Bioinformatics Analysis to Identify of Hub Genes and Pathways in Her-2 Positive Breast Cancer

Bioinformatics Analysis to Identify of Hub Genes and Pathways in Her-2 Positive Breast Cancer by Xinshuai Wang* in Open Access Journal of Biogeneric Science and Research

Abstract

Objective: The aim of this study is to identify key genes and pathways as potential prognostic markers of HER-2 positive breast cancer.

Methods: RNA sequence data with HER-2 positive breast cancer and patient clinic traits were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were screened by Gene ontology (GO) and KEGG pathway enrichment analysis. Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) were performed for the key genes and pathways. The identified hub genes were testified for survival curve using the Kaplan–Meier plotter database.

Results: After removing the outliers from the GSE65212 datasets, 30 HER-2 positive breast cancer samples and 11 normal samples were screened. A total of 628 upregulated and 595 downregulated DEGs were identified in HER-2 positive breast cancer and used to construct the PPI network. 47 modules were constructed by WGCNA, and the genes in the blue module with the threshold (|GS|>0.6) were selected. Nine hub genes were screened out, including AURKA, CCNB1, CCNB2, CENPF, KIF11, KIF20A, MAD2L1, NUSAP and PBK. Among them, only MAD2L1 and PBK were found to be a poor prognostic factor according to survival analysis.

Conclusion: These findings further confirmed the rationality of PI3K/Akt/mTOR inhibitors on the treatment of HER-2 positive breast cancer; and we discovered two novel prognostic markers related to HER-2 positive breast cancer, PBK and MAD2L1, providing new diagnosis and treatment strategies for patients with HER-2 positive breast cancer.

Keywords: HER-2 positive breast cancer, hub genes, key pathways, survival analysis, prognostic markers

Introduction

Breast cancer, as the most commonly diagnosed malignancy, is the leading cause of cancer mortality in women worldwide, according to the Agency for Research on Cancer. It was reported that the incidence rate of breast cancer continued to increase, with an estimated 2088849 new breast cancer cases in 2018 [1]. Different diagnostic and therapeutic methods are required for every subtype, since breast cancer is clinically and histopathologically heterogeneous. Among the subtypes, tumors with positive for human epidermal growth factor receptor 2 (HER2) account for approximately 15% to 20% of breast carcinomas. Due to the higher recurrence and metastasis, the subset of HER-2 positive breast cancer was known to the most aggressive type [2].

With the advent of HER-2-targeted therapy in the late 1990s, the remarkable advances were achieved in the treatment of HER-2-positive breast cancer [3]. Although it has been made a breakthrough on anti-HER2 therapy, because of novo or acquired drug resistance, almost all patients with HER-2-positive breast cancer eventually made progress [4]. The potential resistance mechanisms of anti-HER2 therapy are indeed complex and there is a wide range of mechanisms of resistance may coexist in the same cell. Therefore, exploring novel predictive biomarkers other than HER2 will help us to better select patients and improve their survival.

Numbers of studies have shown that the early stage of HER-2-positive breast cancer was a complicated process, associated with multiple cellular pathways and numerous genes alterations. Additionally, gene expression profiles of various cancers can be obtained from Gene Expression Omnibus (GEO). Based on microarray technology, gene expression analysis is a widely used, high-throughput and powerful research method, which can simultaneously detect expression change of thousands of genes at the mRNA level. In the current study, we aimed to identify the differentially expressed genes and key pathways between cancerous and normal mammary tissues. Bioinformatics analysis including GO term enrichment analysis, KEGG pathway analysis. PPI network analysis and gene co-expression network analysis were performed to discover other potential key genes and pathways in HER-2 positive breast cancer.

Materials and Methods

Acquisition Of Microarray Data And Data Processing

The dataset GSE65212 submitted by Thierry Dubois and based on GPL14877 platform (Affymetrix Human Genome U133 Plus 2.0 Array) was downloaded from the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) database. The gene expression profile of GSE65212 included 30 HER-2 positive breast cancer samples and 11 normal samples. According to micro-expression matrix chip data, we deleted missing values, processed log2, standardized data and took the probe with the highest average expression to match the probe ID and gene name. Then, we used the screened gene expression matrix data as the data of this study.

Differentially Expressed Genes (Degs) Screening

Statistical software R (version 3.6.1, https://www.r-project.org/) and packages of Bioconductor (http://www.bioconductor.org/) were applied for the significant analysis of DEGs between cancerous and normal mammary tissues. The “limma” (linear models for microarray data) R package was used to screen the DEGs between normal mammary tissues and HER-2 positive breast cancer tissues. The SAM (significance analysis of microarrays) with FDR (false discovery rate) <0.01and |log2 fold change (FC)|≥2 were chosen as the cut-off criteria.

Go Term and Kegg Pathway Enrichment Analysis

Biological significance of DEGs was explored by GO term enrichment analysis including biological process, cellular component and molecular function. KEGG pathway enrichment analysis of DEGs was performed to explore the critical pathways closely related to HER-2 positive breast cancer initiation and progression. We used the “ggplot2” package and “pathview” package (version 1.24.0), which were based on Bioconductor, to make the GO function enrichment analysis and the KEGG pathway enrichment analysis visualization.

Protein–Protein Interaction (PPI) Network Analysis

PPI network was used identify the important gene modules and key genes which are involved in HER-2 positive breast cancer development from interaction level. The STRING database (https://string-db.org/) is an online database for constructing protein interaction networks and analyzing and exploring predicted protein interaction networks. The screened differentially expressed genes were submitted to STRING database (version11). Then, Cytoscape software (version3.7.1) was used for construction of PPI network. MCODE, a plug in Cytoscape, was used for the visual analysis with "Combined score＞0.4 and MCODE> 61" as the threshold.

