bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemoresistance of cancer floating cells is independent of their ability to form 3D structures: Implications for anticancer drug screening
Authors: Kaushik Vivek , Yakisich Juan S. , Way Lillian Frances , Azad Neelam , Iyer Anand K. V.
Published: September 2018

Three‐dimensional (3D) culture systems such as floating spheroids (FSs) and floating tumorspheres (FTs) are widely used as tumor models of chemoresistance. FTs are considered to be enriched in cancer stem‐like cells (CS‐LCs). In this study, we used cancer cell lines (lung H460, prostate LnCAP, and breast MCF‐7) able to form FSs under anchorage‐independent conditions and compared with cell lines (prostate PC3 and breast MDA‐MB‐231) that cannot form FSs under similar conditions. Independent of their ability to form FTs all cell lines growing under anchorage‐independent conditions become highly resistant to obatoclax, colchicine, and hydroxyurea. We used anti‐E‐cadherin antibody (that blocked the formation of FSs) and demonstrated that floating LnCAP cells showed similar chemoresistance regardless of the formation of spheroids. Our results demonstrate that the development of chemoresistance is not because of the formation of a complex 3D structure and/or enrichment of CS‐LCs but is likely the result of cell detachment per se and their ability to survive under anchorage‐independent conditions. We propose that FSs and FTs could be useful models to study chemoresistance of cancer cells associated with cell detachment (e.g., circulating tumor cells) but they may not be representative of other types of chemoresistance that arise in vivo in attached cells.
Adipocyte biology: It is time to upgrade to a new model
Authors: Sadie‐Van Gijsen Hanél
Published: September 2018

Globally, the obesity pandemic is profoundly affecting quality of life and economic productivity, but efforts to address this, especially on a pharmacological level, have generally proven unsuccessful to date, serving as a stark demonstration that our understanding of adipocyte biology and pathophysiology is incomplete. To deliver better insight into adipocyte function and obesity, we need improved adipocyte models with a high degree of fidelity in representing the in vivo state and with a diverse range of experimental applications. Adipocyte cell lines, especially 3T3‐L1 cells, have been used extensively over many years, but these are limited in terms of relevance and versatility. In this review, I propose that primary adipose‐derived stromal/stem cells (ASCs) present a superior model with which to study adipocyte biology ex vivo. In particular, ASCs afford us the opportunity to study adipocytes from different, functionally distinct, adipose depots and to investigate, by means of in vivo/ex vivo studies, the effects of many different physiological and pathophysiological factors, such as age, body weight, hormonal status, diet and nutraceuticals, as well as disease and pharmacological treatments, on the biology of adipocytes and their precursors. This study will give an overview of the characteristics of ASCs and published studies utilizing ASCs, to highlight the areas where our knowledge is lacking. More comprehensive studies in primary ASCs will contribute to an improved understanding of adipose tissue, in healthy and dysfunctional states, which will enhance our efforts to more successfully manage and treat obesity.
Heat‐shock protein B1 upholds the cytoplasm reduced state to inhibit activation of the Hippo pathway in H9c2 cells
Authors: Liu Xiehong , Liu Ke , Li Caiyan , Cai Jiaodi , Huang Li , Chen Huan , Wang Hao , Zou Jiang , Liu Meidong , Wang Kangkai , Tan Sipin , Zhang Huali
Published: September 2018

