bluuebunny/crossref_metadata_2025 huggingface dataset:
It is not just about time: Agricultural practices and surrounding forest cover affect secondary forest recovery in agricultural landscapes
Authors: César Ricardo G. , Moreno Vanessa de S. , Coletta Gabriel D. , Schweizer Daniella , Chazdon Robin L. , Barlow Jos , Ferraz Silvio F. B. , Crouzeilles Renato , Brancalion Pedro H. S.
Published: January 2021

Natural regeneration of forests has significantly led to increased native forest cover in some regions. Several studies have explored the spatial drivers of forest cover increase, yet little is known about their effects on forest structure and species richness and diversity. We quantified the effects of local (forest age, remnant Eucalyptus basal area, slope, soil fertility, and clay content) and landscape drivers (surrounding land use, distance from streams, and surrounding forest cover and its change over time) on the aboveground biomass, species density, and phylogenetic diversity of native trees in second‐growth forests. We sampled 44 naturally regenerating forests established on former pastures and abandoned Eucalyptus plantations for 11–46 years in agricultural landscapes of the southeastern Atlantic Forest, Brazil. We used generalized linear mixed effect models to quantify the effect drivers on forest attributes. While only Eucalyptus basal area and proximity to sugarcane plantations had a consistent negative effect on forest biomass, other drivers were among the best models to explain forest attributes, but their effect was variable. Age increased tree biomass but the effect was not consistent. Similarly, species richness and phylogenetic diversity were mainly affected by landscape drivers such as surrounding forest cover. In tropical agricultural landscapes, effective forest recovery requires more than just time, as forest age can be less important in determining forest attributes than human land uses and surrounding native forest cover. Crucially, forest recovery can be improved through interventions and policies that promote less impactful human activities and enhance existing forest cover.

Abstract in Portuguese is available with online material.
Design and synthesis of isothiocyanate‐containing hybrid androgen receptor (AR) antagonist to downregulate AR and induce ferroptosis in GSH–Deficient prostate cancer cells
Authors: Qin Zhihui , Ou Siyu , Xu Liping , Sorensen Kathleen , Zhang Yingxue , Hu Dan‐Ping , Yang Zhe , Hu Wen‐Yang , Chen Fei , Prins Gail S.
Published: January 2021

Sustained androgen receptor (AR) signaling and apoptosis evasion are among the main hurdles of castration‐resistant prostate cancer (CRPC) treatment. We designed and synthesized isothiocyanate (ITC)‐containing hybrid AR antagonist (ITC‐ARi) and rationally combined ITC‐ARi with GSH synthesis inhibitor buthionine sulfoximine (BSO) to efficiently downregulate AR/AR splice variant and induce ferroptosis in CRPC cells. The representative ITC‐ARi 13 is an AR ligand that contains an N‐acetyl cysteine‐masked ITC moiety and gradually releases parental unconjugated ITC 12b in aqueous solution. The in vitro anti‐PCa activities of 13, such as growth inhibition and AR downregulation, are significantly enhanced when combined with BSO. The drug combination caused notable lipid peroxidation and the cell viability was effectively rescued by iron chelator, antioxidants or the inhibitor of heme oxygenase‐1, supporting the induction of ferroptosis. 13 and BSO cooperatively downregulate AR and induce ferroptosis likely through increasing the accessibility of 13/12b to cellular targets, escalating free intracellular ferrous iron and attenuating GSH‐centered cellular defense and adaptation. Further studies on the combination of ITC‐ARi and GSH synthesis inhibitor could result in a new modality against CRPC.
Skill, Thrill, and Will: The Role of Metacognition, Interest, and Self‐Control in Predicting Student Engagement in Mathematics Learning Over Time
Authors: Wang Ming‐Te , Binning Kevin R. , Del Toro Juan , Qin Xu , Zepeda Cristina D.
Published: January 2021

Maintaining learning engagement throughout adolescence is critical for long‐term academic success. This research sought to understand the role of metacognition and motivation in predicting adolescents' engagement in math learning over time. In two longitudinal studies with 2,325 and 207 adolescents (ages 11–15), metacognitive skills, interest, and self‐control each uniquely predicted math engagement. Additionally, metacognitive skills worked with interest and self‐control interactively to shape engagement. In Study 1, metacognitive skills and interest were found to compensate for one another. This compensatory pattern further interacted with time in Study 2, indicating that the decline in engagement was forestalled among adolescents who had either high metacognitive skills or high interest. Both studies also uncovered an interaction between metacognitive skills and self‐control, though with slightly different interaction patterns.
SketchZooms: Deep Multi‐view Descriptors for Matching Line Drawings
Authors: Navarro Pablo , Orlando J. Ignacio , Delrieux Claudio , Iarussi Emmanuel
Published: January 2021

Finding point‐wise correspondences between images is a long‐standing problem in image analysis. This becomes particularly challenging for sketch images, due to the varying nature of human drawing style, projection distortions and viewport changes. In this paper, we present the first attempt to obtain a learned descriptor for dense registration in line drawings. Based on recent deep learning techniques for corresponding photographs, we designed descriptors to locally match image pairs where the object of interest belongs to the same semantic category, yet still differ drastically in shape, form, and projection angle. To this end, we have specifically crafted a data set of synthetic sketches using non‐photorealistic rendering over a large collection of part‐based registered 3D models. After training, a neural network generates descriptors for every pixel in an input image, which are shown togeneralize correctly in unseen sketches hand‐drawn by humans. We evaluate our method against a baseline of correspondences data collected from expert designers, in addition to comparisons with other descriptors that have been proven effective in sketches. Code, data and further resources will be publicly released by the time of publication.
A comparative clinical study on the transfer accuracy of conventional and digital implant impressions using a new reference key‐based method
Authors: Schmidt Alexander , Rein Peter Engelbert , Wöstmann Bernd , Schlenz Maximiliane Amelie
Published: January 2021

Objectives

The objective of this study was to systematically compare the transfer accuracy of conventional and digital implant impressions in patients using a new reference key‐based method.