Weighted Correlation Network Analysis of Degs

Gene co-expression network analysis is a systematic biological method to screen highly correlated gene modules for finding candidate biomarkers and drug targets. In this co-expression network, the nodes represent DEGs and the correlated gene expression patterns were defined as connectivity in genes. In short, the excessive value was missing for the first time by detecting outliers and extracting the expression matrix. The soft threshold power was determined through analysis of the network topology. The co-expression similarity and adjacency of genes were sequentially increased using soft threshold power for calculation. Then, the adjacency was transformed into a topologically overlapping matrix (TOM). Finally, hierarchical clustering was performed to select the modules by using TOM and dynamic tree cutting algorithms, and then Go enrichment analysis was performed for the characteristics of gene modules related toHER-2-positive breast tumor.

Survival prognostic analysis

The prognostic value of critical genes was analyzed by Kaplan-Meier plotter. Overall survival for patients with breast cancer was obtained by the Cancer Genome Atlas (TCGA) in Kaplan Meier - plotter (http://kmplot.com/analysis/) database.

Figure 1A:  Volcano map with differential expression.

The red lines represent 628 up-regulated genes and the blue lines represent 595 down-regulated genes.

Figure 1B:  Heat maps of differentially expressed genes.

Figure 2: GO enrichment analysis result of DEGs with |logFC|≥2.

Figure 2A: Cellular component.

Figure 2B: Biological process.

Figure 2C: Molecular function.

Figure 2D: Visualization of KEGG pathway enrichment of DEGs in normal and HER-2 positive breast cancer tissues (showing hsa04151 pathway).

Figure 3A: Sample clustering to detect outliers and the trait heatmap to display the sample traits

Figure 3B: Analysis of the network topology for various soft thresholding powers.

The left panel shows the scale-free fit index (y-axis) as a function of the soft-thresholding power (x-axis). The right panel displays the mean connectivity (degree, y-axis) as a function of the soft-thresholding power (x-axis). The power was set as 4 for further analysis.

Figure 4A: Clustering dendrograms for the 17522 genes with dissimilarity based on the topological overlap together with the assigned module colors. 47 co-expression modules were constructed with various colors. The relationship between gene dendrogram and gene modules was up and down of then image.

Figure 4B: Module–trait relationships. Each row corresponds to a module eigengene, each column corresponds to a trait, and each cell consists of the corresponding correlation and P-value, which are color-coded by correlated according to the color legend. Among them, Blue module was the most relevant modules to the HER-2 positive breast cancer clinical subtypes.(“H” means HER-2 positive breast cancer tissues).

Figure 4C: Visualizing 1,000 random genes from the network using a heatmap plot to depict the TOM among the genes in the analysis. Then depth of the red color is positively correlated with the strength of the correlation between the pairs of modules on a linear scale. The gene dendrogram and module assignment are shown along the left side and the top.( TOM, topological overlap matrix).

Figure 4D: The eigengene dendrogram and heatmap identify groups of correlated eigengenes termed meta-modules. The dendrogram indicated that the Blue module was highly correlated with HER-2 positive breast cancer The heatmap in the panel shows the eigengene adjacency.

Results

Identification of Degs Between Her-2 Positive Breast Cancer Samples and Normal Mammary Samples

After removing batch differences and data normalization, a total of 1226 DEGs were obtained, including 628 up-regulated genes and 595 down-regulated genes based on cut-off criteria (P <0.01 and |logFC|≥2). All abnormally expressed genes with the log2 FC score and -log10 P value were used to generate Volcano diagram in R, which is an intuitive tool to show the overall gene expression level of the DEGs (Figure 1A). The gene expression pattern was consistent with Volcano diagram, as presented in the heatmap (Figure 1B).

Degs GO and KEGG Pathway Enrichment Analysis

GO term enrichment analysis results varied from GO classification and expression change of DEGs. For cellular component, the DEGs were significantly enriched in extracellular matrix, collagen−containing extracellular matrix, spindle, condensed chromosome, centromeric region and condensed chromosome kinetochore (Figure 2A). As to biological process, the DEGs were significantly enriched in mitotic nuclear division, extracellular structure organization, mitotic sister chromatid segregation, regulation of mitotic nuclear division and extracellular matrix organization (Figure 2B). About molecular function, the upregulated genes were significantly enriched in heparin binding, extracellular matrix structural constituent, sulfur compound binding, glycosaminoglycan binding and chemokine receptor binding (Figure 2C). These significantly enriched pathways and terms could help us to further understand the role of DEGs in HER-2 positive breast cancer occurrence and progress. In addition, KEGG pathway enrichment analysis was used to examine the function of the DEGs. The results of KEGG analysis showed that the upregulated genes were significantly enriched in pathways including Neuroactive ligand-receptor interaction, Human papillomavirus infection and PI3K-Akt signaling pathway and so on. (Table 1 and Figure 2D).

Construction of Co-Expression Network

After eliminating the batch effect, WGCNA analysis was performed to identify modules containing highly correlated genes. Sample clustering was used to detect outliers (Figure 3A) and set the power to 4, 47 modules were mined (Figure 3B). Gene co-expression network was constructed to detect genes showing similar trends in the same module (Figure 4A). Among these modules, the blue module was the most closely related to HER-2 positive breast cancer (Figure 4B). 1,000 genes were randomly selected for heat map analysis (Figure 4C). Trait gene trees and heat maps analysis revealed that the tree indicating modules were significantly associated with the clinical phenotype of HER-2 positive breast cancer (Figure 4D). Next, we performed intramodular analysis of genes in 47 modules in GS and MM. The resluts of GS and MM showed a very significant correlation, indicating that genes in the blue module were highly correlated with HER-2 positive breast cancer. Then, the genes in these modules with relevant cut-off value ≥0.6 were selected as the central genes.

