bluuebunny/crossref_metadata_2025 huggingface dataset:
Functionalized graphene-oxide grids enable high-resolution cryo-EM structures of the SNF2h-nucleosome complex without crosslinking
Authors: Chio Un Seng , Palovcak Eugene , Autzen Anton A. A. , Autzen Henriette E. , Muñoz Elise N. , Yu Zanlin , Wang Feng , Agard David A. , Armache Jean-Paul , Narlikar Geeta J. , Cheng Yifan
Published: June 2023

Single-particle cryo-EM is widely used to determine enzyme-nucleosome complex structures. However, cryo-EM sample preparation remains challenging and inconsistent due to complex denaturation at the air-water interface (AWI). To address this issue, we developed graphene-oxide-coated EM grids functionalized with either single-stranded DNA (ssDNA) or thiol-poly(acrylic acid-co-styrene) (TAASTY) co-polymer. These grids protect complexes between the chromatin remodeler SNF2h and nucleosomes from the AWI and facilitated collection of high-quality micrographs of intact SNF2h-nucleosome complexes in the absence of crosslinking. The data yields maps ranging from 2.3 to 3 Å in resolution. 3D variability analysis reveals nucleotide-state linked conformational changes in SNF2h bound to a nucleosome. In addition, the analysis provides structural evidence for asymmetric coordination between two SNF2h protomers acting on the same nucleosome. We envision these grids will enable similar detailed structural analyses for other enzyme-nucleosome complexes and possibly other protein-nucleic acid complexes in general.
Jointly efficient encoding and decoding in neural populations
Authors: Blanco Malerba Simone , Micheli Aurora , Woodford Michael , Azeredo da Silveira Rava
Published: June 2023

The efficient coding approach proposes that neural systems represent as much sensory information as biological constraints allow. It aims at formalizing encoding as a constrained optimal process. A different approach, that aims at formalizing decoding, proposes that neural systems instantiate a generative model of the sensory world. Here, we put forth a normative framework that characterizes neural systems as jointly optimizing encoding and decoding. It takes the form of a variational autoencoder: sensory stimuli are encoded in the noisy activity of neurons to be interpreted by a flexible decoder; encoding must allow for an accurate stimulus reconstruction from neural activity. Jointly, neural activity is required to represent the statistics of latent features which are mapped by the decoder into distributions over sensory stimuli; decoding correspondingly optimizes the accuracy of the generative model. This framework yields in a family of encoding-decoding models, which result in equally accurate generative models, indexed by a measure of the stimulus-induced deviation of neural activity from the marginal distribution over neural activity. Each member of this family predicts a specific relation between properties of the sensory neurons, such as the arrangement of the tuning curve means (preferred stimuli) and widths (degrees of selectivity) in the population as a function of the statistics of the sensory world. Our approach thus generalizes the efficient coding approach. Notably, here, the form of the constraint on the optimization derives from the requirement of an accurate generative model, while it is arbitrary in efficient coding models. Moreover, solutions do not require the knowledge of the stimulus distribution, but are learned on the basis of data samples; the constraint further acts as regularizer, allowing the model to generalize beyond the training data. Finally, we characterize the family of models we obtain through alternate measures of performance, such as the error in stimulus reconstruction. We find that a range of models admits comparable performance; in particular, a population of sensory neurons with broad tuning curves as observed experimentally yields both low reconstruction stimulus error and an accurate generative model that generalizes robustly to unseen data.
Deriving confidence intervals for mutation rates across a wide range of evolutionary distances using FracMinHash
Authors: Rahman Hera Mahmudur , Pierce-Ward N. Tessa , Koslicki David
Published: June 2023

Sketching methods offer computational biologists scalable techniques to analyze data sets that continue to grow in size. MinHash is one such technique to estimate set similarity that has enjoyed recent broad application. However, traditional MinHash has previously been shown to perform poorly when applied to sets of very dissimilar sizes. FracMinHash was recently introduced as a modification of MinHash to compensate for this lack of performance when set sizes differ. This approach has been successfully applied to metagenomic taxonomic profiling in the widely used tool sourmash gather. Although experimental evidence has been encouraging, FracMinHash has not yet been analyzed from a theoretical perspective. In this paper, we perform such an analysis to derive various statistics of FracMinHash, and prove that although FracMinHash is not unbiased (in the sense that its expected value is not equal to the quantity it attempts to estimate), this bias is easily corrected for both the containment and Jaccard index versions. Next, we show how FracMinHash can be used to compute point estimates as well as confidence intervals for evolutionary mutation distance between a pair of sequences by assuming a simple mutation model. We also investigate edge cases in which these analyses may fail to effectively warn the users of FracMinHash indicating the likelihood of such cases. Our analyses show that FracMinHash estimates the containment of a genome in a large metagenome more accurately and more precisely compared with traditional MinHash, and the point estimates and confidence intervals perform significantly better in estimating mutation distances.
Machine learning regression for estimating the cost range of building projects
Authors: Gurmu Argaw , Miri Mani Pourdadash
Published: June 2023

Purpose

Several factors influence the costs of buildings. Thus, identifying the cost significant factors can assist to improve the accuracy of project cost forecasts during the planning phase. This paper aims to identify the cost significant parameters and explore the potential for improving the accuracy of cost forecasts for buildings using machine learning techniques and large data sets.

