Robots and ICT to support play in children with severe physical disabilities: a systematic review

Purpose: Play is an essential part of children’s lives. Children with physical disabilities experience difficulties in play, especially those with severe physical disabilities. With the progress of innovative technology, the possibilities to support play are increasing. The purpose of this literature study is to gain insight into the aims, control options and commercial availability of information and communication technology (ICT) and robots to support play (especially play for the sake of play) in children with severe physical disabilities. Methods: A systematic literature search in the databases PubMed, CINAHL, IEEE and ERIC was carried out. Titles and abstracts were assessed independently by three reviewers. In addition, studies were selected using Google Scholar, conference proceedings and reference lists. Results: Three main groups of technology for play could be distinguished: robots (n = 8), virtual reality systems (n = 15) and computer systems (n = 4). Besides, ICT and robots developed for specific therapy or educational goals using play-like activities, five of the in total 27 technologies in this study described the aim of “play for play’s sake”. Conclusions: Many ICT systems and robots to support play in children with physical disabilities were found. Numerous technologies use play-like activities to achieve therapeutic or educational goals. Robots especially are used for “play for play’s sake”.

• Implications for Rehabilitation

• This study gives insight into the aims, control options and commercial availability for application of robots and ICT to support play in children with severe physical disabilities.

• This overview can be used in both the fields of rehabilitation and special education to search for new innovative intervention options and it can stimulate them to use these innovative play materials.

• Especially robots may have great potential in supporting “play for play's sake”.

     

Open-access transvaginal sonography in women of reproductive age with abnormal vaginal bleeding: a descriptive study in general practice

Background

Diagnostic ultrasonography is used by GPs in approximately 10% of patients of reproductive age with abnormal vaginal bleeding. Transvaginal sonography is recommended as a first-line diagnostic instrument for assessing uterine pathology.

Aim

To assess if findings resulting from openaccess sonography were in agreement with the GPs’ working hypotheses and if these findings contributed to GPs’ management.

Design and setting

Prospective observational cohort study of GPs working in the health district of the Academic Medical Center, Amsterdam and their patients consulting with abnormal vaginal bleeding.

Method

Data on patients’ history, GPs’ primary working hypotheses, and intended management were recorded. After sonography, GPs recorded their actual management.

Results

A total of 122 patients were included by 18 GPs from June 2003 to December 2004. Data from 89 patients were available for analysis. The GPs’ working hypotheses implied ‘no structural pathology’ in 65/89 patients, and ‘fibroids’ in 24/89 patients. Sonographic findings were confirmed in 50/65 patients where ‘no structural pathology’, and in 14/24 of those where ‘fibroids’ were expected. Initially, GPs had intended to refer nine patients to a gynaecologist. Actual management after sonographic assessment was watchful waiting or drug therapy in 57/89 patients. Eighty-nine per cent of these patients had normal sonographic findings. The actual referral rate rose to 27/89 patients. In 17 referred patients, sonographic findings were suggestive of intracavitary abnormalities.

Conclusion

Open-access sonography contributed to more accurate diagnoses and improved GPs’ management of women with abnormal vaginal bleeding.     

