Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis.

Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.

Pharmacogenomics of coronary artery response to intravenous gamma globulin in kawasaki disease.

Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The mechanism of coronary artery aneurysms (CAA) in KD despite intravenous gamma globulin (IVIG) treatment is not known. We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z ≥ 2.5 and large coronary aneurysm (CAA/L) (N = 92) as z ≥ 5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p < 6.32E-08 most significant). Variants in SMAT4, LOC100127, PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. Functional mapping and annotation (FUMA) analysis identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an area under the receiver operating characteristic curve (AUC) of 0.86. This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD and shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.

Pharmacogenomics of Coronary Artery Response to Intravenous Gamma Globulin in Kawasaki Disease.

Background: Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The pathological walls of afflicted coronary arteries show propensity for forming thrombosis and aneurysms. The mechanism of coronary artery aneurysms (CAA) despite intravenous gamma globulin (IVIG) treatment is not known. Methods: We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z>2.5 and large coronary aneurysm (CAA/L) (N = 92) as z>5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. We performed functional mapping and annotation (FUMA) analysis and further assessed the predictive risk score of genomic risk loci using the area under the receiver operating characteristic curve (AUC). Results: The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p<6.32E-08 most significant). Variants in SMAT4, LOC100127 , PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. FUMA identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an AUC of 0.86. Conclusions: This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD patients. We have identified multiple novel SNPs associated with CAA/L and related genes with potential functional implications. The study shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.

The effects of social determinants on children's health outcomes in Bangladesh slums through an intersectionality lens: An application of multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA).

Empirical evidence suggests that the health outcomes of children living in slums are poorer than those living in non-slums and other urban areas. Improving health especially among children under five years old (U5y) living in slums, requires a better understanding of the social determinants of health (SDoH) that drive their health outcomes. Therefore, we aim to investigate how SDoH collectively affects health outcomes of U5y living in Bangladesh slums through an intersectionality lens. We used data from the most recent national Urban Health Survey (UHS) 2013 covering urban populations in Dhaka, Chittagong, Khulna, Rajshahi, Barisal, Sylhet, and Rangpur divisions. We applied multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA) to estimate the Discriminatory Accuracy (DA) of the intersectional effects estimates using Variance Partition Coefficient (VPC) and the Area Under the Receiver Operating Characteristic Curve (AUC-ROC). We also assessed the Proportional Change in Variance (PCV) to calculate intersectional effects. We considered three health outcomes: cough, fever, and acute respiratory infections (ARI) in U5y.We found a low DA for cough (VPC = 0.77%, AUC-ROC = 61.90%), fever (VPC = 0.87%, AUC-ROC = 61.89%) and ARI (VPC = 1.32%, AUC-ROC = 66.36%) of intersectional strata suggesting that SDoH considered do not collectively differentiate U5y with a health outcome from those with and without a health outcome. The PCV for cough (85.90%), fever (78.42%) and ARI (69.77%) indicates the existence of moderate intersectional effects. We also found that SDoH factors such as slum location, mother's employment, age of household head, and household's garbage disposal system are associated with U5y health outcomes. The variables used in this analysis have low ability to distinguish between those with and without health outcomes. However, the existence of moderate intersectional effect estimates indicates that U5y in some social groups have worse health outcomes compared to others. Therefore, policymakers need to consider different social groups when designing intervention policies aimed to improve U5y health outcomes in Bangladesh slums.

Pharmacogenomics of intravenous immunoglobulin response in Kawasaki disease.

