Systems genetics identifies miRNA-mediated regulation of host response in COVID-19.

BACKGROUND: Individuals infected with SARS-CoV-2 vary greatly in their disease severity, ranging from asymptomatic infection to severe disease. The regulation of gene expression is an important mechanism in the host immune response and can modulate the outcome of the disease. miRNAs play important roles in post-transcriptional regulation with consequences on downstream molecular and cellular host immune response processes. The nature and magnitude of miRNA perturbations associated with blood phenotypes and intensive care unit (ICU) admission in COVID-19 are poorly understood. RESULTS: We combined multi-omics profiling-genotyping, miRNA and RNA expression, measured at the time of hospital admission soon after the onset of COVID-19 symptoms-with phenotypes from electronic health records to understand how miRNA expression contributes to variation in disease severity in a diverse cohort of 259 unvaccinated patients in Abu Dhabi, United Arab Emirates. We analyzed 62 clinical variables and expression levels of 632 miRNAs measured at admission and identified 97 miRNAs associated with 8 blood phenotypes significantly associated with later ICU admission. Integrative miRNA-mRNA cross-correlation analysis identified multiple miRNA-mRNA-blood endophenotype associations and revealed the effect of miR-143-3p on neutrophil count mediated by the expression of its target gene BCL2. We report 168 significant cis-miRNA expression quantitative trait loci, 57 of which implicate miRNAs associated with either ICU admission or a blood endophenotype. CONCLUSIONS: This systems genetics study has given rise to a genomic picture of the architecture of whole blood miRNAs in unvaccinated COVID-19 patients and pinpoints post-transcriptional regulation as a potential mechanism that impacts blood traits underlying COVID-19 severity. The results also highlight the impact of host genetic regulatory control of miRNA expression in early stages of COVID-19 disease.

Low body weight and involuntary weight loss are associated with Raynaud's phenomenon in both men and women.

Objectives: Low body weight is an easily assessable cause of Raynaud's phenomenon (RP), and is frequently overlooked by clinicians. We aim to investigate the association of low body weight (body mass index < 18.5 kg/m2), involuntary weight loss, and nutritional restrictions with the presence of RP.Method: Participants from the Lifelines Cohort completed a validated self-administered connective tissue disease questionnaire. Subjects who reported cold-sensitive fingers and biphasic or triphasic colour changes were considered to suffer from RP. Patient characteristics, anthropometric measurements, and nutritional habits were collected. Statistical analyses was stratified for gender.Results: Altogether, 93 935 participants completed the questionnaire. The prevalence of RP was 4.2% [95% confidence interval (CI) 4.1-4.4%], and was three-fold higher in women than in men (5.7% vs 2.1%, p < 0.001). Subjects with RP had a significantly lower daily caloric intake than those without RP. Multivariate analysis, correcting for creatinine level, daily caloric intake, and other known aetiological factors associated with RP, revealed that low body weight [men: odds ratio (OR) 5.55 (95% CI 2.82-10.93); women: 3.14 (2.40-4.10)] and involuntary weight loss [men: OR 1.32 (1.17-1.48); women: 1.31 (1.20-1.44)] were significantly associated with the presence of RP. Low-fat diet was also associated with RP in women [OR 1.27 (1.15-1.44)].Conclusion: Low body weight and prior involuntary weight loss are associated with an increased risk of RP in both men and women. This study emphasizes that low body weight and weight loss are easily overlooked risk factors for RP, and should be assessed and monitored in subjects with RP.

The prevalence and potential determinants of obesity among school children and adolescents in Abu Dhabi, United Arab Emirates.

