bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydroxychloroquine and maintenance immunosuppression use in kidney transplant recipients: Analysis of linked US registry and claims data
Authors: Lentine Krista L. , Lam Ngan N. , Caliskan Yasar , Alhamad Tarek , Xiao Huiling , Schnitzler Mark A. , Chang Su‐Hsin , Axelrod David , Segev Dorry L. , McAdams‐DeMarco Mara , Kasiske Bertram L. , Hess Gregory P. , Brennan Daniel C.
Published: October 2020

Hydroxychloroquine (HCQ) is an antimalarial drug with immunomodulatory effects used to treat systemic lupus erythematosus (SLE) and scleroderma. The antiviral effects of HCQ have raised attention in the context of the COVID‐19 pandemic, although safety is controversial. We examined linkages of national transplant registry data with pharmaceutical claims and Medicare billing claims to study HCQ use among Medicare‐insured kidney transplant recipients with SLE or scleroderma (2008–2017; N = 1820). We compared three groups based on immunosuppression regimen 7 months‐to‐1 year post transplant: (a) tacrolimus (Tac) + mycophenolic acid (MPA) + prednisone (Pred) (referent group, 77.7%); (b) Tac + MPA + Pred + HCQ (16.5%); or (c) other immunosuppression + HCQ (5.7%). Compared to the referent group, recipients treated with other immunosuppression + HCQ had a 2‐fold increased risk of abnormal ECG or QT prolongation (18.9% vs. 10.7%; aHR,1.121.963.42, p = .02) and ventricular arrhythmias (15.2% vs. 11.4%; aHR,1.001.813.29, p = .05) in the >1‐to‐3 years post‐transplant. Tac + MPA + Pred + HCQ was associated with increased risk of ventricular arrhythmias (13.5% vs. 11.4%; aHR,1.021.542.31, p = .04) and pancytopenia (35.9% vs. 31.4%; aHR,1.031.311.68, p = .03) compared to triple immunosuppression without HCQ. However, HCQ‐containing regimens were not associated with an increased risk of death or graft failure. HCQ may be used safely in selected kidney transplant recipients in addition to their maintenance immunosuppression, although attention to arrhythmias is warranted.
Overview of the Premarketing and Postmarketing Requirements for Drugs Granted Japanese Conditional Marketing Approval
Authors: Matsushita Shunsuke , Tachibana Keisuke , Kusakabe Tetsuya , Hirayama Ryuichi , Tsutsumi Yasuo , Kondoh Masuo
Published: October 2020

For drugs that are intended to fill unmet medical needs, such as the treatment of rare diseases or a subtype of cancer, it can take a long time to conduct confirmatory clinical trials due to limited patient availability. Delayed access to these drugs increases the risk of mortality of patients with these diseases. To address this issue, the Ministry of Health, Labour, and Welfare of Japan has decided to implement the Conditional Early Approval System with issuing the Ministry Notification in 2017. Drugs eligible for conditional early approval are those that are indicated for the treatment of a serious disease, have proven safety and efficacy, and cannot be examined easily by confirmatory clinical trials. When the benefit of immediate availability outweighs the risk of having less comprehensive data with which to confirm the clinical benefit of a product in the premarketing phase, products can be approved under the Conditional Early Approval System, accompanied by postmarketing regulatory requirements to manage postmarketing risks and, if needed, conduct postmarketing confirmatory clinical studies. Overview of the pre‐approval and post‐approval regulatory considerations will promote to more efficiently develop pharmaceutical products that fill unmet medical needs, leading to the prompt delivery of safe and effective drugs to patients who often have few therapeutic options available. As of March 2020, four drugs had been approved under the Conditional Early Approval System. In this review, we describe the premarketing and postmarketing requirements of these drugs and discuss the regulatory landscape around the Conditional Early Approval System.
Therapeutic Opportunities for Intestinal Angioectasia‐ Targeting PPARγ and Oxidative Stress
Authors: Sarangdhar Mayur , Yacyshyn Mary B. , Gruenzel Andrew R. , Engevik Melinda A. , Harris Nathaniel L. , Aronow Bruce J. , Yacyshyn Bruce R.
Published: October 2020

Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)’s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ‐related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene‐regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFβ1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFβ1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA‐Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.
Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies
Authors: Goldstein Matthew J. , Peters Malte , Weber Barbara L. , Davis Charles B.
Published: October 2020

Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP‐ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady‐state concentration (Css) at the approved dose was compared to the in vitro cell potency (half‐maximal inhibitory concentration (IC50)). Average steady‐state area under the plasma concentration‐time curve, the fraction unbound drug in plasma, and the cell potency were taken from the US drug labels, US and European regulatory reviews, and peer‐reviewed journal articles. The Css was remarkably similar to the IC50. The median Css/IC50 value was 1.2, and 76% of the values were within 3‐fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a Css/IC50 value > 25. Seven other therapies targeting the same 3 kinases had much lower Css/IC50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first‐in‐human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and Css exceeds a potency threshold. This potency‐guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.
Digitally Enabled, Patient‐Centric Clinical Trials: Shifting the Drug Development Paradigm
Authors: Dockendorf Marissa F. , Hansen Bryan J. , Bateman Kevin P. , Moyer Matthew , Shah Jyoti K. , Shipley Lisa A.
Published: October 2020

