Genetic predisposition to high BMI increases risk of early life respiratory infections and episodes of severe wheeze and asthma.

BACKGROUND: High BMI is an established risk factor for asthma, but the underlying mechanisms remain unclear.Objective: To increase understanding of the BMI-asthma relationship by studying the association between genetic predisposition to higher body mass index (BMI) and asthma, infections, and other asthma-traits during childhood. METHODS: Data was obtained from the two ongoing COPSAC mother-child cohorts. Polygenic risk score (PRS) for adult BMI were calculated for each child. Replication was done in the large-scale iPSYCH cohort using data on hospitalization for asthma and infections. RESULTS: In the COPSAC cohorts (n=974), the adult BMI PRS was significantly associated with lower respiratory tract infections (LRTI) (IRR 1.20 95% CI 1.08-1.33, FDR=0.005) age 0-3 years and episodes of severe wheeze (IRR 1.30, 1.06-1.60, FDR=0.04) age 0-6 years. LRTI partly mediated the association between the adult BMI PRS and severe wheeze (proportion mediated: 0.59, 0.28-2.24, pACME 2E-16). In contrast, these associations were not mediated through the child's current BMI and the PRS was not associated with an asthma diagnosis or reduced lung function up to age 18. The associations were replicated in iPSYCH (n=114 283), where the adult BMI PRS significantly increased the risk of hospitalizations for LRTI and wheeze or asthma during childhood to age 18 years. CONCLUSION: Children with genetic predisposition to higher BMI had increased risk of LRTI and severe wheeze, independent of the child's current BMI. These results shed further light on the complex relationship between BMI and asthma.

Modelling pesticide degradation and leaching in conservation agriculture: Effect of no-till and mulching.

No-till and mulching are typical management operations in conservation agriculture (CA). To model pesticide degradation and leaching under a CA scenario, as compared to a conventional-tillage scenario (CT), the mulch module of the agro-hydrological model Daisy was extended. A Daisy soil column was parameterized with measurements of topsoil, mulch, and a realistic subsoil, and tested against published experimental data of pesticide fate in laboratory soil columns covered by mulch. Uncertainty and sensitivity analyses of the new Daisy version were conducted for a series of weather, soil, pesticide, and mulch parameters, using 4939 Monte Carlo simulations under each scenario. Results showed that there was no systematic difference in pesticide leaching from the topsoil (to the subsoil and directly to drains via drain-connected biopores) between CA and CT, but pesticide degradation and sorption were significantly different; degradation in the mulch and uppermost soil surface layer (0-3.5 cm) was larger in CA while degradation was larger in CT when considering the whole topsoil (0-30 cm). This difference for the whole topsoil could be explained by pesticide interception in CA in the part of the mulch not in direct contact with the soil where degradation is assumed not to occur. The sensitivity analysis highlighted non-influential parameters and seven parameters out of twenty-five to be better estimated to improve the accuracy of the predictions.

Risk factors for tibial infections following osteosynthesis - a systematic review and meta-analysis.

Aim: This study aimed to quantitatively summarise risk factors associated with surgical site infection (SSI) following surgically managed tibial fractures. Method: We searched the Embase/Medline, Cochrane Library, and Scopus databases for relevant studies in October 2023. We included original studies investigating risk factors for SSI following surgically managed traumatic tibial fractures that included ≥10 adult patients with SSIs. Meta-analysis was performed when >5 studies investigated the same risk factor. The risk of bias was assessed using the critical appraisal checklist from Joanna Briggs Institute for cohort studies. Results: This study included 42 studies comprising 24,610 patients with surgically managed tibial fractures and 2,418 SSI cases. The following were identified as significant risk factors for SSI (p < 0.05): compartment syndrome (odds ratio [OR] = 3.8, 95% confidence interval [CI]: 2.4-6.0), blood transfusion (OR = 3.8, 95% CI: 2.1-6.6), open fracture (OR = 3.6, 95% CI: 2.5-5.1), Gustilo-Anderson classification >2 (OR = 3.1, 95% CI: 2.1-4.6), external fixation (OR = 2.9, 95% CI: 2.3-3.8), American Society of Anesthesiologists classification >2 (OR = 2.5, 95% CI: 1.5-4.1), polytrauma (OR = 2.4, 95% CI: 1.5-4.0), dual incision approach (OR = 2.1, 95% CI: 1.5-3.0), smoking (OR = 1.8, 95% CI: 1.5-2.1), male sex (OR = 1.6, 95% CI: 1.3-1.8), high energy trauma (OR = 1.5, 95% CI: 1.1-2.1), and prolonged surgery time (OR = 0.62, 0.43-0.82). Other factors, including diabetes, hypertension, and time to surgery, were not identified as risk factors for SSI. However, the included studies were generally of poor quality and at risk of bias. Conclusions: The review provides a basis for preoperatively assessing a patient's risk of developing an SSI, which could be used to initiate adjusted antibiotic regimes and more frequent postoperative controls. Furthermore, it indicates the risk factors future research should include when adjusting for confounding factors.