Material and methods

Thirty‐nine cases were included in the study (upper jaw 22 edentulous, 8 partially edentulous, average distance between implants 30.15 ± 11.18 mm; lower jaw 6 cases edentulous, 3 cases partially edentulous, average distance between implants 33.19 ± 14.85 mm). Individual reference keys were manufactured and reversibly fixed on implants. A conventional (CVI) and a digital (DI) implant impression was made. The implant positions (center points) of conventional and digital models were measured (coordinate‐measuring machine/three‐dimensional analysis software) and superimposed with the positions of the reference keys to compare the deviations of the conventional and digital models. For statistical analysis, ANOVA with MIXED procedure was applied (p < .05).

Results

Mean deviation ranged from 0.040±0.029 mm (DI/upper jaw) to 0.079 ± 0.050 mm (DI/lower jaw). There were significant differences between the CVI and DI impressions in the lower jaw (p < .05). No significant differences in transfer accuracy were found between partially and completely edentulous patients for the impression methods.

Conclusions

Within the limits of the present study, it can be concluded that full‐arch digital implant impressions of the upper jaw in partially or completely edentulous patients showed comparable results to conventional implant impressions. However, with regard to the implant position transfer accuracy, there are still limitations for digital impression in the lower jaw.
Regulatory T cells in ischemic stroke
Authors: Wang Huan , Wang Zhao , Wu Qianqian , Yuan Yujia , Cao Wen , Zhang Xiangjian
Published: January 2021

The pathophysiological mechanisms of neuroinflammation, angiogenesis, and neuroplasticity are currently the hotspots of researches in ischemic stroke. Regulatory T cells (Tregs), a subset of T cells that control inflammatory and immune responses in the body, are closely related to the pathogenesis of ischemic stroke. They participate in the inflammatory response and neuroplasticity process of ischemic stroke by various mechanisms, such as secretion of anti‐inflammatory factors, inhibition of pro‐inflammatory factors, induction of cell lysis, production of the factors that promote neural regeneration, and modulation of microglial and macrophage polarization. However, it remains unclear whether Tregs play a beneficial or deleterious role in ischemic stroke and the effect of Tregs in different stages of ischemic stroke. Here, we discuss the dynamic changes of Tregs at various stages of experimental and clinical stroke, the potential mechanisms under Tregs in regulating stroke and the preclinical studies of Tregs‐related treatments, in order to provide a reference for clinical treatment.
The applicability of the global lung initiative equations and other regional equations on a sample of healthy Middle Eastern adolescents
Authors: Al‐Qerem Walid , Alassi Ameen , Jarab Anan S. , Ling Jonathan
Published: January 2021

Background

The Global Lung Initiative 2012 (GLI‐2012) spirometry equations are multi‐ethnic equations that cover all ages between 3 and 95. However, there is a need to evaluate the suitability of these equations to a sample of Middle Eastern adolescents prior to being applied in clinical practice. The aim of this study is to evaluate the suitability of GLI‐2012 equations and two regional equations to a sample of Jordanian adolescents.

Methods

Spirometric measures were collected from 1036 healthy 14 to 17‐year‐old Jordanian children. z‐scores, predicted values, percent predicted values, and frequency of measures below lower limit of normal (LLN) were calculated for each adolescent using the studied equations.

Results

The means of z‐scores produced by GLI‐2012 equations for Caucasians in forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC% and mid forced expiratory flow (FEF25‐75) for boys were 0.12, −0.06, 0.34 and 0.09, respectively, while for girls they were −0.09, −0.16, 0.19 and −0.05, respectively. The mean of z‐scores produced by GLI‐2012 Other or Mixed equations in FEV1, FVC, FEV1/FVC% and FEF25‐75 for boys were 0.74, 072, 021 and 0.33, respectively, and for girls were 0.53, 0.56,0.02 and 0.2, respectively. The frequency of measures below LLN as produced by GLI 2012 for Caucasians were significantly different from the expected 5% in FEV1 and FEF25‐75 in boys only, whereas Other or Mixed produced frequencies significantly different from the expected 5% in most of the parameters.

Conclusion

Spirometry reference equations formulated for Jordanian adolescents may improve the diagnosis and treatment of asthma in Jordan.
Smokeless tobacco policy in Bangladesh: A stakeholder study of compatibility with the World Health Organization's Framework Convention on Tobacco Control
Authors: Naznin Eva , Wynne Olivia , George Johnson , Denham Alexandra M. J. , Hoque Mohammad E. , Milton Abul H. , Bonevski Billie , Stewart Kay
Published: January 2021

Introduction

Smokeless tobacco (ST) is the predominant form of tobacco used in Bangladesh and is associated with adverse health outcomes. Bangladesh ratified the World Health Organization's Framework Convention on Tobacco Control (FCTC) in 2004. There are concerns that FCTC legislation and implementation of ST control policy is insufficient in Bangladesh. The aim of this study was to investigate the achievements and challenges of ST policy in Bangladesh and its alignment with the FCTC.