The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the clinical trial paradigm from a site‐centric to a patient‐centric model. Merck’s (Kenilworth, NJ) digitally enabled clinical trial initiative is focused on introduction of digital technologies into the clinical trial paradigm to reduce patient burden, improve drug adherence, provide a means of more closely engaging with the patient, and enable higher quality, faster, and more frequent data collection. This paper will describe the following four key areas of focus from Merck’s digitally enabled clinical trials initiative, along with corresponding enabling technologies: (i) use of technologies that can monitor and improve drug adherence (smart dosing), (ii) collection of pharmacokinetic (PK), pharmacodynamic (PD), and biomarker samples in an outpatient setting (patient‐centric sampling), (iii) use of digital devices to collect and measure physiological and behavioral data (digital biomarkers), and (iv) use of data platforms that integrate digital data streams, visualize data in real‐time, and provide a means of greater patient engagement during the trial (digital platform). Furthermore, this paper will discuss the synergistic power in implementation of these approaches jointly within a trial to enable better understanding of adherence, safety, efficacy, PK, PD, and corresponding exposure‐response relationships of investigational therapies as well as reduced patient burden for clinical trial participation. Obstacle and challenges to adoption and full realization of the vision of patient‐centric, digitally enabled trials will also be discussed.
A review ofCD30expression in cutaneous neoplasms
Authors: Kampa Franziska , Mitteldorf Christina
Published: October 2020

Background

The surface protein CD30 is a therapeutic target of monoclonal antibody therapy. Knowledge of the frequency of CD30 expression and its prognostic relevance is therefore interesting, not only in lymphoproliferative disorders (LPD) but also in solid tumors of the skin.

Methods

A review was completed in PubMed for all published reports of CD30 expression in cutaneous lymphomas, mastocytosis, epithelial tumors and sarcomas from 1982 to April 2019. Only accessible articles in English and German were considered. Entities with an expected CD30 expression, such as CD30‐positive LPD, were not evaluated.

Results

The electronic research identified 1091 articles and a further 34 articles were obtained from manual bibliographic reference. Overall 91 articles were included that examined CD30 expression in various entities of cutaneous neoplasms and matched the inclusion criteria.

Conclusion

Apart from cutaneous CD30‐positive LPD, the best‐studied group for CD30 expression was mycosis fungoides (MF). CD30 positivity was found in 32% of classical (patch and plaque stage) and in 59.4% cases of transformed MF. CD30 was also frequently expressed in cutaneous mastocytosis (96.5%). In solid tumors, some single reports describe CD30 expression by tumor cells, but CD30‐reactive lymphocytes were frequently observed in the tumor microenvironment (TME), especially in keratoacanthoma (KA).
Interventions for people at ultra‐high risk for psychosis: A systematic review of economic evaluations
Authors: Ologundudu Olajumoke M. , Lau Tammy , Palaniyappan Lena , Ali Shehzad , Anderson Kelly K.
Published: October 2020

Aim

Psychotic disorders have long‐term negative consequences for functioning and quality of life. Ultra‐high risk (UHR) programs aim to identify and treat people during the prodromal period before their first psychotic episode. Though studies on the clinical effectiveness of treating prodromal symptoms in people at UHR for psychosis exist, no review has exclusively and comprehensively evaluated the economic impact of UHR programs. Our objective was to systematically review the literature on economic evaluations of UHR programs.

Methods

We searched the Cochrane, EMBASE, MEDLINE, and PsycInfo electronic databases, in addition to grey literature, from inception to March 2020 to identify economic evaluations of UHR programs. We included all cost and cost‐effectiveness studies of interventions for people at UHR. The data were synthesized qualitatively, and a risk of bias assessment was performed.

Results

Of the 1916 articles retrieved, six studies met our inclusion criteria. These included three cost analysis studies and three cost‐effectiveness studies. Five studies were conducted from the health system perspective and the time horizon varied between six months and ten years. Only two reported quality‐adjusted life‐years (QALYs) as their outcome. Overall, all cost‐effectiveness studies and one cost analysis suggested that UHR programs were cost‐effective and cost saving, respectively. The risk of bias assessment suggested moderate levels of bias across all studies.

Conclusion

Economic evaluations of UHR programs varied in terms of outcomes and length of follow‐up; however, most studies found them to be cost‐effective. Future studies would benefit from long‐term evaluations of UHR programs and consistent valuation of outcomes.
A Cross‐Lagged Panel Model of Coparental Interaction and Father Involvement Shortly After Divorce
Authors: Petren Raymond E. , Ferraro Anthony J. , Zimmermann McKenzie L. , Anthony Michael V. , Pasley Kay
Published: October 2020

Objective

To examine (a) associations among coparental interaction (cooperation, overt conflict, covert conflict) and father involvement (engagement, in‐kind financial support), (b) associations among the three dimensions of coparental interaction, and (c) associations among the two dimensions of father involvement, shortly after divorce.