OBJECTIVES: To estimate the prevalence and determinants of obesity in childhood and adolescence and their association with blood pressure (BP) in Abu Dhabi, United Arab Emirates (UAE). DESIGN: A cross-sectional population-representative study. SUBJECTS: A total of 1541 students (grades 1-12; aged 6-19 years) were randomly selected from 246 schools (50% male). Anthropometric and demographic variables were measured, and CDC criteria were used to classify children's weights. RESULTS: A total of 1440 (93%) students provided complete results. Crude prevalences were: 7.6% underweight, 14.7% overweight and 18.9% obesity. Further analyses were restricted to UAE nationals (n=1035), of whom these figures were: 8.3% underweight (females 6.5%, males 10.1%; P=0.06), 14.2% overweight (females 16.7%, males 11.6%; P<0.01), 19.8% obesity (females 18.1%, males 21.4%; P=0.09). Obesity significantly (P<0.001) increased with age. The majority (61.3%) of students had body mass index (BMI) percentiles above the 50th CDC percentile. Stepwise linear regression of BMI percentile on age, sex, dairy consumption, exercise and family income showed a significant (P<0.01) positive association with age and lack of dairy consumption, but not exercise and income. BP significantly (P<0.01) increased with BMI percentile. CONCLUSIONS: The prevalence of childhood obesity is high across the age spectrum in the UAE. Older age, male sex, lack of dairy intake and higher parental BMI, are independent determinants of childhood obesity in this population. Higher BMI percentile is associated with a higher BP. Prevention strategies should focus on younger children, particularly children of obese parents. Longitudinal studies are needed to investigate trends and the impact of childhood obesity on the risk of non-communicable diseases.

Allergic rhinitis: prevalence and possible risk factors in a Gulf Arab population.

BACKGROUND: Epidemiological studies mainly from Europe, the USA and Asia indicate a high prevalence of allergic rhinitis (AR) in modern societies. However, little is known about AR among the heterogeneous population of the United Arab Emirates (UAE). OBJECTIVES: To estimate the prevalence of AR and its independent risk factors in Al-Ain City, UAE. METHODS: We used a validated, self-administered questionnaire modified from the ISAAC study to collect data from a two stage randomly selected sample of 10 000 school children. Overall, 7550 subjects (aged 13 years and above, siblings, and their parents) responded. We assessed the prevalence of AR (both crude and standardized prevalence of previous 12 months) as well as the independent relationship of AR with age, gender, education, nationality and family history by means of logistic regression. RESULTS: The response rate was 76%. A total of 6543 subjects (median age 30 years) were included in the final analysis. Self-reported prevalence of AR (having symptoms in the past 12 months) was 36%, while adjusted values for sex/age yielded a prevalence of 32%. Regression analysis revealed that AR was independently associated with family history, Arab origin, younger age, female gender and higher education. CONCLUSIONS: The relatively high prevalence of AR found in this study may be attributable to modernization and genetic factors. Further studies on the impact of rapid environmental and cultural changes on AR in the Arab countries are needed and currently planned in conjunction with GA(2)LEN (Global Allergy and Asthma European Network).

Thiols as markers of redox status in type 1 diabetes mellitus.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is associated with inflammation and the production of reactive oxygen species (ROS). Systemically, free thiols (R-SH) can be oxidized by ROS and circulating R-SH concentrations may directly reflect the systemic redox status. In this study the association between R-SH and clinical parameters of T1DM, including glycated haemoglobin A1c (HbA1c), was investigated. This is of particular interest since thiols are amendable to therapeutic intervention. METHODS: As part of a prospective cohort study, data from 216 patients with a mean age of 45 (12) years, 57% male, diabetes duration 22 (16, 30) years and HbA1c of 60 (11) mmol/mol were examined. Baseline data were collected in 2002 and follow-up data in 2018. Cox proportional hazards regression analysis, with age, sex, HbA1c and R-SH, was used to assess prognostic factors for the development of complications. RESULTS: At baseline, the plasma concentration of R-SH was 281.8 ± 34.0 µM. In addition to a lower concentration of NT-proBNP in the highest R-SH quartile (305-379 µM) there were no differences in baseline characteristics between the quartiles of R-SH. The Pearson correlation coefficient for R-SH and NT-proBNP was -0.290 (p < 0.001). No significant correlation between R-SH and baseline HbA1c (r = -0.024, p = 0.726) was present. During follow-up, 42 macrovascular and 92 microvascular complications occurred. In Cox regression, R-SH was not a prognostic factor for the development of microvascular [hazard ratio (HR) 0.999 (95% confidence interval (CI) 0.993, 1.005)] and macrovascular [HR 0.993 (95% CI 0.984, 1.002)] complications. CONCLUSIONS: In addition to a negative association with NT-proBNP, no relevant relationships between R-SH and parameters of T1DM, including HbA1c, were present in this study.