Methods

We conducted semi‐structured key informant interviews with 20 stakeholders from government and non‐government offices and international funding agencies, including tobacco control advocates, policy makers and non‐governmental organisation workers. We used NVivo software to create key themes and the framework method for thematic analysis.

Results

Our findings revealed a lack of national policy in terms of disclosure of harmful contents, illicit trade and standardised packaging of ST. Legislation remains ineffective in relation to graphical health warnings and tax measures. Challenges to ST control identified included inadequate law enforcement; paucity of research, surveillance, and evidence generation; and supply chain control. We identified lack of congruence of ST policies with FCTC due to slow progress in implementation of FCTC measures, lack of a country‐specific policy and industry interference. To comply with FCTC, participants recommended strong leadership and political commitment, co‐ordination between public and private sectors and proper use of tobacco control resources.

Discussion and Conclusions

Bangladesh has adopted several important FCTC measures, but further strengthening of ST policy is needed to enable full implementation of FCTC.
Learning from sticky mittens: Commentary on van den Berg and gredeback (2020)
Authors: Needham Amy Work
Published: January 2021

In their paper, van den Berg & Gredeback (2020) offer many criticisms of the research demonstrating increases in multimodal object exploration following 3‐month‐old infants' experience using sticky mittens to engage with objects. In the current commentary, I offer some clarifying points and some additional information from a new study that may help resolve apparent conflicts in the data.
Early identification of children with/at risk of developmental coordination disorder: a scoping review
Authors: Lee Emily J , Zwicker Jill G
Published: January 2021

Aim

To summarize current evidence for early identification and motor‐based intervention for children aged 5 years and younger with/at risk of developmental coordination disorder (DCD).

Method

Using scoping review methodology and after duplicates were removed, 11 115 peer‐reviewed articles and grey literature were independently screened by two authors. Data from 103 included records were extracted and synthesized by both assessors. One author entered the relevant data into tables, while the other author double‐checked the entries.

Results

Records included peer‐reviewed studies, guidelines, conference presentations, and theses/dissertations. Most literature pertained to early identification (n=78), with fewer studies targeting intervention (n=22) or covering both topics (n=3). Literature was summarized in two main categories: (1) assessments for diagnostic criteria A and B; and (2) motor‐based interventions for young children with/at risk of DCD. This article highlights the findings related to assessments, while a companion article summarizes the intervention literature.

Interpretation

Emerging evidence shows that children, especially those at greatest risk of DCD, may be identified before formal school entry. Earlier identification will allow for earlier intervention, which may help to improve the developmental trajectories of children with/at risk of DCD and prevent secondary consequences of the disorder. It is recommended that health care providers explicitly use the term ‘at risk of DCD’.
Impact of clinical pharmacy interventions on health and economic outcomes in type 2 diabetes: A systematic review and meta‐analysis
Authors: Desse Tigestu A. , Vakil Krishna , Mc Namara Kevin , Manias Elizabeth
Published: January 2021

Aim

To examine the effectiveness of clinical pharmacy interventions on health and economic outcomes of people with type 2 diabetes in hospital settings.

Methods

We searched MEDLINE, EMBASE, PsycInfo, CINAHL, COCHRANE Library and citations and reference lists of key articles. We included randomized and non‐randomized controlled trials, cohort and controlled before‐after studies. Primary outcomes were glycosylated haemoglobin (HbA1c), all‐cause mortality, major cardiovascular events, adverse events (AEs), health‐related quality of life and economic outcomes.

Results

We retrieved 11,853 studies, of which 44 studies were included in the review (n = 8623). We included 29 randomized controlled studies in the meta‐analyses (n = 4055). Clinical pharmacy interventions significantly reduced HbA1c levels compared to usual care (standardized mean difference: −0.52, p < 0.001). The interventions significantly reduced AEs compared to usual care. No studies were reported on the effectiveness of clinical pharmacy interventions on major cardiovascular events. In one study that examined the impact of clinical pharmacy interventions on all‐cause mortality, a non‐significant reduction was observed compared with usual care. There was significant improvement in quality of life and significant reduction in costs of type 2 diabetes care compared to usual care.