PPI Network And Cluster Analysis To Identify Key Genes

Using the STRING online database, 1226 DEGs were filtered into the DEGs PPI network complex containing nodes and edges with a combined score>0.4 (medium confidence). The Cytoscape software was employed to analyze the interactive relationship between the candidate protein and then a cluster containing 74 nodes was selected with a cut-off k-score=2 by the MCODE scoring system. The results showed that the hub genes were the intersections between the initial key genes and the modules highly correlated with phenotypes from the WGCNA.

Survival Prognostic Analysis

To evaluate prognosis value of the potential hub genes with HER-2 positive breast cancer, survival prognosis analysis was performed by Kaplan-Meier plotter. Nine genes (AURKA、CCNB1、CCNB2、CENPF、KIF11、KIF20A、MAD2L1、NUSAP and PBK) were correlated with survival prognosis . Following all the analyses, only MAD2L1 and PBK were closely related to the prognosis of patients (P<0.05).

Table1: KEGG pathway enrichment analysis of DEGs in normal and HER-2 positive breast cancer tissues.

Discussion

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related mortality in women worldwide [5]. HER-2-overexpressing cancer is characterized by a highly aggressive phenotype and associated with metastasis to the lymph nodes and distant organs. HER-2 overexpression is due to the amplification of genes derived from oncogenic signaling in adenocarcinomas including breast cancer [6-8]. At present, anti-HER-2 antibodies, as a molecular target-based therapy, ameliorated the prognosis of HER-2-positive patients.

GO analysis proved that the key genes were enriched in heparin binding, extracellular matrix structural constituent, sulfur compound binding, glycosaminoglycan binding and chemokine receptor binding. According to the KEGG pathway analysis, the differentially expressed genes were enriched in pathways such as neuroactive ligand-receptor interaction, human papillomavirus infection and PI3K-Akt signaling pathway.

The results of KEGG analysis showed that the upregulated genes were significantly enriched in pathways in PI3K-Akt signaling pathway, which is a major signal pathway involved in cellular proliferation, survival, metabolism and motility. This result is consistent with existing researches. PI3K-Akt-mTOR (PAM) pathway is the most frequently altered pathway in human cancers, in which PIK3CA2 and PTEN3 are the most frequently altered oncogenes and tumor suppressor genes respectively. It is estimated that the activation rate of PAM pathway is as frequent as 70% in patients with HER-2-overexpression [9,10]. Resistance to trastuzumab in patients with HER-2-positive breast cancer is associated with higher risk of progression or cancer death, which may be related to the activation of PI3K-AKT-mTOR signaling cascade and the decreased expression level of inhibitor PTEN [11]. Currently, clinical trials of anti-HER2 drugs combined with PI3K/AKT/mTOR inhibitors are undergoing extensive evaluation [4].

Nine hub genes and several pathways were identified by the methods of DEGs and WGCNA. All key genes were selected for survival analysis in the study. However, only MAD2L1 and PBK were significantly related to the prognosis of patients with HER-2 positive breast cancer (P <0.05), which may serve as biomarker for treatment and prognosis. Although there were no significant differences in the survival prognosis analysis of the other seven genes in patients with HER-2 positive breast cancer, it was interesting that there were significant differences among them when we put these key genes in breast cancer patients for survival prognosis analysis, these genes all had statistical differences. We speculated that this may be related to the insufficient sample size of HER-2 positive breast cancer. When the survival prognosis database is expanded, the survival prognosis of the other seven genes may be statistically different. Then we conducted in-depth analysis of the excavated genes from enrichment analysis and found that AURKA, CCNB1, CCNB2, CENPF, MAD2L1 and PBK participated in molecular functions; KIF11 and KIF20A participated in cellular components; NUSAP participated in biological processes.

PBK (PDZ-binding kinase), also known as T-lymphokine-activated killer cell-originated protein kinase (TOPK), is a 322 amino-acid and mitogen-activated serine/threonine protein kinase. PBK/TOPK protein is generally difficult to detect in normal tissues, but frequently elevated in cancer tissues, like breast cancer [12-16]. Furthermore, PBK/TOPK plays vital roles in inflammation, cell apoptosis, and cell-cycle regulation and high expression of PBK/TOPK contributes to tumor growth, proliferation, and metastasis. PBK/TOPK has been repeatedly reported and is correlated with clinical outcomes in various solid cancers [17-22]. In addition, PBK/TOPK acts as an oncogene in multiple cancers and contributes to tumor progression and high expression of PBK/TOPK tends to indicate higher biological malignant aggressiveness [23-26]. Knockout of TOPK could significantly inhibit tumor growth, invasion and metastasis in vitro and in vivo. Conversely, the upregulation of PBK could promote cell growth, metastasis and enhance tumor transformation [24,27,28]. PBK/TOPK also correlates with drug response and tumor resistance, indicating that it is a valid target for anti-neoplastic kinase inhibitors and a potential therapeutic target for various cancers, including breast cancer. Generally, PBK/TOPK, as a candidate molecular marker, exhibits the potential clinical utility for HER-2 positive breast cancer.

