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1.  Antibiotic surveillance on a paediatric intensive care unit: easy attainable strategy at low costs and resources 
BMC Pediatrics  2012;12:196.
Antibiotic surveillance is mandatory to optimise antibiotic therapy. Our objectives were to evaluate antibiotic use in our pediatric intensive care unit (PICU) and to implement a simple achievable intervention aimed at improving antibiotic therapy.
Prospective, 3 months surveillance of antibiotic use on PICU (phase I) and evaluation according to the CDC 12-step campaign with development of an attainable intervention. 3 months surveillance (phase II) after implementation of intervention with comparison of antibiotic use.
Appropriate antibiotic use for culture-negative infection-like symptoms and targeted therapy for proven infections were the main areas for potential improvement. The intervention was a mandatory checklist requiring indication and recording likelihood of infection at start of antibiotic therapy and a review of the continuing need for therapy at 48 h and 5 days, reasons for continuation and possible target pathogen. The percentage of appropriate empiric antibiotic therapy courses for culture-negative infection-like symptoms increased from 18% (10/53) to 74% (42/57; p<0.0001), duration of therapy <3 days increased from 18% (10/53) to 35% (20/57; p=0.05) and correct targeting of pathogen increased from 58% (7/12) to 83% (20/24; p=0.21).
Antibiotic surveillance using the CDC 12-step campaign can help to evaluate institutional antibiotic therapy. Development of an attainable intervention using a checklist can show improved antibiotic use with minimal expense.
PMCID: PMC3534515  PMID: 23259701
Antibiotic surveillance; Paediatric intensive care unit; CDC 12-Step Campaign; Checklist; antimicrobial stewardship program
2.  Relationship between Serum Vitamin D, Disease Severity, and Airway Remodeling in Children with Asthma 
Little is known about vitamin D status and its effect on asthma pathophysiology in children with severe, therapy-resistant asthma (STRA).
Relationships between serum vitamin D, lung function, and pathology were investigated in pediatric STRA.
Serum 25-hydroxyvitamin D [25(OH)D3] was measured in 86 children (mean age, 11.7 yr): 36 with STRA, 26 with moderate asthma (MA), and 24 without asthma (control subjects). Relationships between 25(OH)D3, the asthma control test (ACT), spirometry, corticosteroid use, and exacerbations were assessed. Twenty-two of 36 children with STRA underwent fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy with assessment of airway inflammation and remodeling.
Measurements and Main Results
25(OH)D3 levels (median [IQR]) were significantly lower in STRA (28 [22–38] nmol/L) than in MA (42.5 [29–63] nmol/L) and control subjects (56.5 [45–67] nmol/L) (P < 0.001). There was a positive relationship between 25(OH)D3 levels and percent predicted FEV1 (r = 0.4, P < 0.001) and FVC (r = 0.3, P = 0.002) in all subjects. 25(OH)D3 levels were positively associated with ACT (r = 0.6, P < 0.001), and inversely associated with exacerbations (r=−0.6, P < 0.001) and inhaled steroid dose (r=−0.39, P = 0.001) in MA and and STRA. Airway smooth muscle (ASM) mass, but not epithelial shedding or reticular basement membrane thickness, was inversely related to 25(OH)D3 levels (r=−0.6, P = 0.008). There was a positive correlation between ASM mass and bronchodilator reversibility (r = 0.6, P = 0.009) and an inverse correlation between ASM mass and ACT (r = −0.7, P < 0.001).
Lower vitamin D levels in children with STRA were associated with increased ASM mass and worse asthma control and lung function. The link between vitamin D, airway structure, and function suggests vitamin D supplementation may be useful in pediatric STRA.
PMCID: PMC3471128  PMID: 21908411
vitamin D; asthma; remodeling; airway smooth muscle; pediatrics
3.  Effects of combined deferiprone with deferoxamine on right ventricular function in thalassaemia major 
Combination therapy with deferoxamine and oral deferiprone is superior to deferoxamine alone in removing cardiac iron and improving left ventricular ejection fraction (LVEF). The right ventricle (RV) is also affected by the toxic effects of iron and may cause additional cardiovascular perturbation. We assessed the effects of combination therapy on the RV in thalassaemia major (TM) using cardiovascular magnetic resonance (CMR).