Design/methodology/approach

The Australian State of Victoria Building Authority data sets, which comprise various parameters such as cost of the buildings, materials used, gross floor areas (GFA) and type of buildings, have been used. Five different machine learning regression models, such as decision tree, linear regression, random forest, gradient boosting and k-nearest neighbor were used.

Findings

The findings of the study showed that among the chosen models, linear regression provided the worst outcome (r2 = 0.38) while decision tree (r2 = 0.66) and gradient boosting (r2 = 0.62) provided the best outcome. Among the analyzed features, the class of buildings explained about 34% of the variations, followed by GFA and walls, which both accounted for 26% of the variations.

Originality/value

The output of this research can provide important information regarding the factors that have major impacts on the costs of buildings in the Australian construction industry. The study revealed that the cost of buildings is highly influenced by their classes.
Is ethical human resource management effective for ethical voice? Role of moral efficacy and moral task complexity
Authors: Chen Silu , Liu Wenxing , Zhang Guanglei , Tian Chenling
Published: June 2023

Purpose

The purpose of this study was to examine the underlying mechanism as well as the boundary effect between employees' perceived ethical human resource management (HRM) and ethical voice based on social cognitive theory. The authors expect that employees who perceive ethical HRM could develop their moral reasoning and conduct through one of the cognitive processes (i.e. vicarious experience).

Design/methodology/approach

Based on structural equation modelling and hierarchical regression analysis, the authors conducted a questionnaire survey on 265 employees and their immediate supervisors from a manufacturing company in China.

Findings

Employees' perceived ethical HRM was positively related to ethical voice, and moral efficacy mediated this relationship. Moral task complexity not only moderated the relationship between employees' perceived ethical HRM and moral efficacy but also moderated the indirect effect of employees' perceived ethical HRM on ethical voice such that the impact was stronger when the moral task complexity level is higher and weaker when low.

Practical implications

This research model provides a framework through which organisations can diagnose potential ethical issues with the implementation of ethical HRM, as well as increase employee awareness of ethical values and then enhance their moral efficacy. Moreover, organisations can benefit from combining interventions and practices that influence the task design.

Originality/value

This study fills research gap by examining the mechanisms that shape employees' ethical voice from the perspective of HRM through moral efficacy and demonstrates that higher levels of moral task complexity contribute to higher levels of moral efficacy and ethical voice.
Labour protection, social security contributions and corporate innovation: evidence from China
Authors: Wang Yuanfang , Tian He , Xu Yekun
Published: June 2023

Purpose

As China shifts from a “human capital demographic dividend” to a “demographic dividend” as a source of economic growth, this paper examines the influence of social security system improvement on enterprises efforts to attract talent and enhance innovation ability.

Design/methodology/approach

This study uses a sample of Chinese listed firms from 2008 to 2019 to analyse the influences of social security contributions on enterprise innovation, and the mediating effect of human capital accumulation. The OLS, DID test, placebo test, 2SLS are used to test the research questions.

Findings

The authors find a significant positive correlation between social security contributions and enterprise innovation because social security contributions improve the accumulation of human capital, helping enterprises to attract talent, which in turn has a positive impact on corporate innovation. The positive correlation between social security contributions and enterprise innovation is more significant in private enterprises, STAR Market and GEM listed companies and labour-intensive enterprises.

Practical implications

These findings provide a theoretical basis for the formulation of relevant policies and the current reform of social security collection in China. The findings also have practical significance for the sustainable development of China's economy given its ageing population.

Originality/value

This study provides a new perspective, that is, from the perspective of human capital accumulation, to discuss the impact of social security contributions on enterprise innovation, and enriches the relevant literature on the economic consequences of social security contributions and the influencing factors of corporate innovation.
The role of restrictive covenants in Moody's and standard and Poor's debenture credit ratings
Authors: Simpson Marc , Grossmann Axel
Published: June 2023

Purpose

To determine the effect that covenants have on the credit ratings assigned by the two major agencies.

Design/methodology/approach

The authors examine 1,822 bond issues from 1991 to 2018, with a two-stage methodology to account for the endogeneity of the firms' choices and the ordinal nature of the ratings. The authors use Hendry's model selection method to find the best-fitting models from 37 control variables; the final models feature 20–24 orthogonalized variables, all significant at 5% and most at 1%.

Findings

The study’s results suggest that restrictive covenants positively affect ratings, particularly for bonds on the border of junk and investment grade. However, this effect appears to be decreasing with time, suggesting the financial crisis of 2008 has impacted ratings. Additionally, divergent covenant treatment leads to split ratings where the two agencies assign different levels of ratings on the same bonds. The study’s findings provide key insights into the factors that differentiate ratings given by each agency.

