Tracking Down Antibiotic-Resistant Pseudomonas aeruginosa Isolates in a Wastewater Network

The Pseudomonas aeruginosa-containing wastewater released by hospitals is treated by wastewater treatment plants (WWTPs), generating sludge, which is used as a fertilizer, and effluent, which is discharged into rivers. We evaluated the risk of dissemination of antibiotic-resistant P. aeruginosa (AR-PA) from the hospital to the environment via the wastewater network. Over a 10-week period, we sampled weekly 11 points (hospital and urban wastewater, untreated and treated water, sludge) of the wastewater network and the river upstream and downstream of the WWTP of a city in eastern France. We quantified the P. aeruginosa load by colony counting. We determined the susceptibility to 16 antibiotics of 225 isolates, which we sorted into three categories (wild-type, antibiotic-resistant and multidrug-resistant). Extended-spectrum β-lactamases (ESBLs) and metallo-β-lactamases (MBLs) were identified by gene sequencing. All non-wild-type isolates (n = 56) and a similar number of wild-type isolates (n = 54) were genotyped by pulsed-field gel electrophoresis and multilocus sequence typing. Almost all the samples (105/110, 95.5%) contained P. aeruginosa, with high loads in hospital wastewater and sludge (≥3×10⁶ CFU/l or/kg). Most of the multidrug-resistant isolates belonged to ST235, CC111 and ST395. They were found in hospital wastewater and some produced ESBLs such as PER-1 and MBLs such as IMP-29. The WWTP greatly reduced P. aeruginosa counts in effluent, but the P. aeruginosa load in the river was nonetheless higher downstream than upstream from the WWTP. We conclude that the antibiotic-resistant P. aeruginosa released by hospitals is found in the water downstream from the WWTP and in sludge, constituting a potential risk of environmental contamination.     

Impact of Vitamin D Supplementation during Lactation on Vitamin D Status and Body Composition of Mother-Infant Pairs: A MAVID Randomized Controlled Trial

Objective

The optimal vitamin D intake for nursing women is controversial. Deterioration, at least in bone mass, is reported during lactation. This study evaluated whether vitamin D supplementation during lactation enhances the maternal and infant’s vitamin D status, bone mass and body composition.

Design and Methods

After term delivery, 174 healthy mothers were randomized to receive 1200 IU/d (800 IU/d+400 IU/d from multivitamins) or 400 IU/d (placebo+400 IU/d from multivitamins) of cholecalciferol for 6 months while breastfeeding. All infants received 400 IU/d of cholecalciferol. Serum 25-hydroxyvitamin D [25(OH)D], iPTH, calcium, urinary calcium, and densitometry were performed in mother-offspring pairs after delivery, and at 3 and 6 months later.

Results

A total of 137 (79%) (n = 70; 1200 IU/d, n = 67; 400 IU/d) completed the study. 25(OH)D was similar in both groups at baseline (13.7 ng/ml vs. 16.1 ng/ml; P = 0.09) and at 3 months (25.7 ng/ml vs. 24.5 ng/ml; P = 0.09), but appeared higher in the 1200 IU/d group at 6 months of supplementation (25.6 ng/ml vs. 23.1 ng/ml; P = 0.009). The prevalence of 25(OH)D <20 ng/ml was comparable between groups at baseline (71% vs. 64%, P = 0.36) but lower in the 1200 IU/d group after 3 months (9% vs. 25%, P = 0.009) and 6 months (14% vs. 30%, P = 0.03). Maternal and infants’ iPTH, calciuria, bone mass and body composition as well as infants’ 25(OH)D levels were not significantly different between groups during the study. Significant negative correlations were noted between maternal 25(OH)D and fat mass (R = −0.49, P = 0.00001), android fat mass (R = −0.53, P = 0.00001), and gynoid fat mass (R = −0.43, P = 0.00001) after 6 months of supplementation.

