Economic burden of rotavirus disease in children under 5 years in Kazakhstan

Background

We aimed to estimate the societal costs of rotavirus cases among children less than 5 years in Kazakhstan, an upper-middle income country in Central Asia.

Methods

Data on medical, non-medical and indirect costs were collected for 190 patients less than 5 years, hospitalized with severe diarrhea in 2009 in two pediatric hospitals. Data on resource use for moderate and mild diarrhea cases were obtained from published sources. A probabilistic sensitivity analysis was performed to explore uncertainty in cost estimates.

Results

Approximately 4,000 severe, 30,700 moderate, and 122,900 mild rotavirus cases were estimated annually in children <5 years old. The mean societal cost of a severe, moderate and mild rotavirus case was estimated at US$ 454, 82, and 21, respectively. The total annual cost of rotavirus disease was $37.53 million or on average $107.36 for a child under 5 years old in Kazakhstan. Ninety-four percent of total costs (35.13 million) are indirect costs (productivity losses) from fatal cases and parents’ job absenteeism, while direct medical costs account for 2.04 million (5.4%), and direct non-medical for 0.46 million (1.2%).

Conclusions

Rotavirus-associated diarrhea represents a significant economic burden in Kazakhstan, largely due to indirect costs. The costs of rotavirus infections should be considered when planning further preventive actions, including the introduction of rotavirus vaccination.     

Spatio-temporal activity in real time (STAR): optimization of regional fMRI feedback

The use of real-time feedback has expanded fMRI from a brain probe to include potential brain interventions with significant therapeutic promise. However, whereas time-averaged blood oxygenation level-dependent (BOLD) signal measurement is usually sufficient for probing a brain state, the real-time (frame-to-frame) BOLD signal is noisy, compromising feedback accuracy. We have developed a new real-time processing technique (STAR) that combines noise-reduction properties of multi-voxel (e.g., whole-brain) techniques with the regional specificity critical for therapeutics. Nineteen subjects were given real-time feedback in a cognitive control task (imagining repetitive motor activity vs. spatial navigation), and were all able to control a visual feedback cursor based on whole-brain neural activity. The STAR technique was evaluated, retrospectively, for five a priori regions of interest in these data, and was shown to provide significantly better (frame-by-frame) classification accuracy than a regional BOLD technique. In addition to regional feedback signals, the output of the STAR technique includes spatio-temporal activity maps (movies) providing insight into brain dynamics. The STAR approach offers an appealing optimization for real-time fMRI applications requiring an anatomically-localized feedback signal.     

Dosimetric accuracy of Kodak EDR2 film for IMRT verifications

Patient-specific intensity-modulated radiotherapy (IMRT) verifications require an accurate two-dimensional dosimeter that is not labor-intensive. We assessed the precision and reproducibility of film calibrations over time, measured the elemental composition of the film, measured the intermittency effect, and measured the dosimetric accuracy and reproducibility of calibrated Kodak EDR2 film for single-beam verifications in a solid water phantom and for full-plan verifications in a Rexolite phantom. Repeated measurements of the film sensitometric curve in a single experiment yielded overall uncertainties in dose of 2.1% local and 0.8% relative to 300 cGy. 547 film calibrations over an 18-month period, exposed to a range of doses from 0 to a maximum of 240 MU or 360 MU and using 6 MV or 18 MV energies, had optical density (OD) standard deviations that were 7%-15% of their average values. This indicates that daily film calibrations are essential when EDR2 film is used to obtain absolute dose results. An elemental analysis of EDR2 film revealed that it contains 60% as much silver and 20% as much bromine as Kodak XV2 film. EDR2 film also has an unusual 1.69:1 silver:halide molar ratio, compared with the XV2 film's 1.02:1 ratio, which may affect its chemical reactions. To test EDR2's intermittency effect, the OD generated by a single 300 MU exposure was compared to the ODs generated by exposing the film 1 MU, 2 MU, and 4 MU at a time to a total of 300 MU. An ion chamber recorded the relative dose of all intermittency measurements to account for machine output variations. Using small MU bursts to expose the film resulted in delivery times of 4 to 14 minutes and lowered the film's OD by approximately 2% for both 6 and 18 MV beams. This effect may result in EDR2 film underestimating absolute doses for patient verifications that require long delivery times. After using a calibration to convert EDR2 film's OD to dose values, film measurements agreed within 2% relative difference and 2 mm criteria to ion chamber measurements for both sliding window and step-and-shoot fluence map verifications. Calibrated film results agreed with ion chamber measurements to within 5 % /2 mm criteria for transverse-plane full-plan verifications, but were consistently low. When properly calibrated, EDR2 film can be an adequate two-dimensional dosimeter for IMRT verifications, although it may underestimate doses in regions with long exposure times.     