A systematic review and meta-analysis on absolute eosinophil counts and the risk of asthma in preschool children with wheezing: An EAACI Task Force Report.

Preschool children with wheezing disorders pose diagnostic and therapeutic challenges and consume substantial healthcare resources. Peripheral eosinophil blood count (EBC) has been proposed as a potential indicator for future asthma development. This review by the European Academy of Allergy and Clinical Immunology (EAACI) Preschool Wheeze Task Force aimed to provide systematic evidence for the association between increased EBC and the risk of future asthma, as well as to identify potential cutoff values. In February 2023, a search of PubMed, EMBASE, and Cochrane Library databases was conducted to identify studies comparing EBCs in preschool children with wheezing who continued to wheeze later in life and those who did not. Included observational studies focused on children aged <6 years with a wheezing disorder, assessment of their EBCs, and subsequent asthma status. No language or publication date restrictions were applied. Among the initial 3394 studies screened, 10 were included in the final analysis, involving 1225 patients. The data from these studies demonstrated that high EBC in preschool children with wheezing is associated with future asthma development, with odds ratios of 1.90 (95% CI: 0.45-7.98, p = .38), 2.87 (95% CI: 1.38-5.95, p < .05), and 3.38 (95% CI: 1.72-6.64, p < .05) for cutoff values in the <300, 300-449, and ≥450 cells/µL ranges, respectively. Defining a specific cutoff point for an elevated EBC lacks consistency, but children with EBC >300 cells/µL are at increased risk of asthma. However, further research is needed due to the limitations of the included studies. Future investigations are necessary to fully elucidate the discussed association.

Translation and validation of the Hirschsprung and anorectal malformation quality of life (HAQL) questionnaire in a Danish Hirschsprung population.

BACKGROUND: Hirschsprung's disease (HD) may result in an impaired quality of life (QoL) due to bowel problems, postoperative complications and other health-related issues. The Hirschsprung and Anorectal Malformation Quality of Life (HAQL) questionnaire is a disease-specific instrument developed in the Netherlands to measure the QoL in patients with HD and anorectal malformations. The aim of this study was to translate, culturally adapt and validate HAQL in a Danish Hirschsprung population. MATERIAL AND METHODS: Translation and cultural adaptation were performed according to international guidelines. Invitations to participate in the validation were sent to 401 patients operated for HD during the period from 1985 to 2012. A total of 156 patients completed the translated and culturally adapted Danish versions of HAQL and 35 parents of children and adolescents completed the corresponding parent questionnaire. Reliability was evaluated in terms of internal consistency using Cronbach's α and test-retest reliability using Intraclass Correlation Coefficient for the retest step. Known groups comparison was performed with comparison of mild HD (defined as recto-sigmoidal HD) and serious HD (defined as more proximal disease). RESULTS: The internal consistency of the dimensions was overall satisfactory for adults and adolescents but more problematic for children, where Cronbach's α was less than 0.7 in 60% of the dimensions. For both children and adolescents, the α-value was unsatisfactory for social functioning, emotional functioning, and body image. The test-retest reliability was overall good. The known groups comparison was only able to demonstrate a significant difference between mild and severe HD within one dimension. CONCLUSIONS: The translated version of the HAQL questionnaires provides an overall reliable instrument for evaluating disease-specific QoL in a Danish HD population, but it is important to acknowledge the limitations of the questionnaire, especially in children and adolescents.