Background

Family relationships change shortly after divorce, yet little research has examined coparental interaction and father involvement shortly after divorce and overt and covert conflict are often not included.

Method

Mothers and fathers from different families in a southeastern state (N = 194) participated within 3 months after divorce (Time 1) and 3 to 6 months later (Time 2). A cross‐lagged structural equation model was used to examine reciprocal associations among dimensions of coparental interaction and father involvement.

Results

Higher father engagement and lower overt conflict (Time 1) were associated with higher cooperation (Time 2). Covert conflict was associated with later overt conflict. In‐kind support was not associated with later father engagement or coparental interaction. No reciprocal associations among variables were found.

Conclusion

Coparental conflict and father engagement may be salient to the development of later coparental relationships following divorce.

Implications

Practitioners can help parents manage conflict and encourage father engagement to foster healthy coparental relationships after divorce.
CHRISTIAN ART, MASCULINE CRISIS, AND THE THREAT OF JEWISH CONVERSION IN BERTHA PAPPENHEIM'S SHORT STORIES
Authors: Davies Peter
Published: October 2020

This article discusses a number of short stories by the Austrian‐Jewish writer and feminist campaigner Bertha Pappenheim, showing how the author uses literary narratives to explore anxieties about the perceived threat of Jewish–Christian conversion at the beginning of the twentieth century. In a period of intense debate about the future of Jewish communities and identities within a rapidly modernising and secularising Christian majority culture, Pappenheim campaigned for the protection of Jewish orphans from aggressive missionaries, and for a feminist political and social practice that emerged from within Jewish traditions, rather than rejecting them. Literary narratives allowed her to explore areas of ambivalence and anxiety about this project. She chooses to do this through male protagonists, all of whom have artistic ambitions and experience moments of crisis and failure in encounters with Christian art; threats to Jewish identity are figured in terms of the aesthetic temptations of the embodied, sensual art of Christianity, which lead to decadence, isolation, and death. To set against this, Pappenheim proposes tentatively a mode of socially useful narrative, encoded as specifically Jewish, which offers the potential to preserve the tradition against the shocks of modernity.
Designing regional innovation systems in transitional economies: A creative ecosystem approach
Authors: Gasparin Marta , Quinn Martin
Published: October 2020

Regional Innovation Systems (RIS) have become a policy panacea for states looking to develop their economies. However, much of the research on RIS is from Western developed economies, which have established infrastructures and institutional governance networks. Yet, in transitional economies, the growth rate in some parts of the economy is so rapid that policy makers and institutions are unable to record changes as they occur, including the emergence of new economic sectors, such as the creative industries. This results in knowledge gaps, leading to an inability to understand, identify or react to the needs of those nascent sectors. Our research paper, through the analysis of creative industries in Vietnam, proves that taking a creative ecosystems approach to designing RIS will bridge these knowledge gaps by providing a mechanism through which information can be collated and fed into the policy process. Our paper facilitates this process by developing a model to understand the characteristics of the creative ecosystem and as well as a flipped model of policy diffusion to allow bottom‐up development of policy in transitional economies. We then discuss how these models can be used by policy makers to design a more informed RIS to meet the needs of the sector.
The Politics of Exhaustion and the Externalization of British Border Control. An Articulation of a Strategy Designed to Deter, Control and Exclude
Authors: Welander Marta
Published: October 2020

In response to contemporary forms of human mobility, there has been a continued hardening of borders seeking to deter, control and exclude certain groups of people from entering nation states in Europe, North America and Australasia. Within this context, a disconcerting evolution of new and increasingly sophisticated forms of border control measures have emerged, which often play out within bilateral arrangements of “externalised” or “offshore” border controls. Drawing on extensive first‐hand field research among displaced people in Calais, Paris and Brussels in 2016–2019, this paper argues that the externalization of the British border to France is contingent upon a harmful strategy, which can be understood as the “politics of exhaustion.” This is a raft of (micro) practices and methods strategically aimed to deter, control and exclude certain groups of people on the move who have been profiled as “undesirable,” with a detrimental (un)intended impact on human lives.
Prediction of a competing endogenous RNA co‐expression network as a prognostic marker in glioblastoma
Authors: Peng Qunlong , Li Runmin , Li Ying , Xu Xiaoqian , Ni Wensi , Lin Huiran , Ning Liang
Published: October 2020

