Louise Maranda

Use of high-flow nasal cannula support in the emergency department reduces the need for intubation in pediatric acute respiratory insufficiency

Objectives The objective of this study was to determine whether the use of heated, humidified, high-flow nasal cannula (HFNC) therapy is associated with a decreased need for intubation in patients presenting to a pediatric emergency department (PED) and admitted to a pediatric intensive care unit (PICU) with acute respiratory insufficiency (ARI). Methods A retrospective study of all patients admitted from the PED to the PICU with ARI from January 2006 through December 2009. Patients admitted before the availability of HFNC (cohort 1) were compared with those admitted after the availability of HFNC but before implementation of an institution-wide guideline on pediatric HFNC usage (cohort 2) and those admitted after the implementation of a pediatric HFNC usage guideline (cohort 3). Results After controlling for age, month of admission, type of respiratory illness, and severity of illness, there was an 83% reduction in the odds of intubation in the PED in cohort 3 compared with cohort 1 (odds ratio, 0.17; 95% confidence interval, 0.06-0.50; P = 0.001). There was no significant change in mortality or median PICU length of stay after the introduction of HFNC. Conclusions High-flow nasal cannula used early in the development of pediatric ARI is associated with a decreased the need for intubation and mechanical ventilation.

The Vitamin D Status in Inflammatory Bowel Disease

Context There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD). Aim To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls. Hypothesis Serum 25(OH)D concentration will be lower in patients with IBD compared to controls. Subjects and Methods A case-controlled retrospective study of subjects with IBD (n = 58) of 2–20 years (male n = 31, age 16.38±2.21 years; female n = 27, age16.56±2.08 years) and healthy controls (n = 116; male n = 49, age 13.90±4.59 years; female n = 67, age 15.04±4.12years). Study subject inclusion criteria: diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC). Vitamin D deficiency was defined as 25(OH)D of (<20 ng/mL) (<50 nmol/L), overweight as BMI of ≥85th but <95th percentile, and obesity as BMI ≥95th percentile. Data were expressed as mean ± SD. Results Patients with CD, UC, and their controls had mean serum 25(OH)D concentrations of 61.69±24.43 nmol/L, 53.26±25.51, and 65.32±27.97 respectively (ANOVA, p = 0.196). The overweight/obese controls had significantly lower 25(OH)D concentration compared to the normal-weight controls (p = 0.031); whereas 25(OH)D concentration was similar between the normal-weight and overweight/obese IBD patients (p = 0.883). There was no difference in 25(OH)D between patients with UC and CD, or between subjects with active IBD and controls. However, IBD subjects with elevated ESR had significantly lower 25(OH)D than IBD subjects with normal ESR (p = 0.025), as well as controls (65.3±28.0 nmol/L vs. 49.5±25.23, p = 0.045). Conclusion There is no difference in mean serum 25(OH)D concentration between children and adolescents with IBD and controls. However, IBD subjects with elevated ESR have significantly lower 25(OH)D than controls. Therefore, IBD subjects with elevated ESR should be monitored for vitamin D deficiency.

Comprehensive Identification of Host Modulators of HIV-1 Replication using Multiple Orthologous RNAi Reagents

SUMMARY RNAi screens have implicated hundreds of host proteins as HIV-1 dependency factors (HDFs). While informative, these early studies overlap poorly due to false positives and false negatives. To ameliorate these issues, we combined information from the existing HDF screens together with new screens performed with multiple orthologous RNAi reagents (MORR). In addition to being traditionally validated, the MORR screens and the historical HDF screens were quantitatively integrated by the adaptation of an established analysis program, RIGER, for the collective interpretation of each gene’s phenotypic significance. False positives were addressed by the removal of poorly expressed candidates through gene expression filtering, as well as with GESS, which identifies off-target effects. This workflow produced a quantitatively integrated network of genes that modulate HIV-1 replication. We further investigated the roles of GOLGI49, SEC13, and COG in HIV-1 replication. Collectively, the MORR-RIGER method minimized the caveats of RNAi screening and improved our understanding of HIV-1–host cell interactions.

Serum 25-hydroxyvitamin D levels do not correlate with asthma severity in a case-controlled study of children and adolescents.

Abstract Background: There is no consensus on the association between vitamin D and asthma. Objective: To determine the relationship between 25-hydroxyvitamin D [25(OH)D] levels and asthma symptom severity in children and adolescents. Methods: A retrospective, case-control study of 263 subjects of ages 2–19 years with asthma who were compared to 284 non-asthmatic controls of similar ages. Subjects were excluded if they had diseases of calcium or vitamin D metabolism or were receiving calcium or vitamin D supplementation. Serum 25(OH)D was measured in all subjects. Asthma symptom severity, usually stratified into 6 steps, was stratified into five steps [1–5] based on the number and dose of controller medications used as outlined by the National Heart, Lung, and Blood Institute’s guidelines. Mean 25(OH)D values were compared between the asthmatic patients and controls, as well as among the five steps of asthma symptom severity. Results were adjusted for age, sex, BMI, race and severity of asthma symptoms. Results: There was no difference in 25(OH)D between asthmatic patients and controls (28.64±10.09 vs. 28.42±11.47, p=1.0). However, there was a significant difference in 25(OH)D between obese and non-obese asthmatic patients (23.33±7.67 vs. 30.16±10.20, p<0.0001), as well as obese and non-obese controls (24.56±9.90 vs. 29.50±11.66, p=0.003). Mean 25(OH)D levels did not vary significantly among the five steps of asthma symptom severity. Conclusions: There were no differences in mean 25(OH)D levels between asthmatic patients and controls. Mean 25(OH)D level was significantly lower in both the obese asthmatic patients and obese controls. Asthma severity had no relationship to mean 25(OH)D levels.