Conclusions

Vitamin D supplementation at a dose of 400 IU/d was not sufficient to maintain 25(OH)D >20 ng/ml in nursing women, while 1200 IU/d appeared more effective, but had no effect on breastfed offspring vitamin D status, or changes in the bone mass and the body composition observed in both during breastfeeding.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01506557","term_id":"NCT01506557"}}NCT01506557     

Evaluating the Association between p53 Codon 72 Arg>Pro Polymorphism and Risk of Ovary Cancer: A Meta-Analysis

Aim

Allelic polymorphism in codon 72 of the p53 tumor suppressor gene causes imbalance of p53 protein expression. Earlier studies have shown association between allelic polymorphism in codon 72 of the p53 gene with risk of ovary cancer (OC); however the results are inconclusive and conflicting. Therefore, we performed this meta-analysis to investigate the relation between p53 codon 72 Arg>Pro polymorphism and overall OC susceptibility.

Methods

We searched all eligible published studies based on the association between codon 72 of the p53 Arg>Pro polymorphism and risk of OC. Data were pooled together from individual studies and meta-analysis was performed. Pooled odds ratios (ORs) and 95% CI were calculated for allele contrast, homozygous, heterozygous, dominant and recessive genetic models.

Results

A total of twelve studies comprising of 993 OC cases and 1264 healthy controls were included in this meta-analysis. Overall, no significant association was detected for Pro allele carrier (Pro vs. Arg: p = 0.916; OR = 0.980, 95% CI = 0.677 to 1.419), homozygous (Pro/Pro vs. Arg/Arg: p = 0.419; OR = 0.731, 95% CI = 0.341 to 1.564), heterozygous (Arg/Pro vs. Arg/Arg: p = 0.248; OR = 1.237, 95% CI = 0.862 to 1.773), dominant (Pro/Pro+Arg/Pro vsArg/Arg: p = 0.699; OR = 1.089, 95% CI = 0.706 to 1.681), and recessive (Pro/Pro vs Arg/Arg+Arg/Pro: p = 0.329; OR = 0.754, 95% CI = 0.428 to 1.329) genetic models, respectively. Also, in the stratified analysis by ethnicity, no significant association of this polymorphism with risk of OC was found in the Caucasian population.

Conclusions

This meta-analysis suggested that codon 72 of the p53 Arg>Pro polymorphism may not significantly contribute in ovary cancer susceptibility. However, future large studies with gene-gene and gene-environment interactions are needed to validate these findings.     

Meta-Analysis of the Reduction of Norovirus and Male-Specific Coliphage Concentrations in Wastewater Treatment Plants

Human norovirus (NoV) is the leading cause of foodborne illness in the United States and Canada. Wastewater treatment plant (WWTP) effluents impacting bivalve mollusk-growing areas are potential sources of NoV contamination. We have developed a meta-analysis that evaluates WWTP influent concentrations and log₁₀ reductions of NoV genotype I (NoV GI; in numbers of genome copies per liter [gc/liter]), NoV genotype II (NoV GII; in gc/liter), and male-specific coliphage (MSC; in number of PFU per liter), a proposed viral surrogate for NoV. The meta-analysis included relevant data (2,943 measurements) reported in the scientific literature through September 2013 and previously unpublished surveillance data from the United States and Canada. Model results indicated that the mean WWTP influent concentration of NoV GII (3.9 log₁₀ gc/liter; 95% credible interval [CI], 3.5, 4.3 log₁₀ gc/liter) is larger than the value for NoV GI (1.5 log₁₀ gc/liter; 95% CI, 0.4, 2.4 log₁₀ gc/liter), with large variations occurring from one WWTP to another. For WWTPs with mechanical systems and chlorine disinfection, mean log₁₀ reductions were −2.4 log₁₀ gc/liter (95% CI, −3.9, −1.1 log₁₀ gc/liter) for NoV GI, −2.7 log₁₀ gc/liter (95% CI, −3.6, −1.9 log₁₀ gc/liter) for NoV GII, and −2.9 log₁₀ PFU per liter (95% CI, −3.4, −2.4 log₁₀ PFU per liter) for MSCs. Comparable values for WWTPs with lagoon systems and chlorine disinfection were −1.4 log₁₀ gc/liter (95% CI, −3.3, 0.5 log₁₀ gc/liter) for NoV GI, −1.7 log₁₀ gc/liter (95% CI, −3.1, −0.3 log₁₀ gc/liter) for NoV GII, and −3.6 log₁₀ PFU per liter (95% CI, −4.8, −2.4 PFU per liter) for MSCs. Within WWTPs, correlations exist between mean NoV GI and NoV GII influent concentrations and between the mean log₁₀ reduction in NoV GII and the mean log₁₀ reduction in MSCs.     