Heat‐shock protein B1 (HSPB1) is a multifunctional protein that protects against oxidative stress; however, its function in antioxidant pathways remains largely unknown. Here, we sought to determine the roles of HSPB1 in H9c2 cells subjected to oxidative stress. Using nonreducing sodium dodecyl sulfate polyacrylamide gel electrophoresis, we found that increased HSPB1 expression promoted the reduced states of glutathione reductase (GR), peroxiredoxin 1 (Prx1), and thioredoxin 1, whereas knockdown of HSPB1 attenuated these responses following oxidative stress. Increased HSPB1 expression promoted the activation of GR and thioredoxin reductase. Conversely, knockdown of HSPB1 attenuated these responses following oxidative stress. Importantly, overexpression of HSPB1 promoted the complex formation between HSPB1 and oxidized Prx1, leading to dephosphorylation of STE‐mammalian STE20‐like kinase 1 (MST1) in H9c2 cells exposed to H2O
2, whereas downregulation of HSPB1 induced the opposite results. Mechanistically, HSPB1 regulated the Hippo pathway by enhancing the dephosphorylation of MST1, resulting in reduced phosphorylation of LATS1 and Yes‐associated protein (YAP). Moreover, HSPB1 regulated YAP‐dependent gene expression. Thus, HSPB1 promoted the reduced state of endogenous antioxidant pathways following oxidative stress in H9c2 cells and improved the redox state of the cytoplasm via modulation of the Hippo signaling pathway.
Cover Image, Volume 93, Issue 10
Authors: Wang Guanhua , Xia Yue , Liang Benke , Sui Wenjie , Si Chuanling
Published: September 2018

The cover image, by Guanhua Wang et al., is based on the Research Article Successive ethanol‐water fractionation of enzymatic hydrolysis lignin to concentrate its antimicrobial activity, DOI: 10.1002/jctb.5656.

image
Cobalt‐doped biogenic manganese oxides for enhanced tetracycline degradation by activation of peroxymonosulfate
Authors: Luo Haiqiong , Xie Yi , Niu Jinye , Xiao Yaxiong , Li Yulin , Wang Yabo , Zhang Yongkui , Xie Tonghui
Published: September 2018

BACKGROUND

Tetracycline (TC) residues in water and soil have received wide attention due to their adverse effects on human health and ecosystem. Layer‐structured biogenic manganese oxides (BMOs) could be obtained from fungi Pleosporales sp. Y‐5 culture. Cobalt doping into BMOs (Co‐BMOs) was conducted by a facile impregnation‐calcination method to eliminate TC residues through activation of peroxymonosulfate (PMS).

RESULTS

The TC in aqueous solution could be nearly completely removed in about 10 minutes under the optimal condition ([TC] = 50 mg L−1, [catalyst] = 0.2 g L−1, [PMS] = 0.4 g L−1, 25°C). The electron paramagnetic resonance (EPR) identified the coexistence of SO4−• and OH• during PMS activation. The Co‐BMOs catalyst remained great catalytic activity after five runs. Possible mechanism of PMS activation and TC degradation pathway were proposed. Preliminary biological toxicity test using green algae Chlorella vulgaris (FACHB‐8) as ecological indicator confirmed that TC degradation solution was less toxic than the original solution.

CONCLUSION

This study demonstrated high catalytic activity and stability of Co‐BMOs for degradation of TC by PMS activation. The Co‐BMOs/PMS system is helpful in new efforts for TC degradation without generation of more toxic intermediates. © 2018 Society of Chemical Industry
Epidemiological trends and molecular dynamics of dengue, chikungunya virus infection, coinfection, and other undifferentiated fever during 2015‐2016 in Odisha, India
Authors: Saswat Tanuja , Sahoo Nalinee , Muduli Sagarika , Debata Nagen Kumar , Chattopadhyay Subhasis , Chattopadhyay Soma
Published: September 2018

