiogenesis (14).
In many research studies there are growing suggestions that miRNAs are potential biomarkers for (PE), owing to their stability and presence in tissues and fluids (35). Single nucleotide polymorphisms (SNPs) within miRNA biosynthesis genes can alter miRNA expression and are linked with the risk of some diseases (8)
Long non-coding RNAs (lncRNAs) These are RNA molecules that are larger than 200 nucleotides and do not code for protein and have been involved in the pathogenesis of (PE) and have important participation in genome formation and expression through various mechanisms (8).
H19 lncRNA:H19 polymorphisms are linked to PE susceptibility, and their production governs certain mRNAs via post-transcription modifications and function as a primary microRNA precursor. Moreover, H19 methylation patterns are closely related to (PE) and trophoblast abnormalities (8)
H19 long non-coding RNA modifies trophoblast cell migration and invasion by controlling TβR3 in placenta with intrauterine fetal growth restriction (8).
LINC-HELLP lncRNA: LINC-HELLP is hyper-expressed in PE
It is a specific type of lncRNA found in early pregnancy extra villous trophoblasts and negatively affects their differentiation of the extra villous trophoblasts. It is important to mention that
Mutations in LINC-HELLP recognized in HELLP families negatively influence trophoblast differentiation (8).
TRAF3IP2-AS1 lncRNA: TRAF3IP2-AS1 long non-coding RNA a key controller of IL-17 signaling through the SRSF10-IRF1-Act1 axis in autoimmune diseases. Hence, from all the above we can come to the idea that aberrant lncRNA expression contributes to PE pathogenesis and may act as important biomarkers and influence gene expression in pregnancy complications (8)
Implications for Antenatal Care
The integration of genetic and epigenetic markers into risk prediction models for PE could empower early detection and management by markedly reducing maternal and fetal morbidity and mortality. Markers can be incorporated into predictive models. Here, we delve into some of these promising markers and how they influence antenatal care, highlighting the advantages and obstacles facing such strategies.
Genetic and Epigenetic Markers in Risk Prediction (PE)
Genetic Markers
Genetic studies have identified several susceptibility genes associated with PE, such as COL4A1, SLC2A4, and FLT1, which can be used in risk-prediction models. (37)
The identification of novel candidate genes, such as SORD, DGKI, and ICA1, through whole-genome bisulfite sequencing (WGBS) suggests that genetic markers can provide insights into the heritable components of PE risk (37)
Epigenetic Markers
Epigenetic modifications, particularly DNA methylation, have been linked to PE. Differentially methylated regions (DMRs) associated with genes involved in PE pathogenesis can serve as biomarkers for risk prediction (41)
Studies have shown that epigenetic changes in placental tissues, such as those affecting the TGF-β signaling pathway, are associated with different PE subtypes, indicating their potential utility in personalized risk assessment (42)
The benefits of incorporating markers improved prediction accuracy to illustrate this the
Combining genetic and epigenetic data with traditional clinical factors could enhance the sensitivity and specificity of PE risk prediction models, allowing for more accurate identification of high-risk pregnancies. (43)
The use of machine learning models, such as neural networks, that integrate these markers can improve predictive performance compared to models based solely on clinical data (44)
Personalized Medicine
Genetic and epigenetic markers can facilitate personalized interventions for instances targeted aspirin therapy by recognizing individuals who would benefit the most from preventive measures (40) to clarify more using biomarkers can promote early risk assessment and prediction, leading to individualized preventive therapies. Established biomarkers like PlGF are useful for screening the "placental" subclass. (45)
Challenges in Implementation
Technical and Logistical Barriers
Collaboration of genetic and epigenetic data into clinical practice requires robust and standardized methodologies for data collection and analysis, which can be resource intensive. For example, the 6PLEX assay requires standardization for widespread use (43).
Variability in epigenetic markers owing to environmental factors and differences in laboratory techniques can complicate the interpretation and application of these markers in diverse populations (42).
