► Toxicokinetics (TK) is a key element to integrate the results from in silico, in vitro and in vivo studies. ► TK is needed to estimate target organ doses expected from realistic human external ...exposure scenarios. ► TK is necessary for quantitative in vitro–in vivo extrapolation (IVIVE). ► Physiologically based toxicokinetic modelling (PBTK) is the most adequate approach to simulate human TK. ► PBTK models are mechanism-based, but high-quality in vitro and in silico data is necessary for their success.
Toxicokinetics (TK) is the endpoint that informs about the penetration into and fate within the body of a toxic substance, including the possible emergence of metabolites. Traditionally, the data needed to understand those phenomena have been obtained in vivo. Currently, with a drive towards non-animal testing approaches, TK has been identified as a key element to integrate the results from in silico, in vitro and already available in vivo studies. TK is needed to estimate the range of target organ doses that can be expected from realistic human external exposure scenarios. This information is crucial for determining the dose/concentration range that should be used for in vitro testing. Vice versa, TK is necessary to convert the in vitro results, generated at tissue/cell or sub-cellular level, into dose response or potency information relating to the entire target organism, i.e. the human body (in vitro–in vivo extrapolation, IVIVE). Physiologically based toxicokinetic modelling (PBTK) is currently regarded as the most adequate approach to simulate human TK and extrapolate between in vitro and in vivo contexts. The fact that PBTK models are mechanism-based which allows them to be ‘generic’ to a certain extent (various extrapolations possible) has been critical for their success so far. The need for high-quality in vitro and in silico data on absorption, distribution, metabolism as well as excretion (ADME) as input for PBTK models to predict human dose–response curves is currently a bottleneck for integrative risk assessment.
Parental involvement is an essential component of obesity prevention interventions for children. The present study provides a process and impact evaluation of the family component of SuperFIT. ...SuperFIT is a comprehensive, integrated intervention approach aiming to improve energy balance-related behaviors (EBRBs) of young children (2-4 years). A mixed methods design combined in-depth interviews with parents (
= 15) and implementers (
= 3) with questionnaire data on nutritional and physical activity-related parenting practices (CFPQ and PPAPP), the physical home environment (EPAO_SR) (
= 41), and intervention appreciation (
= 19). Results were structured using the concepts of reach, adoption, implementation, and perceived impact. Findings indicated that the families reached were mostly those that were already interested in the topic. Participants of the intervention appreciated the information received and the on-the-spot guidance on their child's behavior. Having fun was considered a success factor within the intervention. Parents expressed the additional need for peer-to-peer discussion. SuperFIT increased awareness and understanding of parents' own behavior. Parents made no changes in daily life routines or the physical home environment. Translating knowledge and learned strategies into behavior at home has yet to be achieved. To optimize impact, intervention developers should find the right balance between accessibility, content, and intensity of interventions for parents.
Background From a complex systems perspective, implementation should be understood as the introduction of an intervention in a context with which it needs to interact in order to achieve its function ...in terms of improved health. The presence of intervention-context interactions could mean that during implementation particular patterns of crucial interaction points might arise. We examined the presence of - and regularities in - such 'bottlenecks for implementation', as this could create opportunities to predict and intervene in potential implementation problems. Methods We conducted a cross-sectional observational study against the background of municipal intersectoral policymaking in the Netherlands. We asked implementers of health promotion interventions to identify bottlenecks by rating the presence and importance of conditions for implementation in a range of intervention systems. We used descriptive statistics to characterize these systems (by their behaviour change method, health theme and implementation setting) and the conditions that acted as bottlenecks. After stratifying bottlenecks by intervention system and the system's characteristics, we tested our hypotheses by comparing the number and nature of the bottlenecks that emerged. Results More than half of the possible conditions were identified as a bottleneck for implementation. Bottlenecks occurred in all categories of conditions, e.g., relating to the implementer, the intervention, and political and administrative support, and often connected with intersectoral policymaking, e.g., relating to the co-implementer and the co-implementer's organization. Both our hypotheses were supported: (1) Each intervention system came across a unique set of - a limited number of - conditions hampering implementation; (2) Most bottlenecks were associated with the characteristics of the system in which they occurred, but bottlenecks also appeared in the absence of such an association, or remained absent in the presence thereof. Conclusions We conclude that intervention-context interactions in integrated health policymaking may lead to both regularities and variations in bottlenecks for implementation. Regularities may partly be predicted by the function of an intervention system, and may serve as the basis for building the capacity needed for the structural changes that can bring about long-lasting health improvements. Variations may point at the need for flexibility in further tailoring the implementation approach to the - mostly unpredictable - problems at individual sites. Keywords: Implementation, Health promotion, Intervention-context interactions, Bottlenecks
Measurements were done on both arms of ten specially embalmed specimens. Arms were dissected and radiopaque wires attached to the radial nerve in the distal part of the upper arm. Digital radiographs ...were obtained to determine the course of the radial nerve in the distal 20 cm of the humerus in relation to bony landmarks; medial epicondyle and capitellum-trochlea projection (CCT). Analysis was done with ImageJ and Microsoft Excel software. We also compared humeral nail specifications from different companies with the course of the radial nerve to predict possible radial nerve damage.