Klotho Prevents Renal Calcium Loss

Disturbed calcium (Ca²⁺) homeostasis, which is implicit to the aging phenotype of klotho-deficient mice, has been attributed to altered vitamin D metabolism, but alternative possibilities exist. We hypothesized that failed tubular Ca²⁺ absorption is primary, which causes increased urinary Ca²⁺ excretion, leading to elevated 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] and its sequelae. Here, we assessed intestinal Ca²⁺ absorption, bone densitometry, renal Ca²⁺ excretion, and renal morphology via energy-dispersive x-ray microanalysis in wild-type and klotho^−/− mice. We observed elevated serum Ca²⁺ and fractional excretion of Ca²⁺ (FE_Ca) in klotho^−/− mice. Klotho^−/− mice also showed intestinal Ca²⁺ hyperabsorption, osteopenia, and renal precipitation of calcium-phosphate. Duodenal mRNA levels of transient receptor potential vanilloid 6 (TRPV6) and calbindin-D_9K increased. In the kidney, klotho^−/− mice exhibited increased expression of TRPV5 and decreased expression of the sodium/calcium exchanger (NCX1) and calbindin-D_28K, implying a failure to absorb Ca²⁺ through the distal convoluted tubule/connecting tubule (DCT/CNT) via TRPV5. Gene and protein expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D-1-α-hydroxylase (1αOHase), and calbindin-D_9K excluded renal vitamin D resistance. By modulating the diet, we showed that the renal Ca²⁺ wasting was not secondary to hypercalcemia and/or hypervitaminosis D. In summary, these findings illustrate a primary defect in tubular Ca²⁺ handling that contributes to the precipitation of calcium-phosphate in DCT/CNT. This highlights the importance of klotho to the prevention of renal Ca²⁺ loss, secondary hypervitaminosis D, osteopenia, and nephrocalcinosis.Characterization of a mouse that showed a phenotype comparable to human aging led to the identification of the hormone klotho.¹ Klotho^−/− mice have atherosclerosis, osteopenia, soft tissue calcifications, pulmonary emphysema, and altered glucose metabolism.¹ It has been suggested that the etiology of many of these findings is a primary defect in phosphorous [P(i)] and calcium (Ca²⁺) homeostasis.^2,3 Klotho^−/− mice have elevated serum levels of Ca²⁺.^1,4,5 The mechanism mediating hypercalcemia is poorly understood. A possible explanation invokes the role of klotho in vitamin D homeostasis. Klotho has been proposed to participate in a negative feedback circuit to inhibit 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] synthesis.^6,7 Specifically, klotho is necessary to transduce the signal of fibroblast growth factor 23 (FGF23) through the FGF receptor, thereby suppressing CYP1b expression, the enzyme that mediates the conversion of 25-hydroxyvitamin D into 1,25(OH)₂D₃. Thus, the absence of klotho results in increased serum levels of 1,25(OH)₂D₃ and reduced serum concentrations of the calciotropic hormone parathyroid hormone.^4,7,8 This would drive increased resorption of Ca²⁺ from bone, hyperabsorption from the intestine, increased serum levels of Ca²⁺, and consequently increase renal Ca²⁺ excretion. Definitive proof of this is lacking because the molecular control of Ca²⁺ homeostasis in klotho^−/− mice has yet to be delineated.Consistent with the above hypothesis is the observation that klotho^−/− mice display hypercalciuria^4,5,9 and that normalization of serum 1,25(OH)₂D₃ levels reverts many, but not all, of their abnormalities.⁶ The published literature supports an alternative, complementary hypothesis.^9–11 A primary defect in tubular Ca²⁺ handling might cause hypervitaminosis D and renal Ca²⁺ wasting observed in klotho^−/− mice. Consistent with this idea, in vitro, klotho mediates an increase in cell surface expression of transient receptor potential vanilloid 5 (TRPV5)^10,11 the distal convoluted tubule/connecting tubule (DCT/CNT) channel responsible for the transcellular absorption of Ca²⁺.¹² This process is itself implicit to Ca²⁺ homeostasis as TRPV5 is the predominant regulator of urinary Ca²⁺ excretion.¹³ Therefore, we set out to test the hypothesis that klotho^−/− mice have a primary renal Ca²⁺ leak that contributes to a secondary increase in 1,25(OH)₂D₃ synthesis and its consequences.     

