bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of appropriate conditions for Oncomine DxTT testing of FFPE specimens for driver gene alterations in non–small cell lung cancer
Authors: Iwama Eiji , Yamamoto Hidetaka , Okubo Fumihiko , Ijichi Kayo , Ibusuki Ritsu , Shiaraishi Yoshimasa , Yoneshima Yasuto , Tanaka Kentaro , Oda Yoshinao , Okamoto Isamu
Published: June 2023

Background

The Oncomine Dx Target Test Multi‐CDx System (ODxTT) is a next‐generation sequencing panel approved as a companion diagnostic for drugs targeted to corresponding gene alterations in non–small cell lung cancer. However, appropriate slide conditions for ODxTT have remained unclear.

Methods

We focused on the production of the number of tumor cells on a formalin‐fixed paraffin‐embedded (FFPE) section and the number of prepared slides, designated the TS value, and determined a TS value of ≥4000 as a target slide condition for ODxTT. We evaluated the impact of this condition on ODxTT testing with tumor specimens found to have a TS of <4000 (n = 23) or a TS of ≥4000 (n = 142).

Results

A positive correlation was apparent between the TS value and the concentrations of both DNA and RNA. Among the 142 samples with a TS of ≥4000, a sufficient concentration of DNA or RNA for ODxTT analysis was achieved in 100% and 98% samples, respectively. Among samples explored for driver gene alterations after determination of the target slide condition (TS ≥4000), most (84.9%) had a TS of ≥4000 and were submitted for ODxTT analysis.

Conclusion

Our findings indicate that a TS of ≥4000 is a feasible and relevant criterion for ODxTT testing, and its adoption should help to improve the success rate of such testing in clinical practice.
Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision
Authors: Fuchs‐Buder Thomas , Brull Sorin J. , Fagerlund Malin Jonsson , Renew J. Ross , Cammu Guy , Murphy Glenn S. , Warlé Michiel , Vested Matias , Fülesdi Béla , Nemes Reka , Columb Malachy O. , Damian Daniela , Davis Peter J. , Iwasaki Hajime , Eriksson Lars I.
Published: June 2023

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby‐Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59–74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs‐Buder et al., Acta Anaesthesiol Scand 2007, 51, 789–808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three‐dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high‐quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies.

There is growing awareness of the importance of consensus‐based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.
ABC‐training as a new intervention for hazardous alcohol drinking: Two proof‐of‐principle randomized pilot studies
Authors: Van Dessel Pieter , Cummins Jamie , Wiers Reinout W.
Published: June 2023

Background and Aims

ABC‐training is a new intervention to encourage health behavior change that targets the automatic activation of adaptive beliefs (i.e. automatic inferences). The aim of this proof‐of‐principle study was to test the effectiveness of web‐based ABC‐training to change outcome expectancies of alcohol drinking in a sample of hazardous drinkers.

Design

One exploratory and one confirmatory experiment with two between‐subject conditions (online ABC‐ and control‐training) and assessments at baseline and 1 week later (after three sessions of training).

Setting

Participants recruited on Prolific Academic completed the web‐based study.

Participants

Adults with self‐reported hazardous alcohol drinking (Experiment 1: 193 adults, United Kingdom, age mean = 46.7 years; Experiment 2: 282 adults, different nationalities, age mean = 38.3 years).

Intervention and Comparator

ABC‐training involved completing an online task that required choosing personally relevant alternative behaviors to drinking alcohol in personally relevant antecedent contexts to attain personally important outcomes. Comparator was control‐training, in which participants selected both the alternative behaviors and alcohol drinking an equal number of times. Training was completed at baseline, after 3 days and after 1 week.

Measurements

Primary outcome was change in automatic and self‐reported (negative/positive) outcome expectancies of alcohol drinking from baseline to after 1 week. Secondary outcomes were change in weekly alcohol consumption, self‐efficacy, craving and motivation (and approach‐alcohol associations in Experiment 1). Moderators were baseline outcome scores, motivation, age and alcohol dependency.

Findings

Findings of this study are as follows: stronger increase in negative outcome expectancies after ABC‐ than control‐training (Experiment 1: self‐report, 95% confidence interval of difference scores (CIdiff) = [0.04, Inf]; automatic, CIdiff = [0.01, Inf]; Experiment 2: self‐report, CIdiff = [0.16, Inf]; automatic, CIdiff = [0.002, Inf]). Stronger reduction in self‐reported positive outcome expectancies after ABC‐ than control‐training (Experiment 1: CIdiff = [−Inf, −0.01]; Experiment 2: CIdiff = [−Inf, −0.21]) but mixed findings on automatic positive outcome expectancies (Experiment 1: CIdiff = [−Inf, 0.02]; Experiment 2: CIdiff = [−Inf, −0.001]).