Relationship of Circulating Hyaluronic Acid Levels to Disease Control in Asthma and Asthmatic Pregnancy

Uncontrolled asthma is a risk factor for pregnancy-related complications. Hyaluronic acid (HA), a potential peripheral blood marker of tissue fibrosis in various diseases, promotes eosinophil survival and plays a role in asthmatic airway inflammation as well as in physiological processes necessary to maintain normal pregnancy; however the level of circulating HA in asthma and asthmatic pregnancy is unknown. We investigated HA levels in asthmatic patients (N = 52; asthmatic pregnant (AP) N = 16; asthmatic non-pregnant (ANP) N = 36) and tested their relationship to asthma control. Serum HA level was lower in AP than in ANP patients (27 [24.7–31.55] vs. 37.4 [30.1–66.55] ng/mL, p = 0.006); the difference attenuated to a trend after its adjustment for patients’ age (p = 0.056). HA levels and airway resistance were positively (r = 0.467, p = 0.004), HA levels and Asthma Control Test (ACT) total score inversely (r = −0.437, p = 0.01) associated in ANP patients; these relationships remained significant even after their adjustments for age. The potential value of HA in the determination of asthma control was analyzed using ROC analysis which revealed that HA values discriminate patients with ACT total score ≥20 (controlled patients) and <20 (uncontrolled patients) with a 0.826 efficacy (AUC, 95% CI: 0.69–0.97, p = 0.001) when 37.4 ng/mL is used as cut-off value in ANP group, and with 0.78 efficacy (AUC, 95% CI: 0.65–0.92, p = 0.0009) in the whole asthmatic cohort. In conclusion circulating HA might be a marker of asthma control, as it correlates with airway resistance and has good sensitivity in the detection of impaired asthma control. Decrease of HA level in pregnancy may be the consequence of pregnancy induced immune tolerance.     

Vitamin D Levels and Monospot Tests in Military Personnel with Acute Pharyngitis: A Retrospective Chart Review

Some recent studies have proposed an important role for vitamin D in reducing the risk of infection by assisting in the suppression of viruses and by controlling the inflammatory response. A low vitamin D state may have a detrimental effect on the immune system’s ability to produce activated CD8+ T cells, and it may increase the inflammatory reaction to Epstein Barr virus. The aim of this chart review was to see if serum 25 OH vitamin D₃ levels in service members with acute pharyngitis were lower in those who had positive rather than negative monospot tests. A retrospective chart review was conducted on the medical records of service members who presented to sick call at Camp Lejeune, NC with acute pharyngitis from October 8, 2010 until June 30, 2011. Serum 25 OH vitamin D₃ levels were compared between those with positive and negative monospot test results. Of the 25 records that were reviewed, there were 9 (36%) service members with positive results, and they were found to have lower vitamin D levels (Median = 20.80 ng/ml, Interquartile range = 10.15) than those with negative test results (Median = 30.35 ng/ml, Interquartile range = 17.05), Mann-Whitney U = 41, p = .039. Only 1 of the 9 with positive test results had a normal serum 25 OH vitamin D₃ level (30 ng/ml or greater) compared with 9 of the 16 with negative test results. Optimal vitamin D stores may play a significant role in reducing the risk of developing acute mononucleosis but larger, prospective studies will be needed to verify these findings.     