Conclusions

Clinical pharmacy interventions were effective in improving glycaemic control, quality of life and reducing the rate of AEs and costs of type 2 diabetes care.
Hierarchy and the Employer Size Effect on Wages: Evidence from Britain
Authors: Green Colin P. , Heywood John S. , Theodoropoulos Nikolaos
Published: January 2021

We argue that employer size wage effects reflect the role of hierarchy. Using matched employer–employee data and individual longitudinal data, we show that the employer size wage effects for supervisors are approximately twice those for non‐supervisors. We confirm sorting on supervisor ability, and present evidence of additional match‐specific wage returns for supervisors. We demonstrate that spans of control influence the establishment size return for supervisors but not for non‐supervisors. Talented supervisors sort into larger establishments taking a talent premium with them, but they also receive a match‐specific return on that talent only when matched with a larger establishment.
A complete inventory of North American butterfly occurrence data: narrowing data gaps, but increasing bias
Authors: Shirey Vaughn , Belitz Michael W. , Barve Vijay , Guralnick Robert
Published: January 2021

Aggregate biodiversity data from museum specimens and community observations have promise for macroscale ecological analyses. Despite this, many groups are under‐sampled, and sampling is not homogeneous across space. Here we used butterflies, the best documented group of insects, to examine inventory completeness across North America. We separated digitally accessible butterfly records into those from natural history collections and burgeoning community science observations to determine if these data sources have differential spatio‐taxonomic biases. When we combined all data, we found startling under‐sampling in regions with the most dramatic trajectories of climate change and across biomes. We also used multiple methods with each supporting the hypothesis that community science observations are filling more gaps in sampling but are more biased towards areas with the highest human footprint. Finally, we found that both types of occurrences have familial‐level taxonomic completeness biases, in contrast to the hypothesis of less taxonomic bias in natural history collections data. These results suggest that higher inventory completeness, driven by rapid growth of community science observations, is partially offset by higher spatio‐taxonomic biases. We use the findings here to provide recommendations on how to alleviate some of these gaps in the context of prioritizing global change research.
The utility of a formative one‐station objective structured clinical examination for Substance use disorders in a dental curriculum
Authors: Odusola Folarin , Smith Jennifer L. , Turrigiano Eva , Shulman Matisyahu , Grbic John T. , Fine James B. , Hu Mei‐Chen , Nunes Edward V. , Bisaga Adam , Levin Frances R.
Published: January 2021

Substance use disorders (SUD) are chronic relapsing medical conditions characterised by compulsive substance seeking and use. They constitute a substantial disease burden globally. Labelling of persons with SUD has created barriers to treatment but there are effective management strategies. The dental profession has embraced reforms designed to address the SUD epidemic by promoting continuing education for practitioners and initiating curriculum changes in dental schools. Screening, Brief Intervention and Referral to Treatment (SBIRT) is an evidence‐based model for managing patients with SUD. The use of a formative 1‐station Objective Structured Clinical Examination (OSCE) for learning and assessment in SBIRT, operationalised with the MD3 rating scale is presented in this study. In 3 years of implementation, the SBIRT OSCE successfully integrated into the curriculum of the College of Dental Medicine, Columbia University. Mean score of total adherent behaviours was 11.80 (SD =4.23) (range: 2 – 24) and Cronbach's coefficient alpha for across‐items reliability in adherent behaviours was 0.66. Adherent behaviours correlated with the global ratings (r = 0.66). Mean of global rating scores were 2.90 (SD =1.01) for collaboration and 2.97 (SD =1.00) for empathy and the global rating scores correlated with each other (r = 0.85). Histograms of global rating scores resembled normal distribution. The 1‐station OSCE is a good model for learning about SBIRT. Psychometric analysis was useful in understanding the underlying construct of the MD3 rating scale and supported its reliability, validity and utility in dental education.
Neuronal, but not glial, Contactin 2 negatively regulates axon regeneration in the injured adult optic nerve
Authors: Savvaki Maria , Kafetzis George , Kaplanis Stefanos‐Ioannis , Ktena Niki , Theodorakis Kostas , Karagogeos Domna
Published: January 2021

Mammalian adult neurons of the central nervous system (CNS) display limited ability to regrow axons after trauma. The developmental decline in their regenerative ability has been attributed to both intrinsic and extrinsic factors, including postnatal suppression of transcription factors and non‐neuronal inhibitory components, respectively. The cell adhesion molecule Contactin 2 (CNTN2) is expressed in neurons and oligodendrocytes in the CNS. Neuronal CNTN2 is highly regulated during development and plays critical roles in axon growth and guidance and neuronal migration. On the other hand, CNTN2 expressed by oligodendrocytes interferes with the myelination process, with its ablation resulting in hypomyelination. In the current study, we investigate the role of CNTN2 in neuronal survival and axon regeneration after trauma, in the murine optic nerve crush (ONC) model. We unveil distinct roles for neuronal and glial CNTN2 in regenerative responses. Surprisingly, our data show a conflicting role of neuronal and glial CNTN2 in axon regeneration. Although glial CNTN2 as well as hypomyelination are dispensable for both neuronal survival and axon regeneration following ONC, the neuronal counterpart comprises a negative regulator of regeneration. Specifically, we reveal a novel mechanism of action for neuronal CNTN2, implicating the inhibition of Akt signalling pathway. The in vitro analysis indicates a BDNF‐independent mode of action and biochemical data suggest the implication of the truncated form of TrkB neurotrophin receptor. In conclusion, CNTN2 expressed in CNS neurons serves as an inhibitor of axon regeneration after trauma and its mechanism of action involves the neutralization of Akt‐mediated neuroprotective effects.
Meta‐analysis shows the evidence for context‐dependent mating behaviour is inconsistent or weak across animals
Authors: Dougherty Liam R.
Published: January 2021