Due to its high proliferation capacity and rapid intracranial spread, glioblastoma (GBM) has become one of the least curable malignant cancers. Recently, the competing endogenous RNAs (ceRNAs) hypothesis has become a focus in the researches of molecular biological mechanisms of cancer occurrence and progression. However, there is a lack of correlation studies on GBM, as well as a lack of comprehensive analyses of GBM molecular mechanisms based on high‐throughput sequencing and large‐scale sample sizes. We obtained RNA‐seq data from The Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression (GTEx) databases. Further, differentially expressed mRNAs were identified from normal brain tissue and GBM tissue. The similarities between the mRNA modules with clinical traits were subjected to weighted correlation network analysis (WGCNA). With the mRNAs from clinical‐related modules, a survival model was constructed by univariate and multivariate Cox proportional hazard regression analyses. Thereafter, we carried out Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, we predicted interactions between lncRNAs, miRNAs and mRNAs by TargetScan, miRDB, miRTarBase and starBase. We identified 2 lncRNAs (NORAD, XIST), 5 miRNAs (hsa‐miR‐3613, hsa‐miR‐371, hsa‐miR‐373, hsa‐miR‐32, hsa‐miR‐92) and 2 mRNAs (LYZ, PIK3AP1) for the construction of a ceRNA network, which might act as a prognostic biomarker of GBM. Combined with previous studies and our enrichment analysis results, we hypothesized that this ceRNA network affects immune activities and tumour microenvironment variations. Our research provides novel aspects to study GBM development and treatment.
Identification of a prognostic gene signature based on an immunogenomic landscape analysis of bladder cancer
Authors: Luo Yongwen , Chen Liang , Zhou Qiang , Xiong Yaoyi , Wang Gang , Liu Xuefeng , Xiao Yu , Ju Lingao , Wang Xinghuan
Published: October 2020

Cancer immune plays a critical role in cancer progression. Tumour immunology and immunotherapy are one of the exciting areas in bladder cancer research. In this study, we aimed to develop an immune‐related gene signature to improve the prognostic prediction of bladder cancer. Firstly, we identified 392 differentially expressed immune‐related genes (IRGs) based on TCGA and ImmPort databases. Functional enrichment analysis revealed that these genes were enriched in inflammatory and immune‐related pathways, including in ‘regulation of signaling receptor activity’, ‘cytokine‐cytokine receptor interaction’ and ‘GPCR ligand binding’. Then, we separated all samples in TCGA data set into the training cohort and the testing cohort in a ratio of 3:1 randomly. Data set GSE13507 was set as the validation cohort. We constructed a prognostic six‐IRG signature with LASSO Cox regression in the training cohort, including AHNAK, OAS1, APOBEC3H, SCG2, CTSE and KIR2DS4. Six IRGs reflected the microenvironment of bladder cancer, especially immune cell infiltration. The prognostic value of six‐IRG signature was further validated in the testing cohort and the validation cohort. The results of multivariable Cox regression and subgroup analysis revealed that six‐IRG signature was a clinically independent prognostic factor for bladder cancer patients. Further, we constructed a nomogram based on six‐IRG signature and other clinicopathological risk factors, and it performed well in predict patients' survival. Finally, we found six‐IRG signature showed significant difference in different molecular subtypes of bladder cancer. In conclusions, our research provided a novel immune‐related gene signature to estimate prognosis for patients' survival with bladder cancer.
Non‐financial social determinants of diabetes among public assistance recipients in Japan: A cohort study
Authors: Nishioka Daisuke , Saito Junko , Ueno Keiko , Kondo Naoki
Published: October 2020

Aims/Introduction

Poverty is an important social determinant of diabetes. Poverty is a multidimensional concept including non‐financial difficulties, such as social isolation and exclusion from communities. Many countries provide financial social assistance programs for those in need. This study aimed to explore non‐financial social determinants of diabetes among public assistance recipients in Japan, by using linkage data of two municipal public assistance databases and medical assistance claim data.

Materials and Methods

We carried out a retrospective cohort study. Public assistance is provided to households below the poverty line to ensure their income security. We extracted recipients’ sociodemographic factors of January 2016 (household number and employment status as non‐financial social determinants of diabetes) and identified the incidence of diabetes diagnosis until December 2016 as the outcome.

Results

We included the data of 2,698 younger individuals (aged <65 years) and 3,019 older individuals (aged >65 years). A multivariable Poisson regression, with a robust standard error estimator, showed that among 2,144 younger recipients at risk, unemployment and living alone were slightly associated with 1‐year cumulative incidence of diabetes diagnosis (adjusted incidence ratio 1.20, 95% confidence interval 0.93–1.54 and adjusted incidence ratio 1.15, 95% confidence interval 0.89–1.48, respectively). Among 2,181 older recipients at risk, there was no strong association between their sociodemographic factors and incidence of diabetes diagnosis.