EGF Increases TRPM6 Activity and Surface Expression

Recent identification of a mutation in the EGF gene that causes isolated recessive hypomagnesemia led to the finding that EGF increases the activity of the epithelial magnesium (Mg²⁺) channel transient receptor potential M6 (TRPM6). To investigate the molecular mechanism mediating this effect, we performed whole-cell patch-clamp recordings of TRPM6 expressed in human embryonic kidney 293 (HEK293) cells. Stimulation of the EGF receptor increased current through TRPM6 but not TRPM7. The carboxy-terminal α-kinase domain of TRPM6 did not participate in the EGF receptor–mediated increase in channel activity. This activation relied on both the Src family of tyrosine kinases and the downstream effector Rac1. Activation of Rac1 increased the mobility of TRPM6, assessed by fluorescence recovery after photobleaching, and a constitutively active mutant of Rac1 mimicked the stimulatory effect of EGF on TRPM6 mobility and activity. Ultimately, TRPM6 activation resulted from increased cell surface abundance. In contrast, dominant negative Rac1 decreased TRPM6 mobility, abrogated current development, and prevented the EGF-mediated increase in channel activity. In summary, EGF-mediated stimulation of TRPM6 occurs via signaling through Src kinases and Rac1, thereby redistributing endomembrane TRPM6 to the plasma membrane. These results describe a regulatory mechanism for transepithelial Mg²⁺ transport and consequently whole-body Mg²⁺ homeostasis.Recently we described a mutation in the EGF gene, encoding pro-EGF, which is responsible for a rare form of renal magnesium (Mg²⁺) wasting, isolated recessive hypomagnesemia.¹ A link between a defect in EGF and renal Mg²⁺ wasting was made by demonstrating that pro-EGF is expressed in the distal convoluted tubule (DCT), where regulated transcellular Mg²⁺ reabsorption occurs via transient receptor potential M6 (TRPM6). Furthermore, supernatant from the basolateral compartment of polarized epithelial cells expressing pro-EGF was able to activate TRPM6, whereas supernatant from cells expressing the mutant pro-EGF was unable to. The EGF receptor (EGFR/ErbB1) is expressed in the basolateral membrane of DCT, suggesting an autocrine/paracrine activation of TRPM6 by EGF through its receptor. This has not been confirmed, however; neither have the molecular details of this activation been elucidated.EGFR activation mediates its downstream effects via numerous signaling cascades, including the extracellular signal–regulated kinase (ERK) limb of the mitogen-activated protein kinase (MAPK) superfamily, protein kinase A (PKA), protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), and the phospholipases C and D pathways.² Activation of the EGFR in DCT could therefore result in phosphorylation and consequently activation of the previously described target proteins. That EGFR signaling is implicit to Mg²⁺ homeostasis is further supported by the observation that patients treated with cetuximab, a mAb directed against the EGFR, develop hypomagnesemia^{1, 3, 4}; however, the signaling pathway(s) downstream of EGFR activation, which stimulates TRPM6-mediated Mg²⁺ influx, remains to be determined.The aim of this study was to ascertain the downstream signaling events, after EGFR engagement, and ultimately the mechanism responsible for increased TRPM6 activity. Elucidation of the molecular details responsible for EGFR-mediated stimulation of TRPM6 will facilitate the development of treatments for hypomagnesemia in general and during cetuximab treatment. Using electrophysiologic measurements in combination with biochemical and live cell imaging techniques, we provide evidence that EGF stimulates TRPM6 through the specific activation of the EGFR. This activates the Src family of tyrosine kinases and the small Rho-GTPase, Rac1, which results in a redistribution of vesicular TRPM6 to the plasma membrane.     

Does HPA-axis activity mediate the relationship between obstetric complications and externalizing behavior problems? The TRAILS study

To examine whether HPA-axis activity mediates the relationship between obstetric complications (OCs) and externalizing behavior problems, and to investigate whether this model is different for boys and girls. In a population-based cohort of 1,768 10- to 12-year-old early adolescents, we assessed the cortisol awakening response and evening cortisol levels. Externalizing behavior problems were assessed using the Child Behavior Checklist and the Youth Self-Report. OCs were retrospectively assessed in a parent interview. OCs significantly predicted externalizing behavior problems, but OCs did not predict HPA-axis activity. Thus, the mediation model was not supported. In addition to the relationship between HPA-axis activity and externalizing behavior problems, which is specific for girls, there is also a relationship between OCs and externalizing behavior problems. However, these two mechanisms are not related to each other indicating that HPA-axis activity is not a mediator in the relationship between OCs and externalizing behavior problems. Future research should focus on understanding the mechanism through which OCs cause externalizing behavior problems.     