Current maternal-infant micronutrient status and the effects on birth weight in the United Arab Emirates.

Micronutrient deficiencies exist among women of childbearing age in the United Arab Emirates but the effects of maternal micronutrient deficiency on fetal growth are not well documented. To investigate the association between micronutrients and birth weight, we measured maternal and cord blood micronutrients (vitamin A, C, D, and E) and ferritin in 84 term, singleton infants born to healthy Arab and South Asian women at Al-Ain hospital. Median serum ascorbic acid and 25-hydroxyvitamin D (25-OHD) concentrations were low in mothers and infants. In multivariate analysis, maternal serum 25-OHD correlated positively with birth weight while serum ferritin showed a negative correlation.

Plasma N terminal pro-brain natriuretic peptide levels and its determinants in a multi-ethnic population.

This study documents the determinants and plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) among hypertensive and normotensive subjects in a multi-ethnic population in the United Arab Emirates (UAE). We obtained demographic, anthropometric and clinical data, together with fasting NT-proBNP and biochemical indices from 128 hypertensive patients and 138 normotensive subjects matched for age, gender and ethnicity. Plasma NT-proBNP levels were significantly (P<0.001), and several-fold higher among hypertensives (median 5.92, inter quartile range (IQR): 1.79-18.48 pmol/l) than normotensives (median 1.78, IQR: 0.59-4.32 pmol/l) in the total study population, and the same was true for the ethnic groups separately. Similarly, plasma levels of glucose, blood urea nitrogen (BUN) and creatinine, but not insulin, were significantly (P<0.05) higher among hypertensives than normotensives. For all subjects combined, log NT-proBNP correlated positively and significantly with age (P<0.01), log glucose (P<0.05), systolic blood pressure (SBP, P<0.001), log BUN (P<0.001) and log creatinine (P<0.001). Multivariate regression analysis showed that NT-proBNP levels were independently and positively correlated with SBP, age, gender, log BUN, Emirati and South East Asian ethnic groups and inversely associated with current exercise. In conclusion, we found circulating levels of NT-proBNP to be significantly increased in hypertensive versus normotensive subjects in the UAE and independently related to SBP, age, gender, indices of renal function and possibly exercise. Our results further suggest a possible modulating effect of ethnicity on NT-proBNP levels.

Asymptomatic De Novo Inflammatory Bowel Disease Late After Liver Transplantation for Primary Sclerosing Cholangitis: A Case Report.

Guidelines recommend colonoscopy screening for possible asymptomatic inflammatory bowel disease (IBD) in all patients diagnosed with primary sclerosing cholangitis (PSC). PSC-IBD warrants regular dysplasia-surveillance colonoscopy. However, no consensus exists regarding follow-up colonoscopy in PSC patients without IBD who remain asymptomatic. We describe a 43-year-old female who had undergone liver transplantation (LT) due to advanced PSC. Previous colonoscopies had been normal. The post-transplantation course was uneventful, with no rejections and signs of PSC recurrence. Immunosuppression was by tacrolimus monotherapy. She was asymptomatic with normal inflammation markers. A protocol colonoscopy, performed as general dysplasia surveillance 8 years post-transplantation, revealed mucopurulent-covered small superficial ulcerations and erythema diffusely distributed from the cecal to sigmoid colon with intervening normal mucosa and rectal sparing. Histologic examination showed patchy chronic colitis with crypt architectural distortion and mild-moderate inflammation activity. Infection samples were negative. Findings complied with de novo IBD, type unclassified. In conclusion, the link between PSC and clinically silent IBD may manifest after the PSC diagnosis and even several years after LT. Given the increased colorectal cancer risk associated with PSC, IBD, and LT, repeat colonoscopy might be warranted in PSC patients without IBD at initial assessment, and also after LT.

The outcome of a 2-week treatment of Helicobacter pylori-positive duodenal ulcer with omeprazole-based antibiotic regimen in a region with high metronidazole resistance rate.