Conclusions

Unemployment and living alone might be additional risk factors for diabetes among younger public assistance recipients. Multidimensional supports assuring financial and non‐financial securities are required to prevent diabetes among people living in poverty.
The relation between the average diameter of CNTs on Ni–Cu @ a‐C:H catalyst with the optical absorption edge and the optical dispersion parameters
Authors: GOUDARZI S. , DALOUJI V. , SOLAYMANI S.
Published: October 2020

In this study, the average diameter of the grown CNTs on Ni–Cu NPs @ a‐C:H substrates were increased by increasing of Cu content. The obtained results indicated that by increase of Cu content, all films exhibited high‐absorption spectra; therefore, we were facing an increase in the energy gap of films. The values of dT/dλ and dR/dλ measurements for grown CNTs with 75% Cu shown that maximum values of optical band gap correspond to with values of 2.48 eV and 2.90 eV, respectively. It can be seen that with increase of average diameter of the grown CNTs,  the values of Urbach energy of films were increased. The RBS and EDAX measurements were confirmed presence of Ni and Cu atoms into films. The films deposited with 75% Cu were more smooth. Films deposited with 75% Cu have more disordered. Films deposited with 75% Cu atoms have maximum values of the oscillator strength f and the dispersion energy Ed about of 0.108 eV2 and 0.0543 eV, respectively.
Hepatitis B surface antibody titres and hepatitis B reactivation with direct‐acting antiviral therapy for hepatitis C
Authors: Poola Shiva , Sanaka Sirish , Sewell Kerry , Tillmann Hans L.
Published: October 2020

HBV reactivation can occur while undergoing direct‐acting antiviral (DAA) therapy for hepatitis C virus (HCV). The role of hepatitis B surface antibody (HBsAb) has not been systematically explored. Therefore, the purpose of this systematic review was to explore the role of the presence of HBsAb on the risk of HBV reactivation related to DAA therapy. We reviewed MEDLINE, CINAHL, EMBASE and Cochrane Central for studies on DAA therapy and data on HBsAb in patients with resolved hepatitis B (hepatitis B surface antigen–negative and hepatitis B core antibody–positive). We identified twenty‐nine reports: thirteen case reports with HBV reactivation (10 HBsAb‐negative and 3 HBsAb‐positive patients) and sixteen cohort studies totalling 2528 patients with resolved HBV infection (1429 HBsAb negative, 1099 HBsAb positive). Reactivation was found in 12 (0.8%) HBsAb‐negative and 7 (0.6%) HBsAb‐positive individuals of cohort studies. All but two HBV reactivation occurred in patients with HBsAb titre <30 iU/L. The presence of HBsAb showed a trend towards delayed reactivation (median 12 weeks vs 9.5 weeks; P = .07). Importantly, with the exception of a patient with escape variant and an HIV‐infected individual, no HBsAb‐positive individual demonstrated clinical reactivation. HBsAb presence seems to protect from clinical HBV reactivation related to DAA therapy. The most pronounced prevention for reactivation may require titres greater than 30 iU/L.
Mean–field moral hazard for optimal energy demand response management
Authors: Élie Romuald , Hubert Emma , Mastrolia Thibaut , Possamaï Dylan
Published: October 2020

We study the problem of demand response contracts in electricity markets by quantifying the impact of considering a continuum of consumers with mean–field interaction, whose consumption is impacted by a common noise. We formulate the problem as a Principal–Agent problem with moral hazard in which the Principal—she—is an electricity producer who observes continuously the consumption of a continuum of risk‐averse consumers, and designs contracts in order to reduce her production costs. More precisely, the producer incentivizes each consumer to reduce the average and the volatility of his consumption in different usages, without observing the efforts he makes. We prove that the producer can benefit from considering the continuum of consumers by indexing contracts on the consumption of one Agent and aggregate consumption statistics from the distribution of the entire population of consumers. In the case of linear energy valuation, we provide closed‐form expression for this new type of optimal contracts that maximizes the utility of the producer. In most cases, we show that this new type of contracts allows the Principal to choose the risks she wants to bear, and to reduce the problem at hand to an uncorrelated one.
Rapid evolution of genome‐wide gene expression and plasticity during saline to freshwater invasions by the copepod Eurytemora affinis species complex
Authors: Posavi Marijan , Gulisija Davorka , Munro James B. , Silva Joana C. , Lee Carol Eunmi
Published: October 2020