Mitotic arrest deficient 2-like 1 (MAD2L1), as a component of spindle checkpoint, plays an essential role in supervising chromosomal segregation during mitosis [29-31]. Dysregulation of MAD2L1 could lead to chromosomal instability and aneuploidy, which might promote formation of human cancers. Overexpression of MAD2L1 has been discovered in several cancers including breast cancer [32,33]. It was reported that the expression level of MAD2L1 in breast cancer was higher than that in normal tissues, and MAD2L1 was associated with malignant progression and poor disease-free survival of breast cancer patients(30). In addition, MAD2L1 expression also associated with HER-2 positive breast cancer. In summary, overexpression of MAD2L1 plays a key role in the development of HER-2 positive breast cancer, suggesting that MAD2L1 can be used as an effective therapeutic and diagnostic marker for HER-2 positive breast cancer. However, this study only verified the overexpression of MAD2L1 in HER-2 positive breast cancer and its clinical significance. It is necessary to further study the molecular basis of the oncogenic impact of MAD2L1 in HER-2 positive breast cancer.

In this study, gene expression profile was obtained from GEO. WGCNA demonstrated that the blue modules displayed the highest correlation with HER-2 positive breast cancer, and nine hub genes including AURKA、CCNB1、CCNB2、CENPF、KIF11、KIF20A、MAD2L1、NUSAP and PBK were identified. Survival analysis revealed that MAD2L1 and PBK in HER-2 positive breast cancer may be a poor prognosis marker. These findings provided the framework for the identification of important gene modules and identified key pathways and driving genes that may be novel therapeutic targets for this disease.

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Prevalence and Associated Demographic Factors of Urinary Incontinence among Women Attending Postnatal Clinics in Primary Health Care In Qatar. A Descriptive Cross-Sectional Study

Prevalence and Associated Demographic Factors of Urinary Incontinence among Women Attending Postnatal Clinics in Primary Health Care In Qatar. A Descriptive Cross-Sectional Study by
Shajitha Thekke Veettil* in Open Access Journal of Biogeneric Science and Research

Abstract

Background: Urinary Incontinence (UI) is more prevalent among women and is a significant health concern which affects the quality of life (QOL) of half of women of middle and older ages. The objectives of this study was to estimate the prevalence of post-partum UI among women attending postnatal clinics in primary care in Qatar and its association with other demographic factors.

Methods: A descriptive cross-sectional study. International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) was used to collect data. Continuous data was presented as mean (SD) and ordinal and nominal data as frequency and percentage. Chi square test and direct logistic regression was used for bivariate and multivariate analysis with the help of IBM SPSS Statistics 25 software.

Results: Data of 357 women from 3 post-partum clinics was collected from April 2018 to May 2019. A total of 144(40.3%) women had urinary incontinence at 6-week check-up with 109(75.7%) stating the amount leaked was small. No correlation was noted with age, ethnicity or multi parity. However, a higher risk of UI was noted with BMI. A strong correlation was found in women reporting UI with a history of UI before or during pregnancy. About 221(61.9%) respondents stated they would seek medical help. And the prevalence of UI has no association with other demographic factors, it’s varied among different ethnicities.

Conclusion: UI is highly prevalent among postnatal women (40.3%). The most common type of UI is stress UI 72(50%) followed by mixed UI 43(30%). In Qatari population 19(13.2%) had UI. In Non-Qatari population, out of 28 nationalities, Indians 24(16.7%) and Egyptian 21(14.6%) were noted to have more UI than other nationals. Socio-religious factors have a significant effect on the QOL of incontinent women. A well-designed national health intervention early on in pregnancy can bring about significant benefits and improvement of QOL in postnatal women.

Keywords: Urinary Incontinence; stress urinary incontinence; post-natal clinics; women, Qatar

Introduction

The International Continence Society (ICS) and the International Urogynecological Association (IUGA) criteria defined urinary incontinence (UI) as ‘the complaint of any involuntary leakage of urine. UI classified as stress UI (SUI), urgency UI (UUI), mixed UI (MUI), postural UI, nocturnal enuresis, insensible UI and coital UI. Of these, SUI, UUI, and MUI are most common [1].

The prevalence rate of UI in adult women has shown a wide variation from 5 to 69 % with most studies in the range of 25 to 45% [2]. In the Middle East, the prevalence is noted to be between 30-54.8% [3] with 20.6% [4] and 21% [3] reported among women in Qatar. Pregnancy and childbirth seem to be the most consistent and important factor for the development of urinary incontinence [5]. It may be also associated with several factors such as poor education, physical exertion, changes in body position, urgency, obesity indicated by higher BMI, increased waist-hip ratio, visceral obesity, and diseased conditions such as recurrent urinary tract infection and diabetes mellitus [6].

The complaint of involuntary leakage on effort or exertion, or on sneezing or coughing was defined as stress urinary incontinence (SUI). The complaint of involuntary leakage accompanied by or immediately preceded by urgency was defined as urge urinary incontinence (UUI). The complaint of involuntary leakage associated with urgency and with exertion, effort, sneezing, or coughing was defined as mixed urinary incontinence (MUI). Despite significant impact, less than one half of the women with urinary incontinence seek medical care; instead they rely on absorbent pads or lifestyle changes to cope with the condition. These women may become socially isolated by restricting their interaction with family and friends, avoiding trips outside their homes, or being fearful and embarrassed about the odor of urine [6].