Several studies have restrictions owing to small sample sizes that may not include variability of gestational plots. Comprehensive follow-up researches in independent pregnancy cohorts are required to verify the development of PE in prediction models. (46)
In some research articles, the placental cell-type heterogeneity when analyzing bulk tissue specimens is mandatory to clarify molecular mechanisms of PE and strengthen the accuracy of prediction models. (47)
Ethical and Social Considerations
Genetic information use raises ethical alerts regarding privacy and potential for discrimination, necessitating careful consideration of data handling and patient consent. (40,48)
To avoid discrimination and guarantee equitable access, each research study must emphasize the need for the development and use of multiethnic PRSs (49)
In conclusion, incorporating genetic and epigenetic markers into PE risk prediction models holds promise in improving early detection and personalized care. However, addressing technical, logistical, and ethical challenges is crucial for the successful implementation of these strategies in healthcare facilities (50). Further researches have to concentrate on validating these markers throughout populations and enhance cost-effective standardized guidelines and recommendations for their use. (48)
Recent studies on preeclampsia have used innovative approaches such as multi-omics analysis, DNA methylation patterns, and machine learning. These have helped identify biomarkers, understand the disease, and develop risk-prediction models. This has led to the subclassification of preeclampsia and the creation of noninvasive screening methods.
For future research, it is important to validate findings across diverse populations, conduct long-term studies, perform functional studies, integrate multiple data types, and develop diagnostic tools to apply these discoveries clinically.
I express my sincere gratitude to the Elmalik Academy of Research for their invaluable guidance and support throughout this research project. Their expertise in this research field was instrumental in shaping the direction of this study. I am grateful to the entire research team for their collaborative spirit and helpful discussions.
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This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.
The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.
Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.
Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”
Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner
My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.
My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.
My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.
I would like to offer my testimony in the support. I have received through the peer review process and support the editorial office where they are to support young authors like me, encourage them to publish their work in your esteemed journals, and globalize and share knowledge globally. I really appreciate your journal, peer review, and editorial office.
Dear Agrippa Hilda- Editorial Coordinator of Journal of Neuroscience and Neurological Surgery, "The peer review process was very quick and of high quality, which can also be seen in the articles in the journal. The collaboration with the editorial office was very good."
I would like to express my sincere gratitude for the support and efficiency provided by the editorial office throughout the publication process of my article, “Delayed Vulvar Metastases from Rectal Carcinoma: A Case Report.” I greatly appreciate the assistance and guidance I received from your team, which made the entire process smooth and efficient. The peer review process was thorough and constructive, contributing to the overall quality of the final article. I am very grateful for the high level of professionalism and commitment shown by the editorial staff, and I look forward to maintaining a long-term collaboration with the International Journal of Clinical Case Reports and Reviews.
To Dear Erin Aust, I would like to express my heartfelt appreciation for the opportunity to have my work published in this esteemed journal. The entire publication process was smooth and well-organized, and I am extremely satisfied with the final result. The Editorial Team demonstrated the utmost professionalism, providing prompt and insightful feedback throughout the review process. Their clear communication and constructive suggestions were invaluable in enhancing my manuscript, and their meticulous attention to detail and dedication to quality are truly commendable. Additionally, the support from the Editorial Office was exceptional. From the initial submission to the final publication, I was guided through every step of the process with great care and professionalism. The team's responsiveness and assistance made the entire experience both easy and stress-free. I am also deeply impressed by the quality and reputation of the journal. It is an honor to have my research featured in such a respected publication, and I am confident that it will make a meaningful contribution to the field.
"I am grateful for the opportunity of contributing to [International Journal of Clinical Case Reports and Reviews] and for the rigorous review process that enhances the quality of research published in your esteemed journal. I sincerely appreciate the time and effort of your team who have dedicatedly helped me in improvising changes and modifying my manuscript. The insightful comments and constructive feedback provided have been invaluable in refining and strengthening my work".
I thank the ‘Journal of Clinical Research and Reports’ for accepting this article for publication. This is a rigorously peer reviewed journal which is on all major global scientific data bases. I note the review process was prompt, thorough and professionally critical. It gave us an insight into a number of important scientific/statistical issues. The review prompted us to review the relevant literature again and look at the limitations of the study. The peer reviewers were open, clear in the instructions and the editorial team was very prompt in their communication. This journal certainly publishes quality research articles. I would recommend the journal for any future publications.
Dear Jessica Magne, with gratitude for the joint work. Fast process of receiving and processing the submitted scientific materials in “Clinical Cardiology and Cardiovascular Interventions”. High level of competence of the editors with clear and correct recommendations and ideas for enriching the article.
We found the peer review process quick and positive in its input. The support from the editorial officer has been very agile, always with the intention of improving the article and taking into account our subsequent corrections.
My article, titled 'No Way Out of the Smartphone Epidemic Without Considering the Insights of Brain Research,' has been republished in the International Journal of Clinical Case Reports and Reviews. The review process was seamless and professional, with the editors being both friendly and supportive. I am deeply grateful for their efforts.