Conclusions

ABC‐training may change outcome expectancies of alcohol consumption, but testing of clinically relevant effects in other samples is warranted.
The role of hyperbaric oxygen in osteoradionecrosis—a prophylactic insight
Authors: Dang B , Gamage S , Sethi S , Jensen ED , Sambrook P , Goss A
Published: June 2023

Background

Osteoradionecrosis (ORN) is an uncommon and debilitating consequence of head and neck radiotherapy and hyperbaric oxygen therapy (HBOT) has been advocated for prophylaxis prior to performing dentoalveolar procedures. The aim of this study was to evaluate a prophylactic HBOT protocol and describe the outcomes of susceptible individuals.

Methods

A retrospective audit of adults who attended the Oral and Maxillofacial Surgery department at the Royal Adelaide Hospital (South Australia) who received dental extractions with a history of radiotherapy to the jaws from 2008 to 2020. Data including demographic information and outcomes of osteoradionecrosis and delayed healing was recorded.

Results

A total of 121 individuals were eligible for case note review; 68.6% of individuals were male and 55.4% were aged over 67 years. Osteoradionecrosis occurred in 9.1% of individuals and delayed healing for 3.3%; fifteen individuals (12.4%) were unable to complete the HBOT protocol. The individuals who were diagnosed with ORN had a significant association with age (P = 0.006) and binary analysis showed alcohol consumption to be a significant predictor.

Conclusions

Prophylactic HBOT protocol had a lower proportion of individuals diagnosed with ORN and those who were diagnosed were more likely to be younger males and have current alcohol consumption.
Privacy challenges in geodata and open data
Authors: Solymosi Reka , Buil‐Gil David , Ceccato Vania , Kim Eon , Jansson Ulf
Published: June 2023

This article presents a discussion of the emerging ethical issue of geodata privacy in geographical research. The paper highlights the importance of considering challenges to privacy when working with geographically explicit data and explores explicit ways in which researchers and practitioners can be conscious of these issues. Through summarising the key problems in this area and presenting outstanding open research areas and questions from a seminar series on geodata privacy, we highlight important considerations for future research in this field. We focus on the specific topics of appropriate anonymization, responsible data dissemination, the balance between data sharing and privacy, and the challenges posed by working across international contexts. We conclude by recommending approaches to manage various legal and ethical frameworks, raise the importance of the international context, and inspire future research to address the challenges of safeguarding sensitive geodata while promoting openness and transparency.
Comparing the effectiveness of two reciprocal reading comprehension interventions for primary school pupils in disadvantaged schools
Authors: O'Hare Liam , Stark Patrick , Cockerill Maria , Lloyd Katrina , McConnellogue Sheila , Gildea Aideen , Biggart Andy , Bower Christine , Connolly Paul
Published: June 2023

Background

Effective reading comprehension teaching is an aspiration of education systems across the world. Teaching incorporating reciprocal reading theory and evidence is an internationally popular approach for improving comprehension.

Aims

This paper uses two large cluster randomized controlled trials of similar reciprocal reading interventions implemented in different ways to compare their effectiveness.

Sample

The two interventions had the same teacher professional development, reciprocal reading activities and dosage/exposure, but varied in their implementation, with one delivered as a whole‐class (‘universal’) version for pupils aged 8–9 years and the other a small group (‘targeted’) version for pupils aged 9–11 years with specific comprehension difficulties.

Methods

Two large‐scale cluster RCTs were conducted in 98 schools with N = 3699 pupils in the universal trial and N = 1523 in the targeted trial.

Results

Multi‐level models showed significant effects for the targeted version of the intervention on pupil reading comprehension (g = .18) and overall reading (g = .14). No significant effects were found for the whole class version. A sub‐group analyses of disadvantaged pupils showed the targeted intervention's effects were even larger on reading comprehension (g = .25).

Conclusions

The evidence suggested that this reciprocal reading intervention worked best when implemented in small groups and targeted for pupils with specific comprehension difficulties and particularly for pupils in disadvantaged circumstances.

Comments

This evaluation shows that even if a reading comprehension intervention is underpinned by strong theory and evidence‐based practice, its effectiveness can still depend on implementation choices.
NFE2L3 drives hepatocellular carcinoma cell proliferation by regulating the proteasome‐dependent degradation of ISGylated p53
Authors: Ren Yonggang , Yang Jing , Ding Zhiran , Zheng Menghua , Qiu Lu , Tang Aifa , Huang Dandan
Published: June 2023

Nuclear factor erythroid 2‐like 3 (NFE2L3) is a member of the cap ‘n’ collar basic‐region leucine zipper (CNC‐bZIP) transcription factor family that plays a vital role in modulating oxidation–reduction steady‐state and proteolysis. Accumulating evidence suggests that NFE2L3 participates in cancer development; however, little is known about the mechanism by which NFE2L3 regulates hepatocellular carcinoma (HCC) cell growth. Here, we confirmed that NFE2L3 promotes HCC cell proliferation by acting as a transcription factor, which directly induces the expression of proteasome and interferon‐stimulated gene 15 (ISG15) to enhance the proteasome‐dependent degradation of ISGylated p53. Post‐translational ISGylation abated the stability of p53 and facilitated HCC cell growth. In summary, we uncovered the pivotal role of NFE2L3 in promoting HCC cell proliferation during proteostasis. This finding may provide a new target for the clinical treatment of HCC.
Influence of abutment macro‐ and micro‐geometry on morphologic and morphometric features of peri‐implant connective tissue
Authors: Canullo Luigi , Giuliani Alessandra , Furlani Michele , Menini Maria , Piattelli Adriano , Iezzi Giovanna
Published: June 2023

Objectives

The aim of the present human observational study is to provide morphologic and morphometric analysis of peri‐implant connective tissue next to abutments with divergent or convergent macro‐geometry and different surface micro‐characteristics.