Effect of processing time delay on the dose response of Kodak EDR2 film

Kodak EDR2 film is a widely used two-dimensional dosimeter for intensity modulated radiotherapy (IMRT) measurements. Our clinical use of EDR2 film for IMRT verifications revealed variations and uncertainties in dose response that were larger than expected, given that we perform film calibrations for every experimental measurement. We found that the length of time between film exposure and processing can affect the absolute dose response of EDR2 film by as much as 4%-6%. EDR2 films were exposed to 300 cGy using 6 and 18 MV 10 x 10 cm2 fields and then processed after time delays ranging from 2 min to 24 h. An ion chamber measured the relative dose for these film exposures. The ratio of optical density (OD) to dose stabilized after 3 h. Compared to its stable value, the film response was 4%-6% lower at 2 min and 1% lower at 1 h. The results of the 4 min and 1 h processing time delays were verified with a total of four different EDR2 film batches. The OD/dose response for XV2 films was consistent for time periods of 4 min and 1 h between exposure and processing. To investigate possible interactions of the processing time delay effect with dose, single EDR2 films were irradiated to eight different dose levels between 45 and 330 cGy using smaller 3 x 3 cm2 areas. These films were processed after time delays of 1, 3, and 6 h, using 6 and 18 MV photon qualities. The results at all dose levels were consistent, indicating that there is no change in the processing time delay effect for different doses. The difference in the time delay effect between the 6 and 18 MV measurements was negligible for all experiments. To rule out bias in selecting film regions for OD measurement, we compared the use of a specialized algorithm that systematically determines regions of interest inside the 10 x 10 cm2 exposure areas to manually selected regions of interest. There was a maximum difference of only 0.07% between the manually and automatically selected regions, indicating that the use of a systematic algorithm to determine regions of interest in large and fairly uniform areas is not necessary. Based on these results, we recommend a minimum time of 1 h between exposure and processing for all EDR2 film measurements.     

An autosomal genomic screen for autism. Collaborative linkage study of autism

Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. The etiology of idiopathic autism is strongly genetic, and oligogenic transmission is likely. The first stage of a two-stage genomic screen for autism was carried out by the Collaborative Linkage Study of Autism on individuals affected with autism from 75 families ascertained through an affected sib-pair. The strongest multipoint results were for regions on chromosomes 13 and 7. The highest maximum multipoint heterogeneity LOD (MMLS/het) score is 3.0 at D13S800 (approximately 55 cM from the telomere) under the recessive model, with an estimated 35% of families linked to this locus. The next highest peak is an MMLS/het score of 2.3 at 19 cM, between D13S217 and D13S1229. Our third highest MMLS/het score of 2.2 is on chromosome 7 and is consistent with the International Molecular Genetic Study of Autism Consortium report of a possible susceptibility locus somewhere within 7q31-33. These regions and others will be followed up in the second stage of our study by typing additional markers in both the original and a second set of identically ascertained autism families, which are currently being collected. By comparing results across a number of studies, we expect to be able to narrow our search for autism susceptibility genes to a small number of genomic regions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:609-615, 1999.     

A randomized, double-blind, crossover study of once-daily dexmethylphenidate in children with attention-deficit hyperactivity disorder: rapid onset of effect

BACKGROUND: Long-acting methylphenidate formulations provide control of attention-deficit hyperactivity disorder (ADHD) symptoms for up to 12 hours; however, not all formulations have rapid onset of therapeutic effect, which is essential for providing symptom control during morning hours. The primary objective of this randomized, double-blind, crossover study was to assess the efficacy of dexmethylphenidate extended release (ER) versus placebo by measuring the change from pre-dose to 0.5 hours post-dose on the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale. METHODS: Eighty-six children (6-12 years) with ADHD diagnosed using the DSM-IV criteria were randomized to receive dexmethylphenidate ER 20 mg/day or placebo, sequentially, for 7 days, with the final dose administered in a laboratory classroom setting on day 7 of each treatment period. The primary efficacy comparison was change in the SKAMP-Combined score from pre-dose to 0.5 hours post-dose, with additional secondary assessments at 1, 2, 4, 6 and 8 hours post-dose. Secondary efficacy measures included change from pre-dose at all timepoints in the SKAMP-Attention and SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores, and change from baseline on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P). In an exploratory analysis, a daily diary card was completed by parents on the children's in-home behaviour before school. Safety was assessed by occurrence of adverse events, monitoring of vital signs and interpretation of ECGs. RESULTS: Significant improvements were noted at 0.5 hours and at all timepoints post-dose throughout the 8-hour laboratory classroom day for dexmethylphenidate ER vs placebo in the primary outcome measure of the SKAMP-Combined scores (p < 0.001), as well as SKAMP-Attention, SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores (p < 0.05). The changes from baseline in CADS-P scores were significantly greater with dexmethylphenidate ER than placebo (-16.382 vs -4.622; p < 0.001). Responses to all diary questions indicated significant improvement with dexmethylphenidate ER treatment versus placebo (all p < 0.001). The most common adverse events were abdominal pain (dexmethylphenidate ER 3.5%; placebo 4.7%), headache (dexmethylphenidate ER 3.5%; placebo 2.3%) and increased appetite (dexmethylphenidate ER 0%; placebo 3.5%). CONCLUSION: Compared with placebo, once-daily dexmethylphenidate ER 20 mg provided rapid and significant improvement at 0.5 hours post-dose in attention, deportment and academic performance, which was sustained for 8 hours post-dose. Overall, once-daily dexmethylphenidate ER 20 mg was well tolerated. In an analysis of parental assessment of diary responses, children appeared more organized, and morning preparation for school was smoother and less frustrating with once-daily dexmethylphenidate ER compared with placebo.     