Prevalence of human papillomavirus genotypes among African women with normal cervical cytology and neoplasia: a systematic review and meta-analysis.

Background Several meta-analyses confirmed the five most prevalent human papillomavirus (HPV) strains in women with and without cervical neoplastic diseases are HPV16, 18, 31, 52, and 58. HPV16/18 are the predominant oncogenic genotypes, causing approximately 70% of global cervical cancer cases. The vast majority of the women studied in previous analyses were from Europe, North America, Asia, and most recently Latin America and the Caribbean. Despite the high burden of cervical cancer morbidity and mortality in Africa, a robust meta-analysis of HPV genotype prevalence and distribution in African women is lacking. Methods and Findings We systematically searched 14 major databases from inception to August 2013 without language restriction, following the Meta-Analysis of Observational Studies in Epidemiology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Seventy-one studies from 23 African countries were identified after screening 1162 citations and data abstracted and study quality appraised from 195 articles. HPV type-specific prevalence and distribution was estimated from 17,273 cases of women with normal cervical cytology; 1019 women with atypical squamous cells of undetermined significance (ASCUS); 1444 women with low-grade squamous intraepithelial lesion (LSIL); 1571 women with high-grade squamous intraepithelial lesion (HSIL); and 4,067 cases of invasive cervical carcinoma (ICC). Overall prevalence of HPV16/18 were 4.4% and 2.8% of women with normal cytology, 12.0% and 4.4% with ASCUS, 14.5% and 10.0% with LSIL, 31.2% and 13.9% with HSIL, and 49.7% and 18.0% with ICC, respectively. Study limitations include the lack of adequate data from Middle and Northern African regions, and variations in the HPV type-specific sensitivity of different genotyping protocols. Conclusions To our knowledge, this study is the most comprehensive assessment of the overall prevalence and distribution of HPV genotypes in African women with and without different cervical neoplasias. We have established that HPV16/18 account for 67.7% of ICC cases among African women. Based on our findings, we highly recommend the administration of existing prophylactic vaccines to younger women not infected with HPV16/18 and an increase in HPV screening efforts for high-risk genotypes to prevent cervical cancer. Review registration: International Prospective Register of Systematic Reviews CRD42013006558.

Questionnaire assessment of airway disease symptoms in equine barn personnel

BACKGROUND People working in cattle, swine and poultry barns have a higher prevalence of respiratory symptoms and decreased lung function. There is scant evidence regarding the respiratory health of humans working in horse barns, although it is well documented that stabled horses have a high prevalence of airway disease. AIMS To determine whether people spending time in horse barns have a higher prevalence of self-reported respiratory symptoms than non-exposed controls. METHODS A cross-sectional questionnaire study was conducted from May 2005 to January 2006 to investigate the prevalence of self-reported respiratory symptoms in 82 barn-exposed subjects and 74 control subjects. Logistic regression and the chi-square test were used to analyse the data. RESULTS There was a significantly higher prevalence of self-reported respiratory symptoms in the barn-exposed group (50%) versus the control group (15%). Exposure to horse barns, smoking and family history of asthma or allergies was independent risk factors for respiratory symptoms. High exposure to the horse barn yielded a higher odds ratio for self-reported respiratory symptoms (8.9). CONCLUSIONS Exposure to the equine barn is a risk factor for respiratory symptoms. Investigation of organic dust exposures, lung function and horse dander allergies in the barn-exposed group will be necessary to determine how best to protect the health of this group.

The effects of vitamin D supplementation on hepatic dysfunction, vitamin D status, and glycemic control in children and adolescents with vitamin D deficiency and either type 1 or type 2 diabetes mellitus.