Materials and Methods

Thirty patients were rehabilitated with single implants in the posterior area and one out of three different healing abutments with a one‐stage technique: machined divergent abutment (DIV‐MAC), machined convergent abutment (CONV‐MAC) or convergent abutment with ultrathin threaded surface (CONV‐UTM). At 3 months postimplant insertion, peri‐implant soft tissue was harvested; the following outcomes were investigated: histomorphometry (vertical width of connective and epithelial components) as detected by histology and polarized light; and connective tissue vertical width and 3D organization as detected by synchrotron‐based high‐resolution phase‐contrast‐based tomography (PhC‐μCT).

Results

Significant differences in connective tissue vertical dimension (aJE‐AM) were found between DIV‐MAC and both CONV‐MAC and CONV‐UTM, both by histology and PhC‐μCT, with significantly higher values for the last two groups. Moreover, 2D histological analysis did not find significant differences in the junctional epithelium vertical dimension (PM‐aJE). Importantly, PhC‐μCT analysis revealed, at 3D level, significant greater amount and density of collagen bundles for CONV‐UTM compared with the other two groups.

Conclusions

Convergent abutment profiles, regardless of their surface micro‐geometry, seem to favor axial development of peri‐implant connective tissue. Moreover, ultrathin threaded surfaces seem associated with denser and greater connective tissue organization, which might improve peri‐implant soft tissue seal.
Cerebral glucagon‐like peptide‐1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice
Authors: Lv Chuanxiang , Han Shuai , Sha Zhuang , Liu Mingqi , Dong Shiying , Zhang Chunyun , Li Zean , Zhang Kang , Lu Shouyong , Xu Zhiyang , Bie Li , Jiang Rongcai
Published: June 2023

Aim

We aimed to assess the effects of cerebral glucagon‐like peptide‐1 receptor (GLP‐1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI).

Methods

Immunofluorescence was employed to evaluate glymphatic system function. The blood–brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests.

Results

Cerebral GLP‐1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN‐020 abolished the protective effect of the GLP‐1R agonist against cognitive impairment.

Conclusion

Cerebral GLP‐1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.
Cdk5 phosphorylation‐dependent C9orf72 degradation promotes neuronal death in Parkinson's disease models
Authors: Xu Xingfeng , Li Mao , Su Yan , Wang Qi , Qin Peifang , Huang Haitao , Zhang Yuting , Zhou Yali , Yan Jianguo
Published: June 2023

Aims

Chromosome 9 open reading frame 72 (C9orf72) is one of the most dazzling molecules in neurodegenerative diseases, albeit that its role in Parkinson's disease (PD) remains unknown. This article aimed to explore the potential mechanism of C9orf72 involved in the pathogenesis of PD.

Methods

The expression and phosphorylation levels of C9orf72 were examined by Western blotting, RT‐PCR, and immunoprecipitation using PD models. Multiple bioinformatics software was used to predict the potential phosphorylation sites of C9orf72 by Cdk5, followed by verification of whether Cdk5‐inhibitor ROSCOVITINE could reverse the degradation of C9orf72 in PD. By constructing the sh‐C9orf72‐knockdown adenovirus and overexpressing the FLAG‐C9orf72 plasmid, the effects of C9orf72 knockdown and overexpression, respectively, were determined. A short peptide termed Myr‐C9orf72 was used to verify whether interfering with Cdk5 phosphorylation at the Ser9 site of the C9orf72 protein could alleviate autophagy disorder, neuronal death, and movement disorder in PD models.

Results

The expression level of the C9orf72 protein was significantly reduced, albeit the mRNA expression was not changed in the PD models. Moreover, the phosphorylation level was enhanced, and its reduction was mainly degraded by the ubiquitin‐proteasome pathway. The key nervous system kinase Cdk5 directly phosphorylated the S9 site of the C9orf72 protein, which promoted the degradation of the C9orf72 protein. The knockdown of C9orf72 aggravated autophagy dysfunction and increased neuronal loss and motor dysfunction in substantia nigra neurons of PD mice. The overexpression of C9orf72 alleviated autophagy dysfunction in PD neurons. Specifically, interference with Cdk5 phosphorylation at the S9 site of C9orf72 alleviated autophagy dysfunction, neuronal death, and motor dysfunction mediated by C9orf72 protein degradation during PD.