Parasitoids of the cabbage seed weevil deliver high and consistent parasitism in variable landscapes: A showcase of conservation biocontrol.

BACKGROUND: Insect pest resistance to insecticides and societal pressure to reduce pesticide load has increased oilseed rape (OSR) farmers' motivation to protect and exploit parasitoids for pest control. However, parasitoid presence and parasitism must be made visible to influence farmers' spraying decisions. Parasitism of cabbage seed weevil (CSW) (Ceutorhynchus obstrictus (Marsham)) reduces damage to OSR immediately, making them a good case for demonstrating conservation biocontrol to farmers. We assessed the occurrence and activity of CSW parasitoids in 84 OSR fields over 2 years and identified the impact of associated local landscape factors. RESULTS: Mean cabbage seed weevil infestation rates were 11% and 10% in 2020 and 2021, and parasitism rates were high in both years (75% and 74%, respectively). Temporal and spatial dynamics of OSR in the landscape surrounding the focal fields were important for both CSW and parasitoid numbers, suggesting a dilution effect for increasing OSR area since the previous year. A multimodel inference analysis showed that OSR-related factors were important predictors for both the infestation rate of CSW and the number of parasitoids. For parasitoids, protected nature areas and hedgerows were important. Parasitism rates were high and largely unaffected by landscape factors. CONCLUSION: CSW and its parasitoids respond similarly to interannual changes in the OSR resource; in addition, parasitoids benefit from uncropped areas in the surrounding landscape. The complexity of the pest and parasitoid response to landscape factors limits the prospect of designing landscapes for improved pest control by the parasitoids. Parasitoids of CSW may be present as local populations in agricultural landscapes with the potential for consistent and substantial parasitism. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Plant disease detection model for edge computing devices.

In this paper, we address the question of achieving high accuracy in deep learning models for agricultural applications through edge computing devices while considering the associated resource constraints. Traditional and state-of-the-art models have demonstrated good accuracy, but their practicality as end-user available solutions remains uncertain due to current resource limitations. One agricultural application for deep learning models is the detection and classification of plant diseases through image-based crop monitoring. We used the publicly available PlantVillage dataset containing images of healthy and diseased leaves for 14 crop species and 6 groups of diseases as example data. The MobileNetV3-small model succeeds in classifying the leaves with a test accuracy of around 99.50%. Post-training optimization using quantization reduced the number of model parameters from approximately 1.5 million to 0.93 million while maintaining the accuracy of 99.50%. The final model is in ONNX format, enabling deployment across various platforms, including mobile devices. These findings offer a cost-effective solution for deploying accurate deep-learning models in agricultural applications.

Limited clinical role of blood eosinophil levels in early life atopic disease: A mother-child cohort study.

BACKGROUND: Blood eosinophil count is a well-established biomarker of atopic diseases in older children and adults. However, its predictive role for atopic diseases in preschool children is not well established. OBJECTIVE: To investigate the association between blood eosinophil count in children and development of atopic diseases up to age 6 years. METHODS: We investigated blood eosinophil count at age 18 months and 6 years in relation to recurrent wheeze/asthma, atopic dermatitis, allergic rhinitis, and allergic sensitization during the first 6 years of life in the two Copenhagen Prospective Studies on Asthma in Childhood cohorts (n = 1111). Blood eosinophil count was investigated in association with remission of existing atopic disease, current atopic disease, and later development of atopic disease. RESULTS: Blood eosinophil count at 18 months was not associated with current wheezing/asthma or atopic dermatitis, while blood eosinophil count at age 6 years was associated with increased occurrence of current wheezing/asthma (OR = 1.1; 1.04-1.16, p = .0005), atopic dermatitis (OR = 1.06; 1.01-1.1, p = .02), and allergic rhinitis (OR = 1.11; 1.05-1.18, p = .0002). Blood eosinophil count at 18 months did not predict persistence or development of recurrent wheeze/asthma or atopic dermatitis at age 6 years. CONCLUSION: Blood eosinophil count at 18 months was not associated with current wheezing/asthma or atopic dermatitis and did not predict persistence or development of disease. This implies a limited clinical role of blood eosinophil levels in early-life atopic disease and questions the clinical value of blood eosinophil counts measured in toddlers as a predictive biomarker for subsequent atopic disease in early childhood.