Treatment of children with attention-deficit/hyperactivity disorder: results of a randomized, multicenter, double-blind, crossover study of extended-release dexmethylphenidate and D,L-methylphenidate and placebo in a laboratory classroom setting

The purpose of this study was to compare the efficacy and safety of extended-release dexmethylphenidate (d-MPH-ER) to that of d,l-MPH-ER and placebo in children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. This multicenter, double-blind, crossover study randomized 82 children, 6 to 12 years of age, stabilized on a total daily dose to the nearest equivalent of 40 to 60 mg of d,l-MPH or 20 or 30 mg/day of d-MPH. Patients participated in a screening day and practice day, and were randomized to 1 of 10 sequences of all five treatments in five separate periods. Treatments included d-MPH-ER (20 mg/day), d-MPH-ER (30 mg/day), d,l-MPH-ER (36 mg/day), d,l-MPH-ER (54 mg/day), and placebo. Primary efficacy was measured by the change from predose on the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores at 2-h postdose during the 12-h laboratory assessment (d-MPH-ER 20 mg/day vs. d,l-MPH-ER 36 mg/day). Adverse events were monitored throughout the study period. d-MPH-ER (20 mg/day) was significantly more effective than d,l-MPH-ER (36 mg/day) in the primary efficacy variable, change from predose to 2-h postdose in SKAMP-combined score. In general, d-MPH-ER had an earlier onset of action than d,l-MPH-ER, while d,l-MPH-ER had a stronger effect at 12-h postdose. No serious adverse events were reported. Treatment with either agent was associated with significant improvements in ADHD symptoms. d-MPH-ER and d,l-MPH-ER can be differentiated on what part of the day each is more effective.     

Pharmacotherapy of attention-deficit hyperactivity disorder in adolescents

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder in children and adolescents, consisting of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. The majority of children with ADHD will continue to experience significant ADHD symptoms as teens. ADHD in adolescents can result in significant functional impairment and poorer quality of life. Children and adolescents with ADHD are at higher risk of developing other psychiatric illnesses such as mood, conduct and substance abuse disorders. Stimulants (amphetamines and methylphenidates) and nonstimulants (atomoxetine, guanfacine extended-release (XR) and clonidine XR) have been found to be effective and are approved by the US FDA for the treatment of ADHD in adolescents in the US. Of the agents approved in the US, only guanfacine XR and clonidine XR are not approved in any other countries. There is growing evidence that treatment of ADHD with stimulants reduces the risk of development of other psychiatric co-morbidities, including substance abuse disorders. To date, all FDA-approved stimulants and nonstimulants that have been adequately studied have been demonstrated to be safe and effective in treating ADHD in both children and adolescents. Therefore, clinical decisions used in selecting pharmacotherapy to treat ADHD in children aged 6-12 years can be applied in the adolescent population.     

Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice

PTH is a potent calcium-regulating factor that has skeletal anabolic effects when administered intermittently or catabolic effects when maintained at consistently high levels. Bone cells express PTH receptors, but the cellular responses to PTH in bone are incompletely understood. Wnt signaling has recently been implicated in the osteo-anabolic response to the hormone. Specifically, the Sost gene, a major antagonist of Wnt signaling, is down-regulated by PTH exposure. We investigated this mechanism by treating Sost-deficient mice and their wild-type littermates with anabolic and catabolic regimens of PTH and measuring the skeletal responses. Male Sost(+/+) and Sost(-/-) mice were injected daily with human PTH 1-34 (0, 30, or 90 μg/kg) for 6 wk. Female Sost(+/+) and Sost(-/-) mice were continuously infused with vehicle or high-dose PTH (40 μg/kg · d) for 3 wk. Dual energy x-ray absorptiometry-derived measures of intermittent PTH (iPTH)-induced bone gain were impaired in Sost(-/-) mice. Further probing revealed normal or enhanced iPTH-induced cortical bone formation rates but concomitant increases in cortical porosity among Sost(-/-) mice. Distal femur trabecular bone was highly responsive to iPTH in Sost(-/-) mice. Continuous PTH (cPTH) infusion resulted in equal bone loss in Sost(+/+) and Sost(-/-) mice as measured by dual energy x-ray absorptiometry. However, distal femur trabecular bone, but not lumbar spine trabecular bone, was spared the bone-wasting effects of cPTH in Sost(-/-) mice. These results suggest that changes in Sost expression are not required for iPTH-induced anabolism. iPTH-induced resorption of cortical bone might be overstimulated in Sost-deficient environments. Furthermore, Sost deletion protects some trabecular compartments, but not cortical compartments, from bone loss induced by high-dose PTH infusion.