Chikungunya virus (CHIKV) infection is spatiotemporally related to dengue virus (DENV) infection and mostly undiagnosed due to similar primary symptoms. In 2013, a high rate (36%) of coinfection of DENV and CHIKV was reported in Odisha. Hence, the hospital‐based study was continued to synthesis current epidemiological understanding of their single distribution or coinfection. Suspected DENV patients serum samples were tested for DENV and CHIKV by serology and reverse‐transcription polymerase chain reaction. The positive samples were used for analysis of mutation, selection pressure, and phylogenetic relationship. Clinical information was also analyzed. Among 648 (2015 and 2016) suspected DENV patients, 141 (21.7%) were positive for DENV (serotypes 1‐3), 22 (3.4%) were positive for CHIKV (ECSA) and 4 (2.8%) were coinfected with both. Sequence analysis showed four consistent mutations (M104V, V112A, K166N, and F169L) inCprMgene of DENV 2 and two consistent mutations (M269V, D284E) in E1 gene of CHIKV. Interestingly, the CHIKV‐E1A226V mutation was absent in the studied population. It was also noticed that the peak incidence of both the infections occurs in August‐September in 2015‐16. Moreover,Plasmodiumspecies,Salmonella typhi, andRickettsial typhiinfections were also observed in DENV patients. Different etiology was also detected in other undifferentiated fever patients as mixed infections (malaria,S. typhi, andR. typhi). Hence, this investigation shows the significant reduction of DENV‐CHIKV coinfection as compared with previous report, the burden of arboviruses and acute undifferentiated fever in Odisha in 2015‐2016, highlighting the importance of epidemiological picture of febrile patients for appropriate patient management.
Epidemiology of human astroviruses among children younger than 5 years: Prospective hospital‐based sentinel surveillance in South Africa, 2009‐2014
Authors: Nadan Sandrama , Taylor Maureen B. , Groome Michelle J. , Cohen Cheryl , Madhi Shabir A. , Page Nicola A.
Published: September 2018

Background

The epidemiology of human astroviruses (HAstVs) in hospitalised patients less than 5 years of age from selected sites in South Africa was investigated. Diarrheagenic stool specimens collected from April 2009 to May 2014 were screened retrospectively for selected viruses, bacteria and parasites.

Method

Patient data were analysed to identify epidemiologic factors most frequently detected with HAstV infections. The following case‐comparisons were investigated; HAstV‐positive and HAstV‐negative children, human immunodeficiency virus (HIV)‐infected and HIV‐uninfected (HAstV‐positive) children and HIV‐exposed and unexposed (HAstV‐positive HIV‐uninfected) children.

Results

Astrovirus was identified in 7.0% (234/3340) of cases and most frequently in ages 7 to 12 months (9.2%; 90/975) compared with 5.8% to 6.6% in other 6‐month age groups. No seasonal trends were observed. More HAstVs were detected in children from homes that used outdoor water sources (7.6%) compared to indoor sources [5.7%; adjusted odds ratio (aOR), 1.5; 95% CI, 1.1‐2.1;
P = 0.009]. Astroviruses were detected in 8.4% (67/799) of HIV‐uninfected patients that were exposed to HIV compared with 5.9% (74/1257) of HIV‐unexposed patients (
P = 0.032).

Conclusion

Astroviruses were most prevalent in children aged 7 to 12 months and were detected throughout the study period. The study was limited as only hospitalised patients were investigated and no comparisons were made to diarrhoea‐free control groups. Future HAstV surveillance should include community‐based studies and children presenting at outpatient facilities.
The nationwide distribution and trends of hepatitis C virus genotypes in mainland China
Authors: Du Guoping , Li Xiaoshan , Musa Taha Hussein , Ji Yu , Wu Bo , He Yan , Ni Qian , Su Ling , Li Wei , Ge You
Published: September 2018

Comprehensive data on hepatitis C virus (HCV) genotypes distribution is critical for treatment regimen selection, vaccine design, and drug development. This study aimed to understand the dynamic distribution of HCV genotypes in Mainland China. Three hundred sixty‐two studies published from January 1993 to December 2017 involving 64 891 samples (5133 injecting drug users, 2748 volunteer blood donors, 1509 former paid plasma donors, 160 sexually encounters, and 1992 human immunodeficiency virus (HIV)/HCV coinfection patients) were eligible for the quantitative synthesis estimation. Pooled proportion of HCV genotypes (and 95% confidence intervals [CIs]) was estimated through the Freeman‐Tukey double arcsine transformation by period, region, and risk group. A sharp decline of the subtype 1b was observed in all regions except in northwestern and central regions. The genotypes 3 and 6 showed an obvious increase in southern and southwestern regions and have already spread nationwide. After 2010, subtype 1b was the most dominant variant in all regions and risk groups, accounting for 54.0% (95% CI, 51.9‐56.1) of all national infections. Subtype 2a was the second most prevalent strain in all regions except in the south and southwest, with 15.4% (95% CI, 13.1‐17.8) national infections. The subtype 6a in southern region and 3b and 3a in southwestern region had a higher proportion of infections than that in other regions. In addition, the genotypes 3 and 6 are already prevalent in almost all risk groups. The distribution of HCV genotypes were sharply shifting in China in the past three decades. The HCV subtype 1b posed a sharp decline, whereas genotypes 3 and 6 played an increasing role in the regional and populational HCV pandemic.
Sedimentation during Marine Isotope Stage 3 at the eastern margins of the Glacial Lake Humber basin, England
Authors: Evans David J. A. , Roberts David H. , Bateman Mark D. , Medialdea Alicia , Ely Jeremy , Moreton Steven G. , Clark Chris D. , Fabel Derek
Published: September 2018