The distance from the medial epicondyle to point where the radial nerve bends from posterior to lateral was 142 mm on AP radiographs and 152 mm measured on the lateral radiographs. The average distance from the medial epicondyle to point where the radial nerve bends from lateral to anterior on AP radiographs was 66 mm. On the lateral radiographs where the nerve moves away from the anterior cortex 83 mm to the center of capitellum and trochlea (CCT). The distance from the bifurcation of the radial nerve into the posterior interosseous nerve (PIN) and superficial radial nerve was 21 mm on AP radiographs and 42 mm on the lateral radiographs (CCT).
The course of the radial nerve in the distal part of the upper arm has great variety. Lateral fixation is relatively safe in a zone between the center of capitellum-trochlea and 48 mm proximal to this point. The danger zone in lateral fixation is in-between 48-122 mm proximal from CCT. In anteroposterior direction; distal fixation is dangerous between 21-101 mm measured from the medial epicondyle. The more distal, the more medial the nerve courses making it more valuable to iatrogenic damage. The IMN we compared with our data all show potential risk in case of (blind) distal locking, especially from lateral to medial direction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The relatively high experimental animal use in developmental toxicity testing has stimulated the search for alternatives that are less animal intensive. Three widely studied alternative assays are ...the mouse Embryonic Stem cell Test (EST), the Zebrafish Embryotoxicity Test (ZET) and the rat postimplantation Whole Embryo Culture (WEC). The goal of this study was to determine their efficacy in assessing the relative developmental toxicity of six 1,2,4-triazole compounds,
1
1
In this paper, the name triazoles is used as synonym for 1,2,4-triazoles.
flusilazole, hexaconazole, cyproconazole, triadimefon, myclobutanil and triticonazole. For this purpose, we analyzed effects and relative potencies of the compounds in and among the alternative assays and compared the findings to their known
in vivo developmental toxicity. Triazoles are antifungal agents used in agriculture and medicine, some of which are known to induce craniofacial and limb abnormalities in rodents. The WEC showed a general pattern of teratogenic effects, typical of exposure to triazoles, mainly consisting of reduction and fusion of the first and second branchial arches, which are in accordance with the craniofacial malformations reported after
in vivo exposure. In the EST all triazole compounds inhibited cardiomyocyte differentiation concentration-dependently. Overall, the ZET gave the best correlation with the relative
in vivo developmental toxicities of the tested compounds, closely followed by the EST. The relative potencies observed in the WEC showed the lowest correlation with the
in vivo developmental toxicity data. These differences in the efficacy between the test systems might be due to differences in compound kinetics, in developmental stages represented and in the relative complexity of the alternative assays.
Although the genus Prevotella is part of the general human microbiota, species of this anaerobic gram-negative bacterium have been described as causes of persisting nonpuerperal breast abscesses. ...Collecting punctate samples and testing these samples for anaerobic bacteria is not part of the common diagnostic workflow in atypical breast abscesses. The causative anaerobic micro-organism can remain unclear and patients can be treated with multiple inadequate antibiotics and/or extensive surgical procedures. The aim of this cohort study of Prevotella induced breast abscesses is to gain more insights into the diagnostic procedures and treatment.
Medical charts of patients with a Prevotella induced breast abscess between 2015 and 2021, were retrospectively reviewed on patient characteristics, diagnostic procedures, treatment and outcome.
Twenty-one patients were included. Six subspecies of Prevotella were determined by culturing. High susceptibility was observed for amoxicillin/clavulanic acid (100%, n = 12). Nine patients (43%) were treated with antibiotics, eight patients (38%) with antibiotics and incision and drainage, and four patients (19%) with only incision and drainage. Recurrence was observed in nine patients (43%), of whom five patients were treated with antibiotics and three patients had surgery. The mean duration of antibiotic administration in patients with recurrence was significantly shorter compared to those without recurrence (5.6 days vs. 19.5 days, p = 0.039).
Specific anaerobic culturing should be common practice in atypical breast abscesses to confirm Prevotella species. The high recurrence rate emphasizes the need of further research for optimal treatment. Prolonged duration of antibiotics could be considered and amoxicillin/clavulanic acid seems to be the first choice.
•Prevotella has been described as a cause of persisting nonpuerperal breast abscesses.•It is essential to exclude cancer as soon as possible in atypical breast abscesses.•The diagnostic process of Prevotella is challenging.•Anaerobic culturing with a punctate/aspirate should be added to the diagnostic process.•Prolonged duration of antimicrobial therapy could be considered.
