bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and verification of a physiologically based pharmacokinetic model of dronedarone and its active metabolite N‐desbutyldronedarone: Application to prospective simulation of complex drug–drug interaction with rivaroxaban
Authors: Leow Jacqueline Wen Hui , Ang Xiao Jun , Chan Eric Chun Yong 
Published: January 2023

AimsDespite potential enzyme‐ and transporter‐mediated drug–drug interactions (DDIs) between dronedarone and rivaroxaban in atrial fibrillation (AF) patients, pharmacokinetic/pharmacodynamic data remain limited to guide clinical practice. We aimed to develop, verify and validate a physiologically based pharmacokinetic (PBPK) model of dronedarone and its major metabolite, N‐desbutyldronedarone (NDBD), to prospectively interrogate this clinically relevant DDI in healthy and mild renal impairment populations.MethodsThe middle‐out development of our PBPK model combined literature‐derived or in‐house in vitro data, predicted in silico data and in vivo clinical data. Model verification was performed for intravenous and oral (single and multiple) dosing regimens. Model validation for the accurate prediction of cytochrome P450 (CYP)3A4‐ and P‐glycoprotein‐mediated DDI utilized simvastatin and digoxin as respective victim drugs. Rivaroxaban‐specific inhibitory parameters of dronedarone and/or NDBD against CYP3A4, CYP2J2, OAT3 and P‐glycoprotein were incorporated into the PBPK‐DDI model for prospective dronedarone–rivaroxaban DDI simulation.ResultsDronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single and multiple oral dosing were accurately simulated by incorporating effect of auto‐inactivation on dose nonlinearities. Following successful model validation, nondose‐adjusted rivaroxaban–dronedarone DDI in healthy and mild renal impairment populations revealed simulated rivaroxaban area under the plasma concentration–time curve up to 24 h fold change greater than dose exposure equivalence (0.70–1.43) at 1.65 and 1.84, respectively. Correspondingly, respective major bleeding risk was 4.24 and 4.70% compared with threshold of 4.5% representing contraindicated rivaroxaban–ketoconazole DDI.ConclusionOur PBPK‐DDI model predicted clinically significant dronedarone–rivaroxaban DDI in both healthy and mild renal impairment subjects. Greater benefit vs. risk could be achieved with rivaroxaban dose reductions to at least 15 mg in mild renal impairment subjects on concomitant dronedarone and rivaroxaban.
Myelodysplastic syndromes, thy name is heterogeneity
Authors: Greenberg Peter L. 
Published: January 2023

Classification of the heterogeneous spectrum of myelodysplastic syndromes (MDS) requires both morphologic and molecular analysis to effectively subgroup patients. The paper by Zhang et al demonstrated the positive impact of combining the International Consensus Consortium (ICC) morphologic approach with prior clinical (IPSS‐R) and mutational (IPSS‐M) categorization to provide useful clinical evaluation of MDS patients.Commentary on: Zhang et al. Impact of the International Consensus Classification of Myelodysplastic Syndromes. Br J Haematol 2022 (Online ahead of print). doi: 10.1111/bjh.18628.
Predictors of brown bear predation events on livestock in the Romanian Carpathians
Authors: Pop Mihai I. , Dyck Marissa A. , Chiriac Silviu , Lajos Berde , Szabó Szilárd , Iojă Cristian I. , Popescu Viorel D. 
Published: January 2023

AbstractLivestock depredation by brown bears is one of the main source of human–wildlife conflict in rural Eastern Europe. Thus, identifying environmental and anthropogenic drivers of human–bear conflict, and developing spatial predictions for predation intensity are critical to mitigate such conflicts. We used 756 records of bear‐caused livestock predation collected between 2008 and 2016 in the Romanian Carpathians and evaluated predictors and spatial distribution of bear livestock predation events (BPEs) using separate binomial generalized linear mixed models for cows, sheep, and other livestock. Despite differences in the direction and magnitude of the effect, the prevalence of BPE for all livestock was driven by the interaction between environmental drivers along with relative bear abundance. Distance from forest was a strong negative predictor for cows and sheep, while distance to villages was a strong negative predictor for cows. Landscape heterogeneity was positively associated with cow and other livestock predation and negatively associated with sheep. Relative bear abundance data collected by wildlife managers was a positive predictor for predation on all livestock. Livestock damage was more prevalent near villages, showcasing plasticity of food resources sought by bears. Our work informs brown bear and livestock management strategies to develop awareness and implement damage prevention measures.
The indigenous African cultural value of human tissues and implications for bio‐banking
Authors: Nderitu David , Emerson Claudia 
Published: January 2023