Practical implications

Managers must balance the perceived benefits of covenants against the costs, included lower credit ratings.

Originality/value

No other study has examined this issue controlling for both the ordinal nature of the ratings and the endogeneity in the decision to include specific covenants.
Earnings management in European real estate firms during crisis periods
Authors: Brannan Håkon Bergseng , Pjaaka Christian , Oust Are , Sønstebø Ole Jakob
Published: June 2023

Purpose

In periods of economic distress, expectations for businesses change and there is a heightened need for reporting quality. This study investigates the impact of crises on earnings management in the real estate sector.

Design/methodology/approach

The data consisted of financial statements from 2005 to 2021 from real estate firms listed on 10 European stock exchanges. Estimated discretionary accruals from four standard accruals models were used as a proxy for earnings management, using cross-sectional industry and firm fixed effects models. The authors examined earnings management during three crises: the financial crisis (2008–2009), the debt crisis (2011–2012) and the COVID-19 pandemic (2020–2021).

Findings

The results showed less earnings management during the COVID-19 crisis and more earnings management during the financial crisis, though with slightly weaker evidence. The authors did not find significant evidence of earnings management related to the debt crisis. These results suggest that stakeholders in the real estate sector should be extra vigilant in crisis periods.

Originality/value

This study is the first to investigate earnings management in European real estate firms, focusing on the impact of crises.
Organizational sustainability and TQM practices in hospitality industry: employee-employer perception
Authors: Olaleye Banji Rildwan , Abdurrashid Ibrahim , Mustapha Bojuwon
Published: June 2023

Purpose

Practitioners and academics have recently put a lot of emphasis on studying and improving how likely an organization will be successful in the long run. A company's capacity to thrive, excel and gain a competitive edge in today's market is increasingly dependent on the company's ability to adopt and successfully execute sustainable practices. The aim of this paper is to take a critical look at the relationship between total quality management (TQM) practices and business sustainability in the hospitality industry, with a focus on the hospitality sector; to evaluate the role of perceived organizational support (POS) and sustainable behavior in promoting long-term success and to make some suggestions for how these practices could be put into place.

Design/methodology/approach

The data used were randomly collected from 361 hotel employees, covering both the five-star and four-star hotels. Descriptive and inferential statistics were employed to analyze the data. With the use of partial least squares structural equation modeling (PLS-SEM), the heuristic model was tested.

Findings

The results show that putting TQM practices into place leads to better company performance, higher productivity and steady growth for the business. In addition, empirical studies show that the link between sustainable behavior in TQM implementation and a sustainable company is strong, especially when coming to better governance and sustainability related to employees.

Research limitations/implications

This paper offers guidelines for gauging employee's opinions of an organization's long-term viability. A two-factor model has been used to measure the sustainability of an organization and possible factors that can aid effective implementation of TQM practices have been suggested.

Originality/value

There is increasing recognition of the organizational support for successful TQM implementation, while yearning toward sustainability. Within the context of the hospitality industry, no previous research has empirically examined the synergistic moderating effect of POS and sustainable behavior on the relationship between TQM and sustainability.
Huoxue Jiedu Recipe represses mitochondrial fission to alleviate submandibular gland inflammation in Sjögren's syndrome
Authors: Xu Jiangxi , Shen Zhengdong , Du Yun , Zhang Shai , Xi Yajing , Zhang Yuting , Wang Dan , Zhu Yuelan
Published: June 2023

Sjögren's syndrome (SS) is the second most common autoimmune rheumatism. Huoxue Jiedu Recipe (HXJDR) is a kind of traditional Chinese medicine with a variety of pharmacological functions; however, its biological function in SS has not been studied yet. Peripheral blood mononuclear cells (PBMCs) and serum samples were isolated from healthy controls and patients with SS. NOD/Ltj mice were used for developing the SS mouse model. The levels of inflammatory cytokines and NOD‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome–related markers as well as dynamin‐related protein 1 (Drp1) were determined by ELISA, quantitative real‐time PCR, and western blot analysis, respectively. Hematoxylin and eosin and TUNEL staining detected the pathological damage. A transmission electron microscope was used to observe the mitochondrial microstructure. Inflammatory cytokines IL‐18, IL‐1β, B‐cell activating factor (BAFF), BAFF‐receptor (BAFF‐R), IL‐6, and TNF‐α in serum samples and NLRP3 inflammasome–related makers (NLRP3, cysteinyl aspartate–specific proteinase 1 [caspase‐1], apoptosis‐associated speck‐like protein containing a caspase‐1 recruitment domain [ASC], IL‐1β) in PBMCs were greatly upregulated in patients with SS. Furthermore, cytoplasmic phosphorylation of Drp1 and mitochondrial Drp1 level were significantly increased in PBMCs, while mitochondrial swelling and fuzzy inner ridge were observed in PBMCs of patients with SS, suggesting increased mitochondrial fission. Compared with control mice, SS mice showed decreased salivary flow rate, increased submandibular gland index, and more severe inflammatory infiltration and damage as well as mitochondrial fission in submandibular gland tissues. After HXJDR administration, these effects were significantly reversed. HXJDR treatment could alleviate the inflammatory infiltration and pathological damage in submandibular glands of SS mice by inhibiting Drp‐1–dependent mitochondrial fission.
Small‐scale habitat complexity preserves ecosystem services on coral reefs
Authors: Beese Chelsey M. , Mumby Peter J. , Rogers Alice
Published: June 2023

Coral reef habitat quality is declining in many locations because of heatwaves (coral bleaching) and other disturbances. Reef‐building corals provide refuge from predation, so declining complexity restricts the transfer of energy to upper trophic levels.