Characterization of Respiratory and Cardiac Motion from Electro-Anatomical Mapping Data for Improved Fusion of MRI to Left Ventricular Electrograms

Accurate fusion of late gadolinium enhancement magnetic resonance imaging (MRI) and electro-anatomical voltage mapping (EAM) is required to evaluate the potential of MRI to identify the substrate of ventricular tachycardia. However, both datasets are not acquired at the same cardiac phase and EAM data is corrupted with respiratory motion limiting the accuracy of current rigid fusion techniques. Knowledge of cardiac and respiratory motion during EAM is thus required to enhance the fusion process. In this study, we propose a novel approach to characterize both cardiac and respiratory motion from EAM data using the temporal evolution of the 3D catheter location recorded from clinical EAM systems. Cardiac and respiratory motion components are extracted from the recorded catheter location using multi-band filters. Filters are calibrated for each EAM point using estimates of heart rate and respiratory rate. The method was first evaluated in numerical simulations using 3D models of cardiac and respiratory motions of the heart generated from real time MRI data acquired in 5 healthy subjects. An accuracy of 0.6–0.7 mm was found for both cardiac and respiratory motion estimates in numerical simulations. Cardiac and respiratory motions were then characterized in 27 patients who underwent LV mapping for treatment of ventricular tachycardia. Mean maximum amplitude of cardiac and respiratory motion was 10.2±2.7 mm (min = 5.5, max = 16.9) and 8.8±2.3 mm (min = 4.3, max = 14.8), respectively. 3D Cardiac and respiratory motions could be estimated from the recorded catheter location and the method does not rely on additional imaging modality such as X-ray fluoroscopy and can be used in conventional electrophysiology laboratory setting.     

N-Terminal Pro-Brain Natriuretic Peptide Is a Useful Prognostic Marker in Patients with Pre-Capillary Pulmonary Hypertension and Renal Insufficiency

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a routinely used prognostic parameter in patients with pre-capillary pulmonary hypertension (PH). As it accumulates in the presence of impaired renal function, the clinical utility of NT-proBNP in PH patients with concomitant renal insufficiency remains unclear. In a retrospective approach, patients with pre-capillary PH (group I or IV) and concomitant renal insufficiency at time of right heart catheterization (glomerular filtration rate (GFR) ≤60 ml/min/1.73 m²) were identified out of all prevalent pre-capillary PH patients treated at a single center. Forty patients with renal insufficiency (25.8%) were identified and matched regarding hemodynamic parameters with a control group of 56 PH patients with normal renal function (GFR >60 ml/min/1.73 m²). Correlations of NT-proBNP levels with hemodynamic and prognostic parameters (time to clinical worsening and overall survival) were assessed. Overall, GFR correlated inversely with NT-proBNP and had the strongest influence on NT-proBNP levels in a stepwise multiple linear regression model including hemodynamic parameters and age (r² = 0.167). PH patients with renal insufficiency had significant higher levels of NT-proBNP (median: 1935 ng/l vs. 573 ng/l, p = 0.001). Nevertheless, NT-proBNP correlated with invasive hemodynamic parameters in these patients. Using higher cut-off values than in patients with preserved renal function, NT-proBNP levels were significantly associated with time to clinical worsening (>1660 ng/l, p = 0.001) and survival (>2212 ng/l, p = 0.047) in patients with renal insufficiency. Multivariate Cox’s proportional hazards analysis including established prognostic parameters, age and GFR confirmed NT-proBNP as an independent risk factor for clinical worsening in PH patients with renal insufficiency (hazard ratio 4.8, p = 0.007). Thus, in a retrospective analysis we showed that NT-proBNP levels correlated with hemodynamic parameters and outcome regardless of renal function. By using higher cut-off values, NT-proBNP seems to represent a valid clinical marker even in PH patients with renal insufficiency.     