The prognostic value of coronary flow reserve in patients with non-obstructive coronary artery disease and microvascular dysfunction: a systematic review and meta-analysis with focus on imaging modality and sex difference.

To clarify prognosis of patients with non-obstructive coronary artery disease (NOCAD) and coronary microvascular disease (CMD) assessed as low coronary flow reserve (CFR) according to imaging modalities and sex difference. Comprehensive systematic literature review and meta-analyses were conducted. Risk of death and major adverse cardiac events (MACE) were pooled and compared in patients with abnormally low versus normal CFR using cut-off limits 2.0-2.5. Random effects model used for estimation of odds ratios (OR) and hazard ratios (HR) with 95% confidence interval (CI). Nineteen eligible observational studies provided data for death and MACE, publication bias was insignificant, p = 0.62. Risk of death and MACE were significantly higher in patients with low (n = 4.612, 29%) than normal CFR (n = 11.367, 71%): using transthoracal echocardiography (TTE) (OR 4.25 (95% CI 2.94, 6.15) p < 0.001) and (OR 6.98 (95% CI 2.56, 19.01) p < 0.001), positron emission tomography (PET) (OR 2.51 (CI 95%: 1.40, 4..49) p = 0.002) and (OR 2.87 (95% CI 2.16, 3.81) p < 0.001), and invasive intracoronary assessment (OR 2.23 (95% CI 1.15, 4.34) p < 0.018), and (OR 4.61 (95% CI 2.51, 8.48) p < 0.001), respectively. Pooled adjusted HR for death and MACE were (HR 2.45(95% CI 1.37, 3.53) p < 0.001) and (HR 2.08 (95% CI 1.54, 2.63) p < 0.001) respectively. Studies comparing men and women with abnormally low CFR demonstrated similar worse prognosis in both sexes. Low CFR is associated with poorer prognosis in patients with NOCAD regardless of sex. TTE may overestimate risk of death and MACE, while PET seems to be more appropriate. Future studies are needed to consolidate the current evidence.

Practical guidance to evaluate in vitro dermal absorption studies for pesticide registration: An industry perspective.

While there are some regulatory assessment criteria available on how to generally evaluate dermal absorption (DA) studies for risk assessment purposes, practical guidance and examples are lacking. The current manuscript highlights the challenges in interpretating data from in vitro assays and proposes holistic data-based assessment strategies from an industry perspective. Inflexible decision criteria may be inadequate for real data and may lead to irrelevant DA estimates. We recommend the use of mean values for reasonably conservative DA estimates from in vitro studies. In cases where additional conservatism is needed, e.g., due to non-robust data and acute exposure scenarios, the upper 95% confidence interval of the mean may be appropriate. It is critical to review the data for potential outliers and we provide some example cases and strategies to identify aberrant responses. Some regional regulatory authorities require the evaluation of stratum corneum (SC) residue, but here, as a very simple pro-rata approach, we propose to review whether the predicted post 24-h absorption flux exceeds the predicted elimination flux by desquamation because otherwise it is not possible for the SC residue to contribute to systemic dose. Overall, the adjustment of DA estimates due to mass balance (normalization) is not recommended.

Early versus late weight-bearing in operatively treated ankle fractures with syndesmotic injury: A systematic review.

BACKGROUND: Over the past 30 years, several studies have compared early weight-bearing versus late weight-bearing following open reduction and internal fixation of ankle fractures; however, no review strictly including patients with ankle fractures and complete syndesmotic disruption has been performed. OBJECTIVE: The objective of this systematic review was to compare early versus late weight-bearing following surgery for ankle fracture with syndesmotic injury regarding clinical and patient-reported outcomes. METHODS: A comprehensive search strategy was applied to the Cochrane Library, MEDLINE, Embase, CINAHL and PubMed databases from their inception to the 17th of January 2022. The articles were screened independently by two blinded reviewers. Data were extracted by one author, then cross-checked and approved by the other. RESULTS: No comparative studies were found; therefore, studies describing either early or late weight-bearing were included. It was thus not possible to perform a meta-analysis. 11 studies and 751 patients were included. An early partial weight-bearing protocol was used in three studies (253 patients) and late in eight studies (498 patients). Functional outcomes suggested that there were no clear differences between early partial weight-bearing and late weight-bearing. The reoperation rate was 9-31% in the early group and 0-11% in the late. Similar results were seen for loss of syndesmotic reduction, malreduction, infection, and fixation failure. CONCLUSION: Pros and cons were reported for early partial weight-bearing and late weight-bearing, but the evidence was very limited as our results were based on noncomparative studies. In the future, high-quality comparative studies focusing on functional outcomes within 6 months postoperatively are needed. LEVEL OF CLINICAL EVIDENCE: 1.