We use a size‐based ecosystem model to test systematically the effects of refuge at specific sizes and the impacts of distributions of refuges that vary in size. Outcomes are assessed in terms of ecosystem service provision.

Simulations indicate that refuge sheltering fish between 5 and 10 cm in length enhances fish biomass and fisheries productivity, for example, increasing herbivore biomass by up to 80%.

We identify and present a range of refuge profiles that can theoretically improve ecosystem service provision by as much as sixfold. Profiles where refuge availability decreases with increasing fish size consistently outrank other designs.

Synthesis and application: These results highlight how critical small‐scale refuge is for coral reefs, and how we might design artificial reefs to maximise service provision.
Your phrases matter: Third waves in research approaches and new contexts for formulaic language
Authors: Davis Boyd H. , Troutman‐Jordan Meredith , Maclagan Margaret
Published: June 2023

Background

This study reports on new contexts in which formulaic language has been used in the years since 2013 when the last synthesis was carried out. The background presents an old but still useful definition and lists themes under which research was arranged in 2013 and which continue to be used.

Aims

This study has a particular emphasis on the relevance of formulaic language to people living with dementia.

Methods

Section 3, identifying new directions, reviews new ‘third waves’ of research priorities in several fields in which formulaic sequences play a major role, including sociolinguistic variation, corpus‐based and corpus‐driven analyses, pragmatics, human‐computer interaction, and psycholinguistics, all of which are relevant to speech‐language therapists. Section 4, outreach and expansions, illustrates new contributions from cognitively impaired person‐to‐person exchanges in online environments, recent examinations of infant‐ and pet‐directed speech incorporating formulaic language, and online graphic explorations such as emojis. Section 5 focuses on growth of research in theoretical and clinical applications by Van Lancker Sidtis, as illustrated by references to her recent work.

Main Contribution

The paper's main contribution is to summarize the work on formulaic language over the last 10 years, to indicate its continued importance and relevance in ordinary conversation, and especially in allowing people living with dementia to continue to interact with others.

Conclusion

The paper concludes by suggesting that more focus be placed on the analysis of formulaic language with an emphasis on its relevance for speech‐language therapists and other clinicians.

WHAT THIS PAPER ADDS

What is already known on the subject

Research has been growing since the late 1970s and early 1980s on non‐propositional language (as opposed at that time to the Chomskyan paradigm) and especially on lexical bundles, idioms, second language acquisition and multiword expressions. Studies beginning with Hughlings Jackson (1874) have been annotated through early 2012 (Wray, 2013).

What this study adds

This study examines ‘third waves’ in pragmatics, sociolinguistics and areas of neurology and speech perception contributing to what Van Lancker Sidtis (2021) calls the third wave of acceptance of the range and depth of formulaic sequences in ordinary or familiar language.

What are the clinical implications of this work?

Conversations with pet robots or web‐based composition with emojis are but two of the developing areas built on formulaic sequences currently being used for communication interventions with persons living with dementia or other major neurocognitive disorder. Overviews of major contributions in theory and social contexts by Wray (2020, 2021) and theoretical and cognitive applications by Van Lancker Sidtis (2021) detail new areas for the study of formulaic sequences and their contributions to a range of neurocognitive disorders.
Urban Residential Water Demand and Household Size: A Robust Meta‐Regression Analysis*
Authors: Jegnie Alemken , Fogarty James , Iftekhar Sayed
Published: June 2023

We present the results of a meta‐analysis of household‐size water demand elasticity. The analysis is based on 75 primary studies. As there is evidence of publication bias, publication bias–corrected estimates are reported. For indoor water use, we find that in countries with gross domestic product (GDP) per capita below $10,000, the household‐size elasticity is approximately 0.4–0.5, and in countries with GDP per capita above $10,000, it is approximately 0.5–0.6. For outdoor water use, we find that there is no increase in water use as household size increases, at low incomes (GDP less than $5000 per capita), but the effect becomes positive at higher incomes. In countries with a GDP per capita between $5000 and $15,000, the household‐size outdoor water use elasticity is approximately 0.1, and in countries with a GDP per capita above $15,000, it is approximately 0.2. The positive household‐size elasticity implies that the cost of meeting basic water needs, per person, increases with household size in countries that use increasing block pricing for water. The use of a single volumetric price, equal to marginal cost, combined with a fixed charge, would lessen this effect and also improve system efficiency.
Inference of the distribution of fitness effects of mutations is affected by single nucleotide polymorphism filtering methods, sample size and population structure
Authors: Andersson Bea Angelica , Zhao Wei , Haller Benjamin C. , Brännström Åke , Wang Xiao‐Ru
Published: June 2023