We retrieved imaging data from 2 treatment trials and re-analyzed the data for the RV responses: Trial 1 was a randomized controlled trial (RCT) of 65 TM patients with mild-moderate cardiac siderosis receiving combination therapy or deferoxamine with placebo; Trial 2 was an open label longitudinal trial assessing combination therapy in 15 TM patients with severe iron loading.
In the RCT, combination therapy with deferoxamine and deferiprone was superior to deferoxamine alone for improving RVEF (3.6 vs 0.7%, p = 0.02). The increase in RVEF was greater with lower baseline T2* 8-12 ms (4.7 vs 0.5%, p = 0.01) than with T2* 12-20 ms (2.2 vs 0.8%, p = 0.47). In patients with severe cardiac siderosis, substantial improvement in RVEF was seen with open-label combination therapy (10.5% ± 5.6%, p < 0.01).
In the RCT of mild to moderate cardiac iron loading, combination treatment improved RV function significantly more than deferoxamine alone. Combination treatment also improved RV function in severe cardiac siderosis. Therefore adding deferiprone to deferoxamine has beneficial effects on both RV and LV function in TM patients with cardiac siderosis.
PMCID: PMC3278357  PMID: 22277065
thalassaemia major; deferiprone; deferoxamine; right ventricular function
4.  Right ventricular dysfunction is a predictor of non-response and clinical outcome following cardiac resynchronization therapy 
Cardiac resynchronization therapy (CRT) is an established treatment in advanced heart failure (HF). However, an important subset does not derive a significant benefit. Despite an established predictive role in HF, the significance of right ventricular (RV) dysfunction in predicting clinical benefit from CRT remains unclear. We investigated the role of RV function, assessed by cardiovascular magnetic resonance (CMR), in predicting response to and major adverse clinical events in HF patients undergoing CRT.
Sixty consecutive patients were evaluated with CMR prior to CRT implantation in a tertiary cardiac centre. The primary end-point was a composite of death from any cause or unplanned hospitalization for a major cardiovascular event. The secondary end-point was response to therapy, defined as improvement in left ventricular ejection fraction ≥ 5% on echocardiography at one year.
Eighteen patients (30%) met the primary end-point over a median follow-up period of 26 months, and 27 out of 56 patients (48%) were considered responders to CRT. On time-to-event analysis, only atrial fibrillation (HR 2.6, 95% CI 1.02-6.84, p = 0.047) and RV dysfunction, either by a reduced right ventricular ejection fraction-RVEF (HR 0.96, 95% CI 0.94-0.99, p = 0.006) or tricuspid annular plane systolic excursion-TAPSE (HR 0.88, 95% CI, 0.80-0.96, p = 0.006), were significant predictors of adverse events. On logistic regression analysis, preserved RVEF (OR 1.05, 95% CI 1.01-1.09, p = 0.01) and myocardial scar burden (OR 0.90, 95% CI 0.83-0.96, p = 0.004) were the sole independent predictors of response to CRT. Patients with marked RV dysfunction (RVEF < 30%) had a particularly low response rate (18.2%) to CRT.
Right ventricular function is an important predictor of both response to CRT and long-term clinical outcome. Routine assessment of the right ventricle should be considered in the evaluation of patients for CRT.
PMCID: PMC3217913  PMID: 22040270
heart failure; cardiac resynchronization therapy; right ventricular function; cardiovascular magnetic resonance
5.  Assessment of data quality in an international multi-centre randomised trial of coronary artery surgery 
Trials  2011;12:212.
ART is a multi-centre randomised trial of cardiac surgery which provided a unique opportunity to evaluate the data from a large number of centres from a variety of countries. We attempted to assess data quality, including recruitment rates, timeliness and completeness of the data obtained from the centres in different socio-economic strata.