Prevalence of all types of UI in pregnancy varies from 32 to 64%2 with 30% persisting with symptoms in first 3 months of postpartum [7]. Higher rates of depression with low scores on other aspects of quality of life (QOL) involving mobility, physical, mental, emotional, sexual health and relationships have been documented [8]. This descriptive study is to establish the prevalence of UI among postpartum women in Qatar and to check whether any association between the different socio-demographic variables.

Materials and Methods

The study was carried out in accordance with the guidelines of the Primary Health Care Corporation, Research Section, Qatar, after passing through the ethical committee. A descriptive, cross-sectional study was conducted on females attending their 6-week routine post-natal check-up. Participants was selected from three Health Centers representing the three different regions in Qatar providing postnatal clinics between March 2018 and Feb 2019.

A total of 357 women participated in the study after obtaining the consent. A non-probability purposive sampling technique was used where the targeted sample is all post-natal women who are coming for their routine six weeks checkup. The criteria included all healthy postnatal women attending their postnatal clinic check-up. Exclusion criteria were any history of abdominal or vaginal surgery leading to urinary incontinence in the past. The International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) was the main study tool used to diagnose and evaluate the severity of UI. It comprises three scored items (Questions 1– 3), frequency of UI (score range, 0–5), usual amount of UI (score range, 0–6), interference with everyday life (score range, 0–10), and a self-diagnostic item (Question 4, not scored). Due to a paucity of any national studies on postnatal UI prevalence and the wide variation in literature, 33 per cent from a systematic review [7] was chosen as the estimated prevalence in Qatar.

General socio-demographic detail was also taken to identify patient characteristics including age, ethnicity, multi parity and body mass index (BMI). A computerised database was used to analyse and compare various parameters. Continuous data were presented as mean (SD) and ordinal and nominal data as the frequency and percentage. Student t-test was performed for continuous data, Chi square test for categorical data and direct logistic regression was used to determine independent risk factors. Data were analysed using IBM SPSS Statistics 25 software.

The type of questions with related scores and socio demographic characteristics are described in table 1 (Table 1).

Table 1: Sociodemographic characteristics of women with and without UI.

Results

A total of 357 women were recruited in the study from March 2018 to February 2019. Among these 144 (40.3%) women confirmed that they had urinary incontinence at the 6 weeks postpartum checkups, whilst 213 (59.7%) women felt that urinary competency was not a major problem (Figure 1). Of these 50 (14%) were Qatari patients while the remaining 307(86%) were non-Qatari. Out of 28 nationalities, Indian (13.4%) and Egyptian (10.6%) were the two other major ethnic group in the study. Among Qatari, 19 (13.2%) had UI. Indian 24(16.7%), Egyptian 21(14.6%) and Yemeni 11(7.6%) were noted to have more UI than other nationalities following with Pakistani 9(6.3%) and Jordan 8(5.6%) postpartum women (Table 2).

Most participants whom experienced urinary incontinence 87(60.4%) were in 30-39-year age group. The majority were multipara 216 (60.5%), followed by primipara 85 (23.8%). Among 213 women without urinary incontinence 99 (46.5%) were multipara and followed by 58(27.2%) with primipara. Among 144 women with urinary incontinence 117 (81.2%) were multipara and followed by 27(18.8%) with primipara (Table 1). An independent-samples t-test was conducted to compare the parity with impact on daily life for women with and without UI. Our results show there was no significant difference in scores for women with UI (2.79± 1.55) and women without UI (m= 2.63, SD =1.65). (P value= 0.4, 95% CI -0.5 to 0.2). However, it was statistically significant when comparing women with UI, P value <0.05 (95% CI -3.4 to 2.6). About 127 (35.6%) participants stated they had urinary incontinence before and during pregnancy. The majority of women 124 (86.1%) stated that they have history of UI before and during pregnancy while 20(13.9%) women with UI confirmed that they don’t have UI before and during pregnancy (Table 2).

Of those affected, 55 (38.2%) had UI at least once a week, while 42 (29.2%) were affected two to three times a week and 47(42%) had more pronounced UI with leaks several times a day or all the time. Majority 109 (75.7%) out of 144 stated that the amount of urine leaked was small and 30 (20.8%) felt it was moderate while 5(3.5%) declared it was a large amount. About 72 (50%) women suffered from stress incontinence and 43 (30%) of them had a mixed type while 26 (18%) had urge incontinence (Table 2). BMI data was missing in 10 of the patients. Majority of 264 out of 347 patients (76.1%) had a BMI of over 25. Only 80 (22.4%) had a BMI between 19-24. With BMI <=25 as a reference, the odds of developing any incontinence and frequent UI was increased by 181% and 28% respectively in overweight women (BMI 25-30). For the obese group (BMI >=30), the odds of developing any UI was increased by 121% and the odds of developing frequent UI was reduced by 47% [9] (Table 3).

Direct logistic regression was performed to assess the impact of several factors on the likelihood that respondents would report that they had a UI. The model contained four independent variables (age, parity, BMI, and history of UI before or during pregnancy). The full model containing all predictors was statistically significant, χ2 (4, N = 357) = 319.5, p < 0.001, indicating that the model was able to distinguish between respondents who reported and did not report a UI. As shown in Table 3, only one of the independent variables made a unique statistically significant contribution to the model (history of UI before or during pregnancy). The strongest predictor of reporting a UI was the history of UI before or during pregnancy, recording an odds ratio of 527.1. This indicated that respondents who had a history of UI before were over 500 times more likely to report a UI problem than those who did not have UI before, controlling for all other factors in the model. Overall, 221(61.9%) women stated that they would seek medical help for their incontinence. Among them around 36 (72%) was Qatari stated that they would seek medical help if they had urinary incontinence (Figure 2).