AbstractBio‐banking in research elicits numerous ethical issues related to informed consent, privacy and identifiability of samples, return of results, incidental findings, international data exchange, ownership of samples, and benefit sharing etc. In low and middle income (LMICs) countries the challenge of inadequate guidelines and regulations on the proper conduct of research compounds the ethical issues. In addition, failure to pay attention to underlying indigenous worldviews that ought to inform issues, practices and policies in Africa may exacerbate the situation. In this paper we discuss how the African context presents unique and outstanding cultural thought systems regarding the human body and biological materials that can be put into perspective in bio‐bank research. We give the example of African ontology of nature presented by John Samwel Mbiti as foundational in adding value to the discourse about enhancing relevance of bio‐bank research in the African context. We underline that cultural rites of passage performed on the human body in majority of communities in Africa elicit quintessential perspective on beliefs about handling of human body and human biological tissues. We conclude that acknowledgement and inclusion of African indigenous worldviews regarding the human body is essential in influencing best practices in biobank research in Africa.
Clinical assessment of impulsiveness and defence mechanisms in young patients with mood disorders in a two‐year prospective study
Authors: Rajewska‐Rager Aleksandra , Dmitrzak‐Weglarz Monika , Lepczynska Natalia , Kapelski Pawel , Pawlak Joanna , Skibinska Maria 
Published: January 2023

AbstractAimThere have been limited prospective investigations of early clinical markers involved in mood regulation and diagnosis change in young patients. This study aimed to evaluate the changes in impulsivity and defence mechanisms in patients with major depressive disorder (MDD) and bipolar disorder (BD) with acute symptoms and remission compared to healthy controls (HC), and possible psychological predictors of diagnosis conversion.MethodsSeventy‐nine young MDD or BD patients and 40 HC were enrolled in a two‐year prospective study. A comprehensive clinical interview focused on clinical and psychological evaluation during follow‐up visits. The severity of depressive symptoms was evaluated using the Hamilton Depression Rating Scale (HDRS‐17), whilst the Young Mania Rating Scale (YMRS) was used for hypo/manic symptoms during each control visit. All patients completed the Defence Style Questionnaire (DSQ‐40) and Barratt Impulsiveness Scale (BIS‐11).ResultsPatients used more immature defences, and had significantly higher total impulsivity scores than controls. BD patients had elevated motor and non‐planning impulsivity compared with HC and MDD subjects. Total and non‐planning impulsiveness remained elevated in euthymia in BD and MDD compared to HC. There were no statistically significant differences in total defence styles and impulsiveness scores at baseline vs. euthymia in MDD or BD patients groups. Significantly higher dissociation scores at baseline discriminated depressive patients who convert to BD in their diagnosis.ConclusionsPatients with acute mood symptoms used more frequent immature defences and had significantly higher total impulsivity scores than healthy persons. A lack of differences in total defence styles and impulsiveness between patients with acute symptoms and after reaching euthymia in both MDD and BD groups indicates that they are independent of disease status. Dissociation defence mechanisms may be an early diagnostic indicator of BD.
Potential accumulation of toxic trace elements in soils during enhanced rock weathering
Authors: Dupla Xavier , Möller Benjamin , Baveye Philippe C. , Grand Stéphanie 
Published: January 2023