Saline migrants into freshwater habitats constitute among the most destructive invaders in aquatic ecosystems throughout the globe. However, the evolutionary and physiological mechanisms underlying such habitat transitions remain poorly understood. To explore the mechanisms of freshwater adaptation and distinguish between adaptive (evolutionary) and acclimatory (plastic) responses to salinity change, we examined genome‐wide patterns of gene expression between ancestral saline and derived freshwater populations of the Eurytemora affinis species complex, reared under two different common‐garden conditions (0 versus 15 PSU). We found that evolutionary shifts in gene expression (between saline and freshwater inbred lines) showed far greater changes and were more widespread than acclimatory responses to salinity (0 versus 15 PSU). Most notably, 30–40 genes showing evolutionary shifts in gene expression across the salinity boundary were associated with ion transport function, with inorganic cation transmembrane transport forming the largest Gene Ontology category. Of particular interest was the sodium transporter, the Na+/H+ antiporter (NHA) gene family, which was discovered in animals relatively recently. Thirty key ion regulatory genes, such as NHA paralogue #7, demonstrated concordant evolutionary and plastic shifts in gene expression, suggesting the evolution of ion transporter function and plasticity during rapid invasions into novel salinities. Moreover, freshwater invasions were associated with the evolution of reduced plasticity in the freshwater population, again for the same key ion transporters, consistent with the predicted evolution of canalization following adaptation to stressful conditions. Our results have important implications for understanding evolutionary and physiological mechanisms of range expansions by some of the most widespread invaders in aquatic habitats.
Movement of transposable elements contributes to cichlid diversity
Authors: Carleton Karen L. , Conte Matthew A. , Malinsky Milan , Nandamuri Sri Pratima , Sandkam Benjamin A. , Meier Joana I. , Mwaiko Salome , Seehausen Ole , Kocher Thomas D.
Published: October 2020

African cichlid fishes are a prime model for studying speciation mechanisms. Despite the development of extensive genomic resources, it has been difficult to determine which sources of genetic variation are responsible for cichlid phenotypic variation. One of their most variable phenotypes is visual sensitivity, with some of the largest spectral shifts among vertebrates. These shifts arise primarily from differential expression of seven cone opsin genes. By mapping expression quantitative trait loci (eQTL) in intergeneric crosses of Lake Malawi cichlids, we previously identified four causative genetic variants that correspond to indels in the promoters of either key transcription factors or an opsin gene. In this comprehensive study, we show that these indels are the result of the movement of transposable elements (TEs) that correlate with opsin expression variation across the Malawi flock. In tracking the evolutionary history of these particular indels, we found they are endemic to Lake Malawi, suggesting that these TEs are recently active and are segregating within the Malawi cichlid lineage. However, an independent indel has arisen at a similar genomic location in one locus outside of the Malawi flock. The convergence in TE movement suggests these loci are primed for TE insertion and subsequent deletions. Increased TE mobility may be associated with interspecific hybridization, which disrupts mechanisms of TE suppression. This might provide a link between cichlid hybridization and accelerated regulatory variation. Overall, our study suggests that TEs may be an important driver of key regulatory changes, facilitating rapid phenotypic change and possibly speciation in African cichlids.
Genomic basis of the loss of diadromy inGalaxias maculatus: Insights from reciprocal transplant experiments
Authors: Delgado M. Lisette , Manosalva Aliro , Urbina Mauricio A. , Habit Evelyn , Link Oscar , Ruzzante Daniel E.
Published: October 2020

Diadromy is known for having major effects on the distribution and richness of aquatic species, and so does its loss. The loss of diadromy has led to the diversification of many species, yet research focusing on understanding its molecular basis and consequences are limited. This is particularly true for amphidromous species despite being the most abundant group of diadromous species.Galaxias maculatus, an amphidromous species and one of the most widely distributed fishes in the Southern Hemisphere, exhibits many instances of nonmigratory or resident populations. The existence of naturally replicated resident populations in Patagonia can serve as an ideal system for the study of the mechanisms that lead to the loss of the diadromy and its ecological and evolutionary consequences. Here, we studied two adjacent river systems in which resident populations are genetically differentiated yet derived from the same diadromous population. By combining a reciprocal transplant experiment with genomic data, we showed that the two resident populations followed different evolutionary pathways by exhibiting a differential response in their capacity to survive in salt water. While one resident population was able to survive salt water, the other was not. Genomic analyses provided insights into the genes that distinguished (a) migratory from nonmigratory populations; (b) populations that can vs those that cannot survive a saltwater environment; and (c) between these resident populations. This study demonstrates that the loss of diadromy can be achieved by different pathways and that environmental (selection) and random (genetic drift) forces shape this dynamic evolutionary process.
Neural reading
Authors: Orekhov Boris , Fischer Frank
Published: October 2020

The creation of poems via neural networks is relatively easy nowadays and the internet is replete with corresponding examples. However, it largely lacks interpretive concepts. What should be done with the results generated in this way? How can we draw scientific conclusions from them? This is all the more difficult to answer as it still remains unclear where to position deep‐learning approaches in the canon of digital‐humanities methods. But it is clear that humanities scholars must reckon with machines being responsible for, or at least involved in, the creation of their objects of study. After a historical introduction to automated poetry generation, we try to conceptualize neural‐net poetry and argue that its interpretation, i.e. the close reading of texts generated that way, based on large source corpora, can be an insightful addition to the toolbox of computational literary studies, an approach in development that we suggest calling “neural reading.” Our main argument is that artificial neural networks are able to reproduce parts of the stylistic features of a training sample, in our case poetic corpora, acting as a kind of digital echo chamber of literary history. These features are mainly observed in smaller language units, at the level of morphology, vocabulary, syntax, and prosody. Our findings open new directions for the study of style in larger corpora. We will illustrate this with three Russian corpora (a selection of translated hexameters from the eighteenth to the twentieth century and the poetry of Natalia Azarova and Vladimir Vysotsky) and one German corpus (collected poems of Friedrich Hölderlin).
Prophylactic Closed Suction Drainage Is Irrelevant to Accelerated Rehabilitation after Open Reduction and Internal Fixation for Closed Distal Femur Fractures
Authors: Zhang Jun‐zhe , Zhao Kuo , Li Jun‐yong , Meng Hong‐yu , Zhu Yan‐bin , Zhang Ying‐ze
Published: October 2020

Objective

To investigate whether closed suction drainage (CSD) is related to accelerated rehabilitation of patients after open reduction and internal fixation (ORIF) for closed distal femur fractures.