Conclusions

Cumulatively, our findings illustrate the importance of the role of C9orf72 in the regulation of neuronal death during PD progression via the Cdk5‐dependent degradation.
MiR‐199a‐5p enhances neuronal differentiation of neural stem cells and promotes neurogenesis by targeting Cav‐1 after cerebral ischemia
Authors: Jin Hua‐Qian , Jiang Wei‐Feng , Zheng Xin‐Tian , Li Lin , Fang Yan , Yang Yan , Hu Xiao‐Wei , Chu Li‐Sheng
Published: June 2023

Aims

MicroRNAs (miRs) are involved in endogenous neurogenesis, enhancing of which has been regarded as a potential therapeutic strategy for ischemic stroke treatment; however, whether miR‐199a‐5p mediates postischemic neurogenesis remains unclear. This study aims to investigate the proneurogenesis effects of miR‐199a‐5p and its possible mechanism after ischemic stroke.

Methods

Neural stem cells (NSCs) were transfected using Lipofectamine 3000 reagent, and the differentiation of NSCs was evaluated by immunofluorescence and Western blotting. Dual‐luciferase reporter assay was performed to verify the target gene of miR‐199a‐5p. MiR‐199a‐5p agomir/antagomir were injected intracerebroventricularly. The sensorimotor functions were evaluated by neurobehavioral tests, infarct volume was measured by toluidine blue staining, neurogenesis was detected by immunofluorescence assay, and the protein levels of neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), caveolin‐1 (Cav‐1), vascular endothelial growth factor (VEGF), and brain‐derived neurotrophic factor (BDNF) were measured by Western blotting.

Results

MiR‐199a‐5p mimic enhanced neuronal differentiation and inhibited astrocyte differentiation of NSCs, while a miR‐199a‐5p inhibitor induced the opposite effects, which can be reversed by Cav‐1 siRNA. Cav‐1 was through the dual‐luciferase reporter assay confirmed as a target gene of miR‐199a‐5p. miR‐199a‐5p agomir in rat stroke models manifested multiple benefits, such as improving neurological deficits, reducing infarct volume, promoting neurogenesis, inhibiting Cav‐1, and increasing VEGF and BDNF, which was reversed by the miR‐199a‐5p antagomir.

Conclusion

MiR‐199a‐5p may target and inhibit Cav‐1 to enhance neurogenesis and thus promote functional recovery after cerebral ischemia. These findings indicate that miR‐199a‐5p is a promising target for the treatment of ischemic stroke.
Poor dental service utilization in those with clinically severe obesity: A neglected issue with solutions needed
Authors: Malik Zanab , Sohn Woosung , Nanayakkara Shanika , Williams Kathryn
Published: June 2023

Data linking body mass index (BMI) and dental service utilization with oral and general health, quality of life, wellbeing, and mental health are lacking. Adult patients with clinically severe obesity attending a hospital‐based obesity service in Greater Western Sydney were invited to participate in a cross‐sectional survey that collected data on dental utilization and visiting patterns, dental anxiety, and oral health‐related quality of life (OHRQoL). General health data were obtained from participants' medical records. Of the 82 individuals who consented to participate, 81 (98.8%) completed the study questionnaire, and 74 (91.3%) answered additional screening questions related to their general wellbeing and mental health. Of the participants, 50 (61.7%) reported that their last dental visit was more than 1 year ago, 43 (53.1%) visited only as needed and 22 (27.2%) participants reported favourable dental visiting patterns. Twenty‐four (29.6%) participants reported high levels of dental anxiety, and low levels of OHRQoL compared with national data. Screening questions suggested low general wellbeing and poor mental health in this patient cohort. Within this group, BMI was not significantly correlated with any of the variables of dental service utilization, dental anxiety, OHRQoL, wellbeing, or mental health (p > .05). There was a negative correlation between dental anxiety and dental utilization (p < .05). Patients with clinically severe obesity reported poor dental utilization, low OHRQoL, and high levels of dental anxiety. This study highlighted the frequency of medical complications, lack of wellbeing, and poor mental health, which were evident in this cohort and may complicate dental management.
“It's like a forgotten issue sometimes …”: Qualitative study of individuals living and caring for people with chronic breathlessness
Authors: Sunjaya Anthony , Martin Allison , Arnott Clare , Marks Guy , Jenkins Christine
Published: June 2023

Introduction

This study aims to explore the perspectives of patients and carers with chronic breathlessness on current provision of care, care expectations, and self‐management needs to develop relevant health services and resources to improve clinical outcomes.

Methods

In‐depth semistructured interviews were conducted on patients living with chronic breathlessness and carers.

Results

Thirteen patients (cardiac, respiratory, and noncardiorespiratory) and two carers were interviewed (mean age 57 years, 47% female, median duration with breathlessness 5 years). Four main themes were identified: (1) living with breathlessness, (2) diagnosis delays, misdiagnosis, and knowledge gaps, (3) beyond curing disease: symptom relief and improving quality of life, and (4) self‐management and limited support for it.