The distribution of fitness effects (DFE) of new mutations has been of interest to evolutionary biologists since the concept of mutations arose. Modern population genomic data enable us to quantify the DFE empirically, but few studies have examined how data processing, sample size and cryptic population structure might affect the accuracy of DFE inference. We used simulated and empirical data (from Arabidopsis lyrata) to show the effects of missing data filtering, sample size, number of single nucleotide polymorphisms (SNPs) and population structure on the accuracy and variance of DFE estimates. Our analyses focus on three filtering methods—downsampling, imputation and subsampling—with sample sizes of 4–100 individuals. We show that (1) the choice of missing‐data treatment directly affects the estimated DFE, with downsampling performing better than imputation and subsampling; (2) the estimated DFE is less reliable in small samples (<8 individuals), and becomes unpredictable with too few SNPs (<5000, the sum of 0‐ and 4‐fold SNPs); and (3) population structure may skew the inferred DFE towards more strongly deleterious mutations. We suggest that future studies should consider downsampling for small data sets, and use samples larger than 4 (ideally larger than 8) individuals, with more than 5000 SNPs in order to improve the robustness of DFE inference and enable comparative analyses.
An exploratory study of the impact of tax freedom on geographic living‐cost differentials
Authors: Cebula Richard J. , Duquette Christopher M. , Jolley G. Jason
Published: June 2023

In the United States, there exist enormous geographic differentials in the cost of living. A sound, basic understanding of factors that influence such geographic living‐cost differentials is important to help formulate useful policies to address various contemporary economic and social problems such as public‐school funding across counties. In this exploratory study of the effects of tax freedom on geographic living‐cost differentials, the following hypothesis is investigated using panel data for the period 2009 through 2020. The higher the average overall freedom from taxation in a state in the forms of personal income taxation, property taxation, and sales taxation, the lower the overall cost of living in the state. In this exploratory study, strong empirical support is obtained for this heretofore effectively overlooked hypothesis.
Pars plana vitrectomy versus intravitreal antibiotics for endophthalmitis management following intravitreal anti‐VEGF agents: A meta‐analysis
Authors: Issa Mariam , Balas Michael , Popovic Marko M. , Lytvyn Yuliya , Kertes Peter J. , Muni Rajeev H.
Published: June 2023

In this meta‐analysis, we aim to compare the efficacy and safety of pars plana vitrectomy (PPV) versus tap‐and‐inject (TAI) of intravitreal antibiotics for the management of endophthalmitis secondary to intravitreal injections of anti‐vascular endothelial growth factor (VEGF) agents. A systematic literature search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Central (January 2005–October 2022). The primary analysis compared initial PPV versus TAI and the secondary analysis examined the efficacy and safety of TAI alone compared to TAI followed by PPV. The quality of non‐randomized observational studies was assessed using the Newcastle‐Ottawa Scale. The quality of the evidence was assessed for each outcome. A random effects meta‐analysis was performed. Weighted mean differences (WMDs) with 95% confidence intervals were reported. Of the 7474 screened studies, nine studies reporting on 153 eyes were included. The change in mean best corrected visual acuity (BCVA) between endophthalmitis presentation and last follow‐up did not significantly differ between the initial TAI versus PPV groups (WMD = 0.05 units; 95% CI −0.12 to 0.22; p = 0.59; heterogeneity p = 0.41). The difference in pre‐ to post‐treatment mean BCVA did not significantly differ between eyes that received TAI alone or TAI followed by PPV (WMD = 0.04 units; 95% CI −0.42 to 0.51; p = 0.85; heterogeneity p = 0.74). While the meta‐analysis revealed no significant difference in the change in BCVA between PPV and TAI to treat endophthalmitis secondary to anti‐VEGF agents, the quality of evidence was low with potential for confounding and selection bias. Further well‐designed studies in this setting are needed.
Do farmers' professional cooperatives improve agricultural technical efficiency? Evidence using a national‐level dataset of China
Authors: Li Menglu , Zhang Shemei , Khan Nawab
Published: June 2023

This study examines the impact of farmers' professional cooperatives (FPCs) on agricultural technical efficiency (TE), using panel data from 30 provinces of China from 2015 to 2020 and the stochastic frontier function (SFF) method. The number of members of each cooperative, the proportion of demonstration cooperatives, and the proportion of standard cooperatives are introduced as proxy variables for the development level of FPCs. The results show that although the development of FPCs is imperfect, its development has a significant positive impact on improving China's agricultural TE. Through the continuous increase in the number of cooperative members and the vigorous promotion of standardized production, agricultural TE has been significantly improved. However, the construction of model cooperatives has not played a positive role but inhibited the growth of agricultural TE. It is suggested to expand the cooperative membership and promote standardized production. The government and policymakers should focus on improving the standardization level of cooperatives and the development quality of FPCs from the aspects of innovating cooperation models, standardizing internal governance, and giving full play to the synergistic effect of agricultural science and technology.
ICU triage decisions and biases about time and identity
Authors: Räsänen Joona
Published: June 2023