Communicating Risk to Aboriginal Peoples: First Nations and Metis Responses to H1N1 Risk Messages

Developing appropriate risk messages during challenging situations like public health outbreaks is complicated. The focus of this paper is on how First Nations and Metis people in Manitoba, Canada, responded to the public health management of pandemic H1N1, using a focus group methodology (n = 23 focus groups). Focus group conversations explored participant reactions to messaging regarding the identification of H1N1 virus risk groups, the H1N1 vaccine and how priority groups to receive the vaccine were established. To better contextualize the intentions of public health professionals, key informant interviews (n = 20) were conducted with different health decision makers (e.g., public health officials, people responsible for communications, representatives from some First Nations and Metis self-governing organizations). While risk communication practice has improved, ‘one size’ messaging campaigns do not work effectively, particularly when communicating about who is most ‘at-risk’. Public health agencies need to pay more attention to the specific socio-economic, historical and cultural contexts of First Nations and Metis citizens when planning for, communicating and managing responses associated with pandemic outbreaks to better tailor both the messages and delivery. More attention is needed to directly engage First Nations and Metis communities in the development and dissemination of risk messaging.     

A Randomized Controlled Trial of the Efficacy and Safety of CCX282-B,an Orally-Administered Blocker of Chemokine Receptor CCR9, for Patients with Crohn’s Disease

CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn’s disease. Crohn’s Disease Activity Index (CDAI) scores were 250–450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn’s medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn’s disease.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00306215","term_id":"NCT00306215"}}NCT00306215.     

Resistance Mutation R292K Is Induced in Influenza A(H6N2) Virus by Exposure of Infected Mallards to Low Levels of Oseltamivir

Resistance to neuraminidase inhibitors (NAIs) is problematic as these drugs constitute the major treatment option for severe influenza. Extensive use of the NAI oseltamivir (Tamiflu®) results in up to 865 ng/L of its active metabolite oseltamivir carboxylate (OC) in river water. There one of the natural reservoirs of influenza A, dabbling ducks, can be exposed. We previously demonstrated that an influenza A(H1N1) virus in mallards (Anas platyrhynchos) exposed to 1 µg/L of OC developed oseltamivir resistance through the mutation H274Y (N2-numbering). In this study, we assessed the resistance development in an A(H6N2) virus, which belongs to the phylogenetic N2 group of neuraminidases with distinct functional and resistance characteristics. Mallards were infected with A(H6N2) while exposed to 120 ng/L, 1.2 µg/L or 12 µg/L of OC in their sole water source. After 4 days with 12 µg/L of OC exposure, the resistance mutation R292K emerged and then persisted. Drug sensitivity was decreased ≈13,000-fold for OC and ≈7.8-fold for zanamivir. Viral shedding was similar when comparing R292K and wild-type virus indicating sustained replication and transmission. Reduced neuraminidase activity and decrease in recovered virus after propagation in embryonated hen eggs was observed in R292K viruses. The initial, but not the later R292K isolates reverted to wild-type during egg-propagation, suggesting a stabilization of the mutation, possibly through additional mutations in the neuraminidase (D113N or D141N) or hemagglutinin (E216K). Our results indicate a risk for OC resistance development also in a N2 group influenza virus and that exposure to one NAI can result in a decreased sensitivity to other NAIs as well. If established in influenza viruses circulating among wild birds, the resistance could spread to humans via re-assortment or direct transmission. This could potentially cause an oseltamivir-resistant pandemic; a serious health concern as preparedness plans rely heavily on oseltamivir before vaccines can be mass-produced.     

Characterization of DNA Binding Property of the HIV-1 Host Factor and Tumor Suppressor Protein Integrase Interactor 1 (INI1/hSNF5)