AbstractTerrestrial enhanced rock weathering (ERW) is a carbon dioxide removal technology that aims at accelerating one of the most powerful negative feedbacks on Earth's climate, the chemical weathering of silicates. To achieve this, ERW proposes to spread ground silicate rock on agricultural soils. According to many models, global application rates of 40 tonnes of ground basaltic rock per hectare and per year would be necessary to sequester a significant amount of CO2, representing up to 24% of the current net annual increase in atmospheric CO2. When assessing the viability of ERW as a global geo‐engineering strategy, a pivotal but overlooked question to address is whether ERW may lead to toxic trace element accumulation in soils at unauthorized and potentially harmful levels. This study evaluates the legal sustainability of ERW with regard to trace element contents in soils. We compare different trace element accumulation scenarios considering a range of rock sources, application rates and national regulatory limits. The results indicate that, at the suggested annual application rate of 40 tonnes per hectare, the first regulatory limits would be exceeded after 6 and 10 years for copper and nickel, respectively. This study argues in favour of close tailoring of ERW deployment to local conditions in order to tap into its climate mitigation potential while preserving long‐term soil uses.Highlights
Terrestrial enhanced rock weathering (ERW) is a carbon sequestration technology that consists in applying rock powder to soils.
This study evaluates whether rock powder application can lead to trace metals accumulation in soils beyond regulatory limits.
ERW can lead to the overrun of some environmental regulatory limits within less than a decade.
Specific site and rock selection will be necessary for this method to preserve long‐term soil uses.
Mommy brain in the United States
Authors: Miller Valerie , Price‐Crist Marcy 
Published: January 2023

AbstractWomen undergo profound psychological and cognitive shifts throughout their life course, and motherhood entails dramatic mind–body adjustments. Growing maternal responsibilities and evidence from social sciences suggest motherhood enhances cognitive functioning, but mothers typically claim otherwise. This article uses maternal life stories to reveal cultural schemas of mommy brain as told by mothers in the United States. Our findings illustrate what mommy brain is in practice and how cultural narratives promote associations between motherhood and diminished cognitive functioning. We found that interruptions, cognitive overload, and newfound anxieties were fundamental components in mothers’ mommy brain experiences. We believe that these factors, along with social isolation, play a salient role in self‐reported deficits in maternal cognition. Understandings of mommy brain must move beyond neurobiology and attention and memory studies and consider how interruptions, overload, and other subjective experiences shape our definitions and what we know about maternal cognition.
Transformative change comes from more than structured content: Qualitative exploration of parent experiences of a post‐separation group program
Authors: Bayliss Luke T. , Krishnamoorthy Govind , Malhotra Aastha , Beel Nathan , du Plessis Carol , Crathern Jennifer , Hall Stuart , Burton Lorelle 
Published: January 2023

AbstractObjectiveIn this research, we explore participant experiences of a post‐separation parenting program as a protective factor for helping with post‐separation adjustment.BackgroundSeparation is a difficult process for children and families. It often involves distress and conflict that can negatively affect well‐being. Post‐separation programs are a protective factor to help parents adjust post‐separation. However, there is a dearth of qualitative research exploring how these programs help with post‐separation adjustment.MethodIn‐depth semistructured interviews were conducted with a sample of 13 parents who had attended a post‐separation program. Thematic analysis was used for data analysis. Two reviewers independently coded data inductively, and coding was subsequently independently reviewed by a third reviewer.ResultsGroup processes accompanying the program helped participants reduce distress in the acute post‐separation phase. Participants reported enhanced management of personal responses to the separation that contributed to personal development. Peer learning and support during this phase may be a relatively unexplored area.ConclusionPost‐separation programs that normalize separation and include practical strategies for emotion regulation and effective communication may be helpful for individuals' adjustment post‐separation.ImplicationsPost‐separation programs should be offered by organizations that support separated parents to help adjust during the early phase of separation.
What ultimately matters in root canal treatment success and tooth preservation: A 25‐year cohort study
Authors: Van Nieuwenhuysen Jean Pierre , D'Hoore William , Leprince Julian G. 
Published: January 2023