Conclusion

Breathlessness has a high personal impact but remains a neglected condition in Australia. Patients suffer from lack of personal, community, and provider awareness, discontinuity of care, and too few clinical and self‐management options.
First‐in‐human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC‐2394, in healthy volunteers
Authors: Tang Fei , Kunder Rebecca , Chu Tom , Hains Avis , Nguyen Allen , McBride Jacqueline M. , Zhong Yu , Santagostino Sara , Wilson Maria , Trenchak Abigail , Chen Liuxi , Ly Justin , Moein Anita , Lewin‐Koh Nicholas , Raghavan Vibha , Osaghae Uyi , Wynne Chris , Owen Ryan , Place David
Published: June 2023

Inappropriate and chronic activation of the cytosolic NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first‐in‐human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150–1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC‐2394, a small‐molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC‐2394 and its CYP3A4 induction potential in food‐effect (FE) and drug–drug interaction (DDI) stages, respectively. Although GDC‐2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug‐induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC‐2394 was rapidly absorbed; exposure increased in an approximately dose‐proportional manner with low‐to‐moderate intersubject variability. The mean terminal half‐life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high‐fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC‐2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole‐blood stimulation assays showed rapid, reversible, and near‐complete inhibition of the selected PD biomarkers, IL‐1β and IL‐18, across all tested doses. Despite favorable PK and target engagement PD, the GDC‐2394 safety profile precludes its further development.
Longitudinal estimated glomerular filtration rate (eGFR) modeling in long‐term renal function to inform clinical trial design in kidney transplantation
Authors: Kosinski Luke , Frey Eric , Klein Amanda , O'Doherty Inish , Romero Klaus , Stegall Mark , Helanterä Ilkka , Gaber Ahmed Osama , Fitzsimmons William E. , Aggarwal Varun ,   Transplant Therapeutics Consortium (TTC)
Published: June 2023

Kidney transplantation is the preferred treatment for individuals with end‐stage kidney disease. From a modeling perspective, our understanding of kidney function trajectories after transplantation remains limited. Current modeling of kidney function post‐transplantation is focused on linear slopes or percent decline and often excludes the highly variable early timepoints post‐transplantation, where kidney function recovers and then stabilizes. Using estimated glomerular filtration rate (eGFR), a well‐known biomarker of kidney function, from an aggregated dataset of 4904 kidney transplant patients including both observational studies and clinical trials, we developed a longitudinal model of kidney function trajectories from time of transplant to 6 years post‐transplant. Our model is a nonlinear, mixed‐effects model built in NONMEM that captured both the recovery phase after kidney transplantation, where the graft recovers function, and the long‐term phase of stabilization and slow decline. Model fit was assessed using diagnostic plots and individual fits. Model performance, assessed via visual predictive checks, suggests accurate model predictions of eGFR at the median and lower 95% quantiles of eGFR, ranges which are of critical clinical importance for assessing loss of kidney function. Various clinically relevant covariates were also explored and found to improve the model. For example, transplant recipients of deceased donors recover function more slowly after transplantation and calcineurin inhibitor use promotes faster long‐term decay. Our work provides a generalizable, nonlinear model of kidney allograft function that will be useful for estimating eGFR up to 6 years post‐transplant in various clinically relevant populations.
Estimating potential global sources and secondary spread of freshwater invasions under historical and future climates
Authors: Hubbard Justin A. G. , Drake D. Andrew R. , Mandrak Nicholas E.
Published: June 2023

Aim

We employed a climate‐matching method to evaluate potential source regions of freshwater invasive species to an introduced region and their potential secondary spread under historical and future climates.

Location

Global source regions, with primary introductions to the Laurentian Great Lakes and secondary introductions throughout North America.

Methods

We conducted a climate‐match analysis using the CLIMATE algorithm to estimate global source freshwater ecoregions under historical and future climates with an ensemble of global climate models for climate‐change scenario SSP5‐8.5. Given existing research, we use a climate match of ≥71.7% between ecoregions to indicate climatic conditions that will not inhibit the survival of introduced freshwater organisms. Further, we estimate the secondary spread of freshwater invaders to the ecoregions of North America under historical and future climates.

Results

We identified 54 global freshwater ecoregions with a climate match ≥71.7% to the recipient Laurentian Great Lakes under historical climatic conditions, and 11 additional ecoregions were predicted to exceed the threshold under climate change. Three of the 11 ecoregions were located in South America, a continent where no matches existed under historical climates and eight were located in the southern United States, southern Europe, Japan and New Zealand. Further, we identify 34 North American ecoregions of potential secondary spread of freshwater invasions from the Great Lakes under historical climatic conditions, and five ecoregions were predicted to exceed the threshold under climate change.