We often show a greater inclination to assist and avoid harming people identified as those at high risk of great harm than to assist and avoid harming people who will suffer similar harm but are not identified (as yet). Call this the identified person bias. Some ethicists think such bias is justified; others disagree and claim that the bias is discriminatory against statistical people. While the issue is present in public policy and politics, perhaps the most notable examples can be found in medical ethics such as in ICU triage decisions made during the COVID‐19 pandemic. The Rule of Rescue, as the application of the identified person bias is sometimes called, states that spending large amounts of resources rescuing identifiable individuals who are in imminent danger is justified. In this paper, I show that our distorted attitudes toward time play a role in identified person bias. I claim that ICU triage decisions are better explained by a preference to treat people sooner rather than later, which is at least partially due to near bias (positive events are to be preferred to be near rather than distant), than by a preference to treat identified lives over statistical lives. Thus, another bias, near bias, is involved in the reasoning behind the identified person bias and the Rule of Rescue.
Accelerated drug approval: Meeting the ethical yardstick
Authors: Andreoletti Mattia , Blasimme Alessandro
Published: June 2023

Drugs addressing unmet medical needs can change the lives of millions. Developing and validating new drugs can, however, take many years. To streamline the assessment of new drugs, regulatory agencies have long established shortened review pathways. Among these programs, Accelerated Approval (AA) has recently come under scrutiny due to the U.S. Food and Drug Administration's decision to authorize Aducanumab, the first Alzheimer's disease drug. This decision attracted fierce criticism due to the allegedly insufficient evidence about the safety and efficacy of the drug. While considerable scholarly attention has been devoted to this case, the ethical aspects of the AA regulatory pathway have so far remained relatively unexplored. In this paper, we set out to fill this gap. We illustrate six conditions that should be met for AA to be ethically acceptable: moral solicitude, evidence, risk mitigation, impartiality, sustainability, and transparency. We discuss such conditions and suggest practical steps to implement them in regulatory and oversight processes. Taken together, our six conditions represent a benchmark for assessing the ethical validity of AA processes and decisions.
An automatic workflow for risk analysis on spatial output properties using kriging‐based surrogate models—Application to stratigraphic forward modelling
Authors: Gervais Véronique , Granjeon Didier , Bouquet Sarah
Published: June 2023

Stratigraphic numerical forward process‐based models represent the formation and evolution of sedimentary basins through time. Their main deliverable is a 3D digital grid which can help to better understand the sedimentary basin infill. These models depend on several input parameters that need to be characterized for the studied basin. However, available data such as well logs and seismic data may not provide enough information to identify a unique possible value for these parameters. It is then crucial to take the uncertainty induced by this non‐uniqueness into account in the decision‐making process. As a single numerical stratigraphic forward simulation can be very time consuming, solutions are needed to limit the computational cost required to estimate such uncertainties. In particular, machine learning techniques can be used to build meta‐models that mimic the simulator and provide fast estimations of its outputs for any values of the input parameters. The key step for the efficiency of such an approach stands in the choice of the set of simulations (or training set) used to build the meta‐models: it should be informative enough to obtain accurate predictions for the output properties of interest, but also of reasonable size to limit simulation time. Then, meta‐models can be used to investigate a large number of models and make uncertainty quantification easier. Here, we focus on the prediction of spatial outputs of interest approximated from the joint use of several kriging‐based meta‐models combined to reduced basis decomposition. Sequential approaches have been proposed in the literature to identify training sets iteratively for a kriging‐based meta‐model, building upon the specific structure of such surrogates. We propose here to extend these approaches to the context of spatial output predictors. The results obtained on two synthetic test cases, representing a carbonate platform and a clastic environment, highlight the potential of the proposed approach for risk analysis to iteratively build training sets with a satisfactory efficiency in terms of simulation time and prediction accuracy.
Metronomic chemotherapy for indolent T‐cell lymphoproliferative disorder of the gastrointestinal tract
Authors: Liu Hailing , Cao Lei , Zhao Xiaoli , Miao Yi , Wu Wei , Shi Xiao , Zhang Xiaoyan , Yin Hua , Zhu Huayuan , Xu Wei , Li Jianyong , Fan Lei
Published: June 2023

The present study proposes metronomic chemotherapy (CPT), including prednisolone, cyclophosphamide, and thalidomide, as a treatment for patients with severe symptomatic indolent T‐cell lymphoproliferative disorder of the gastrointestinal tract. The encouraging efficacy and excellent safety profile of CPT suggest the clinical potential of this combination.
Intratumor heterogeneity in colorectal cancer: Distribution of tumor suppressor gene variants with regard to patient lymph node status
Authors: Wątor Gracjan , Seweryn Michał , Kapusta Przemysław , Świrta Jarosław , Wałęga Piotr , Barczyński Marcin , Wołkow Paweł P.
Published: June 2023