AbstractAimThere are currently no prospective studies evaluating the long‐term outcomes of non‐surgical root canal treatments beyond 5 years, both in terms of treatment success and tooth preservation, and identifying factors predictive of treatment outcome. The aim of the present work was therefore to fill this gap by assessing these outcomes over time and identifying predictive variables based on systematic data collection over a 25‐year period.MethodologyData concerning the treatments (N = 2500) were systematically collected since 1990. Information was recorded among clinical, technical, radiographic and patient‐related characteristics, i.e., approximately 150 variables for each treatment. The data were analysed regarding both treatment success and tooth preservation by multivariable Cox proportional hazards model, and survival curves were generated. The statistical significance level was set at 0.0125.ResultsIn total, 56.4% of the treatments could be followed over time (0–25 years, mean = 6.5 years, median = 5 years). Survival probability decreased almost linearly for treatment success, with about 85% after 5 years and 60% after 20 years, and for tooth preservation, with about 90% at 5 years and 50% at 20 years. The variables significantly associated with treatment failure were: pre‐operative pain (Hazard Ratio—HR = 1.56 [95% CI 1.23–1.97]), persistent pain (HR = 2.63 [95% CI 1.44–4.80]), good operator rating of treatment prognosis (HR = 0.46 [95% CI 0.36–0.58]), size of periapical bone radiolucency (HR = 1.88 [95% CI 1.67–2.11]), and tooth type (p = .0006). For tooth extraction, they were: combined endodontic‐periodontal lesion (HR = 3.37 [95% CI 1.88–6.05]), pre‐existing complication before treatment (HR = 1.67 [95% CI 1.26–2.21]), good operator rating of treatment prognosis (HR = 0.45 [95% CI 0.33–0.60]), clinical failure of root canal treatment (HR = 2.78 [95% CI 1.98–3.89]) and tooth type (p = .0012).ConclusionRoot canal treatment success and tooth preservation on the arch are not static outcomes, but evolve with time. Among a substantial set of potential predictors, only a small proportion was significantly predictive of treatment success and tooth preservation, most of them being disease and patient characteristics, and not technical aspects, except pre‐existing complications. These observations challenge the importance frequently given to byzantine considerations related to the numerous technical details of endodontic procedures, as opposed to general concepts of good clinical practice.
Hen egg only diets support healthy aging in adult mice
Authors: Nishio Naomi , Isobe Ken‐ichi 
Published: January 2023

AbstractHen eggs (eggs) are a conventional food, known to contain the nutrients required for the growth of chicken embryos. These eggs are rich in important proteins and fats, with a very low amount of carbohydrate, and include all of the vitamins and minerals needed for the development of mice. We found that mice fed eggs grew to the same weight as mice fed a normal chow diet (ND) and remained healthy until the 20‐months. As expected, the serological indicators of fat content were higher in egg‐only mice than in ND mice. However, surprisingly the serum glucose levels in the egg‐only mice were nearly identical to those in the ND mice. Given the high fat content in eggs, we expected that our egg‐only mice would develop fatty liver or other metabolic diseases. However, we observed no pathological changes in the livers of egg‐only mice until 20‐months with their serological indicators (ALT and AST) and histological features (no fat droplets) remaining normal. However, when we examined the pups nursed by mothers of the egg‐only diet group we noted that almost the animals died 2 to 4 weeks after birth. This is likely because these pups presented with reduced enzymes for metabolism in their liver when compared to pups of the ND group. In addition, we also found that the expression of various development proteins were severely lacking in liver of these pups. From these results, our report suggested that eggs could support healthy aging in adult mice, but not in pups.
Insomnia and risk of dementia in a large population‐based study with 11‐year follow‐up: The HUNT study
Authors: Selbæk‐Tungevåg Selma , Selbæk Geir , Strand Bjørn Heine , Myrstad Christian , Livingston Gill , Lydersen Stian , Bergh Sverre , Ernstsen Linda 
Published: January 2023

SummaryDespite evidence suggesting that insomnia is associated with the risk of dementia and cognitive dysfunction, studies have shown mixed results. Dementia has a long prodromal phase, and studies with long follow‐up are required to avoid reverse causality. In our 11‐year follow‐up study, we assessed whether probable insomnia disorder (PID) based on diagnostic criteria, and insomnia symptoms were associated with risk of all‐cause dementia, Alzheimer's disease (AD) and cognition, measured with the Montreal Cognitive Assessment scale. We also examined if Apolipoprotein E genotype modified any associations with dementia through interaction. We analysed data from 7492 participants in the Norwegian Trøndelag Health Study. PID was not associated with all‐cause dementia (odds ratio = 1.03, 95% confidence interval = 0.74–1.43), AD (odds ratio = 1.07, 95% confidence interval = 0.71–1.60) or Montreal Cognitive Assessment score (regression coefficient = 0.37, 95% confidence interval = −0.06 to 0.80). The insomnia symptom “difficulties maintaining sleep” was associated with a lower risk of all‐cause dementia (odds ratio = 0.81, 95% confidence interval = 0.67–0.98), AD (odds ratio = 0.73, 95% confidence interval = 0.57–0.93), and better Montreal Cognitive Assessment score, mean 0.40 units (95% confidence interval = 0.15–0.64). No interaction with Apolipoprotein E genotype was found. PID and insomnia symptoms did not increase the risk of dementia in our study. More research with longer follow‐up is needed, and future studies should explore if the associations to dementia risk vary across insomnia subtypes.
The hypothalamic‐pituitary‐adrenal axis response to ovine corticotropin‐releasing‐hormone stimulation tests in healthy and hospitalized foals
Authors: Johnson Katheryn , Peterson Jackie , Kopper Jamie , Dembek Katarzyna 
Published: January 2023

