Host and pathogen genomics of severe pediatric infections

Infectious diseases are among the leading causes of human morbidity and mortality, with the greatest burden felt in the pediatric population. For any infectious disease, only a fraction of the exposed individuals develop clinical symptoms. These inter-individual differences can be due to variation in pathogen virulence or in host susceptibility. The recent advent of high-throughput sequencing (HTS) technology has enabled studies of both human and pathogen genetic factors that have the potential to influence infectious diseases pathogenesis and alter clinical presentation. In this thesis, I present a set of genomic studies that used HTS to dissect the genetic basis of life-threatening infections with Pseudomonas aeruginosa (P. aeruginosa) and respiratory syncytial virus (RSV). This work provides conclusive evidence for the role of rare human genetic variants in susceptibility to life-threatening P. aeruginosa and RSV infections in previously healthy children. Furthermore, in an attempt to determine the role of viral genetic factors in severe presentations of RSV infection, I established a framework for exploring RSV genetic variation using HTS technology and bioinformatic analysis. Together, theses studies demonstrate that current genomic technology, bioinformatic analysis and functional follow-up have the potential to give us novel insight into the molecular basis of host-pathogen interactions and infectious disease pathogenesis

OR models in urban service facility location : a critical review of applications and future developments

[EN] Facility location models are well established in various application areas with more than a century of history in academia. Since the 1970s the trend has been shifting from manufacturing to service industries. Due to their nature, service industries are frequently located in or near urban areas that results in additional assumptions, objectives and constraints other than those in more traditional manufacturing location models. This survey focuses on the location of service facilities in urban areas. We studied 110 research papers across different journals and disciplines. We have analyzed these papers on two levels. On the first, we take an Operations Research perspective to investigate the papers in terms of types of decisions, location space, main assumptions, input parameters, objective functions and constraints. On the second level, we compare and contrast the papers in each of these applications categories: (a) Waste management systems (WMS), (b) Large-scale disaster (LSD), (c) Small-scale emergency (SSE), (d) General service and infrastructure (GSI), (e) Non-emergency healthcare systems (NEH) and (f) Transportation systems and their infrastructure (TSI). Each of these categories is critically analyzed in terms of application, assumptions, decision variables, input parameters, constraints, objective functions and solution techniques. Gaps, research opportunities and trends are identified within each category. Finally, some general lessons learned based on the practicality of the models is synthesized to suggest avenues of future research.Ruben Ruiz is partially supported by the Spanish Ministry of Economy and Competitiveness, under the project "SCHEYARD - Optimization of Scheduling Problems in Container Yards (No. DPI2015-65895-R) financed by FEDER funds.Farahani, RZ.; Fallah, S.; Ruiz García, R.; Hosseini, S.; Asgari, N. (2019). OR Models in Urban Service Facility Location: A Critical Review of Applications and Future Developments. European Journal of Operational Research. 276(1):1-27. https://doi.org/10.1016/j.ejor.2018.07.036S127276

A Wegner's Granulomatosis Risk Prediction Model Based on Machine Learning Algorithms

Introduction: Prediction of Wegener's granulomatosis diagnosis and relapse is a complex process. In this study, we applied machine learning algorithms to predict Wegener's granulomatosis relapse. Methods: In this research, 189 patients admitted to Amiralam Hospital were studied and followed for approximately 2 years. Patient features included demographics, organ involvement, symptoms, and other clinical data. Different popular machine learning algorithms were applied for predicting Wegener's granulomatosis relapse, including Support Vector Machines, Random Forest, Gradient Boosting, and XGBoost algorithms. The prediction model performance was measured for the different candidate prediction algorithms using accuracy, precision, recall, and F1-measure. The selected prediction model performance was calculated based on different relapse rates and major relapse occurrence according to Birmingham Vasculitis Activity Score (BVAS) fields. Results: Applying different machine learning algorithms, the XGBoost algorithm performed the best. The results indicated that the prediction model's performance increased when calculating higher relapse rate possibilities. The XGBoost model had 82% accuracy while predicting more than one relapse rate and 92% accuracy in predicting more than twice the relapse rate. We also calculated the SHAP value for the prediction model. The results indicated that Cr, BVAS, lymphocyte percentage, vitamin D, nose involvement, alkaline phosphatase, diagnosis age, white blood cell count, erythrocyte sedimentation rate, and initial nose presentation are the 10 most important features according to SHAP value. Conclusion: In this study, we have developed Wegener's granulomatosis relapse prediction model using machine learning algorithms. We achieved reasonable precision and recall for early prediction and decision- making regarding Wegener's granulomatosis relaps

