Objective
The Dutch law on youth care (the Youth Act) was implemented from 2015 onwards. One of the government’s aims by implementing this new policy was de-medicalization of youths by separating ...youth mental healthcare from the rest of the healthcare system. A previous study conducted by our research group showed that prevalence rates of antipsychotic drug prescriptions stabilized among Dutch youth in the period 2005–2015, just before the introduction of the Youth Act. In our study, we aimed to describe antipsychotic drug use among Dutch children aged 0–19 years old before and after implementation of the Youth Act (2010–2019).
Methods
We analyzed prescription data of 7405 youths aged 0–19 years using antipsychotic drugs between 2010 and 2019, derived from a large Dutch community pharmacy-based prescription database (IADB.nl).
Results
Prevalence rates of antipsychotic drug use per thousand youths decreased significantly in youths aged 7–12 years old in 2019 compared to 2015 (7.9 vs 9.0
p
< 0.05). By contrast, prevalence rates increased in adolescent females in 2019 compared to 2015 (11.8 vs 9.5
p
< 0.05). Incidence rates increased significantly in adolescent youths in 2019 compared to 2015 (3.9 vs 3.0
p
< 0.05), specifically among adolescent girls (4.2 per thousand in 2019 compared to 3.0 per thousand in 2015). Dosages in milligram declined for the most commonly prescribed antipsychotic drugs during the study period. The mean duration of antipsychotic drug use in the study period was 5.7 (95% CI 5.2–6.2) months.
Conclusion
Despite the aim of the Youth Act to achieve de-medicalization of youths, no clear reduction was observed in prevalence rates of antipsychotic drugs or treatment duration in all subgroups. Prevalence rates even increased in adolescent females.
Management options such as the intensity of tillage are known to influence the turnover dynamics of soil organic matter. However, less information is available about the influence of the tillage ...intensity on individual soil organic matter pools with different turnover dynamics in surface as compared with sub‐surface soils. This study aimed to analyse the impact of no tillage (NT), reduced tillage (RT) and conventional tillage (CT) on labile, intermediate and stable carbon (C) and nitrogen (N) pools in surface and sub‐surface soils. We took surface and sub‐surface soil samples from the three tillage systems in three long‐term field experiments in Germany. The labile, intermediate and stable C and N pool sizes were determined by using the combined application of a decomposition experiment and a physical‐chemical separation procedure. For the surface soils, we found larger stocks of the labile C and N pool under NT and RT (C, 1.7 and 1.3 t ha⁻¹; N, 180 and 160 kg ha⁻¹) than with CT (C, 0.5 t ha⁻¹; N, 60 kg ha⁻¹). In contrast, we found significantly larger stocks of the labile C pool under CT (2.7 t ha⁻¹) than with NT and RT (2 t ha⁻¹) for the sub‐surface soils. The intermediate pool accounted for 75–84% of the soil organic C and total N stocks. However, the stocks of the intermediate N and C pools were only distinctly larger for NT than for CT in the surface soils. The stocks of the stable C and N pools were not affected by the tillage intensity but were positively correlated with the stocks of the clay‐size fraction and oxalate soluble aluminum, indicating a strong influence of site‐specific mineral characteristics on the size of these pools. Our results indicate soil depth‐specific variations in the response of organic matter pools to tillage of different intensity. This means that the potential benefits of decreasing tillage intensity with respect to soil functions that are closely related to organic matter dynamics have to be evaluated separately for surface and sub‐surface soils.
Human temporal bone specimens are used in experiments measuring the sound transfer of the middle ear, which is the standard method used in the development of active and passive middle ear implants. ...Statistical analyses of these experiments usually require that the TB samples are representative of the population of non-pathological middle ears. Specifically, this means that the specimens must be mechanically well-characterized. We present an in-depth statistical analysis of 478 data sets of middle ear transfer functions (METFs) from different laboratories. The data sets are preprocessed and various contributions to the variance of the data are evaluated. We then derive a statistical range as a reference against which individual METF measurements may be validated. The range is calculated as the two-sided 95% tolerance interval at audiological frequencies. In addition, the mean and 95% confidence interval of the mean are given as references for assessing the validity of a sample group. Finally, we provide a suggested procedure for measuring METFs using the methods described herein.