Predictors of asthma control in children from different ethnic origins living in Amsterdam

To identify factors associated with asthma control in a multi-ethnic paediatric population. We interviewed 278 children with paediatrician diagnosed asthma (aged 7-17 years) and one of their parents. Asthma control was assessed with the Asthma Control Questionnaire (ACQ). Detailed information about sociodemographic variables, asthma medication, knowledge of asthma, inhalation technique and environmental factors were collected. Turkish and Moroccan parents were interviewed in their language of choice. Logistic regression analyses were used to identify correlates of asthma control. Of the 278 children, 85 (30.6%) were Dutch, 84 (30.2%) were Moroccan, 58 (20.9%) were Turkish and 51 (18.3%) were Surinamese. Overall, almost 60% had a status of well-controlled asthma, as indicated by the ACQ. Only 51 of the 142 (35.9%) Moroccan and Turkish parents had a good comprehension of the Dutch language. In logistic regression analyses the risk of having uncontrolled asthma was significantly higher among Surinamese children (OR 2.3; 95% CI 1.06-4.83), respondents with insufficient comprehension of the Dutch language (OR 2.3; 95% CI 1.08-4.78), children using woollen blankets (OR 9.8; 95% CI 1.52-63.42), and significantly lower among male (OR 0.5; 95% CI 0.31-0.91) and non-daily users of inhaled corticosteroids (OR 0.6; 95% CI 0.38-1.07). In conclusion, ethnicity as well as insufficient comprehension of the Dutch language appeared to be independent risk factors for uncontrolled asthma. Special attention should be given to children from immigrants groups for example by calling in an interpreter by physicians when comprehension is insufficient.     

The Influence that Electronic Prescribing Has on Medication Errors and Preventable Adverse Drug Events: an Interrupted Time-series Study

Objective

This study evaluated the effect of a Computerized Physician Order Entry system with basic Clinical Decision Support (CPOE/CDSS) on the incidence of medication errors (MEs) and preventable adverse drug events (pADEs).

Design

Interrupted time-series design.

Measurements

The primary outcome measurements comprised the percentage of medication orders with one or more MEs and the percentage of patients with one or more pADEs.

Results

Pre-implementation, the mean percentage of medication orders containing at least one ME was 55%, whereas this became 17% post-implementation. The introduction of CPOE/CDSS has led to a significant immediate absolute reduction of 40.3% (95% CI: −45.13%; −35.48%) in medication orders with one or more errors.Pre-implementation, the mean percentage of admitted patients experiencing at least one pADE was 15.5%, as opposed to 7.3% post-implementation. However, this decrease could not be attributed to the introduction of CPOE/CDSS: taking into consideration the interrupted time-series design, the immediate change was not significant (−0.42%, 95% CI: −15.52%; 14.68%) because of the observed underlying negative trend during the pre-CPOE period of −4.04% [95% CI: −7.70%; −0.38%] per month.

Conclusions

This study has shown that CPOE/CDSS reduces the incidence of medication errors. However, a direct effect on actual patient harm (pADEs) was not demonstrated.     

Immunological Risk of Injectable Drug Delivery Systems

Injectable drug delivery systems (DDS) such as particulate carriers and water-soluble polymers are being used and developed for a wide variety of therapeutic applications. However, a number of immunological risks with serious clinical implications are associated with administration of DDS. These immunological events can compromise the efficacy and safety of these systems by changing the pharmacokinetics, biodistribution and targeting capability of DDS, and by inducing hypersensitivity reactions. Antibodies induced by administration of DDS can be directed against the carrier material, the drug and/or targeting ligands associated with the DDS. Complement activation and opsonization of DDS, which may or may not be associated with antibody formation, may lead to accelerated clearance, hypersensitivity reactions and formation of membrane attack complexes resulting in premature release of the drug. Also platelets have been reported to play a role in DDS immunogenicity. Despite our curtailed understanding of the relationships between physicochemical characteristics and immunogenicity of DDS, several risk factors have been identified. Insight into these factors should be employed in the development of novel DDS with low immunological risk.