Methods

This study was a prospective, randomized controlled clinical trial. Between October 2018 and June 2020, 160 closed distal femur fracture patients who were prepared for ORIF were prospectively randomized into two groups: a CSD group with the mean age of 57.91 ± 14.38 years (32 [40%] men and 48 [60%] women) and a non‐CSD group with the mean age of 59.73 ± 17.55 years (27 [34%] men and 54 [66%] women). Wound visual analogue scale (VAS) pain scores, peri‐wound skin temperature, hematocrit (Hct), hemoglobin (Hb) concentrations, hidden blood loss (HBL), dressing change, period of wound oozing, postoperative blood transfusion, and length of postoperative hospital stay were recorded. Postoperative wound complications, namely wound infections, wound haematoma, wound dehiscence, erythema of wound, and lower limb deep vein thrombosis (DVT) were collected. All the patients were administrated by a single surgical team and followed up for 1 month after the ORIF.

Results

The patients without CSD were identified with lower peri‐wound skin temperature and wound VAS pain scores during the first three postoperative days (36.69 ± 0.33 vs 36.86 ± 0.38 °C, P = 0.002; 1.88 ± 0.82 vs 3.15 ± 1.15, P = 0.000). However, both the peri‐wound skin temperature and wound VAS pain scores did not differ significantly between the two groups on the fifth postoperative day. In addition, patients with CSD had a longer length of postoperative hospitalization time (11.45 ± 5.95 vs 9.78 ± 4.64 days, P = 0.049). There was no statistically significant difference between CSD and non‐CSD groups within 1 month after the ORIF regarding blood loss, period of wound oozing, and postoperative complications, such as incidence of wound infection, haematoma, erythema, dehiscence, and lower limb DVT.

Conclusion

Prophylactic CSD after primary ORIF for closed distal femur fractures not only had no significant advantage to minimize blood loss and wound complications, but increased local inflammation and postoperative hospital stay, and thus we suggest that prophylactic CSD after primary ORIF for closed distal femur fractures is not recommended for optimized clinical pathways and accelerated recovery.
Successful navigation of late career transitions
Authors: Cox Robin G.
Published: October 2020

The purpose of this educational review was to describe the challenges that may face the anesthesiologist near the end of their career and to propose strategies that will enable the individual to continue to be a productive and valued member of their Department, both clinically and by other contributions.
Comparative efficacy between localized 308‐nm excimer light and targeted 311‐nm narrowband ultraviolet B phototherapy in vitiligo: A randomized, single‐blind comparison study
Authors: Poolsuwan Pimsiri , Churee Chutima , Pattamadilok Bensachee
Published: October 2020

Background

There are limited data to compare efficacy between recent 308‐nm excimer and conventional 311‐nm narrowband ultraviolet B (NB‐UVB) light in the treatment of vitiligo.

Objective

To compare efficacy between 308‐nm excimer light and 311‐nm NB‐UVB in patients with symmetrical vitiligo lesions.

Methods

Thirty‐six symmetrically paired vitiligo lesions on the same anatomical area were enrolled. One side of the symmetrical lesions was treated with localized 308‐nm excimer light, and the opposite side was treated with targeted 311‐nm NB‐UVB assigned randomly by computer. All lesions were treated with the same protocol, for 48 sessions. Repigmentation was evaluated using Vitiligo Area Scoring Index (VASI) and grading the repigmentation was carried out with three independent investigators.

Results

Thirty‐six symmetrically vitiligo lesions were randomly treated, one side with 308‐nm excimer light and the opposite side with 311‐nm NB‐UVB. After 48 sessions, a significantly lower VASI score and a higher grade of repigmentation were observed in 308‐nm excimer light–treated side (P < .001). Nine lesions (25%) treated with 308‐nm excimer light and only five lesions (13.89%) treated with 311‐nm NB‐UVB achieved excellent repigmentation. The 308‐nm excimer light and 311‐nm NB‐UVB–treated sides rapidly obtained 25% repigmentation within a mean of 19.42 sessions and 26.25 sessions, respectively (P = .002). There was no significant difference in mean cumulative UV dosage (P = .065). Side effect as phototoxicity was similar in both sides (P = .08).