Main Conclusion

We provide a climate‐match method that can be employed to assess the sources and spread of freshwater invasions under historical and future climate scenarios. Our climate‐match method predicted increases in climate match between the recipient region and several potential source regions, and changes in areas of potential spread under climate change. The identified ecoregions are candidates for detailed biosecurity risk assessments and related management actions.
Social versus non‐social behavioral inhibition: Differential prediction from early childhood of long‐term psychosocial outcomes
Authors: Tan Enda , Zeytinoglu Selin , Morales Santiago , Buzzell George A. , Almas Alisa N. , Degnan Kathryn A. , Chronis‐Tuscano Andrea , Henderson Heather , Pine Daniel S. , Fox Nathan A.
Published: June 2023

Behavioral inhibition (BI) is a temperamental style characterized by cautious and fearful behaviors in novel situations. The present multi‐method, longitudinal study examined whether young children's observed and parent‐reported BI in social versus non‐social contexts predicts different long‐term psychosocial outcomes. Participants (N = 279) were drawn from a longitudinal study of socioemotional development. BI in social contexts (“social BI”) was measured via children's observed wariness toward unfamiliar adults and peers at 24 and 36 months and parents’ reports of children's social fear/shyness at 24, 36, and 48 months. BI in non‐social contexts (“non‐social BI”) was measured via children's observed fearful responses to masks and novel toys, and parents’ reports of children's distress to non‐social novelty at 9 months and non‐social fear at 48 months. At 15 years, anxiety was assessed via adolescent‐ and parent‐reports, and global internalizing and externalizing problems were assessed via parent‐reports. Confirmatory factor analysis showed that a two‐factor model fit the BI data significantly better than a single‐factor model, providing evidence for the dissociation of BI in social versus non‐social contexts. Social BI was uniquely associated with adolescent social anxiety, whereas non‐social BI was specifically associated with adolescent separation anxiety. Neither social BI nor non‐social BI predicted global internalizing and externalizing problems, providing evidence for the specific relations between BI and anxiety problems. Together, these results suggest that young children's inhibited responses in social versus non‐social situations predict different subtypes of anxiety problems in adolescence, highlighting the multifaceted nature of BI and the divergent trajectories of different anxiety problems.
Moving forward: The importance of tailored orthotic management in children with cerebral palsy
Authors: Bayón Cristina
Published: June 2023

This commentary is on the original article by Bjornson et al. on pages 52–60 of this issue.
Tirzepatide 10 and 15 mg compared with semaglutide 2.4 mg for the treatment of obesity: An indirect treatment comparison
Authors: le Roux Carel W. , Hankosky Emily R. , Wang Duzhe , Malik Raleigh , Yu Maria , Hickey Ana , Kan Hong , Bunck Mathijs C. , Stefanski Adam , Garcia‐Perez Luis‐Emilio , Wharton Sean
Published: June 2023

Aim

To compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison.

Materials and Methods

Using SURMOUNT‐1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching‐adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points.

Results

Greater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: −4.67% [95% CI −5.91%, −3.43%]; tirzepatide 15 mg mean difference: −5.92% [95% CI −7.16%, −4.68%]; both P < .001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P < .001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P < .001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P = .074).

Conclusions

Currently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching‐adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg.
How did COVID‐19 lockdowns affect firms and workers? Evidence from Jordan and Morocco
Authors: Baltaji Rihab , Fakih Ali , Sayour Nagham
Published: June 2023

Motivation

The COVID‐19 pandemic harmed business and employment in two ways: ill health reduced consumer demand for goods and services; and lockdowns to control disease prevented businesses from operating. This article is concerned with the latter effect.

Purpose

This article assesses the losses of full‐time and part‐time jobs as well as wage cuts in Jordan and Morocco as a result of businesses having to close down under lockdowns.

Methods and approach

We compared firms that closed down under lockdown to those that did not in the two countries. We used propensity score matching to balance the two sets of firms.

We drew on data from two rounds of the COVID‐19 World Bank Enterprise Survey, carried out in June–August 2020 for both countries; and November–December 2020 for Jordan and January–February 2021 for Morocco. The surveys included 601 firms in Jordan and 1,096 in Morocco. We used results from the first round to estimate short‐term effects, and those from the second round to estimate medium‐term effects.

The survey differentiated firms by sector—manufacturing, retailing, and other services—by firm size, by whether they were under foreign ownership, and by whether they were engaged in exporting.

Findings

First we checked the likelihood that firms closed: larger firms and non‐exporting firms were significantly less likely than smaller and exporting firms to close down.

When firms closed, they shed jobs, but with marked differences across sectors.

Manufacturing firms laid workers off in the short term, an effect that did not increase in the medium term. However, manufacturing firms did reduce wages in the medium term.

Retail firms shed fewer jobs in the short term but cut more jobs in the medium term—mainly of part‐time workers. They also cut wages in the medium term.

For other services, job losses were observed for part‐time workers in both the short term and the medium term.

Policy implications

Policy‐makers should consider promoting digitization of the economy; programmes to reform and repurpose businesses; and targeted unemployment benefits to protect workers from loss of jobs and earnings from lockdowns.
Tacit knowledge and the role of the dental educator
Authors: Matharu Karanveer Singh , Wareing Mark Philip
Published: June 2023

Introduction

This article seeks to explore tacit knowledge in the context of the practice and the role of a dental educator in a workplace learning environment.