Animals often need to invest significantly in mating behaviour in order to successfully mate. However, the expression of mating behaviour can be costly, especially in unfavourable environments, so animals are expected to adjust their behaviour in a context‐dependent way to mitigate these costs. I systematically searched the literature for studies measuring animal mating behaviour (sexual signalling, response to sexual signals or the strength of mate choice) in more than one environment, and used a phylogenetically controlled meta‐analysis to identify environmental factors influencing these behaviours. Across 222 studies, the strength of mate choice was significantly context‐dependent, and most strongly influenced by population density, population sex ratio and predation risk. However, the average effect sizes were typically small. The amount of sexual signalling and the strength of response to sexual signals were not significantly related to the environment. Overall, this suggests that the evidence for context‐dependent mating behaviour across animals is surprisingly weak.
Increasing temperature elevates the variation and spatial differentiation of pesticide tolerance in a plant pathogen
Authors: Lurwanu Yahuza , Wang Yan‐Ping , Wu E‐Jiao , He Dun‐Chun , Waheed Abdul , Nkurikiyimfura Oswald , Wang Zhen , Shang Li‐Ping , Yang Li‐Na , Zhan Jiasui
Published: January 2021

Climate change and pesticide resistance are two of the most imminent challenges human society is facing today. Knowledge of how the evolution of pesticide resistance may be affected by climate change such as increasing air temperature on the planet is important for agricultural production and ecological sustainability in the future but is lack in scientific literatures reported from empirical research. Here, we used the azoxystrobin‐Phytophthora infestans interaction in agricultural systems to investigate the contributions of environmental temperature to the evolution of pesticide resistance and infer the impacts of global warming on pesticide efficacy and future agricultural production and ecological sustainability. We achieved this by comparing azoxystrobin sensitivity of 180 P. infestans isolates sampled from nine geographic locations in China under five temperature schemes ranging from 13 to 25°C. We found that local air temperature contributed greatly to the difference of azoxystrobin tolerance among geographic populations of the pathogen. Both among‐population and within‐population variations in azoxystrobin tolerance increased as experimental temperatures increased. We also found that isolates with higher azoxystrobin tolerance adapted to a broader thermal niche. These results suggest that global warming may enhance the risk of developing pesticide resistance in plant pathogens and highlight the increased challenges of administering pesticides for effective management of plant diseases to support agricultural production and ecological sustainability under future thermal conditions.
Evolutionary fusion of classifiers trained on linear prediction based features for replay attack detection
Authors: Nasersharif Babak , Yazdani Morteza
Published: January 2021

Recently, linear prediction analysis (LP) related features have been successfully used for replay attack detection due to the imperfection in the LP‐based signal produced by recording and playback devices. In this paper, we propose a weighted linear combination of classifier scores for replay attack detection where our classifiers, including Gaussian mixture models (GMMs) and support vector machines (SVMs), are trained on a variety of LP and LP residual‐based features. In this way, we can benefits from all of the LP‐related features when we combine classifiers trained on these features. We determine classifier weights using two evolutionary algorithms: genetic algorithm and particle swarm optimization. Furthermore, we propose a new feature based on performing LP residuals analysis of Mel sub‐band energies. We also propose a deep structure for extracting deep features from LP‐based coefficients to consider the class labels (genuine or spoofed speaker) in the feature extraction process. Results of our classifier system on the ASVspoof 2017 version 2 dataset show equal error rates of 0.3% and 4.8% for its development and evaluation subset, respectively. We also applied our proposed replay attack detection method to an ASV system that has acceptable results.
Pharmacological validation of TDO as a target for Parkinson’s disease
Authors: Perez‐Pardo Paula , Grobben Yvonne , Willemsen‐Seegers Nicole , Hartog Mitch , Tutone Michaela , Muller Michelle , Adolfs Youri , Pasterkamp Ronald Jeroen , Vu‐Pham Diep , van Doornmalen Antoon M. , van Cauter Freek , de Wit Joeri , Gerard Sterrenburg Jan , Uitdehaag Joost C.M. , de Man Jos , Buijsman Rogier C. , Zaman Guido J.R. , Kraneveld Aletta D.
Published: January 2021

Parkinson’s disease patients suffer from both motor and nonmotor impairments. There is currently no cure for Parkinson’s disease, and the most commonly used treatment, levodopa, only functions as a temporary relief of motor symptoms. Inhibition of the expression of the L‐tryptophan‐catabolizing enzyme tryptophan 2,3‐dioxygenase (TDO) has been shown to inhibit aging‐related α‐synuclein toxicity in Caenorhabditis elegans. To evaluate TDO inhibition as a potential therapeutic strategy for Parkinson’s disease, a brain‐penetrable, small molecule TDO inhibitor was developed, referred to as NTRC 3531‐0. This compound potently inhibits human and mouse TDO in biochemical and cell‐based assays and is selective over IDO1, an evolutionary unrelated enzyme that catalyzes the same reaction. In mice, NTRC 3531‐0 increased plasma and brain L‐tryptophan levels after oral administration, demonstrating inhibition of TDO activity in vivo. The effect on Parkinson’s disease symptoms was evaluated in a rotenone‐induced Parkinson’s disease mouse model. A structurally dissimilar TDO inhibitor, LM10, was evaluated in parallel. Both inhibitors had beneficial effects on rotenone‐induced motor and cognitive dysfunction as well as rotenone‐induced dopaminergic cell loss and neuroinflammation in the substantia nigra. Moreover, both inhibitors improved intestinal transit and enhanced colon length, which indicates a reduction of the rotenone‐induced intestinal dysfunction. Consistent with this, mice treated with TDO inhibitor showed decreased expression of rotenone‐induced glial fibrillary acidic protein, which is a marker of enteric glial cells, and decreased α‐synuclein accumulation in the enteric plexus. Our data support TDO inhibition as a potential therapeutic strategy to decrease motor, cognitive, and gastrointestinal symptoms in Parkinson’s disease.
Exploring political personalities: The micro‐foundation of local policy innovation in China
Authors: Lewis Orion A. , Teets Jessica C. , Hasmath Reza
Published: January 2021