BACKGROUND/OBJECTIVE: Metronidazole resistance is a major problem in many developing countries. Our main objective was to study the outcome of a non-metronidazole and omeprazole-based antibiotic regimen in eradicating Helicobacter pylori in patients with duodenal ulcer. DESIGN: A prospective study of 50 consecutive patients with proven peptic ulcer (mean age 36.6 +/- 10.5 years, range 17-60, male:female = 2), referred from the primary health centres. MAIN OUTCOME MEASURE: The primary outcome of the study was H. pylori eradication, at least 4 weeks after stopping antibiotic treatment. METHODS: Patients were considered eligible for the study if they had endoscopic evidence or a past medical history of peptic ulcer and had not received any antibiotics for at least 4 weeks prior to admission into the study. H. pylori infection was confirmed by serology, histology, a rapid urease test (RUT) and culture. After an initial oesophago-gastroduodenoscopy (OGD), each patient received a 2-week course of omeprazole (20 mg twice daily), and each of amoxycillin capsules (500 mg) and clarithromycin tablets (250 mg) thrice daily after food. The follow-up OGDs were performed after a mean period of 10.04 weeks (range 4-48) and at 10.4 +/- 2.5 months (range 6-14 months) after stopping treatment. RESULTS: All 50 patients completed the study. The sensitivity values for serology, RUT and histopathology were 98, 96 and 100%, respectively. H. pylori culture was positive in only 15 of 50 patients (30% sensitivity). H. pylori was eradicated in 47 (94%) patients. There was no evidence of H. pylori infection in the 27 of 35 (77%) patients, who returned for a third OGD. At the time of the second OGD, there was a significant reduction of pain-days (from 5.47 to 1.16), and antral (from 1.95 to 0.78) and corpus (from 1.8 to 0.6) mucosal cellular infiltrate scores, when compared with the first OGD (P < 0.001 in each case). CONCLUSION: Exclusion of metronidazole from the treatment regimen of patients with H. pylori-positive duodenal ulcer in a region with metronidazole resistance yielded an excellent H. pylori eradication rate of 94%, when omeprazole, amoxicillin and clarithromycin were used.

Lecithin: cholesterol acyltransfer, dyslipoproteinaemia and membrane lipids in uraemia.

BACKGROUND: Dyslipoproteinaemia is the most important complication linked to the increased morbidity and mortality of uraemic patients from cardiovascular disease. Many factors contribute to the dyslipoproteinaemia, including increased production of very low density lipoproteins (VLDL), decreased lipolysis and impaired low density lipoprotein (LDL) receptor activity. In this study, the role of decreased lecithin:cholesterol acyltransferase (LCAT) activity in relation to plasma and membrane lipid changes is examined. METHODS: Fasted blood samples were taken from 65 uraemic patients, including roughly equal numbers of haemodialysis, peritoneal dialysis and undialysed subjects, and from 29 apparently healthy individuals. Plasma total and free cholesterol, cholesteryl esters (CE), total and individual phospholipids, high density lipoprotein (HDL)-, LDL- and VLDL-cholesterol were all measured, as were erythrocyte and lymphocyte free cholesterol and phospholipids. RESULTS: More than half of all patients, including those both on haemodialysis and peritoneal dialysis, as well as untreated individuals, had relative plasma concentrations of CE below the normal mean - 2SD. These patients had significantly decreased LDL- (2.62 +/- 1.04 compared to 3.61 +/- 0.97 mmol/L; p < 0.001) and HDL-cholesterol (0.71 +/- 0.30 compared to 0.94 +/- 0.27 mmol/L; p < 0.01) and increased VLDL-cholesterol (0.60 +/- 0.50 compared to 0.47 +/- 0.26 mmol/L; p < 0.05) as well as significant increases in membrane cholesterol and cholesterol/phospholipid molar ratio in erythrocytes (3.30 +/- 0.49 and 0.87 +/- 0.08 compared to 2.95 +/- 0.18 mmol/g wet weight and 0.76 +/- 0.04 mol/mol respectively, both p < 0.001) and cholesterol/phospholipid molar ratio of lymphocytes (0.58 +/- 0.14 compared to 0.45 +/- 0.04 mol/mol; p < 0.001). They were markedly deficient in LCAT activity (56.1 +/- 20.4 compared to 105.5 +/- 17.5 nmol/ml/h; p < 0.001). The LCAT activity in plasma of patients with high CE was higher than for those with low CE, but it was also significantly less than normal and this group showed smaller changes in other lipid parameters. CONCLUSIONS: LCAT deficiency is common in uraemia and is associated with changes not just in plasma lipids, but also in membrane lipids which may be relevant to the progression of the disease.