The Hepatotoxic Effects of Stachys Lavandulifolia Vahl on Wistar Rat

Background and purpose: Stachys lavandulifolia is a plant commonly used for many diseases. But so far there is no report indicating its toxicity. The aim of this study was to investigate the probable hepatoxicity of S. lavandulifolia extract on Wistar rats. Materials and methods: In this experimental study, 100 Wistar rats (about 250gr, 8-12 weeks old) were randomly divided into 10 groups (8 groups as case and 2 groups as control). They were intraperitoneally injected with S. lavandulifolia extract with doses of 50, 100, 150 and 200mg/kg per day for 28 days. Afterwards, the serum parameters level (ALP, AST, ALT) and pathological samples were evaluated and compared in four case group and one control group after 28 days and other groups after one month. Results: On the first month there was significant increase on AST level only in 200mg/kg dose while ALP level significantly increased in all doses (P<0.05). There was no significant difference among all doses regarding their effects on the increase of liver enzymes (P>0.05). On the second month, the changes in liver enzymes were almost the same as first month, except 150mg/kg dose that significantly increased the AST level compared to control group and also this dose significantly increased the ALP level compared to 100mg/kg dose (P<0.05). In examining liver samples obtained from rats in the first and second months, necrotic inflammatory reactions and fibrotic lesions significantly increased compared to control group (P<0.001). In the first month we also found that there was significant difference between higher doses (150 and 200mg/kg) and lower doses (50 and 100mg/kg) regarding their effects on hepatic lesion (P<0.05). Conclusion: Since the extract of S. lavandulifolia causes toxicity it should be consumed with caution in people with underlying cholestatic diseases

Antioxidant activity and the lowering effect of hydroalcoholic extract of Allium hirtifolium boisson some haemostatic factors in hypercholesterolemic rabbits

Background and purpose: Hypercholesterolemia and the activity of haemostatic factors may trigger cardiovascular diseases. Allium hirtifolium Boiss (Persian shallot) has been shown to have cardioprotective effects. This study evaluated the effects of A. hirtifoliumon on factor VII and serum fibrinogen levels in hypercholesterolemic rabbits. Also, the antioxidant capacity of A. hirtifolium was measured. Materials and methods: In an experimental study, 24 NewZealand male rabbits were randomly assigned into three groups of eight. The groups' diet which was followed for 60 days included normal diet, hypercholestrol diet (1%) or hypercholestrol diet (1%) + A. hirtifolium. The blood fibrinogen and factor VII were measured pre and post study in all groups. The A. hirtifolium antioxidant capacity was measured using beta-carotene linoleate. Results: The study showed that serum fibrinogen level and factor VII increased significantly in hypercholesterolemic group (329.22 ± 26.7 and 277.7 ± 17.1 mg/dl) compared to normal diet group (287.25 ± 13.7 and 230.0 ± 18.2 mg/dl), respectively (P<0.05). The amount of serum fibrinogen and factor VII decreased in hypercholesterol+A. hirtifolium group (180.0 ± 23.9 and 237.0 ± 53.3 mg/dl) compared to hypercholesterol diet group (P<0.05). The antioxidant capacity of A. hirtifolium extract was 52.1 ± 3.3% in 0.2 g/L. The plasma antioxidant capacity in the group fed with hypercholesterol + A. hirtifolium was 943.907 ± 249.51 µM which was higher compared to that of the normal diet group (629.675 ± 130.73 µM). Conclusion: A. hirtifolium decreases serum fibrinogen level and factor VII, therefore, it might be helpful in reducing risk factors of cardiovascular diseases. These influences are of great importance in patients with haemostatic disorder

Genetic Linkage Analysis of the DFNB21 Locus in Autosomal Recessive Hearing Loss in Large Families from Khuzestan Province

Background: Hearing loss (HL) is the most common congenital defect in humans. One or two in thousand newborn babies have prelingual hearing loss. Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of hereditary deafness. Hearing loss is more common in the developing countries which is due to genetic and environmental (cultural -health factors) reasons. HL has a wide range of clinical demonstrations including: congenital or late onset, conductive or sensoryneural, syndromic or non-syndromic hearing loss. The goal of this project is to determine the portion of the DFNB21 (TECTA) in ARNSHL in families with negative GJB2 gene in Khuzestan province. Materials and Methods: We studied 21 families with ARNSHL with at least 4 patients and negative for GJB2 mutations from Khuzestan province. Genetic linkage analysis was performed using STR markers linked to DFNB21 locus. Results: Following genetic linkage analysis and haplotyping, out of 21 families with ARNSHL, one family showed linkage to the DFNB21 (TECTA) locus. Conclusion: The results of this project confirm other studies in Iran and give insight into the most common loci causing ARNSHL in Iran which could be helpful in research and clinic