This article argues that policymakers' individual attributes influence their willingness to engage in policy innovation, and that this influence is responsive to, but not determined by, changes in the institutional structure. We derive these findings by employing principal component analysis of original data from surveys of local policymakers in China, to inductively locate different personalities. We find statistically significant personalities that influence a willingness to innovate, and that this influence is responsive to changes such as heightened risk. In addition to parsing the influence of extrinsic and intrinsic motivations on policy innovation, we further find that the traditional risk‐acceptant policy‐entrepreneur personality does not explain innovation well.
Outsourced internal audit function and real earnings management: The role of industry and firm expertise of external providers
Authors: Baatwah Saeed Rabea , Omer Waddah Kamal , Aljaaidi Khaled Salmen
Published: January 2021

As the outsourced internal audit function (IAF) and real earnings management are attracting widespread attention among firms, it is vital for stakeholders to understand how these two practices affect the quality of financial reporting. This study examines how the expertise of an external IAF provider reduces real earnings management. Using a pooled panel data regression of 928 firm‐observations, we find that the external IAF provider's firm‐specific expertise is significantly associated with lower real earnings management. Conversely, we report no such association for external IAF providers with industry expertise. These findings are robust under a battery of sensitive analyses. The results of additional analyses show that the industry and firm‐specific expertise of external IAF provider interact with each other, resulting in a significant reduction in real earnings management. We also find significant differences in the IAF quality between big4 and second‐tier audit firms in which the latter are associated with lower real earnings management and the former with higher real earnings management. Finally, we observe low real earnings management for important clients and/or those with influential CEOs if the external IAF provider has firm‐specific expertise.
Otoferlin is a prognostic biomarker in patients with clear cell renal cell carcinoma: A systematic expression analysis
Authors: Cox Alexander , Tolkach Yuri , Stein Johannes , Kristiansen Glen , Ritter Manuel , Ellinger Jörg
Published: January 2021

Objectives

To comprehensively investigate the role of otoferlin as a prognostic and diagnostic biomarker in clear cell renal cell carcinoma.

Methods

Three independent cohorts were used to study otoferlin in clear cell renal cell carcinoma: The Cancer Genome Atlas cohort (messenger ribonucleic acid expression; clear cell renal cell carcinoma n = 514, normal renal tissue n = 81); study validation cohort (messenger ribonucleic acid expression; clear cell renal cell carcinoma n = 79, normal renal tissue n = 44); and immunohistochemistry cohort (protein expression; clear cell renal cell carcinoma n = 142, normal renal tissue n = 30). Otoferlin gene expressions were extracted from The Cancer Genome Atlas database or determined using quantitative real‐time polymerase chain reaction, respectively. Protein expression was assessed using immunohistochemistry staining against otoferlin on tissue microarrays. Correlations between otoferlin messenger ribonucleic acid/protein expression and clinicopathological data/patient survival were statistically tested.

Results

Otoferlin messenger ribonucleic acid expression was significantly upregulated in clear cell renal cell carcinoma compared with normal renal tissue. High expression levels correlated with advanced stage, higher grade and metastatic tumors, accompanied by independent prognostic significance for overall and cancer‐specific survival. In contrast, otoferlin protein expression was downregulated in tumor tissue. Although, high otoferlin expression in clear cell renal cell carcinoma was positively correlated with histological grading and independently predictive of a shortened progression‐free survival.

Conclusion

Our data suggest otoferlin as an indicator of tumor aggressiveness and as a prognostic biomarker for patients with clear cell renal cell carcinoma, leading to the conclusion that otoferlin could promote the malignancy of clear cell renal cell carcinoma.
Mycobacterium tuberculosis Rv1987 protein induces M2 polarization of macrophages through activating the PI3K/Akt1/mTOR signaling pathway
Authors: Sha Shanshan , Shi Yang , Tang Yawei , Jia Liqiu , Han Xiuyan , Liu Yuxin , Li Xia , Ma Yufang
Published: January 2021

Mycobacterium tuberculosis (Mtb) can subvert host immune responses and survive in macrophages. Specific Mtb antigens play a critical role in this process. Rv1987, a secretory protein encoded by the gene rv1987 in the region of difference‐2 (RD2) of the Mtb genome, is specifically expressed in pathogenic mycobacteria. Our previous work proved that Rv1987 induced a Th2 response in mice and enhanced mycobacterial survival in mouse lungs, but its effect on macrophages, the most important effector immune cell involved in killing Mtb, remains unclear. In this study, we used an M. smegmatis strain overexpressing Rv1987 protein to infect alveolar macrophages and the macrophage cell line RAW264.7 and analyzed the effect of Rv1987 protein on macrophage polarization. Rv1987 induced M2 polarization in macrophages both in vivo and in vitro. The bactericidal ability of these M2 polarized macrophages decreased remarkably, which resulted in the increased survival of bacteria in macrophages. Proteomics, RT‐qPCR and western blotting results revealed that the PI3K/Akt1/mTOR signaling pathway was activated in Rv1987‐induced M2 macrophages. Meanwhile, the SHIP molecule, a negative regulator of the PI3K/Akt1/mTOR signaling pathway, was significantly downregulated. These results suggest that Rv1987 plays an important role in modulating the host immune response and could be established as a potential drug target.
Alcohol misuse and critical care admissions in the Northern Territory
Authors: Secombe Paul , Campbell Lewis , Brown Alex , Bailey Michael , Pilcher David
Published: January 2021