Material and Methods

The key theoretical ideologies which underpin the definition of tacit knowledge have been outlined and practical examples to enable conceptualisation. The role tacit knowledge plays in procedural knowledge, performance of a skill and diagnosis and decision‐making has been explained in further detail. Approaches to maximise the educational output of learning opportunities by using tacit knowledge and how an awareness of tacit knowledge can complement reflection have been considered.

Results

It is acknowledged that workplace learning is of mutual benefit to the dental educator, trainee and clinical team and that the development of the educator to make tacit knowledge explicit, can be achieved through peer observation, amongst other methods.

Conclusion

Tacit knowledge is a key element underpinning learning in the workplace; the use of this knowledge can be applied in an advantageous manner, from both an educational and a personal developmental perspective.
Evaluation of a new 3D‐printed tooth model allowing preoperative ICDAS assessment and caries removal
Authors: Ballester Benoit , Pilliol Virginie , Allaerd Perrine , Jacquot Bruno , Guivarc'h Maud
Published: June 2023

Introduction

Teaching caries lesion management with operative care requires tooth models with highly realistic anatomical detail and caries lesions that can be assessed using ICDAS. This study aimed to develop and evaluate a new 3D‐printed teeth model for ICDAS assessment and caries removal for pre‐clinical hands‐on education.

Methods

Printable tooth with different layers for enamel, dentin and carious lesions was designed and tested by 31 dental students. They were asked to visually and radiologically assess the ICDAS severity of the simulated carious lesions, establish the therapeutic strategy according to CariesCare 4D, and perform a qualitative assessment of the models based on five‐point Likert scale items.

Results

Concerning carious lesions, the texture was realistic, and the shade was adequate for 94% and 97% of the participants. Ninety per cent of the participants found the model adequate to perform an ICDAS visual assessment. Seventy‐four per cent of the students found the hardness adequate. Concerning the difference in shade and the noticeable hardness difference between enamel and dentin, participants have mixed agreement with a proportion of 61% and 55%, respectively. All the participants agreed these 3D‐printed models provide a good caries simulation, are suitable for hands‐on operative dentistry courses, and that learning outcomes better than the standard model.

Conclusion

The present work shows that rapid prototyping paves the way for customized educational models capable of supporting operative but also preoperative skills. 3D printing opens up new opportunities by reducing the gap between pre‐clinical training and clinical reality in caries management, which can positively impact the quality of patient care.
Contrasting levels of β‐diversity and underlying phylogenetic trends indicate different paths to chemical diversity in highland and lowland willow species
Authors: Volf Martin , Leong Jing Vir , de Lima Ferreira Paola , Volfová Tereza , Kozel Petr , Matos‐Maraví Pável , Hörandl Elvira , Wagner Natascha D. , Luntamo Niko , Salminen Juha‐Pekka , Segar Simon T. , Sedio Brian E.
Published: June 2023

Diverse specialised metabolites contributed to the success of vascular plants in colonising most terrestrial habitats. Understanding how distinct aspects of chemical diversity arise through heterogeneous environmental pressures can help us understand the effects of abiotic and biotic stress on plant evolution and community assembly. We examined highland and lowland willow species within a phylogenetic framework to test for trends in their chemical α‐diversity (richness) and β‐diversity (variation among species sympatric in elevation). We show that differences in chemistry among willows growing at different elevations occur mainly through shifts in chemical β‐diversity and due to convergence or divergence among species sharing their elevation level. We also detect contrasting phylogenetic trends in concentration and α‐diversity of metabolites in highland and lowland willow species. The resulting elevational patterns contribute to the chemical diversity of willows and suggest that variable selective pressure across ecological gradients may, more generally, underpin complex changes in plant chemistry.
The effects of urbanization on pollinators and pollination: A meta‐analysis
Authors: Liang Huan , He Yong‐Deng , Theodorou Panagiotis , Yang Chun‐Feng
Published: June 2023

Urbanization is increasing worldwide, with major impacts on biodiversity, species interactions and ecosystem functioning. Pollination is an ecosystem function vital for terrestrial ecosystems and food security; however, the processes underlying the patterns of pollinator diversity and the ecosystem services they provide in cities have seldom been quantified. Here, we perform a comprehensive meta‐analysis of 133 studies examining the effects of urbanization on pollinators and pollination. Our results confirm the widespread negative impacts of urbanization on pollinator richness and abundance, with Lepidoptera being the most affected group. Furthermore, pollinator responses were found to be trait‐specific, with below‐ground nesting and solitary Hymenoptera, and spring flyers more severely affected by urbanization. Meanwhile, cities promote non‐native pollinators, which may exacerbate conservation risks to native species. Surprisingly, despite the negative effects of urbanization on pollinator diversity, pollination service measured as seed set is enhanced in non‐tropical cities likely due to abundant generalists and managed pollinators therein. We emphasize that the richness of local flowering plants could mitigate the negative impacts of urbanization on pollinator diversity. Overall, the results demonstrate the varying magnitudes of multiple moderators on urban pollinators and pollination services and could help guide conservation actions for biodiversity and ecosystem function for a sustainable future.
Predictors for the development of neurological immune‐related adverse events of immune checkpoint inhibitors and impact on mortality
Authors: Yan Chen , Huang Merry , Swetlik Carol , Toljan Karlo , Mahadeen Ahmad Z. , Bena James , Kunchok Amy , Funchain Pauline , McGinley Marisa
Published: June 2023