There are few validated predictors of the need for additional surgery in idiopathic clubfeet treated according to the Ponseti method. Our aim was to examine if physical examination (Pirani score) and ...radiographs at the age of three months (after initial correction of the clubfeet) can predict the future need for additional surgery. In this retrospective cohort study, radiographs of idiopathic clubfeet were made at the age of three months. The Pirani score was determined at the first cast, before tenotomy, and at the age of three months. Follow-up was at least five years. The correlation between the radiograph, Pirani score, and the need for additional surgery was explored with logistic regression analysis. Parent satisfaction was measured with a disease-specific instrument. The study included 72 clubfeet (50 children) treated according to the Ponseti method. Additional surgery was needed on 27 feet (38%). A larger lateral tibiocalcaneal angle (i.e., equinus) and a smaller lateral talocalcaneal angle (i.e., hindfoot varus) at the age of three months were correlated with the need for additional surgery. Higher Pirani scores before tenotomy and at the age of three months also correlated with additional surgery. Parent satisfaction was lower in patients who needed additional surgery. Both the Pirani scores and the lateral radiographs are predictive for future additional surgery.
In recent years, the nutritional pattern of the Dutch adolescent has cautiously improved. However, progress can be gained if more Dutch adolescents adhere to the nutritional guidelines. School-based ...initiatives offer opportunities to deal with the unhealthy eating behaviours of adolescents via nutrition educational interventions. In designing and/or re-designing school-based interventions, it is important to enhance optimal context-oriented implementation adaptation by involving the complex adaptive school system. This paper elaborates on the way of dealing with the dynamic implementation context of the educational programme “Krachtvoer” (ENG: “Power food”) for prevocational schools, how the programme can be adapted to each unique implementation context, and how the programme can be progressively kept up to date. Following a co-creation-guided approach with various intersectoral stakeholders within and outside the school setting, action-oriented mixed research methods (i.e., observations, semi-structured interviews, focus group interviews, programme usage monitoring, and questionnaires) constantly provide input to develop the programme and its implementation strategy via continuous micro-process cycles. Successful co-creation of school-based health promotion seems to be dependent on proper intersectoral cooperation between research and practice communities, a national partner network that can provide project-relevant insights and establish capacity building aimed at improving contextual fit, and a time-investment balance in and between sectors.
Although the genus Prevotella is part of the general human flora, species of this anaerobic gram-negative bacteria have been described as cause of persisting nonpuerperal breast abscesses. Collecting ...punctate samples and testing these samples for anaerobic bacteria, is not part of the common diagnostic workflow in atypical breast abscesses. The causative anaerobic micro-organism can remain unclear and patients can be treated with multiple inadequate antibiotics and/or extensive surgical procedures. The aim of this cohort study of Prevotella induced breast abscesses is to gain more insights into the diagnostic procedures and treatment.
Medical charts of patients with a Prevotella induced breast abscess between 2015 and 2021, were retrospectively reviewed on patient characteristics, diagnostic procedures, treatment and outcome.
Twenty-one patients were included. Six subspecies of Prevotella were determined by culturing. High susceptibility was observed for amoxicillin/clavulanic acid (100%, n = 12). Nine patients (43%) were treated with antibiotics, eight patients (38%) with antibiotics and incision and drainage, and four patients (19%) with only incision and drainage. Recurrence was observed in nine patients (43%), of whom five patients were treated with antibiotics and three patients had surgery. The mean duration of antibiotic administration in patients with recurrence was significantly shorter compared to those without recurrence (5.6 days vs. 19.5 days, p = 0.039).
Specific anaerobic culturing should be common practice in atypical breast abscesses to confirm Prevotella species. The high recurrence rate emphasizes the need of further research for optimal treatment. Prolonged duration of antibiotics could be considered and amoxicillin/clavulanic acid seems to be the first choice.
If in vitro data are to be used as a basis for hazard characterization, a translation of an in vitro concentration toward an in vivo dose must be made. In this study we examined the correlation ...between dose descriptors from the in vitro Whole Embryo Culture (WEC) test and in vivo developmental toxicity tests. We applied the Benchmark Dose (BMD) approach to estimate equipotent in vitro concentrations (Benchmark Concentrations BMCs) and equipotent in vivo doses (BMDs). Using the data generated in an European Center for the Validation of Alternative Methods validation study we found that the BMCs were highly reproducible among laboratories. The three endpoints analyzed (head length, crown–rump length, and total morphological score) were strongly correlated. A clear in vitro–in vivo correlation was found between BMCs and BMDs. However, a considerable uncertainty would remain if the BMDs were estimated from the BMC using this correlation: the confidence interval of such an in vivo dose estimate would span various orders of magnitude. Differences in toxicokinetic properties among the compounds explained at least part of the scatter of the in vitro–in vivo correlation. But also heterogeneity in the design of the available in vivo studies underlies much of the scatter, and this puts a limit on validating in vitro data as predictors of in vivo data. Further analysis of the in vitro–in vivo correlation would therefore require high-quality in vivo data, generated by appropriate (and similar) study designs.
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