Introduction: Kawasaki disease (KD) is a diffuse vasculitis in children. Response to high dose intravenous gamma globulin (IVIG), the primary treatment, varies according to genetic background. We sought to identify genetic loci, which associate with treatment response using whole genome sequencing (WGS). Method: We performed WGS in 472 KD patients with 305 IVIG responders and 167 non-responders defined by AHA clinical criteria. We conducted logistic regression models to test additive genetic effect in the entire cohort and in four subgroups defined by ancestry information markers (Whites, African Americans, Asians, and Hispanics). We performed functional mapping and annotation using FUMA to examine genetic variants that are potentially involved IVIG non-response. Further, we conducted SNP-set [Sequence] Kernel Association Test (SKAT) for all rare and common variants. Results: Of the 43,288,336 SNPs (23,660,970 in intergenic regions, 16,764,594 in introns and 556,814 in the exons) identified, the top ten hits associated with IVIG non-response were in FANK1, MAP2K3:KCNJ12, CA10, FRG1DP, CWH43 regions. When analyzed separately in ancestry-based racial subgroups, SNPs in several novel genes were associated. A total of 23 possible causal genes were pinpointed by positional and chromatin mapping. SKAT analysis demonstrated association in the entire MANIA2, EDN1, SFMBT2, and PPP2R5E genes and segments of CSMD2, LINC01317, HIVEPI, HSP90AB1, and TTLL11 genes. Conclusions: This WGS study identified multiple predominantly novel understudied genes associated with IVIG response. These data can serve to inform regarding pathogenesis of KD, as well as lay ground work for developing treatment response predictors.

COVID-19 Vaccine Refusal among Nurses Worldwide: Review of Trends and Predictors.

COVID-19 vaccination hesitancy has become a major concern around the world. Recent reports have also highlighted COVID-19 vaccination hesitancy in healthcare workers. Despite media reports and scientific publications, little is known about the extent and predictors of COVID-19 vaccination refusal among nurses. Thus, the purpose of this study was to assess COVID-19 vaccine refusal rates among nurses globally and to explore the reasons for refusal and factors associated with the uptake of the vaccines. A scoping review of the published literature was conducted, and a final pool of 51 studies (n = 41,098 nurses) from 36 countries was included in this review. The overall pooled prevalence rate of COVID-19 vaccine refusal among 41,098 nurses worldwide was 20.7% (95% CI = 16.5-27%). The rates of vaccination refusal were higher from March 2020-December 2020 compared to the rates from January 2021-May 2021. The major reasons for COVID-19 vaccine refusal were concerns about vaccine safety, side effects, and efficacy; misinformation and lack of knowledge; and mistrust in experts, authorities, or pharmaceutical companies. The major factors associated with acceptance of the vaccines were: male sex, older age, and flu vaccination history. Evidence-based strategies should be implemented in healthcare systems worldwide to increase the uptake of COVID-19 vaccines among nurses to ensure their safety and the safety of their patients and community members.

A Clinical Investigation of the Performance and Safety of Epaderm®, an Emollient Cream.

INTRODUCTION: Emollients provide an occlusive barrier for dry and atopic skin, retain moisture, protect it from irritants, and form the basis of eczema treatment. METHODS AND ANALYSIS: A prospective interventional single arm study to evaluate the performance and safety of Epaderm® Cream, an emollient and cleanser containing 25% (w/w) paraffin and 5% (w/w) glycerine (thereafter, an emollient cream), in patients with dry skin conditions. The primary outcome measure was participant evaluation of skin moisturisation after treatment with an emollient cream for up to 4 weeks. Secondary outcome measures included: evaluation of skin softness using a questionnaire and of pruritus on a visual analogue scale (VAS); clinician assessment of xerosis using Overall Dry Skin (ODS) score and measurement of skin hydration using a non-invasive device (MoistureMeterEpiD, Delfin Technologies) at each visit. Sign test and Wilcoxon signed rank test were used to analyse changes from baseline. RESULTS: A total of 114 participants completed the study. 84.2% (80 out of 95) of participants or parents strongly agreed or agreed that the cream improved skin moisturisation at 4 weeks of treatment at the target area (p<0.0001). 86.3% of participants agreed that skin softness improved after 4 weeks (p <0.0001). ODS score improved from 2.1 (standard deviation (SD) 1.0) to 0.7 (SD 0.8) at 4 weeks. Skin hydration at the target area improved from 31.5 (SD 9.3) to 40.5 (SD 8.3) (p<0.001) at 4 weeks. Mean skin itchiness reduced from 38.0 (SD 25.4) to 17.7 (SD 19.8) at 4 weeks (p<0.0001). Ten (8.3%) adverse device events (ADEs) were reported. CONCLUSION: The emollient cream was well tolerated and demonstrated significant improvements in patient-reported skin moisturisation and softness as well as in clinical measurement of xerosis and skin hydration across all age groups including infants. The emollient cream can be recommended for dry skin conditions including atopic dermatitis and psoriasis.