A comparison of plasma polymorphonuclear leucocyte elastase levels in obese and lean individuals.

Increased release of polymorphonuclear leucocyte (PMNL) elastase, when the PMNLs are activated, can damage tissues in vivo. It was postulated that PMNL elastase might have a tissue-remodelling effect in the body and that obese individuals might have less PMNL elastase activity than lean individuals. To test this hypothesis, plasma PMNL elastase levels were determined in 70 obese individuals and 30 lean normal controls. The PMNL elastase levels (determined by enzyme-linked immunosorbent assay) in the obese group (median 36.2 ng/ml) did not differ significantly from those in the lean healthy controls (32.6 ng/ml; P = 0.5).

Levels of cholesteryl esters and other lipids in the plasma of patients with end-stage renal failure.

BACKGROUND: The importance of plasma lipid abnormalities in chronic renal failure (CRF) is well recognized, but surprisingly little attention has been given to the study of some plasma lipid fractions, including cholesteryl esters (CE) and phospholipids, which might be expected to be important factors in the pathogenesis of the disease. MATERIALS AND METHODS: Fasting blood samples were taken from 25 control subjects and 53 CRF patients (29 predialysis and 24 on hemodialysis). Samples were analyzed for urea nitrogen, creatinine, triacylglycerols, total and individual phospholipids, total and free cholesterol, as well as cholesterol bound to very low-, low- and highdensity lipoproteins (VLDL, LDL and HDL). Plasma CE was calculated and expressed as a percentage of total cholesterol. RESULTS: Over half of the patients had CE levels more than two standard deviations below the control value. In this subgroup of low CE patients, total, LDL- and HDL-cholesterol levels were also significantly lower than for controls, while levels of phosphatidylcholine and lysophosphatidylcholine were decreased and increased, respectively. In patients with high CE, no significant lipid abnormalities were observed. CONCLUSION: In this study, CE was an excellent marker for lipid disturbances--if CE was high, then the other lipid fractions were normal, but if CE was low, most other lipid fractions were abnormal. The changes noted appear to be consequences of or related to deficiency of the plasma enzyme lecithin-cholesterol acyltransferase.

Reduced-order modelling numerical homogenization.

A general framework to combine numerical homogenization and reduced-order modelling techniques for partial differential equations (PDEs) with multiple scales is described. Numerical homogenization methods are usually efficient to approximate the effective solution of PDEs with multiple scales. However, classical numerical homogenization techniques require the numerical solution of a large number of so-called microproblems to approximate the effective data at selected grid points of the computational domain. Such computations become particularly expensive for high-dimensional, time-dependent or nonlinear problems. In this paper, we explain how numerical homogenization method can benefit from reduced-order modelling techniques that allow one to identify offline and online computational procedures. The effective data are only computed accurately at a carefully selected number of grid points (offline stage) appropriately 'interpolated' in the online stage resulting in an online cost comparable to that of a single-scale solver. The methodology is presented for a class of PDEs with multiple scales, including elliptic, parabolic, wave and nonlinear problems. Numerical examples, including wave propagation in inhomogeneous media and solute transport in unsaturated porous media, illustrate the proposed method.

Comparison of maternal and cord blood polymorphonuclear leukocyte elastase levels.