Intratumor heterogeneity (ITH) results from accumulation of somatic mutations in the fractions of successive cancer cell generations. We aimed to use deep sequencing to investigate ITH in colorectal tumors with particular emphasis on variants in oncogenes (ONC) and tumor suppressor genes (TSG). Samples were collected from 16 patients with colorectal cancer and negative or positive lymph node status (n = 8 each). We deep‐sequenced a panel of 56 cancer‐related genes in the central and peripheral locations of T3 size primary tumors and healthy mucosa. The central region of T3 tumors has a different frequency profile and composition of genetic variants. This mutation profile is capable of independently discriminating patients with different lymph node status (p = 0.028) in the central region. We noted an increasing number of mutations outside of the central region of the tumor and a higher number of mutations in tumors from node‐positive patients. Unexpectedly, in the healthy mucosa, we identified somatic mutations with variant allele frequencies, characteristic not only of heterozygotes and homozygotes but also of other discrete peaks (e.g., around 10%, 20%), suggestive of clonal expansion of certain mutant alleles. We found differences in the distribution of variant allele frequencies in TSGs when comparing node‐negative and node‐positive tumors (p = 0.029), as well as central and peripheral regions (p = 0.00399). TSGs may play an important role in the escape of the tumor toward metastatic colonization.
Tacrolimus pharmacokinetics are influenced by CYP3A5, age, and concomitant fluconazole in pediatric kidney transplant patients
Authors: Alghamdi Alaa , Seay Sarah , Hooper David K. , Varnell Charles D. , Darland Leanna , Mizuno Tomoyuki , Lazear Danielle , Ramsey Laura B.
Published: June 2023

Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged <21 years for the first 8 weeks after a kidney transplant between January 2010 and December 2021. The target tacrolimus trough was 10–15 ng/mL in the first 4 weeks and 7–10 ng/mL in the next 4 weeks. Banked DNA was collected and genotyped for CYP3A5*3, *6, *7, and *8 alleles. We found that CYP3A5 IM/NM (n = 21) took longer than PM (n = 72) to reach the therapeutic range (7 vs. 4 days, p = 0.048). IM/NM had more dose adjustments (8 vs. 6, p = 0.025) and needed >150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03–8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre‐transplant CYP3A5 testing at our institution.
Associations between infant amygdala functional connectivity and social engagement following a stressor: A preliminary investigation
Authors: Hu Yannan , Chen Haitao , Li Xiaomei , Larsen Ryan J. , Sutton Bradley P. , Gao Wei , McElwain Nancy L.
Published: June 2023

Functional architecture of the infant brain, especially functional connectivity (FC) within the amygdala network and between the amygdala and other networks (i.e., default‐mode [DMN] and salience [SAL] networks), provides a neural basis for infant socioemotional functioning. Yet, little is known about the extent to which early within‐ and between‐network amygdala FC are related to infant stress recovery across the first year of life. In this study, we examined associations between amygdala FC (i.e., within‐network amygdala connectivity, and between‐network amygdala connectivity with the DMN and SAL) at 3 months and infant recovery from a mild social stressor at 3, 6 and 9 months. At 3 months, thirty‐five infants (13 girls) underwent resting‐state functional magnetic resonance imaging during natural sleep. Infants and their mothers completed the still‐face paradigm at 3, 6, and 9 months, and infant stress recovery was assessed at each time point as the proportion of infant social engagement during the reunion episode. Bivariate correlations indicated that greater positive within‐network amygdala FC and greater positive amygdala‐SAL FC, but not amygdala‐DMN FC, at 3 months predicted lower levels of stress recovery at 3 and 6 months, but were nonsignificant at 9 months. These findings provide preliminary evidence that early functional synchronization within the amygdala network, as well as segregation between the amygdala and the SAL, may contribute to infant stress recovery in the context of infant–mother interaction.
Individualized orthotic alignment and footwear for balance and mobility in children with bilateral spastic cerebral palsy: A randomized trial
Authors: Bjornson Kristie F. , Fatone Stefania , Orendurff Michael , Zhou Chuan , Hurvitz Philip M. , Shippen Garth
Published: June 2023

Aim

To examine whether designed‐to‐be‐rigid ankle–foot orthoses and footwear combinations with individualized alignment and footwear designs (AFO‐FC/IAFD) would be more effective than designed‐to‐be‐rigid AFO with non‐individualized alignment and footwear designs (AFO‐FC/NAFD) in children with cerebral palsy (CP).