The analysis was based on the 2-page CRF completed at the 6 week follow-up. CRF pages were categorised into "clean" (no edit query) and "dirty" (any incomplete, inconsistent or illegible data). The timelines were assessed on the basis of the time interval from the visit and receipt of complete CRF. Data quality was defined as the number of data queries (in percent) and time delay (in days) between visit and receipt of correct data. Analyses were stratified according to the World Bank definitions into: "Developing" countries (Poland, Brazil and India) and "Developed" (Italy, UK, Austria and Australia).
There were 18 centres in the "Developed" and 10 centres in the "Developing" countries. The rate of enrolment did not differ significantly by economic level ("Developing":4.1 persons/month, "Developed":3.7 persons/month). The time interval for the receipt of data was longer for "Developing" countries (median:37 days) compared to "Developed" ones (median:11 days) (p < 0.001). The median number of data queries was 23% in "Developed" countries compared to 19% in "Developing" ones (p = ns).
In this study we showed that data quality was comparable between centres from "Developed" and "Developing" countries. Data was received in a less timely fashion from Developing countries and appropriate systems should be instigated to minimize any delays. Close attention should be paid to the training of centres and to the central management of data quality.
Trial registration
PMCID: PMC3205027  PMID: 21943128
8.  Right ventricular volumes and function in thalassemia major patients in the absence of myocardial iron overload 
We aimed to define reference ranges for right ventricular (RV) volumes, ejection fraction (EF) in thalassemia major patients (TM) without myocardial iron overload.
Methods and results
RV volumes, EF and mass were measured in 80 TM patients who had no myocardial iron overload (myocardial T2* > 20 ms by cardiovascular magnetic resonance). All patients were receiving deferoxamine chelation and none had evidence of pulmonary hypertension or other cardiovascular comorbidity. Forty age and sex matched healthy non-anemic volunteers acted as controls. The mean RV EF was higher in TM patients than controls (males 66.2 ± 4.1% vs 61.6 ± 6%, p = 0.0009; females 66.3 ± 5.1% vs 62.6 ± 6.4%, p = 0.017), which yielded a raised lower threshold of normality for RV EF in TM patients (males 58.0% vs 50.0% and females 56.4% vs 50.1%). RV end-diastolic volume index was higher in male TM patients (mean 98.1 ± 17.3 mL vs 88.4 ± 11.2 mL/m2, p = 0.027), with a higher upper limit (132 vs 110 mL/m2) but this difference was of borderline significance for females (mean 86.5 ± 13.6 mL vs 80.3 ± 12.8 mL/m2, p = 0.09, with upper limit of 113 vs 105 mL/m2). The cardiac index was raised in TM patients (males 4.8 ± 1.0 L/min vs 3.4 ± 0.7 L/min, p < 0.0001; females 4.5 ± 0.8 L/min vs 3.2 ± 0.8 L/min, p < 0.0001). No differences in RV mass index were identified.
The normal ranges for functional RV parameters in TM patients with no evidence of myocardial iron overload differ from healthy non-anemic controls. The new reference RV ranges are important for determining the functional effects of myocardial iron overload in TM patients.
PMCID: PMC2867986  PMID: 20416084
10.  Genetic Regulation of Acquired Immune Responses to Antigens of Mycobacterium tuberculosis: a Study of Twins in West Africa 
Infection and Immunity  2001;69(6):3989-3994.
The role of genetic factors in clinical tuberculosis is increasingly recognized; how such factors regulate the immune response to Mycobacterium tuberculosis in healthy individuals is unclear. In this study of 255 adult twin pairs residing in The Gambia, West Africa, it is apparent that memory T-cell responses to secreted mycobacterial antigens (85-kDa antigen complex, “short-term culture filtrate,” and peptides from the ESAT-6 protein), as well as to the 65-kDa heat shock protein, are subject to effective genetic regulation. The delayed hypersensitivity response to intradermal tuberculin also demonstrates significant genetic variance, while quantitative T-cell and antibody responses to the 38-kDa cell membrane protein appear to be determined largely by environmental factors. Such findings have implications for vaccine development.
PMCID: PMC98461  PMID: 11349068

Results 1-10 (10)