Background

The Northern Territory (NT) has a long history of heavy alcohol consumption with a correspondingly high attributable morbidity and mortality.

Aims

To describe the number of admissions to intensive care associated with alcohol misuse.

Methods

This is a prospective case–control study including all admissions to NT intensive care units (ICU) between 1 July 2018 and 30 June 2019. Characteristics and outcomes of patients who had an admission associated with alcohol misuse (a composite measure of acute and/or chronic misuse) were compared to those who did not. Primary outcome was the number of admissions associated with alcohol misuse. Secondary outcomes included measures of resource use (length of stay (LoS), need for mechanical ventilation) and mortality adjusted for illness severity.

Results

Over the sampling period there were 1664 admissions. After exclusions, 1471 admissions were analysed, of which 307 (21%) were associated with alcohol misuse. Acute or chronic misuse was associated with 3.7% and 12.1% of admissions respectively, while 5.1% met criteria for both. Admissions associated with alcohol misuse more frequently required ventilation (38.4% vs 20.7%, P < 0.01) and had longer ICU (2.8 vs 2.1 days, P < 0.01) and hospital LoS (9.1 vs 7.1 days, P < 0.01). There was no difference in hospital mortality (7.2% vs 7.7%, P = 0.94), even after adjustment for illness severity, hospital and diagnostic category.

Conclusions

Alcohol misuse is associated with a substantial number of critical care admissions and consumes considerable acute care resources. Further policy directed at harm minimisation and epidemiological work at jurisdictional and national level is necessary.
Economic evaluations in paediatric dentistry clinical trials
Authors: Rogers Helen Jessica , Freitas Raiza Dias , Beeson Morgan James , Vernazza Christopher Robert
Published: January 2021

Economic evaluations play an important role in identifying the cost‐effectiveness of alternative healthcare programmes, informing decisions surrounding funding and the allocation of resources. This paper outlines the basic principles of economic evaluation and how it can be conducted alongside a clinical trial. Furthermore, it considers the ways in which evidence from these studies can be used, and the challenges researchers are faced with when conducting economic evaluations in the field of children’s oral health.
A qualitative study of adolescent cancer survivors perspectives on social support from healthy peers – A RESPECT study
Authors: Ingersgaard Marianne Vie , Fridh Martin Kaj , Thorsteinsson Troels , Adamsen Lis , Schmiegelow Kjeld , Bækgaard Larsen Hanne
Published: January 2021

Background

Adolescents’ psychosocial development is generally influenced by their peers. Those facing hospital‐based cancer treatment are particularly challenged as they are isolated from their social network and lack sufficient coping resources.

Aim

This study explores the adolescent cancer survivor's perceptions and experiences with healthy classmate socialization support efforts via hospital co‐admittance, from diagnosis to reinstatement in school, as an intervention of the RESPECT (REhabilitation including Social and Physical Activity and Education in Children and Teenagers with cancer) Study.

Design

A phenomenological, descriptive study.

Methods

Using variation sampling, 14 adolescents (aged 14–19), who completed the RESPECT intervention (April 2016–July 2017), participated in qualitative, in‐depth, semi‐structured interviews that were thematically analysed.

Findings

Four themes emerged: (a) Ambassadors as liaison persons; (b) Ambassadors as promoters of normalization and identity continuity; (c) Ambassadors as ‘behind the scenes’ friends; and (d) feelings of vulnerability and inferiority. Ambassadors reinstated a sense of normalcy in the adolescents’ daily life. They supported identity construction and served as liaison persons who buffered loneliness and social isolation as well as bridging a continued sense of belonging to one's school peer network. In contrast with other peers, ambassadors understood cancer‐related issues, knowledge which they partially gained witnessing the impact of treatment‐related side effects on their hospitalized classmates. However, the consequence of this trade‐off was an asymmetry in their relationship, with the adolescents requiring a certain level of safeguard from their ambassadors to maintain equal power in the relationship.

Conclusion

The ambassadors enhanced the adolescents’ ability to cope with their altered social position during treatment and to psychosocially reinstate it on their return to school.