Integrase Interactor 1 (INI1/hSNF5) is a component of the hSWI/SNF chromatin remodeling complex. The INI1 gene is either deleted or mutated in rhabdoid cancers like ATRT (Atypical terratoid and rhabdoid tumor). INI1 is also a host factor for HIV-1 replication. INI1 binds DNA non-specifically. However, the mechanism of DNA binding and its biological role are unknown. From agarose gel retardation assay (AGRA), Ni-NTA pull-down and atomic force microscopy (AFM) studies we show that amino acids 105–183 of INI1 comprise the minimal DNA binding domain (DBD). The INI1 DBD is absent in plants and in yeast SNF5. It is present in Caenorhabditis elegans SNF5, Drosophila melanogaster homologue SNR1 and is a highly conserved domain in vertebrates. The DNA binding property of this domain in SNR1, that is only 58% identical to INI1/hSNF5, is conserved. Analytical ultracentrifugation studies of INI1 DBD and INI1 DBD:DNA complexes at different concentrations show that the DBD exists as a monomer at low protein concentration and two molecules of monomer binds one molecule of DNA. At high protein concentration, it exists as a dimer and binds two DNA molecules. Furthermore, isothermal calorimetry (ITC) experiments demonstrate that the DBD monomer binds DNA with a stoichiometry (N) of ∼0.5 and K_d  = 0.94 µM whereas the DBD dimer binds two DNA molecules sequentially with K’_d1 = 222 µM and K’_d2 = 1.16 µM. Monomeric DBD binding to DNA is enthalpy driven (ΔH = –29.9 KJ/mole). Dimeric DBD binding to DNA is sequential with the first binding event driven by positive entropy (ΔH’₁ = 115.7 KJ/mole, TΔS’₁ = 136.8 KJ/mole) and the second binding event driven by negative enthalpy (ΔH’₂ = –106.3 KJ/mole, TΔS’₂ = –75.7 KJ/mole). Our model for INI1 DBD binding to DNA provides new insights into the mechanism of DNA binding by INI1.     

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) III: Endogenous Inhibition of Angiotensin Converting Enzyme (ACE) Provides Protection against Cardiovascular Diseases

ACE inhibitor drugs decrease mortality by up to one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors. Here we investigated the clinical significance of this potential endogenous ACE inhibition.ACE concentration and activity was measured in patient''s serum samples (n = 151). ACE concentration was found to be in a wide range (47–288 ng/mL). ACE activity decreased with the increasing concentration of the serum albumin (HSA): ACE activity was 56±1 U/L in the presence of 2.4±0.3 mg/mL HSA, compared to 39±1 U/L in the presence of 12±1 mg/mL HSA (values are mean±SEM). Effects of the differences in ACE concentration were suppressed in human sera: patients with ACE DD genotype exhibited a 64% higher serum ACE concentration (range, 74–288 ng/mL, median, 155.2 ng/mL, n = 52) compared to patients with II genotype (range, 47–194 ng/mL, median, 94.5 ng/mL, n = 28) while the difference in ACE activities was only 32% (range, 27.3–59.8 U/L, median, 43.11 U/L, and range 15.6–55.4 U/L, median, 32.74 U/L, respectively) in the presence of 12±1 mg/mL HSA. No correlations were found between serum ACE concentration (or genotype) and cardiovascular diseases, in accordance with the proposed suppressed physiological ACE activities by HSA (concentration in the sera of these patients: 48.5±0.5 mg/mL) or other endogenous inhibitors.Main implications are that (1) physiological ACE activity can be stabilized at a low level by endogenous ACE inhibitors, such as HSA; (2) angiotensin II elimination may have a significant role in angiotensin II related pathologies.     

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 ≥85^th but <95^th percentile, and obesity as BMI ≥95^th 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.     

Association of Thymidylate Synthase Polymorphisms with Acute Pancreatitis and/or Peripheral Neuropathy in HIV-Infected Patients on Stavudine-Based Therapy

Background

Low expression thymidylate synthase (TS) polymorphism has been associated with increased stavudine triphosphate intracellular (d4T-TP) levels and the lipodystrophy syndrome. The use of d4T has been associated with acute pancreatitis and peripheral neuropathy. However, no relationship has ever been proved between TS polymorphisms and pancreatitis and/or peripheral neuropathy.

Methods

We performed a case-control study to assess the relationship of TS and methylene-tetrahydrofolate reductase (MTHFR) gene polymorphisms with acute pancreatitis and/or peripheral neuropathy in patients exposed to d4T. Student’s t test, Pearson’s correlations, one-way ANOVA with Bonferroni correction and stepwise logistic regression analyses were done.