Sequestration of infected red blood cells (iRBCs) in the microcirculation is a hallmark of cerebral malaria (CM) in post-mortem human brains. It remains controversial how this might be linked to the ...different disease manifestations, in particular brain swelling leading to brain herniation and death. The main hypotheses focus on iRBC-triggered inflammation and mechanical obstruction of blood flow. Here, we test these hypotheses using murine models of experimental CM (ECM), SPECT-imaging of radiolabeled iRBCs and cerebral perfusion, MR-angiography, q-PCR, and immunohistochemistry. We show that iRBC accumulation and reduced flow precede inflammation. Unexpectedly, we find that iRBCs accumulate not only in the microcirculation but also in large draining veins and sinuses, particularly at the rostral confluence. We identify two parallel venous streams from the superior sagittal sinus that open into the rostral rhinal veins and are partially connected to infected skull bone marrow. The flow in these vessels is reduced early, and the spatial patterns of pathology correspond to venous drainage territories. Our data suggest that venous efflux reductions downstream of the microcirculation are causally linked to ECM pathology, and that the different spatiotemporal patterns of edema development in mice and humans could be related to anatomical differences in venous anatomy.
DEMO is the name for the first stage prototype fusion reactor considered to be the next step after ITER towards realizing fusion. For the realization of fusion energy especially, materials questions ...pose a significant challenge already today. Heat, particle and neutron loads are a significant problem to material lifetime when extrapolating to DEMO. For many of the issues faced, advanced materials solutions are under discussion or already under development. In particular, components such as the first wall and the divertor of the reactor can benefit from introducing new approaches such as composites or new alloys into the discussion. Cracking, oxidation as well as fuel management are driving issues when deciding for new materials. Here composites as well as strengthened CuCrZr components together with oxidation resilient tungsten alloys allow the step towards a fusion reactor. In addition, neutron induced effects such as transmutation, embrittlement and after-heat and activation are essential. Therefore, when designing a component an approach taking into account all aspects is required.
Fracture-related infection is a serious complication after trauma. CERAMENT® G combines dead-space management with local release of gentamicin in a single-stage procedure. Bacterial resistance ...against antibiotics is increasing. The local effect of CERAMENT® G on bacteria resistant to systemically administered gentamicin is unknown.
(1) What is the in vitro elution pattern of gentamicin from CERAMENT® G using a full washout model? (2) What is the in vitro antimicrobial activity (zone of inhibition) of CERAMENT® G against bacterial isolates found in fracture-related infection with different susceptibility levels toward gentamicin?
Elution of gentamicin from CERAMENT® G was determined in vitro over a period of 2 months. Elution experiments were performed in fivefold, with gentamicin being sampled in threefold at 19 different timepoints within 2 months. Antimicrobial activity was determined using the four most-frequently cultured bacterial species found in fracture-related infection: Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Enterobacter cloacae . For each of the species, four different isolates with a different susceptibility to gentamicin were used. According to the European Committee on Antimicrobial Susceptibility Testing, the susceptibility of each isolate was classified into four different groups: fully susceptible (minimum inhibitory concentration 0.064 to 4 mg/L), minimally resistant (minimum inhibitory concentration 4 to 16 mg/L), moderately resistant (minimum inhibitory concentration 8 to 96 mg/L), and highly resistant (minimum inhibitory concentration 24 to 1024 mg/L), depending on each organism. The antimicrobial activity of CERAMENT® G was determined according to the European Committee on Antimicrobial Susceptibility Testing disk protocol. The experiment was performed in fivefold for each isolate. The zone of inhibition was compared between each bacterial isolate and within each of the four separate species. Nonlinear regression statistics were calculated between the zone of interest and logarithmic minimum inhibitory concentration for each bacterial species.
After 24 hours, 95% of all available gentamicin was eluted, and gentamicin was still detectable after 2 months. CERAMENT® G showed antimicrobial activity against all bacterial species; only S taphylococcus aureus (with a minimum inhibitory concentration > 1024 mg/L) was not susceptible. The zone of interest of the different bacterial isolates was correlated with the logarithmic minimum inhibitory concentration.