Table 2: The distribution of frequency of urine leakage, amount of urine leakage and types of urine incontinence in women with UI and association of BMI with UI in total population.

Table 3: Logistic Regression Predicting Likelihood of prevalence of UI.

Figure 1: Prevalence of UI in postnatal women with and without UI.

Figure 2: Seeking medical help among women with UI.

Discussion

Postpartum urinary incontinence is a disorder of incontinence starting before, during and after pregnancy [10]. The usual postnatal follow up appointment in the community after pregnancy was at 6 weeks. 3-40% is the usual prevalence for postpartum UI reported in other studies [7]. The prevalence in this study was 40.3% which was higher than the overall prevalence in Qatar (20.6%4 and 21%3).

In this study stress (50%) and mixed UI (30%) were the most predominant type of UI. The most common type of urinary incontinence in pregnant women is SUI8 which was used as a single case definition in this study to compare prevalence with other studies. A PubMed review on global prevalence found similar results of SUI in China (18.6%) and India (19.2%) [7]. In a multiethnic study in Norway [11], Middle Eastern (36%) and African origin women (26%) had lower rates of SUI compared to European and American women (45%) [12]. Unfortunately, comparison with other studies is challenging since different factors like population, study design including questionnaire types, wordings, data collection methods and mode of delivery have resulted in a wide variation in prevalence [6,12]. However, SUI (as well as mixed or other types) is seen as a higher risk among white women compared to black and Hispanics [13]. USA (60% - 75%), Australia (36.9%) and European countries like UK (59%), Spain (30.3%) and Scotland (54.3%) have a much higher prevalence [7] of SUI.

As in other studies [3,12], majority (75.7%) stated that the amount of urine leaked was small. Parity, BMI, age and mode of delivery are the major risk factors associated with urinary incontinence especially SUI in young and middle aged women14. Increasing number of childbirths increases risk of developing pelvic organ prolapse later in life while obesity increases intra-abdominal pressure resulting in SUI [14]. No association with age (OR 1, p value =0.926) was seen in this study despite majority 60.4% of 30-39-year-old with urinary incontinence making up more than half the participants (55.2%). Nor was any link seen with parity (Odds ratio=1.006, p value = 0.97) considering 60.5% of women were multipara. This was similar to previous studies in Qatar3,4. BMI, however had a higher risk of SUI in this study [15] which was similar to other studies12. Unfortunately, mode of delivery was not included in our questionnaire.

Many women do not take action over UI symptoms [16]. The most significant correlation in our study was the higher likelihood of reporting UI as a problem among women who had a history of UI before or during pregnancy as compared to those who did not have UI before (odds ratio of 527.1). Majority of the respondents (61.9%) in our study including those without UI, would seek medical help. However, comparisons between ethnicities was not possible due to the range in sample size making it hard for any meaningful inference.

The challenges in accurately estimating the prevalence of postpartum UI has been highlighted in many studies due to the nature of the condition [6]. There is a high respondent bias when self-reporting stress incontinence in epidemiological studies especially when the presentation of the consultation is for other reasons [6,14]. There is no test which is universally accepted or which is objective available in the community to define significant incontinence [14]. Many cultures still accept UI as an expected consequence of childbirth [4,16]. Factors such as degree of symptoms [12], embarrassment [16], fear of stigmatisation14, conservative social values4, education3 and role of friends and relatives [16] plays a significant role in the help seeking behavior especially among women from different multiethnic and socio-economic background. There are also limitations to a cross sectional study. Soon after pregnancy, some women may be willing to lie about their symptoms to avoid further interventions and examination [16]. The dynamic nature of UI with high incidence rates along with equally significant remission12 also makes it hard to estimate the true prevalence. SUI in pregnancies can therefore range from 18.6 % to 60 %7 depending on which trimester and time period the studies were done. The reported prevalence is highest in the third trimester, which then gradually decreases in the first year postpartum period [7]. The overall high prevalence of 40.3% in our study at 6 weeks which is similar to 38% in another study at 8 weeks [17] may well change at 3 months with similar values of 30% highlighted in other studies [13].

Conclusion

Establishing prevalence of postpartum UI in the 6-week postnatal period was the initial step to developing future new strategies to empower both women and health professionals to address this important and often overlooked form of maternal morbidity. Among 28 nationalities, our findings confirm that UI is highly prevalent in postnatal women especially SUI which was the aim of the study. A longitudinal study of the same population may have help to differentiate true positives from transitional cases.

Nevertheless, this study does highlight the importance of considering the individuality of a woman in the multi-ethnic large expat population of Qatar in terms of culture, needs, beliefs, attitudes, knowledge and close family support. Further research is recommended on whether knowledge, screening and other interventions early on in pregnancy can bring about significant benefits and improve QOL in postnatal women.

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An Atypical Cause of Potential Reversible Dementia

An Atypical Cause of Potential Reversible Dementia by Ecler Jaqua* in Open Access Journal of Biogeneric Science and Research

Abstract

Background

Neurosyphilis is defined as an infection of the central nervous system by spirochete bacterium, Treponema pallidum (T. pallidum). After infection by T. pallidum, symptoms may develop from weeks to months, most commonly within two years. The clinical manifestations of neurosyphilis are classified into two forms: early and late forms.

Early Neurosyphilis

Can be asymptomatic or symptomatic, and it involves the invasion of T. pallidum into the cerebrospinal fluid (CSF), meninges, and the vasculature. However, invasion of CSF does not always result in symptoms and that spontaneous resolution can occur.