Changes in the incidence and treatment of distal radius fractures in adults - a 22-year nationwide register study of 276,145 fractures.

INTRODUCTION: The incidence of distal radius fractures (DRFs) is reported, with conflicting results. To ensure evidence-based practice, the variation in treatment over time should be monitored. Treatment in the elderly population is particularly interesting because newer guidelines find little indication for surgery. Our primary aim was to assess the incidence and treatment of DRFs in the adult population. Secondly, we assessed the treatment stratified on non-elderly (aged 18-64 years) and elderly (aged 65+ years) patients. METHODS: This is a population-based register study comprising all adult patients (i.e. aged over 18 years) with DRFs in the Danish National Patient Register from 1997 to 2018. Data were extracted using the ICD-10 code for DRF (DS52.5), and the incidence was calculated using data from Statistics Denmark. We defined a case as surgically treated if a relevant procedure was performed within three weeks of the DRF diagnosis. Nordic procedure codes were used to define surgical treatments as either plate (KNCJ65), external fixation (KNCJ25), k-wire (KNCJ45), or 'other' (KNCJ35,55,75,85,95). RESULTS: A total of 276,145 fractures were included, with an overall increase in DRFs of 31% during the study period. The overall incidence was 228/100,000/year, which increased by 20% during the study period. The increased incidence was especially notable among women and those aged 50-69 years. Surgical treatment steadily increased from 8% in 1997 to 22% in 2010, thereafter reaching a plateau at 24% in 2018. The surgical rate in the elderly group was as high as in the non-elderly group. In 1997, the treatment distribution of DRFs was as follows: 59% external fixation, 20% plate fixation, and 18% k-wire fixation. From 2007 and onwards, plating was the primary choice of surgery, and in 2018, 96% of patients were treated with a plate. CONCLUSION: We found a 31% increase in DRFs over a 22-year period, mostly driven by an increase in the size of the elderly population. The surgical rate increased markedly even in the elderly group. There is a lack of evidence on how beneficial surgery is for elderly patients, and similar surgical rate between the elderly and non-elderly calls for hospitals to re-evaluate their treatment strategies.

Risk Factors and Age-Related Patterns of Asthma-Like Symptoms in Early Childhood.

BACKGROUND: Episodes of asthma-like symptoms in young children are common, but little is known about risk factors and their patterns for the daily symptom burden. OBJECTIVE: We investigated a variety of possible risk factors and their age-related impact on the number of asthma-like episodes during age 0 to 3 years. METHODS: The study population included 700 children from the Copenhagen Prospective Studies on Asthma in Childhood2010 mother-child cohort followed prospectively from birth. Asthma-like symptoms were recorded until age 3 by daily diaries. Risk factors were analyzed by quasi-Poisson regressions, and interaction with age was explored. RESULTS: Diary data were available in 662 children. Male sex, maternal asthma, low birth weight, maternal antibiotic use, high asthma exacerbation polygenic risk score, and high airway immune score were associated with a higher number of episodes in a multivariable analysis. Maternal asthma, preterm birth, caesarean section, and low birth weight showed an increasing impact with age, whereas sibling(s) at birth showed a decreased association with age. The remaining risk factors had a stable pattern during age 0 to 3 years. For every additional clinical risk factor (male sex, low birth weight, and maternal asthma) a child had, we found 34% more episodes (incidence rate ratio: 1.34, 95% confidence interval: 1.21-1.48; P < .001). CONCLUSION: Using unique day-to-day diary recordings, we identified risk factors for the burden of asthma-like symptoms in the first 3 years of life and described their unique age-related patterns. This provides novel insight into the origin of asthma-like symptoms in early childhood that potentially pave a path for personalized prognostics and treatment.