The main objective of this study was to examine the influence of parturition on the polymorphonuclear leukocyte elastase release in the fetus and the mother. There were 32 babies and parturients. The mean arterial cord blood elastase level was 294.8 +/- 129.15 ng/ml (median 304.25), while the mean plasma (venous) level in the adult normal controls was 35.66 +/- 14.1 ng/ml. The difference was highly significant at p < 0.0001 (Student's t test, two-tailed). The mean elastase level of the mothers was 143.45 +/- 109 ng/ml (median 115.25). This was significantly lower than the mean arterial cord blood elastase level (p < 0.0001) but higher than the mean elastase level in healthy adults (p < 0.0001). The mean cord blood and the mothers' white blood cell counts were 11.9 +/- 3.1 (median 11.8, range 6.3-18.7 x 10(9)/l) and 12.4 +/- 2.8 (median 12.4, range 7.3-17.1 x 10(9)/l) respectively. The difference was not statistically significant (p = 0.4). The WBC counts correlated significantly with the mothers' (r = 0.4, p = 0.03) and cord blood (r = 0.7, p < 0.0001) elastase levels. These results suggest that the raised arterial cord blood elastase levels during parturition may reflect the disturbance of fetal homeostasis during parturition.

Evaluation of Plasma Beta-2-microglobulin in Patients with the Nephrotic Syndrome.

In patients with the nephrotic syndrome, it is often desirable to assess the disease process, not only by proteinuria but also by indices of glomerular inflammatory process. We investigated the importance of beta-microglobulin (betaM) as a means of assessing renal function in patients with the nephrotic syndrome with normal or abnormal values of creatinine clearance. There were 46 patients (mean age, 42.2 + 10.4 years; male/female (M/F) ratio = 31/15) and 35 healthy controls (mean age 39 + 4.5 years, M/F ratio 25/10). We subdivided the study patients into group A (n = 18, mean age 39.6 + 10.6 years, M/F ratio 8/10) and group B patients (n = 28, mean age 45.6 + 8.9 years, M/F ratio 23/5) who had normal and abnormal values of creatinine clearance respectively. An enzyme-linked-immunosorbent assay (ELISA) was used to quantitate plasma beta2M in the study patients and controls. The median 132M levels of the study patients and controls were 44.0 and 1.7 mg/l respectively (p < 0.0001). Beta-2-M levels correlated significantly with serum creatinine (r = 0.56, p < 0.0001), and creatinine clearance (r = -0.6, p < 0.0001). In group A patients, the median beta2M level was significantly higher than normal (4.1 vs. 1.7 mg/1, p < 0.01). Plasma beta2M levels did not correlate well with any other parameter measured in group A patients. When groups A and B were compared, the median plasma beta2M level in group B was significantly higher than group A (20.3 vs. 4.1 mg/1, p < 0.0001). The urinary beta2M (expressed per mg urine creatinine) was also higher in group B than group A patients (6.8 vs. 0.7 p < 0.05). We conclude that elevation of beta2M-microglobulin in patients with the nephrotic syndrome who have normal creatinine clearance suggests early abnormal renal function in these patients. It may be used to assess the rate of normalisation of renal function or progression to chronic renal failure.

Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a gulf population.

To date, the human angiotensinogen (AGT) gene and some of its variants represent the best examples of genetic influences that are involved in the determination of essential hypertension (EH) and associated cardiovascular diseases (CVDs). To assess the value of genotyping AGT in a genetically homogeneous population, we carried out a retrospective, case control study of variants M235T and T174M for putative correlations with CVDs among nationals from the United Arab Emirates (Emirati)--an ethnic group characterized by no alcohol intake and no cigarette smoking. We investigated a sample population of 229 Emirati (119 males and 110 females), comprising groups of controls and patients with clinical diagnoses of EH, left ventricular hypertrophy (LVH), ischaemic heart disease (IHD) and myocardial infarction (MI). M235T and T174M alleles were determined via assays based on the polymerase chain reaction. T174M showed no correlation with any of the four clinical entities included in this study. T235 alleles, however, occurred more frequently in the EH group and less frequently in the group of MI survivors. We also found that T235 allele frequencies decreased with age, indicating that in the Emirati population, T235 alleles are associated with a reduced life span and that this effect could occur through independent mechanisms underlying genetic susceptibilities to both EH and MI.