Late Neurosyphilis

Occurs when the brain and spinal cord parenchyma are invaded. The two major manifestations are tabes dorsalis and general paresis. Tabes dorsalis is a disease of the posterior columns of the spinal cord and of the dorsal roots. Individuals with tabes dorsalis often have sensory ataxia and sudden, brief, stabbing pain affecting the face, back, or extremities [1]. They can also have paresthesia and severe nausea, vomiting, and epigastric pain. Another sign seen in patients with tabes dorsalis is the Argyll-Robertson pupils that accommodate but do not respond to light. General paresis usually develops about 20 years after infection and is associated with progressive dementia and personality change. Some individuals with general paresis may develop depression, mania, psychosis, and abnormal behaviors.

Case

84-year-old male who presented to the adult specialty clinic because of forgetfulness in the past 5-10 years.

History

An 84-year-old male with past medical history of type 2 diabetes mellitus with retinopathy, dementia, hyperlipidemia, colon polyps, CKD stage 3a who presented to the adult specialty clinic referred by his primary care physician due to forgetfulness and a possible diagnosis of dementia. His wife and daughter provided collateral history. His wife reported forgetfulness/short-term memory loss for more than 5 years, which worsened over the past year. She stated that patient forgets doctor’s appointments, family members’ names, directions, and keeps asking about the same things repeatedly. He cannot drive because he gets lost sometimes. He also wandered away from home and got lost many times in the neighborhood. As a result, his wife had to place locks on all the doors of their home. Nonetheless, his wife denied any other significant behavior disturbances. Patient scored 12/15 on the Geriatric Depression Scale. He was taking Sertraline 25 mg PO daily for major depressive disorder. His wife and daughter believed he was depressed [2]. They did not think the medication was working well. They believed Sertraline was making him more agitated. During the last visit with his primary care physician, he was prescribed Memantine 5 mg PO BID for his short-term memory loss, which he tolerated without side effects. A cholinesterase inhibitor was not prescribed because patient had intermittent bradycardia. Because his PCP characterized his dementia as moderate to severe, Memantine was the appropriate treatment.

Geriatric Assessment

Activities of Daily Living: Bathing, Dressing, Grooming, Toileting, Transfer, Eating – 6/6

Instrumental Activities of Daily Living: Shopping, Cooking, managing medications, Using the phone and looking up numbers, doing housework, doing laundry, Driving or using public transportation, Managing finances –0/8

Geriatric Depression Screening: 12/15

Mini-Mental State Examination (MMSE): 10/30 (<24 abnormal)

Physical exam

Vitals signs: Temp 98.4F, HR 76, RR 16, pulse ox 98% on room air. Caucasian male in nonapparent distress. No oral lesions. No throat erythema. No chest retractions. No crackles or wheezes. No heart murmurs appreciated. Abdomen soft, non-tender and non-distended. No lower extremity edema. No focal neurologic findings.

Mental Status Exam

General appearance:84-year-old male who appears stated age, calm, cooperative, in no acute distress, dressed in street clothes.

• Behavior: evidence of psychomotor agitation, some PMR, good eye contact.
• Speech: normal rate, normal rhythm and tone.
• Mood: agitated. Affect: Blunted range and appropriate.
• Thought process: Tangential and repetitive at times, but mostly linear and goal directed.
• Thought content: Does not endorse suicidal or homicidal ideation, auditory or visual hallucinations or paranoia.
• Insight: poor.
• Judgment: poor.
• Decision Making Capacity: no.
• Motor Vehicle Operation ability: no.
• FAST scale: Stage 4
• Mild Dementia Characteristics: IADLs become affected, such as bill paying, cooking, cleaning, traveling.

Assessment and Plan

Likely major neurocognitive disorder secondary to Alzheimer’s disease versus vascular dementia.

Ordered Syphilis total, TSH with reflex FT4, vitamin B12, folic acid levels, HIV, MRI brain without contrast.

Stop sertraline and start citalopram 10 mg PO daily. Continue memantine 5 MG BID, titrate up weekly to 10mg BID, instructions given verbal and written instructions [3].

Follow up in 1-2 months or PRN.

Follow up with primary care within 3 weeks.

Patient/Caregiver understands the recommendations.

Follow up

Labs Results

CMP, TSH within normal limits. Vitamin B12 >2000, Folate >20, A1c 6.6%, HIV negative. Syphilis T 1.3, Syphilis Ab IgG reactive, RPR Ab Titer 1 non-reactive, Syphilis Ab by TP-PA positive. Results suggested infection with T. Pallidum at some time in the past but does not distinguish between treated and untreated syphilis as Treponemal antibodies can remain elevated despite proper treatment. RPR testing was recommended to distinguish between treated and untreated syphilis.

Imaging

MRI brain without contrast

• History: 84-year-old M with Alzheimer's disease.
• Comparison: 1/22/2016
• Findings: There is mild sulcal and ventricular prominence. There is mild interval increase in periventricular and subcortical white matter confluent T2 hyperintensity. The brain otherwise shows normal morphology and signal characteristics. No abnormal diffusion restriction, or susceptibility hypointensity is present. There is a partial empty sella. The major intracranial flow voids are present. The aerated spaces are normal. The orbital contents and extracranial soft tissues appear normal.
• Impression: Mild cerebral atrophy with mild progression mild to moderate nonspecific white matter changes compared to 1/22/2016.

After reviewing results with patient and wife, they both agreed to proceed with a lumbar puncture to rule out neurosyphilis.

Differential Diagnosis

Alzheimer dementia, Lewy body dementia, vascular dementia, frontotemporal dementia, and possibly dementia related to neurosyphilis.