From Your Nose to Your Toes: A Review of Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic‒Associated Pernio

Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pernio in uninfected children is associated with monogenic disorders of excessive IFN-1 immunity, whereas severe COVID-19 pneumonia can result from insufficient IFN-1. Moreover, SARS-CoV-2 spike protein and robust IFN-1 response are seen in the skin of patients with pandemic-associated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate the host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets

Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

Abstract: Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5–15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response. Here, in a genome-wide genetic study of early TB progression, we genotype 4002 active TB cases and their household contacts in Peru. We quantify genetic heritability (hg2) of early TB progression to be 21.2% (standard error 0.08). This suggests TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases. We identify a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 × 10−8). With in silico and in vitro analyses we identify rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function

Admixture mapping of peripheral artery disease in a Dominican population reveals a putative risk locus on 2q35

Peripheral artery disease (PAD) is a form of atherosclerotic cardiovascular disease, affecting ∼8 million Americans, and is known to have racial and ethnic disparities. PAD has been reported to have a significantly higher prevalence in African Americans (AAs) compared to non-Hispanic European Americans (EAs). Hispanic/Latinos (HLs) have been reported to have lower or similar rates of PAD compared to EAs, despite having a paradoxically high burden of PAD risk factors; however, recent work suggests prevalence may differ between sub-groups. Here, we examined a large cohort of diverse adults in the BioMe biobank in New York City. We observed the prevalence of PAD at 1.7% in EAs vs. 8.5% and 9.4% in AAs and HLs, respectively, and among HL sub-groups, the prevalence was found at 11.4% and 11.5% in Puerto Rican and Dominican populations, respectively. Follow-up analysis that adjusted for common risk factors demonstrated that Dominicans had the highest increased risk for PAD relative to EAs [OR = 3.15 (95% CI 2.33–4.25), p &lt; 6.44 × 10−14]. To investigate whether genetic factors may explain this increased risk, we performed admixture mapping by testing the association between local ancestry and PAD in Dominican BioMe participants (N = 1,813) separately from European, African, and Native American (NAT) continental ancestry tracts. The top association with PAD was an NAT ancestry tract at chromosome 2q35 [OR = 1.96 (SE = 0.16), p &lt; 2.75 × 10−05) with 22.6% vs. 12.9% PAD prevalence in heterozygous NAT tract carriers versus non-carriers, respectively. Fine-mapping at this locus implicated tag SNP rs78529201 located within a long intergenic non-coding RNA (lincRNA) LINC00607, a gene expression regulator of key genes related to thrombosis and extracellular remodeling of endothelial cells, suggesting a putative link of the 2q35 locus to PAD etiology. Efforts to reproduce the signal in other Hispanic cohorts were unsuccessful. In summary, we showed how leveraging health system data helped understand nuances of PAD risk across HL sub-groups and admixture mapping approaches elucidated a putative risk locus in a Dominican population

Multimodal memory T cell profiling identifies a reduction in a polyfunctional Th17 state associated with tuberculosis progression

Mycobacterium tuberculosis (M.tb) results in 10 million active tuberculosis (TB) cases and 1.5 million deaths each year, making it the world's leading infectious cause of death. Infection leads to either an asymptomatic latent state or TB disease. Memory T cells have been implicated in TB disease progression, but the specific cell states involved have not yet been delineated because of the limited scope of traditional profiling strategies. Furthermore, immune activation during infection confounds underlying differences in T cell state distributions that influence risk of progression. Here, we used a multimodal single-cell approach to integrate measurements of transcripts and 30 functionally relevant surface proteins to comprehensively define the memory T cell landscape at steady state (i.e., outside of active infection). We profiled 500,000 memory T cells from 259 Peruvians > 4.7 years after they had either latent M.tb infection or active disease and defined 31 distinct memory T cell states, including a CD4+CD26+CD161+CCR6+ effector memory state that was significantly reduced in patients who had developed active TB (OR = 0.80, 95% CI: 0.73-0.87, p = 1.21 x 10-6). This state was also polyfunctional; in ex vivo stimulation, it was enriched for IL-17 and IL-22 production, consistent with a Th17-skewed phenotype, but also had more capacity to produce IFNgamma than other CD161+CCR6+ Th17 cells. Additionally, in progressors, IL-17 and IL-22 production in this cell state was significantly lower than in non-progressors. Reduced abundance and function of this state may be an important factor in failure to control M.tb infection. ### Competing Interest Statement The authors have declared no competing interest