The stratigraphic sequence at North Cave, on the eastern margins of the Lake Humber basin, records the deposition of a fluvioperiglacial fan (LFs 1–4), with early sedimentation (LF1) dating to Marine Isotope Stage (MIS) 3 (optically stimulated luminescence date range 41.8–38.6 ka and14C dates 41.6–49 ka BP). Three phases of permafrost and ice wedge development during MIS 3 are evident and indicate possible fan abandonment and hence periods of reduced nival runoff. Involution structures dated to 11.1 ka with large boulders and fine‐grained sorted circles in LF4b are interpreted as periglacially cryoturbated littoral deposits with boulders derived from anchor ice, initially deposited at the margins of Lake Humber up to an altitude of 8 m OD during MIS 2. The style and age of fluvioperiglacial fan deposition at North Cave is compatible with several mid‐Devensian sites around Britain characterized by significant nival melt and run‐off from steeply incised valleys in permafrozen cuesta landscapes. This phase of fluvioperiglacial fan aggradation to near or below 0 m OD is recorded around the glacial lakes Humber and Fenland basins and indicates that no glacial lakes existed at that time.
What does an author want from a university publisher?
Authors: Winters Jane
Published: September 2018

Key points

Automated responsiveness is efficient and reassuring, but personalized responsiveness makes an author feel valued.

On a very practical level, authors value timely peer review, perhaps above anything else.

The perceived drop in copyediting and production quality is a common author gripe.

Publishers need to be open about open access – many authors are not as knowledgeable as assumed.
The academic eBook ecosystem reinvigorated: A perspective from the USA
Authors: Watkinson Charles
Published: September 2018

The development of infrastructure to support new forms of long‐form digital scholarship that go ‘beyond the eBook’ has been an active area of humanities publishing over the last 5 years. Proactive philanthropic support for this work has energized the US non‐profit publishing community, especially university presses and library‐based publishers. This article describes the various strands of work that are ongoing and identifies some common themes: an emphasis on shared values; a focus on building an ecosystem of interoperable platforms and tools; and engagement with the challenges facing new‐form digital publications (especially preservation, discovery, and accessibility). This article also considers how publishers who are looking for new platforms and processes can navigate the variety of options now on offer.
African university presses and the institutional logic of the knowledge commons
Authors: Luescher Thierry M. , van Schalkwyk François
Published: September 2018

This article investigates the current status and challenges faced by university presses in Africa, looking particularly at the institutional perspective. Four case studies from Ethiopia, Kenya, and South Africa show how different presses adapt their practices and adopt new technologies. Interpreted through an institutional logics perspective, the status of the university presses is described according to established editorial and market logics, to which a third, hypothetical logic of the knowledge commons is added. The logic of the knowledge commons accounts for changes advanced by the digitization of content, peer‐to‐peer networks as the basis for production, the rise of open access, and an emerging social capitalism. In two cases, we find university presses constrained by traditional editorial logics, while a third one exhibits a hybrid editorial–market model with the purposive adoption of new technologies. Only the fourth, recently established press has embraced the new logic of the knowledge commons wholeheartedly. Thus, if there is a second transition of the academic publishing industry underway, it is in its early stages, partial, and limited in the African context. We thus show that the logic of the knowledge commons provides a useful theoretical lens for studying the far‐reaching and rapid ongoing changes in international academic publishing in Africa and further afield.
‘Publication favela’ or bibliodiversity? Open access publishing viewed from a European perspective
Authors: Mounier Pierre
Published: September 2018