Translation and cultural adaption of the emergency department-consumer assessment of healthcare providers and systems (ED CAPHS)-A questionnaire to measure patient experience in Denmark.

AIM: The aim of this study was to translate and culturally adapt The Emergency Department-Consumer Assessment of Healthcare Providers and Systems (ED CAPHS) to the Danish ED context. BACKGROUND: In Denmark, a large number of patients attend emergency departments (ED) every year. During their ED visits, examinations, tests and encounters with different healthcare professionals occur frequently. Moreover, patients receive much information. Patients' direct experiences of care can provide valuable insights into what works and what does not in health care. The emergency department-consumer assessment of healthcare providers and systems (ED CAPHS) is a valid questionnaire designed to measure patients' experiences with ED care and is intended for patients discharged home following their ED visit. METHOD: The translation process was systematically planned and executed using the principles of good practice for the translation and cultural adaptation process for patient-reported outcomes (PRO) guidelines by the ISPOR. RESULTS: The translation and cultural adaption process were successfully conducted. Three items concerning language and race were omitted as they are not distinct in Danish ED context. Furthermore, a few conceptual factors and linguistic challenges were discussed and harmonised during the reconciliation and harmonisation process respectively. The Danish survey ED CAPHS DK containing 32 items was proofread and finalised. CONCLUSION: Overall, patients reported that the survey was relevant and comprehensive, as it focused on essential factors when discharged directly home after an ED admission. ED CAPHS DK is found to be content valid and ready for use. However, a future study testing the Danish version using confirmative factor analysis and internal consistency reliability is needed to ensure construct validity and reliability.

Using R in Regulatory Toxicology.

Statistical analyses are an essential part of regulatory toxicological evaluations. While projects would be ideally monitored by both toxicologists and statisticians, this is often not possible in practice. Hence, toxicologists should be trained in some common statistical approaches but also need a tool for statistical evaluations. Due to transparency needed in regulatory processes and standard tests that can be evaluated with template approaches, the freely available open-source statistical software R may be suitable. R is a well-established software in the statistical community. The principal input method is via software code, which is both benefit and weakness of the tool. It is increasingly used by regulating authorities globally and can be easily extended by software packages, e.g., for new statistical functions and features. This manuscript outlines how R can be used in regulatory toxicology, allowing toxicologists to perform all regulatory required data evaluations in a single software solution. Practical applications are shown in case studies on simulated and experimental data. The examples cover a) Dunnett testing of treatment groups against a common control and in relation to a biological relevance threshold, assessing the test's assumptions and plotting the results; b) dose-response analysis and benchmark dose derivation for chronic kidney inflammation as a function of Pyridine; and c) graphical/exploratory data analysis of previously published developmental neurotoxicity data for Chlorpyrifos.

Risk factors for nonunion following surgically managed, traumatic, diaphyseal fractures: a systematic review and meta-analysis.

Background: There are several studies on nonunion, but there are no systematic overviews of the current evidence of risk factors for nonunion. The aim of this study was to systematically review risk factors for nonunion following surgically managed, traumatic, diaphyseal fractures. Methods: Medline, Embase, Scopus, and Cochrane were searched using a search string developed with aid from a scientific librarian. The studies were screened independently by two authors using Covidence. We solely included studies with at least ten nonunions. Eligible study data were extracted, and the studies were critically appraised. We performed random-effects meta-analyses for those risk factors included in five or more studies. PROSPERO registration number: CRD42021235213. Results: Of 11,738 records screened, 30 were eligible, and these included 38,465 patients. Twenty-five studies were eligible for meta-analyses. Nonunion was associated with smoking (odds ratio (OR): 1.7, 95% CI: 1.2-2.4), open fractures (OR: 2.6, 95% CI: 1.8-3.9), diabetes (OR: 1.6, 95% CI: 1.3-2.0), infection (OR: 7.0, 95% CI: 3.2-15.0), obesity (OR: 1.5, 95% CI: 1.1-1.9), increasing Gustilo classification (OR: 2.2, 95% CI: 1.4-3.7), and AO classification (OR: 2.4, 95% CI: 1.5-3.7). The studies were generally assessed to be of poor quality, mainly because of the possible risk of bias due to confounding, unclear outcome measurements, and missing data. Conclusion: Establishing compelling evidence is challenging because the current studies are observational and at risk of bias. We conclude that several risk factors are associated with nonunion following surgically managed, traumatic, diaphyseal fractures and should be included as confounders in future studies.