Impact

Future interventions should offer opportunities for healthy peers to be educated in what it means to live with cancer. Future programs to sustain socialization in adolescents with cancer should involve healthy peers for the entirety of the treatment period.
Improved blood pressure control via a novel chronic disease management model of care in sub‐Saharan Africa: Real‐world program implementation results
Authors: Otieno Harun A. , Miezah Charles , Yonga Gerald , Kueffer Fred , Guy Molly , Lang'At Chemuttaai , Hettrick Douglas A. , Schmieder Roland
Published: January 2021

A chronic disease management model of care (Empower Health) was launched in rural and urban areas of Ghana and Kenya in 2018. The goal was to improve disease awareness, reduce the burden of disease, and improve the clinical effectiveness and efficiency of managing hypertension. Leveraging the model, clinicians provide patients with tailored management plans. Patients accessed regular blood pressure checks at home, at the clinic, or at community‐partner locations where they received real‐time feedback. On the mobile application, clinicians viewed patient data, provided direct patient feedback, and wrote electronic prescriptions accessible through participating pharmacies. To date, 1266 patients had been enrolled in the “real‐world” implementation cohort and followed for an average of 351 ± 133 days across 5 facilities. Average baseline systolic blood pressure (SBP) was 145 ± 21 mmHg in the overall cohort and 159 ± 16 mmHg in the subgroup with uncontrolled hypertension (n = 743) as defined by baseline SBP ≥ 140 mmHg. SBP decreased significantly through 12 months in both the overall cohort (−9.4 mmHg, p < .001) and in the uncontrolled subgroup (−17.6 mmHg, p < .001). The proportion patients with controlled pressure increased from 46% at baseline to 77% at 12 months (p < .001). In summary, a new chronic disease management model of care improved and sustained blood pressure control to 12 months, especially in those with elevated blood pressure at enrollment.
PGC‐1α protects from myocardial ischaemia‐reperfusion injury by regulating mitonuclear communication
Authors: Li Yan‐Qing , Jiao Yan , Liu Ya‐Nan , Fu Jia‐ying , Sun Lian‐Kun , Su Jing
Published: January 2021

The recovery of blood supply after a period of myocardial ischaemia does not restore the heart function and instead results in a serious dysfunction called myocardial ischaemia‐reperfusion injury (IRI), which involves several complex pathophysiological processes. Mitochondria have a wide range of functions in maintaining the cellular energy supply, cell signalling and programmed cell death. When mitochondrial function is insufficient or disordered, it may have adverse effects on myocardial ischaemia‐reperfusion and therefore mitochondrial dysfunction caused by oxidative stress a core molecular mechanism of IRI. Peroxisome proliferator‐activated receptor gamma co‐activator 1α (PGC‐1α) is an important antioxidant molecule found in mitochondria. However, its role in IRI has not yet been systematically summarized. In this review, we speculate the role of PGC‐1α as a key regulator of mitonuclear communication, which may interacts with nuclear factor, erythroid 2 like ‐1 and ‐2 (NRF‐1/2) to inhibit mitochondrial oxidative stress, promote the clearance of damaged mitochondria, enhance mitochondrial biogenesis, and reduce the burden of IRI.
Differential effects of mesalazine formulations on thiopurine metabolism through thiopurine S‐methyltransferase inhibition
Authors: Morikubo Hiromu , Kobayashi Taku , Ozaki Ryo , Okabayashi Shinji , Kuronuma Satoshi , Takeuchi Osamu , Shiba Tenyo , Kiyohara Hiroki , Matsubayashi Mao , Sagami Shintaro , Nakano Masaru , Ikezaki Osamu , Hisamatsu Tadakazu , Tanaka Yoichi , Hibi Toshifumi
Published: January 2021

Background and Aim

Thiopurines are often used in combination with mesalazine for the treatment of ulcerative colitis (UC). Mesalazine formulations are delivered to the digestive tract by various delivery systems and absorbed as 5‐aminosalicylic acid (5‐ASA). 5‐ASA is known to inhibit thiopurine S‐methyltransferase (TPMT) activity and to affect thiopurine metabolism. There have been no studies comparing TPMT inhibition by multimatrix mesalazine (MMX) with other formulations. We investigated the difference in TPMT inhibition by different mesalazine formulations and prospectively confirmed the clinical relevance.

Methods

Plasma concentrations of 5‐ASA, N‐acetyl‐5‐aminosalicylic acid (N‐Ac‐5‐ASA), and TPMT activities were measured in UC patients receiving various mesalazine formulations (time‐dependent or pH‐dependent mesalazine or MMX) as monotherapy. Patients already on both time‐dependent or pH‐dependent mesalazine and thiopurines switched their mesalazine to MMX, examining 6‐thioguanine nucleotide (6‐TGN) and 6‐methylmercaptopurine (6‐MMP) 0 and 8 weeks after switching. Clinical relapse after switching was also monitored for 24 weeks.

Results

Plasma 5‐ASA and N‐Ac‐5‐ASA levels were significantly higher in patients receiving time‐dependent mesalazine (n = 12) compared with pH‐dependent mesalazine (n = 12) and MMX (n = 15), accompanied by greater TPMT inhibition. Prospective switching from time‐dependent mesalazine to MMX decreased 6‐TGN levels, increased those of 6‐MMP, and increased 6‐MMP/6‐TGN ratios. Furthermore, this resulted in significantly more relapses than switching from pH‐dependent mesalazine to MMX.

Conclusions

Time‐dependent mesalazine has higher plasma 5‐ASA and N‐Ac‐5‐ASA levels and greater TPMT inhibition than MMX. Therefore, switching from time‐dependent mesalazine to MMX may lead to an increase of 6‐MMP/6‐TGN, which may reduce the clinical effectiveness of thiopurines, warranting close monitoring after switch.