A number of initiatives exist in European countries to support open scholarly communication in humanities and social sciences. This article looks at the work of Open Access in the European Research Area through Scholarly Communication (OPERAS), a consortium of 36 partners from all over Europe, including many university presses, that is working to build a future European infrastructure to address the challenges in open access publishing. Their initial study, OPERAS‐D, revealed a variety of models among the partners influenced by national cultures. Although the partners’ activities were found to be fragmented, they also reflect the ‘bibliodiversity’ that exists in European societies. To address the challenge of fragmentation, it is argued that, by following a cooperative model, European actors can benefit by sharing expertise, resources, and costs of development for the good of all. As a future infrastructure to support open scholarly communication across Europe, OPERAS aims to coordinate a range of publishers and service providers to offer researchers and societies a fully functional web of services to cover the entire research lifecycle.
Voluntary Corn Oil Ingestion Increases Energy Expenditure and Interscapular UCP1 Expression Through the Sympathetic Nerve in C57BL/6 Mice
Authors: Matsumura Shigenobu , Ishikawa Fuka , Sasaki Tsutomu , Odanaka Mayuki , Manio Mark Christian C. , Fushiki Tohru , Inoue Kazuo
Published: September 2018

Scope

Previously, it has been found that corn oil ingestion activates both the gustatory system and brain reward system, stimulating motivation for eating. In the present study, the effect of voluntary corn oil ingestion on body weight gain and energy metabolism in mice is investigated.

Methods and results

Voluntary corn oil ingestion with normal chow feeding does not lead to higher body weight than that of only the chow‐fed control group. Mice that ingested corn oil have a higher total caloric intake and energy expenditure than did mice in the control group. Further, voluntary corn oil ingestion significantly upregulates Ucp1 mRNA and protein in interscapular brown adipose tissue (IBAT). Finally, the sympathetic nerve connected to IBAT was surgically transacted, then the body weight is measured for 8 weeks. IBAT sympathetic nerve transection surgery does not affect the body weight gain and food intake; however, when mice ingested corn oil, it induces significant body weight gain without changing the total caloric intake. IBAT sympathetic nerve transection surgery significantly suppresses UCP1 upregulation by corn oil ingestion.

Conclusion

The present data suggest that corn oil ingestion activates IBAT through the sympathetic nerve, upregulating UCP1 expression and increasing energy expenditure.
Comprehensive characterisation of polyphenols in leaves and stems of three anti‐dengue virus type‐2 active Brazilian Faramea species (Rubiaceae) by HPLC‐DAD‐ESI‐MS/MS
Authors: Wolff Thiago , Berrueta Luis A. , Valente Ligia M.M. , Barboza Rodolfo S. , Neris Rômulo L.S. , Guimarães‐Andrade Iris P. , Assunção‐Miranda Iranaia , Nascimento Adriana C. , Gomes Mário , Gallo Blanca , Iriondo Carmen
Published: September 2018

Introduction

The methanol (MeOH) leaf extracts of the species Faramea bahiensis, F. hyacinthina and F. truncata (Rubiaceae) have previously shown in vitro non‐cytotoxic and anti‐dengue virus serotype 2 (DENV2) activities in human hepatocarcinoma cell lineage (HepG2). Chemical studies have led to the isolation of major flavonoids, but quite complex fractions of phenolic compounds still remain.

Objective

To complete the study of phenolic compounds in the leaves and to access the presence of these compounds in the stems of these Faramea spp. by online high‐performance liquid chromatography‐diode array detector‐electrospray ionisation tandem mass spectrometry (HPLC‐DAD‐ESI‐MS/MS), as well as to evaluate the in vitro cytotoxic and anti‐DENV2 activities of their MeOH stem extracts.