To Dear Erin Aust – Editorial Coordinator of Journal of General Medicine and Clinical Practice! I declare that I am absolutely satisfied with your work carried out with great competence in following the manuscript during the various stages from its receipt, during the revision process to the final acceptance for publication. Thank Prof. Elvira Farina
Dear Jessica, and the super professional team of the ‘Clinical Cardiology and Cardiovascular Interventions’ I am sincerely grateful to the coordinated work of the journal team for the no problem with the submission of my manuscript: “Cardiometabolic Disorders in A Pregnant Woman with Severe Preeclampsia on the Background of Morbid Obesity (Case Report).” The review process by 5 experts was fast, and the comments were professional, which made it more specific and academic, and the process of publication and presentation of the article was excellent. I recommend that my colleagues publish articles in this journal, and I am interested in further scientific cooperation. Sincerely and best wishes, Dr. Oleg Golyanovskiy.
Dear Ashley Rosa, Editorial Coordinator of the journal - Psychology and Mental Health Care. " The process of obtaining publication of my article in the Psychology and Mental Health Journal was positive in all areas. The peer review process resulted in a number of valuable comments, the editorial process was collaborative and timely, and the quality of this journal has been quickly noticed, resulting in alternative journals contacting me to publish with them." Warm regards, Susan Anne Smith, PhD. Australian Breastfeeding Association.
Dear Jessica Magne, Editorial Coordinator, Clinical Cardiology and Cardiovascular Interventions, Auctores Publishing LLC. I appreciate the journal (JCCI) editorial office support, the entire team leads were always ready to help, not only on technical front but also on thorough process. Also, I should thank dear reviewers’ attention to detail and creative approach to teach me and bring new insights by their comments. Surely, more discussions and introduction of other hemodynamic devices would provide better prevention and management of shock states. Your efforts and dedication in presenting educational materials in this journal are commendable. Best wishes from, Farahnaz Fallahian.
Dear Maria Emerson, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews, Auctores Publishing LLC. I am delighted to have published our manuscript, "Acute Colonic Pseudo-Obstruction (ACPO): A rare but serious complication following caesarean section." I want to thank the editorial team, especially Maria Emerson, for their prompt review of the manuscript, quick responses to queries, and overall support. Yours sincerely Dr. Victor Olagundoye.
Dear Ashley Rosa, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews. Many thanks for publishing this manuscript after I lost confidence the editors were most helpful, more than other journals Best wishes from, Susan Anne Smith, PhD. Australian Breastfeeding Association.
Dear Agrippa Hilda, Editorial Coordinator, Journal of Neuroscience and Neurological Surgery. The entire process including article submission, review, revision, and publication was extremely easy. The journal editor was prompt and helpful, and the reviewers contributed to the quality of the paper. Thank you so much! Eric Nussbaum, MD
Dr Hala Al Shaikh This is to acknowledge that the peer review process for the article ’ A Novel Gnrh1 Gene Mutation in Four Omani Male Siblings, Presentation and Management ’ sent to the International Journal of Clinical Case Reports and Reviews was quick and smooth. The editorial office was prompt with easy communication.
Dear Erin Aust, Editorial Coordinator, Journal of General Medicine and Clinical Practice. We are pleased to share our experience with the “Journal of General Medicine and Clinical Practice”, following the successful publication of our article. The peer review process was thorough and constructive, helping to improve the clarity and quality of the manuscript. We are especially thankful to Ms. Erin Aust, the Editorial Coordinator, for her prompt communication and continuous support throughout the process. Her professionalism ensured a smooth and efficient publication experience. The journal upholds high editorial standards, and we highly recommend it to fellow researchers seeking a credible platform for their work. Best wishes By, Dr. Rakhi Mishra.
Dear Jessica Magne, Editorial Coordinator, Clinical Cardiology and Cardiovascular Interventions, Auctores Publishing LLC. The peer review process of the journal of Clinical Cardiology and Cardiovascular Interventions was excellent and fast, as was the support of the editorial office and the quality of the journal. Kind regards Walter F. Riesen Prof. Dr. Dr. h.c. Walter F. Riesen.
Dear Ashley Rosa, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews, Auctores Publishing LLC. Thank you for publishing our article, Exploring Clozapine's Efficacy in Managing Aggression: A Multiple Single-Case Study in Forensic Psychiatry in the international journal of clinical case reports and reviews. We found the peer review process very professional and efficient. The comments were constructive, and the whole process was efficient. On behalf of the co-authors, I would like to thank you for publishing this article. With regards, Dr. Jelle R. Lettinga.