Results

Forty-three cases and 129 controls were studied. Eight patients (18.6%) had acute pancreatitis, and 35 (81.4%) had peripheral neuropathy. Prior AIDS was more frequent in cases than in controls (OR = 2.36; 95%CI 1.10–5.07, P = 0.0247). L7ow expression TS and MTHFR genotype associated with increased activity were more frequent in patients with acute pancreatitis and/or peripheral neuropathy than in controls (72.1% vs. 46.5%, OR = 2.97; 95%CI: 1.33–6.90, P = 0.0062, and 79.1% vs. 56.6%, OR = 2.90, 95%CI: 1.23–7.41, P = 0.0142, respectively). Independent positive or negative predictors for the development of d4T-associated pancreatitis and/or peripheral neuropathy were: combined TS and MTHFR genotypes (reference: A+A; P = 0.002; OR_A+B = 0.34 [95%CI: 0.08 to 1.44], OR_B+A = 3.38 [95%CI: 1.33 to 8.57], OR_B+B = 1.13 [95%CI: 0.34 to 3.71]), nadir CD4 cell count >200 cells/mm³ (OR = 0.38; 95%CI: 0.17–0.86, P = 0.021), and HALS (OR = 0.39 95%CI: 0.18–0.85, P = 0.018).

Conclusions

Low expression TS plus a MTHFR genotype associated with increased activity is associated with the development of peripheral neuropathy in d4T-exposed patients.     

Pandemic pharmaceutical dosing effects on wastewater treatment: no adaptation of activated sludge bacteria to degrade the antiviral drug oseltamivir (Tamiflu®) and loss of nutrient removal performance

The 2009-2010 influenza pandemic saw many people treated with antivirals and antibiotics. High proportions of both classes of drugs are excreted and enter wastewater treatment plants (WWTPs) in biologically active forms. To date, there has been no study into the potential for influenza pandemic-scale pharmaceutical use to disrupt WWTP function. Furthermore, there is currently little indication as to whether WWTP microbial consortia can degrade antiviral neuraminidase inhibitors when exposed to pandemic-scale doses. In this study, we exposed an aerobic granular sludge sequencing batch reactor, operated for enhanced biological phosphorus removal (EBPR), to a simulated influenza-pandemic dosing of antibiotics and antivirals for 8 weeks. We monitored the removal of the active form of Tamiflu(?), oseltamivir carboxylate (OC), bacterial community structure, granule structure and changes in EBPR and nitrification performance. There was little removal of OC by sludge and no evidence that the activated sludge community adapted to degrade OC. There was evidence of changes to the bacterial community structure and disruption to EBPR and nitrification during and after high-OC dosing. This work highlights the potential for the antiviral contamination of receiving waters and indicates the risk of destabilizing WWTP microbial consortia as a result of high concentrations of bioactive pharmaceuticals during an influenza pandemic.     

Influenza Forecasting in Human Populations: A Scoping Review

Forecasts of influenza activity in human populations could help guide key preparedness tasks. We conducted a scoping review to characterize these methodological approaches and identify research gaps. Adapting the PRISMA methodology for systematic reviews, we searched PubMed, CINAHL, Project Euclid, and Cochrane Database of Systematic Reviews for publications in English since January 1, 2000 using the terms “influenza AND (forecast* OR predict*)”, excluding studies that did not validate forecasts against independent data or incorporate influenza-related surveillance data from the season or pandemic for which the forecasts were applied. We included 35 publications describing population-based (N = 27), medical facility-based (N = 4), and regional or global pandemic spread (N = 4) forecasts. They included areas of North America (N = 15), Europe (N = 14), and/or Asia-Pacific region (N = 4), or had global scope (N = 3). Forecasting models were statistical (N = 18) or epidemiological (N = 17). Five studies used data assimilation methods to update forecasts with new surveillance data. Models used virological (N = 14), syndromic (N = 13), meteorological (N = 6), internet search query (N = 4), and/or other surveillance data as inputs. Forecasting outcomes and validation metrics varied widely. Two studies compared distinct modeling approaches using common data, 2 assessed model calibration, and 1 systematically incorporated expert input. Of the 17 studies using epidemiological models, 8 included sensitivity analysis. This review suggests need for use of good practices in influenza forecasting (e.g., sensitivity analysis); direct comparisons of diverse approaches; assessment of model calibration; integration of subjective expert input; operational research in pilot, real-world applications; and improved mutual understanding among modelers and public health officials.     