Benchmark dose modelling in regulatory ecotoxicology, a potential tool in pest management.

For several authorities, benchmark dose (BMD) methodology has become the recommended approach by which to derive reference values for risk assessment. However, in practice, the BMD approach is not standard use in risk assessment for pesticides where the no observed adverse effect level, lowest observed adverse effect level and effective dose (ED50 or EDx ) prevail. Regression-based BMD and the benchmark dose lower confidence limit (BMDL) have several advantages, such as utilizing more information from the generated data and being less dependent on tested dose levels. However, the BMD approach requires some degree of expert knowledge for defining an appropriate risk level for estimating the BMD and using more sophisticated statistical methods to calculate BMD and BMDL. The BMD approach is one way to move away from p value-based binary decision-making towards putting the weight on effect sizes. We review the advantages and disadvantages of focusing on the BMD approach for risk assessment of pesticides. Further, we discuss potential applications in efficacy trials for pest management purposes. © 2021 Society of Chemical Industry.

Using historical control data in bioassays for regulatory toxicology.

Historical control data (HCD) consist of pooled control group responses from bioassays. These data must be collected and are often used or reported in regulatory toxicology studies for multiple purposes: as quality assurance for the test system, to help identify toxicological effects and their effect-size relevance and to address the statistical multiple comparison problem. The current manuscript reviews the various classical and potential new approaches for using HCD. Issues in current practice are identified and recommendations for improved use and discussion are provided. Furthermore, stakeholders are invited to discuss whether it is necessary to consider uncertainty when using HCD formally and statistically in toxicological discussions and whether binary inclusion/exclusion criteria for HCD should be revised to a tiered information contribution to assessments. Overall, the critical value of HCD in toxicological bioassays is highlighted when used in a weight-of-evidence assessment.

A Systematic Review and Meta-Analysis Finds Increased Blood Levels of All Forms of Ghrelin in Both Restricting and Binge-Eating/Purging Subtypes of Anorexia Nervosa.

Anorexia nervosa (AN) is a severe psychiatric condition associated with high mortality and chronicity. The hunt for state, trait, subtyping, and prognostic biomarkers is ongoing and the orexigenic hormone ghrelin and its different forms, acyl ghrelin and desacyl ghrelin, have been proposed to be increased in AN, especially in the restrictive subtype. A systematic literature search was performed using established databases up to 30 November 2020. Forty-nine studies met inclusion criteria for cross-sectional and longitudinal meta-analyses on total ghrelin, acyl ghrelin, and desacyl ghrelin. All forms of ghrelin were increased in the acute stage of anorexia nervosa during fasting compared to healthy controls. Previous notions on differences in ghrelin levels between AN subtypes were not supported by current data. In addition, a significant decrease in total ghrelin was observed pre-treatment to follow-up. However, total ghrelin levels at follow-up were still marginally elevated compared to healthy controls, whereas for acyl ghrelin, no overall effect of treatment was observed. Due to heterogeneity in follow-up designs and only few data on long-term recovered patients, longitudinal results should be interpreted with caution. While the first steps towards a biomarker in acute AN have been completed, the value of ghrelin as a potential indicator of treatment success or recovery status or its use in subtype differentiation are yet to be established.

A Nonmechanistic Parametric Modeling Approach for Benchmark Dose Estimation of Event-Time Data.

We propose benchmark dose estimation for event-time data, using a two-step approach. This approach avoids estimation of complex models and has been previously shown to give robust results for summarizing relevant parameters for risk assessment. In the first step, the probability of the event of interest to occur (in a certain time interval) is described as a function of time, resulting in an event-time model; such a model is fitted allowing an individual curve for each dose, and relevant estimates are extracted. In the second step, a dose-response model is fitted to the estimates of t50 obtained from the event-time model in the first step. Given a predefined benchmark response, the benchmark dose is then estimated from the resulting model. This novel approach is demonstrated in two examples. Our application of the time-to-event model showed a gain in power compared to the traditional analysis of end-of-study summary data.