Background and purpose

Little is known about risk factors for developing neurological immunological adverse events (neuro‐irAEs) from immune checkpoint inhibitors (ICIs). We report the incidence, predictors for development, impact on mortality of neuro‐irAEs, and impact of ICIs on pre‐existing neurological conditions in a large clinical cohort.

Methods

Patients who received ICIs between January 2011 and December 2018 were identified from a tertiary cancer center registry. Descriptive statistics were used to summarize patient, cancer, and treatment data. Odds ratios from univariable and multivariable logistic regression models were calculated to identify potential predictors for developing a neuro‐irAE. Impact of neuro‐irAEs on overall survival was estimated by Kaplan–Meier and Cox proportional hazard models.

Results

Overall frequency of neurological irAEs was 2.3%. Peripheral nervous system complications were most frequent (53.6%). Melanoma, younger age, prior chemotherapy, prior resection, CTLA‐4 ICIs exposure, and combination PD‐1 and CTLA‐4 ICIs exposure had significantly higher odds for developing a neuro‐irAE (p < 0.05) in univariate but not multivariate models. Those with a neuro‐irAE were less likely to die at 3 years compared to those without a neuro‐irAE (69% vs. 55%,p = 0.004) in univariate but not multivariate model. Flare of pre‐existing neurological condition after exposure to ICIs was present (15.4%, 2 of 13 patients) but manageable. One patient was rechallenged with ICIs without recurrent flare.

Conclusions

Neuro‐irAEs are not associated with increase in overall mortality. Potential predictors for the development of neuro‐irAEs are younger age, melanoma, prior chemotherapy and resection, CTLA‐4, or combination ICIs exposure.
A method for harvesting viable cells from wound dressings
Authors: Qin Qi , Haba Daijiro , Takizawa Chihiro , Tomida Sanai , Kunimitsu Mao , Minematsu Takeo , Sanada Hiromi , Nakagami Gojiro
Published: June 2023

Wound fluid has been well studied for exploring protein biomarkers contained in it. However, cells in wound fluid have not received much attention due to the difficulty in their collection. Our study aimed to establish a method for collecting viable cells from discarded wound dressings. A protocol was designed to wash out nonadherent cells and detach adherent cells from silicone‐faced foam wound dressings using trypsin–EDTA. The optimal concentration and incubation time of trypsin–EDTA for collecting equivalent proportions of different cell types to the original cell population were determined in vitro. Cell composition and gene expression changes in monocytes, lymphocytes, neutrophils, fibroblasts and keratinocytes were confirmed using immunocytochemistry and RNA‐sequencing ex vivo. Full‐thickness wounds were created on 9‐week‐old male C57BL/6J mice. Wound fluid was collected, and half of it was applied to the wound dressings. The original cell population in the wound fluid and the cell population collected from wound dressings were compared. In the in vitro study, 0.25% trypsin–EDTA and 2.5‐min incubation time were considered optimal for collecting adherent cells from wound dressings. In the ex vivo study, among all cell types, only CD3+ lymphocytes showed a significantly higher cell proportion in the collected group. The relative gene expression of the five selected cells showed no significant changes (p‐value >0.05, |log2 fold change| < 1.5, differential gene expression analysis). Viable nonadherent and adherent cells were collected from wound dressings without altering gene expression and could be used in future studies for cellular analysis of wound fluid.
The opposite effect of tapinarof between IMQ and IL‐23 induced psoriasis mouse models
Authors: Zhu Xingyu , Han Ruomei , Tian Xiaoxue , Hochgerner Mathias , Li Hui , Wang Jiucun , Xia Jingjing
Published: June 2023

Tapinarof is an aryl hydrocarbon receptor (AHR) ligand which is used to treat plaque psoriasis in adults. However, the underlying mechanism is not yet fully understood. In this study, we applied two of the most studied psoriasis mouse models: topical application of imiquimod (IMQ) and subcutaneous injection of IL‐23. Although both models successfully induced psoriasis‐like lesions in mice, tapinarof had a completely opposite effect on the two models. Tapinarof decreased the expression of multiple essential cytokines involved in the pathological IL‐23/IL‐17/IL‐22 axis and ameliorated IMQ‐induced psoriatic dermatitis, inhibiting keratinocyte proliferation and abnormal differentiation. However, in the IL‐23‐injection‐model, tapinarof instead aggravated the disease. Here, tapinarof increased epidermal thickness and differentiated epidermal dysplasia in mice. Our data suggest that tapinarof may have different effects on varied types of psoriasis.