Comparison and Relative Utility of Inequality Measurements: As Applied to Scotland’s Child Dental Health

This study compared and assessed the utility of tests of inequality on a series of very large population caries datasets. National cross-sectional caries datasets for Scotland’s 5-year-olds in 1993/94 (n = 5,078); 1995/96 (n = 6,240); 1997/98 (n = 6,584); 1999/00 (n = 6,781); 2002/03 (n = 9,747); 2003/04 (n = 10,956); 2005/06 (n = 10,945) and 2007/08 (n = 12,067) were obtained. Outcomes were based on the d₃mft metric (i.e. the number of decayed, missing and filled teeth). An area-based deprivation category (DepCat) measured the subjects’ socioeconomic status (SES). Simple absolute and relative inequality, Odds Ratios and the Significant Caries Index (SIC) as advocated by the World Health Organization were calculated. The measures of complex inequality applied to data were: the Slope Index of Inequality (absolute) and a variety of relative inequality tests i.e. Gini coefficient; Relative Index of Inequality; concentration curve; Koolman & Doorslaer’s transformed Concentration Index; Receiver Operator Curve and Population Attributable Risk (PAR). Additional tests used were plots of SIC deciles (SIC¹⁰) and a Scottish Caries Inequality Metric (SCIM¹⁰). Over the period, mean d₃mft improved from 3.1(95%CI 3.0–3.2) to 1.9(95%CI 1.8–1.9) and d₃mft = 0% from 41.1(95%CI 39.8–42.3) to 58.3(95%CI 57.8–59.7). Absolute simple and complex inequality decreased. Relative simple and complex inequality remained comparatively stable. Our results support the use of the SII and RII to measure complex absolute and relative SES inequalities alongside additional tests of complex relative inequality such as PAR and Koolman and Doorslaer’s transformed CI. The latter two have clear interpretations which may influence policy makers. Specialised dental metrics (i.e. SIC, SIC¹⁰ and SCIM¹⁰) permit the exploration of other important inequalities not determined by SES, and could be applied to many other types of disease where ranking of morbidity is possible e.g. obesity. More generally, the approaches described may be applied to study patterns of health inequality affecting worldwide populations.     

Reproductive and Exogenous Hormone Factors in Relation to Risk of Meningioma in Women: A Meta-Analysis

Background and Objective

A number of studies have focused on the association between oral contraceptive (OC), hormonal replacement therapy (HRT) and reproductive factors and meningioma risk, but the results were inconsistent. Thus, a meta-analysis was performed to obtain more precise estimates of risk.

Methods

We conducted a literature search using PubMed and EMBASE databases to July2013, without any limitations. Random effects models were used to summarize results.

Results

Twelve case-control and six cohort studies were included in this meta-analysis. We found that an increased risk of meningioma was associated with HRT use(RR = 1.19, 95% CI = 1.01–1.40), postmenopausal women(RR = 1.32, 95% CI = 1.07–1.64) and parity(RR = 1.18, 95% CI = 1.00–1.40).No significant associations were observed for OC use (RR = 0.93, 95% CI = 0.83–1.03), age at menarche(RR = 1.06, 95% CI = 0.92–1.21), age at menopause(RR = 1.03, 95% CI = 0.81–1.30), or age at first birth(RR = 0.94, 95% CI = 0.80–1.10).

Conclusion

In conclusion, the results of our study support the hypothesis that longer exposure to effect of female sex hormones may increase the risk of meningioma in women, yet additional studies are warranted to confirm our findings and identify the underlying biological mechanisms.