Methodology

The identification was performed by comparing retention times, UV and mass spectra with those of available standards and by using the mechanisms and fragmentation patterns established in previous studies. The effects of the extracts in DENV2 infected HepG2 cell viability was determined by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The virus titer was quantified by plaque assay.

Results

The study led to the characterisation of 31 phenolic compounds including flavonoid O‐ and C‐glycosides, phenolic acids and one coumarin. The stem extracts from F. hyacinthina and F. bahiensis presented a similar bioactivity to those of their leaves but a loss of cytoprotective activity of F. bahiensis and a higher cytotoxicity of F. truncata were observed.

Conclusions

This research allowed a detailed phenolic composition of three bioactive Faramea species to be achieved, thus contributing to the study of this genus and providing valuable information for further phytotherapeutic applications.
Same Same, but Different? Relations between Facets of Conscientiousness and Grit
Authors: Schmidt Fabian T.C. , Nagy Gabriel , Fleckenstein Johanna , Möller Jens , Retelsdorf Jan
Published: September 2018

The constructs grit and conscientiousness are closely connected. However, this relationship has not been analysed while accounting for the complex structure of conscientiousness and the multifaceted conception of grit (perseverance of effort; consistency of interest). In this study, we analysed the connection while considering the hierarchical structure of conscientiousness, differentiating between a superordinate factor, a first–level common factor (industriousness), and lower level unique factors. Drawing on two samples ( N = 413, Mage = 15.29, and N = 530, Mage = 31.75), we applied an extension procedure for confirmatory factor analysis that enables a simultaneous investigation of the relationships on all levels. The perseverance facet of grit was tightly aligned to the common factors (95% shared variance) and was strongly related to the industriousness factor. Consistency shared less variance with the common factors of conscientiousness (53%), but it was additionally correlated with the self–discipline facet. The results for the global grit scale were most similar to the results for perseverance. Grit appears to be a construct that combines the superordinate and industrious aspects of conscientiousness and shares the unique aspect of the self–discipline facet; this suggests that grit and its facets can be fully integrated into the hierarchical structure of conscientiousness.
Context and Implications Document for: From accountability to digital data: The rise and rise of educational governance
Authors: Watson Cate
Published: September 2018

This guide accompanies the following article: Watson, C., From accountability to digital data: The rise and rise of educational governance, Review of Education, https://doi.rg/10.1002/rev3.3125
Waterfall formation at a desert river–reservoir delta isolates endangered fishes
Authors: Cathcart Charles N. , Pennock Casey A. , Cheek Christopher A. , McKinstry Mark C. , MacKinnon Peter D. , Conner Mary M. , Gido Keith B.
Published: September 2018

Unforeseen interactions of dams and declining water availability have formed new obstacles to recovering endemic and endangered big‐river fishes. During a recent trend of drying climate and declining reservoir water levels in the Southwestern United States, a large waterfall has formed on two separate occasions (1989–1995 and 2001–present) in the transition zone between the San Juan River and Lake Powell reservoir because of deposited sediments. Since recovery plans for two large‐bodied endangered fish species, razorback sucker (Xyrauchen texanus) and Colorado pikeminnow (Ptychocheilus lucius), include annual stockings in the San Juan River, this waterfall potentially blocks upstream movement of individuals that moved downstream from the river into the reservoir. To quantify the temporal variation in abundance of endangered fishes aggregating downstream of the waterfall and determine population demographics, we remotely monitored and sampled in spring 2015, 2016, and 2017 when these fish were thought to move upstream to spawn. Additionally, we used an open population model applied to tagged fish detected in 2017 to estimate population sizes. Colorado pikeminnow were so infrequently encountered (<30 individuals) that population estimates were not performed. Razorback sucker captures from sampling (335), and detections from remote monitoring (943) showed high abundance across all 3 years. The razorback sucker population estimate for 2017 alone was 755 individuals and, relative to recent population estimates ranging from ~2,000 to ~4,000 individuals, suggests that a substantial population exists seasonally downstream of this barrier. Barriers to fish movement in rivers above reservoirs are not unique; thus, the formation of this waterfall exemplifies how water development and hydrology can interact to cause unforeseen changes to a riverscape.
Nonparametric adaptive enrichment designs using categorical surrogate data
Authors: Brückner Matthias , Burger Hans U. , Brannath Werner
Published: September 2018