AbstractBackgroundThe hypothalamic‐pituitary‐adrenocortical axis (HPAA) response to sepsis can be impaired in critical illness. Corticotropin‐releasing hormone (CRH) stimulation test might assess HPAA function in foals.ObjectiveTo evaluate plasma cortisol, ACTH, arginine vasopressin (AVP), and endogenous CRH (eCRH) response to different doses of ovine CRH (oCRH).AnimalsHealthy (n = 14) and hospitalized (n = 15) foals <7 days of age.MethodsIn this prospective randomized study, oCRH (0.1, 0.3, and 1 μg/kg) was administered intravenously and blood samples were collected before, 15, 30, 60, and 90 minutes after administration of oCRH to determine plasma hormone concentrations. The hormonal response was evaluated as the difference (Delta; μg/dL or pg/mL) or percent change between baseline hormone concentration and each time point after oCRH stimulation.ResultsCortisol concentrations increased from baseline at 15 minutes with 0.1 and 0.3 μg/kg and at 30 and 60 minutes from baseline with 1 μg/kg oCRH (P < .05) in healthy and hospitalized foals. ACTH concentrations increased from baseline at 15 minutes with 0.1 μg/kg and at 30 minutes with 1 μg/kg oCRH (P < .05) in hospitalized foals. Delta cortisol 0 – 30, ACTH 0 – 30, and eCRH 0 – 30 was higher for the 1 μg/kg compared with 0.1 μg/kg oCRH in healthy foals (P < .05). Delta ACTH 0 – 15 and eCRH 0 – 30 was higher for the 1 μg/kg compared with the lower doses of oCRH in hospitalized foals (P < .05).Conclusions and Clinical ImportanceCortisol, ACTH, and eCRH concentrations increased in response to administration of all doses of oCRH. One microgram per kilogram of oCRH appears to be optimal for the assessment of HPAA in healthy and hospitalized foals.
Landscape characteristics influence regional dispersal in a high‐elevation specialist migratory bird, the water pipit Anthus spinoletta
Authors: Ceresa Francesco , Brambilla Mattia , Kvist Laura , Vitulano Severino , Pes Michele , Tomasi Laura , Pedrini Paolo , Hilpold Andreas , Kranebitter Petra 
Published: January 2023

AbstractSpecies living in high mountain areas are currently threatened by climate change and human land use changes. High‐elevation birds frequently inhabit island‐like suitable patches around mountain peaks, and in such conditions the capability to exchange individuals among patches is crucial to maintain gene flow. However, we lack information regarding the dispersal ability of most of these species and the possible influence of landscape features on dispersal. In this study, we used population genomics and landscape resistance modelling to investigate dispersal in a high‐elevation specialist migratory bird, the water pipit Anthus spinoletta. We aimed to assess the levels of gene flow in this species within a wide area of the European Alps, and to assess the effects of environmental characteristics on gene flow, by testing the isolation by distance (IBD) hypothesis against the isolation by resistance (IBR) hypothesis. We found clear support for IBR, indicating that water pipits preferentially disperse across suitable breeding habitat (i.e., high‐elevation grassland). IBR was stronger in the part of the study area with less extended suitable habitat. Landscape resistance was slightly better described by habitat suitability models than landscape connectivity models. Despite the observed IBR, gene flow within the study area was high, probably also because of the still wide and relatively continuous breeding range. The forecasted reduction of range of this species may lead to stronger effects of IBR on gene flow. Other high‐elevation specialist birds may show similar IBR patterns, but with possibly stronger effects on gene flow because of their more reduced and patchy habitats.