Background The effects of vitamin D supplementation on mild hepatic dysfunction and glycemic control are unclear in children and adolescents with either type 1 (T1D) or type 2 diabetes (T2D). Hypothesis Vitamin D supplementation will improve hepatic dysfunction and glycemic control. Aim To determine the effect of vitamin D supplementation on alanine transaminase (ALT), hemoglobin A1c (HbA1c), and serum 25-hydroxyvitamin D [25(OH)D] concentration. Subjects and Methods A retrospective study of 131 subjects with either T1D (n = 88∶46 females, 42 males), or T2D (n = 43∶26 females, 17 males) of ages 3–18 years between 2007–2013. All subjects had (1) a diagnosis of diabetes for >12 mo, (2) received vitamin D supplementation for the management of vitamin D deficiency (3) had baseline and subsequent simultaneous measurements of HbA1c, ALT, and 25(OH)D. Vitamin D deficiency was defined as 25(OH)D concentration of <50 nmol/L (20 ng/mL). Results At baseline, vitamin D deficiency occurred in 72.1% of patients with T2D and in 37.5% of T1D patients (p<0.001). Patients with T2D had significantly higher values for BMI SDS (p<0.001), alanine transaminase (ALT) (p = 0.001), but lower 25(OH)D (p<0.001), and no difference in HbA1c (p = 0.94), and total daily dose (TDD) of insulin per kg body weight (p = 0.48) as compared to T1D patients. After 3 months of vitamin D supplementation, there was a significant increase in 25(OH)D in both T2D (p = 0.015), and T1D patients (p<0.001); significant reduction in BMI SDS (p = 0.015) and ALT (p = 0.012) in T2D, but not in T1D. There was a clinically-significant decrease in HbA1c in T2D from 8.5±2.9% at baseline to 7.7±2.5 at 3 mo, but not in T1D, 8.5±1.2 to 8.53±1.1%. Conclusions Vitamin D supplementation in subjects with T2D was associated with statistically significant decreases in BMI SDS, ALT, and a clinically-significant decrease in HbA1c.

A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes.

Context Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear. Objective To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D. Hypothesis Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D. Design, Setting, and Participants A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage. Results Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups. Conclusions This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group. Trial Registration ClinicalTrial.gov NCT01334125

Hepatic dysfunction is associated with vitamin D deficiency and poor glycemic control in diabetes mellitus.

Abstract Background/Aims: The effect of the rising prevalence of nonalcoholic fatty liver disease on the 25-hydroxylation of pre-vitamin D in the liver, and consequent glycemic control in children with diabetes mellitus is not known. Our aim was to determine whether mild hepatic dysfunction was associated with impaired 25-hydroxylation of pre-vitamin D, and if this vitamin D deficiency was associated with impaired glycemic control in children and adolescents with type 1 diabetes (TIDM) and type 2 diabetes (T2DM). Methods: We analyzed simultaneously measured HbA1c, ALT, AST, and 25OHD levels and clinical parameters in 121 children and adolescents with T1DM (n=81) and T2DM (n=40). The subjects, ages 11–21 years, all had diabetes of >6 months duration. Multivariate linear regression was used to analyze the associations, while comparisons between subgroups were made using two-tailed Student’s t-test. Results: Vitamin D deficiency (25OHD <15 ng/mL (37.5 nmol/L) was more prevalent in T2DM patients (47.5%) compared to T1DM patients (18.5%). Subjects with T2DM had significantly elevated transaminases (AST 39.3±2.0 vs. 22.4±1.4, p<0.001; ALT 30.6±1.8 vs. 18.7±1.3, p<0.001) compared to T1DM patients, and demonstrated a significant inverse relationship between their HbA1c and 25OHD levels (β=–0.42, p=0.02), compared to T1DM subjects (β=–0.06, p=0.62). Conclusions: The association of elevated ALT with vitamin D deficiency suggests that hepatic dysfunction could impair vitamin D metabolism and negatively impact glycemic control in youth with T2DM.

The nondietary determinants of vitamin D status in pediatric inflammatory bowel disease

OBJECTIVES The aim of this study was to investigate the relationships between 25-hydroxy vitamin D (25[OH]D) and markers of vitamin D status in inflammatory bowel disease (IBD). METHODS We conducted a retrospective case-control study of 59 pediatric patients with IBD (age 16.4 ± 2.2 y) and 116 controls (age 14.6 ± 4.4 y), to investigate the association between 25(OH)D and albuminemia for protein-losing enteropathy (PLE) and hepatic dysfunction; alanine transaminase (ALT) for hepatic inflammation; erythrocyte sedimentation rate (ESR) for intestinal inflammation; body mass index (BMI) for adiposity; seasons and skin pigmentation for insolation. Vitamin D deficiency was defined as 25(OH)D < 50 nmol/L; abnormal liver enzyme by ALT >40 U/L; overweight status by BMI of ≥85th but <95th percentile, and obesity by BMI ≥95th percentile. Seasons were categorized as summer, winter, spring, and fall. RESULTS Patients with IBD had a higher prevalence of vitamin D deficiency (42.4% versus 26.7%; P = 0.04), elevated ALT (16.9% versus 2.6%; P < 0.001), and lower albumin (41.1 ± 4.8 versus 45.1 ± 3.8; P < 0.001) than controls. In both the IBD cohort and controls, 25(OH)D was highest in summer and lowest in winter, and significantly higher in white than in non-white patients. ESR varied significantly with 25(OH)D (R(2) = 0.24; β = -0.32; P = 0.010), and only patients with IBD with elevated ESR had lower 25(OH)D than controls (49.5 ± 25.2 versus 65.3 ± 28.0 nmol/L; P = 0.045). CONCLUSION Intestinal inflammation, not the loss of albumin-bound vitamin D in the gut, is the primary intestinal determinant of vitamin D status in IBD. The extraintestinal determinants are seasons and skin pigmentation, but not adiposity and hepatic inflammation.