CERAMENT® G offers a bone substitute capable of releasing high levels of gentamicin within a short period of time. This study shows that CERAMENT® G has antimicrobial activity against bacterial isolates that are resistant to gentamicin when systemically administered. This finding raises the question of whether European Committee on Antimicrobial Susceptibility Testing cutoff points for systemic application are useful for the use of local CERAMENT® G. Standardized experiments to determine local antibiotic antimicrobial activity in fracture-related infection treatment are needed to form guidelines for the use of local antibiotics and ultimately improve fracture-related infection treatment.
Local concentrations of gentamicin with CERAMENT® G are much higher than when systemically administered. It seems effective against certain bacterial strains that are not affected by systemically reachable concentrations of gentamicin. CERAMENT® G might still be effective when bacteria that are resistant to systemically administered concentrations of gentamicin are occulated from patients with fracture-related infection.
Antipsychotic drugs are an important part of the treatment of irritability and aggression in children with an autism spectrum disorder (ASD). However, significant weight gain and metabolic ...disturbances are clinically relevant side effects of antipsychotic use in children. In the SPACe study, we showed positive correlations between both risperidone and aripiprazole plasma trough concentrations and weight gain over a 6-month period. The trial SPACe 2: STAR is designed as a follow-up study, in which we aim to research whether therapeutic drug monitoring in clinical practice can prevent severe weight gain, while retaining clinical effectiveness.
SPACe 2: STAR is an international, multicentre, randomised controlled trial (RCT). One hundred forty children aged 6 to 18 who are about to start risperidone or aripiprazole treatment for ASD related behavioural problems will be randomised into one of two groups: a therapeutic drug monitoring (TDM) group, and a care as usual (CAU) group. Participants will be assessed at baseline and 4, 10, 24, and 52 weeks follow-up. In the TDM group, physicians will receive dosing advice based on plasma levels of risperidone and aripiprazole and its metabolites at 4 and 10 weeks. Plasma levels will be measured in dried blood spots (DBS). The primary outcome will be BMI z-score at 24 weeks after start of antipsychotic treatment. Among the secondary outcomes are effectiveness, metabolic laboratory measurements, levels of prolactin, leptin and ghrelin, extrapyramidal side effects, and quality of life.
This will be the first RCT evaluating the effect of TDM of antipsychotic drugs in children and adolescents. Thus, findings from SPACe 2: STAR will be of great value in optimising treatment in this vulnerable population.
ClinicalTrials.gov Identifier: NCT05146245. EudraCT number: 2020-005450-18. Sponsor protocol name: SPACe2STAR. Registered 8 June 2021. Protocol Version 6, Protocol date: 18 august 2022.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Axonal degeneration is one of the earliest features of Parkinson's disease pathology, which is followed by neuronal death in the substantia nigra and other parts of the brain. Inhibition of axonal ...degeneration combined with cellular neuroprotection therefore seem key to targeting an early stage in Parkinson's disease progression. Based on our previous studies in traumatic and neurodegenerative disease models, we have identified rho kinase as a molecular target that can be manipulated to disinhibit axonal regeneration and improve survival of lesioned central nervous system neurons. In this study, we examined the neuroprotective potential of pharmacological rho kinase inhibition mediated by fasudil in the in vitro 1-methyl-4-phenylpyridinium cell culture model and in the subchronic in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Application of fasudil resulted in a significant attenuation of dopaminergic cell loss in both paradigms. Furthermore, dopaminergic terminals were preserved as demonstrated by analysis of neurite network in vitro, striatal fibre density and by neurochemical analysis of the levels of dopamine and its metabolites in the striatum. Behavioural tests demonstrated a clear improvement in motor performance after fasudil treatment. The Akt survival pathway was identified as an important molecular mediator for neuroprotective effects of rho kinase inhibition in our paradigm. We conclude that inhibition of rho kinase using the clinically approved small molecule inhibitor fasudil may be a promising new therapeutic strategy for Parkinson's disease.
Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene ...reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5'-untranslated region (5'-UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Family-based association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5'-UTR repeat (PDT P-value=0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.
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