Method

Nineteen children with bilateral spastic CP were randomized to AFO‐FC/NAFD (n = 10) or AFO‐FC/IAFD (n = 9) groups. Fifteen were male, average age 6 years 11 months (range 4 years 2 months–9 years 11 months), classified in Gross Motor Function Classification System levels II (n = 15) and III (n = 4). The Pediatric Balance Scale (PBS), Gait Outcomes Assessment List (GOAL), Patient‐Reported Outcomes Measurement Information System (PROMIS), and Orthotic and Prosthetic Users' Survey (OPUS) measures of satisfaction were collected at baseline and after 3 months' wear.

Results

Compared with the AFO‐FC/NAFD group, those with AFO‐FC/IAFD demonstrated greater change in PBS total scores (mean 12.8 [standard deviation 10.5] vs 3.5 [5.8]; p = 0.03) and GOAL total scores (3.5 [5.8] vs −0.44 [5.5]; p = 0.03). There were no significant changes in OPUS or PROMIS scores.

Interpretation

After 3 months, individualized orthosis alignment and footwear designs had a greater positive effect on balance and parent‐reported mobility than a non‐individualized approach. No effect was documented for the PROMIS and OPUS. Results may inform orthotic management for ambulatory children with bilateral spastic CP.

What this paper adds

Balance and parent‐reported mobility increased more over time for the ankle–foot orthoses and footwear combinations with individualized alignment and footwear designs (AFO‐FC/IAFD) group.

Changes in balance over time suggest a therapeutic effect of the AFO‐FC/IAFD approach.
Diamondback moth egg susceptibility to rainfall: effects of leaf surface properties on the direct and indirect impact of simulated rain
Authors: Rahman Md Mahbubur , Zalucki Myron P. , Furlong Michael J.
Published: June 2023

Diamondback moth (DBM), Plutella xylostella L. (Lepidoptera: Plutellidae), eggs are vulnerable to rainfall, but the impact is dependent on host plant properties and the nature of oviposition sites. The effects of host plants, common cabbage (Brassica oleracea L. var. capitata) and Chinese cabbage (Brassica rapa L. var. pekinensis) (Brassicaceae), and oviposition sites on the fate of eggs subjected to simulated raindrops were investigated in laboratory experiments. In oviposition studies, DBM deposited more eggs on leaf veins than on leaf laminas on both host plants. In common cabbage plants, eggs laid on lower leaves (leaf 2) were less susceptible to dislodgment by rainfall than eggs laid on upper leaves (leaf 6). Eggs laid on the veins on the abaxial surfaces of leaves 2 and 6 of common cabbage plants were less susceptible to dislodgment by raindrops than eggs laid at other sites on this host plant. In Chinese cabbage plants, eggs laid on the veins were less susceptible to dislodgment by raindrops than eggs laid on leaf laminas. When DBM laid eggs in clusters, eggs were less susceptible to dislodgment by raindrops. The presence of waxes on leaf surfaces and concave veins affected egg placement and the retention of eggs at oviposition sites when subjected to raindrops. Eggs were more resistant to raindrops on the concave veined and less waxy leaves of Chinese cabbage plants than on waxy surfaces of smooth common cabbage leaves. When epicuticular wax crystals were removed from common cabbage leaves before oviposition, eggs were more resistant to dislodgment by raindrops. Leaf orientation or angle (horizontal plane vs. an angle of 45°) did not affect the susceptibility of eggs to raindrops. However, eggs were affected indirectly, and vibrations caused by the impact of raindrops resulted in egg removal from both adaxial and abaxial surfaces. Overall, eggs were less likely to be dislodged by raindrops when laid on concave veins and less waxy leaf surfaces. In oviposition tests, DBM laid fewer eggs on plant parts from which they were most easily removed by raindrops, and when they did lay eggs at these sites, they often deposited them in clusters which were more resistant than single eggs to removal by raindrops. The study reiterates the species‐specific nature of DBM‐host plant interactions and shows that female DBM can modify their behaviour to improve the probability of egg survival when substrates available for oviposition are sub‐optimal.
Simulated climate warming causes asymmetric responses in insect life‐history timing potentially disrupting a classic ecological speciation system
Authors: Lackey Alycia C. R. , Deneen Pheobe M. , Ragland Gregory J. , Feder Jeffrey L. , Hahn Daniel A. , Powell Thomas H. Q.
Published: June 2023

Climate change may alter phenology within populations with cascading consequences for community interactions and on‐going evolutionary processes. Here, we measured the response to climate warming in two sympatric, recently diverged (~170 years) populations of Rhagoletis pomonella flies specialized on different host fruits (hawthorn and apple) and their parasitoid wasp communities. We tested whether warmer temperatures affect dormancy regulation and its consequences for synchrony across trophic levels and temporal isolation between divergent populations. Under warmer temperatures, both fly populations developed earlier. However, warming significantly increased the proportion of maladaptive pre‐winter development in apple, but not hawthorn, flies. Parasitoid phenology was less affected, potentially generating ecological asynchrony. Observed shifts in fly phenology under warming may decrease temporal isolation, potentially limiting on‐going divergence. Our findings of complex sensitivity of life‐history timing to changing temperatures predict that coming decades may see multifaceted ecological and evolutionary changes in temporal specialist communities.