Conclusion

Localized 308‐nm excimer light appears to be more effective and also more rapidly induces repigmentation than targeted 311‐nm NB‐UVB for treatment of vitiligo.
Accommodation and new hurdles: The increasing importance of politics for immigrants' access to social programmes in Western democracies
Authors: Koning Edward A.
Published: October 2020

Although immigrants' place in welfare state systems is of large relevance to academics and policymakers alike, there have been few attempts to compare immigrants' social rights in different countries at different moments in time systematically. This article presents the results from a comparative policy analysis that maps immigrants' access to seven different social programmes, in 20 different Western democracies, at four different points in time. The main findings are threefold. First, there are large differences in the extent to which different welfare states differentiate in benefit extension between immigrants and native‐born citizens. Second, over the last two decades, many countries have adjusted their welfare systems with the specific aim to accommodate immigrants, whereas many have also introduced punitive barriers that require immigrants to satisfy additional requirements. Third, these developments seem largely driven by politics: in particular, the adoption of punitive barriers has been more common in places where the political climate is more hostile to immigrants. These findings raise important questions about the future of social protection in an era of cross‐border mobility.
Risk factors for intra‐abdominal fungal infection after simultaneous pancreas‐kidney transplantation: A single‐center retrospective experience
Authors: Flateau Clara , Aït‐Ammar Nawel , Angebault Cécile , Salomon Laurent , Matignon Marie , Lepeule Raphaël , Melica Giovanna , Grimbert Philippe , Lelièvre Jean‐Daniel , Gallien Sébastien , Botterel Françoise
Published: October 2020

Background

Data on the risk factors and outcome of intra‐abdominal fungal infections (IAFI) following simultaneous pancreas‐kidney transplantation (PKT) are scarce.

Materials/methods

A retrospective monocentric study was conducted on all patients who underwent simultaneous PKT from January 2007 to December 2016. Deep sites positive cultures for fungi during the first post‐transplantation year were collected. Clinical, radiological, and microbiological data of proven and probable invasive fungal infections were analysed.

Results

Among sixteen PKT patients, 15 were included. Seven patients (47%) developed an invasive fungal infection, exclusively IAFI (six proven, one probable). The proven IAFI included four peritonitis, one pancreatic necrosis with infected hematoma, and one patient with positive preservation fluid only (PF).Candida albicans(n = 4) was the most prevalent species (associated withGalactomyces candidusin one case),C glabrata,C dubliniensis,andC kruseiwere found in one case each. Three patients had either a positive direct examination and/or culture for renal or pancreatic PF and the culture of PF was positive for the same species that caused IAFI. IAFIs were significantly associated with pancreatic graft arterial thrombosis (5/7 vs 0/8,P = .007) and fungal contamination of PF (3/7 vs 0/8,P = .008). Among patients with IAFI, all required an early surgical revision post‐transplantation [1‐18 days] and six had early or delayed pancreatic graft removal. One patient died in the first post‐transplant year.

Conclusion

IAFI is a common complication in PKT, associated with pancreatic graft thrombosis or fungal contamination of the graft PF, and can sometimes lead to pancreatic detransplantation.
Sequence analysis of the Petunia inflata S‐locus region containing 17 S‐Locus F‐Box genes and the S‐RNase gene involved in self‐incompatibility
Authors: Wu Lihua , Williams Justin S. , Sun Linhan , Kao Teh‐Hui
Published: October 2020

Self‐incompatibility in Petunia is controlled by the polymorphic S‐locus, which contains S‐RNase encoding the pistil determinant and 16–20 S‐locus F‐box (SLF) genes collectively encoding the pollen determinant. Here we sequenced and assembled approximately 3.1 Mb of the S2‐haplotype of the S‐locus in Petunia inflata using bacterial artificial chromosome clones collectively containing all 17 SLF genes, SLFLike1, and S‐RNase. Two SLF pseudogenes and 28 potential protein‐coding genes were identified, 20 of which were also found at the S‐loci of both the S6a‐haplotype of P. inflata and the SN‐haplotype of self‐compatible Petunia axillaris, but not in the S‐locus remnants of self‐compatible potato (Solanum tuberosum) and tomato (Solanum lycopersicum). Comparative analyses of S‐locus sequences of these three S‐haplotypes revealed potential genetic exchange in the flanking regions of SLF genes, resulting in highly similar flanking regions between different types of SLF and between alleles of the same type of SLF of different S‐haplotypes. The high degree of sequence similarity in the flanking regions could often be explained by the presence of similar long terminal repeat retroelements, which were enriched at the S‐loci of all three S‐haplotypes and in the flanking regions of all S‐locus genes examined. We also found evidence of the association of transposable elements with SLF pseudogenes. Based on the hypothesis that SLF genes were derived by retrotransposition, we identified 10 F‐box genes as putative SLF parent genes. Our results shed light on the importance of non‐coding sequences in the evolution of the S‐locus, and on possible evolutionary mechanisms of generation, proliferation, and deletion of SLF genes.