Discussion

When there is clinical suspicion of neurosyphilis, CSF analysis should be done to make the diagnosis. In individuals with suspected asymptomatic neurosyphilis (who do not have HIV infection), the diagnosis based on CSF abnormalities including lymphocytic pleocytosis between 5-100 cells/microL, an elevated protein concentration between 45-100mg/dL, or a reactive CSF-Venereal Disease Research Laboratory (VDRL) test. CSF abnormalities in symptomatic meningitis include lymphocytic pleocytosis to 200-400 cells/microL, an elevated protein concentration between 100-200 mg/dL, and CSF-VDRL is almost reactive. Neuroimaging often shows enhancement of the spinal fluid, cranial nerves, spinal roots, or the meninges. If the infection leads to arteritis (meningovascular syphilis), the affected individuals may present with a stroke. The CSF abnormalities accompanying meningovascular neurosyphilis include lymphocytic pleocytosis between 10-100 cells/microL, a protein concentration of 100-200mg/dL, and CSF-VDRL is usually but not always reactive. Neuroimaging may show area(s) of infarction.

Treatment and Surveillance

This patient’s CSF analysis was pending at the time of submission of this case report. However, if his CSF shows abnormalities consistent with neurosyphilis, the treatment will be:

1. Aqueous crystalline penicillin G 3-4 million units IV every 4 hours or 18-24 million units continuous IV infusion for 10-14 days, or
2. Procaine penicillin G 2.4 million units IM once daily plus probenecid 500mg PO 4 times daily for 10-14 days.
3. For those with mild penicillin allergy, an alternative treatment based on limited data is ceftriaxone 2g IV or IM daily for 10 to 14 days. High dose of doxycycline 200 mg PO BID for 21 to 28 days is another alternative.

Neurologic examination and lumbar puncture should be repeated at 3 to 6 months after treatment and every 6 months thereafter until CSF white blood cell (WBC) count is normal and CSF-VDRL is non-reactive. The individual will need to be retreated if the CSF WBC count does not decline by 6 months and all other CSF abnormalities are not normalized by 2 years. Re-treatment is also indicated if any subsequent CSF samples show an increase in CSF WBC count or a fourfold increase in CSF-VDRL titers.

Dementia related to neurosyphilis is one of the possibly reversible forms of dementia. Therefore, patients who present for evaluation of dementia should always be tested for syphilis, even if their history does not suggest exposure to syphilis.

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Are Children and Adolescents More Susceptible to the New Strains of SARS-Cov-2 Than the Earlier Ones?

Are Children and Adolescents More Susceptible to the New Strains of SARS-Cov-2 Than the Earlier Ones? by Mohammad Abu Bashar*  in Open Access Journal of Biogeneric Science and Research

Abstract

The clinical impact of the new SARS-CoV-2 lineage B.1·1.7 on children and young people (aged 18 years or younger) regarding acute respiratory COVID-19 is yet to be fully defined. Media reports of increases in admissions to hospital and more serious illness in children and young people have resulted in public confusion and implicated the B.1.1.7 variant as a more pathogenic infection within this group.

Introduction

According to the Centres for Disease Control and Prevention (CDC), it has been reported that children are less susceptible to develop severe manifestations of COVID-19; however, they can be infected with the virus, get sick from COVID-19, and spread the virus [1]. The majority of the children infected with COVID-19 have been reported to have mild or no symptoms. However, with the emergence of new variants of SARS-CoV-2, concerns have been raised regarding the susceptibility of the infection from these new variants among the paediatric population.

Current evidence

According to the CDC, there are currently five variants of concerns (VOCs) in the United States, including B.1.1.7 (UK variant), B.1.351 (South African variant), P.1 (initially detected in Brazil), and B.1.427 and B.1.429 (both of which were first identified in California, US) [2]. Studies have also shown that these variants, including 501Y.V1 (B.1.1.7) in UK, P.1 (501Y.V3) in Brazil, and 501Y.V2 (B.1.351) in South Africa, contribute to increased transmission of COVID-19. According to the report of Davies et al.3, the UK variant has been estimated to be more transmissible than the precursor lineage but has no clear evidence for a change in disease severity; however, the greater transmission will lead to higher incidence and more hospital admissions [3].

The clinical impact of the new SARS-CoV-2 lineage B.1.1.7 on children and young adults (under the age of 18 years) with acute respiratory COVID-19 has yet to be determined. Also, it has been hypothesized in the earlier reports that the paediatric population might be more susceptible to infections with VOC as compared to the original strain of SARS-CoV-2; however, till date, no such evidence has come up. Media reports of increases in hospital admissions and more serious illnesses in children and young people have caused public chaos and panic, and the latest variants, especially the B.1.1.7 variant, have been implicated in causing a more pathogenic infection in this population. However, recent data show that B.1.1.7 has not changed the paediatric hospitalization rate and that severe COVID-19 remains rare among the kids. No significant differences were found with respect to age, the proportion of patients with comorbidities, the proportion of patients from Black, Asian, and minority ethnic background, or deprivation score between groups denoting first and second waves [4]. There was also no evidence of more severe disease in children and adolescents during the second wave of COVID-19, implying that the infection with the B.1.1.7 variant might have a similar clinical course to infection with the original strain.

Conclusion

No evidence of more severe disease has occurred in children and young people during the second wave, suggesting that infection with the B.1.1.7 variant does not result in an appreciably different clinical course to the original strain. Severe acute respiratory COVID-19 remains an uncommon occurrence in children and young people.

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