Adaptive survival trials are particularly important for enrichment designs in oncology and other life‐threatening diseases. Current statistical methodology for adaptive survival trials provide type I error rate control only under restrictions. For instance, if we use stage‐wise P values based on increments of the log‐rank test, then the information used for the interim decisions need to be restricted to the primary survival endpoint. However, it is often desirable to base interim decisions also on correlated short‐term endpoints like tumor response. Alternative statistical approaches based on a patient‐wise splitting of the data require unnatural restrictions on the follow‐up times and do not permit to efficiently account for an early rejection of the primary null hypothesis. We therefore suggest new approaches that enable us to use discrete surrogate endpoints (like tumor response status) and also to incorporate interim rejection boundaries. The new approaches are based on weighted Kaplan‐Meier estimates and thereby have additional advantages. They permit us to account for nonproportional hazards and are robust against informative censoring based on the surrogate endpoint. We will show that nonproportionality is an intrinsic and relevant issue in enrichment designs. Moreover, informative censoring based on the surrogate endpoint is likely because of withdrawals and treatment switches after insufficient treatment response. It is shown and illustrated how nonparametric tests based on weighted Kaplan‐Meier estimates can be used in closed combination tests for adaptive enrichment designs, such that type I error rate control is achieved and justified asymptotically.
Nonlinear model with random inflection points for modeling neurodegenerative disease progression
Authors: Sun Ming , Wang Yuanjia
Published: September 2018

Due to a lack of a gold standard objective marker, the current practice for diagnosing a neurological disorder is mostly based on clinical symptoms, which may occur in the late stage of the disease. Clinical diagnosis is also subject to high variance due to between‐ and within‐subject variability of patient symptomatology and between‐clinician variability. Effectively modeling disease course and making early prediction using biomarkers and subtle clinical signs are critical and challenging both for improving diagnostic accuracy and designing preventive clinical trials for neurological disorders. Leveraging the domain knowledge that certain biological characteristics (ie, causal genetic mutation) is part of the disease mechanism, and certain markers (eg, neuroimaging measures, motor and cognitive ability measures) reflect pathological process, we propose a nonlinear model with random inflection points depending on subject‐specific characteristics to jointly estimate the changing trajectories of the markers in the same disease domain. The model scales different markers into comparable progression curves with a temporal order based on the mean inflection point and establishes the relationship between the progression of markers with the underlying disease mechanism. The model also assesses how subject‐specific characteristics affect the dynamic trajectory of different markers, which offers information on designing preventive therapeutics and personalized disease management strategy. We perform extensive simulation studies and apply our method to markers in neuroimaging, cognitive, and motor domains of Huntington's disease using the data collected from a large multisite natural history study of Huntington's disease, where we assess the temporal ordering of disease impairment between domains. We show that atrophy from certain brain area occurs first, followed by motor and cognitive domain, and show that an average patient has already experienced substantial regional brain atrophy when reaching clinical diagnosis age.
Rational Design Principles for the Transport and Subcellular Distribution of Nanomaterials into Plant Protoplasts
Authors: Lew Tedrick Thomas Salim , Wong Min Hao , Kwak Seon‐Yeong , Sinclair Rosalie , Koman Volodymyr B. , Strano Michael S.
Published: September 2018

The ability to control the subcellular localization of nanoparticles within living plants offers unique advantages for targeted biomolecule delivery and enables important applications in plant bioengineering. However, the mechanism of nanoparticle transport past plant biological membranes is poorly understood. Here, a mechanistic study of nanoparticle cellular uptake into plant protoplasts is presented. An experimentally validated mathematical model of lipid exchange envelope penetration mechanism for protoplasts, which predicts that the subcellular distribution of nanoparticles in plant cells is dictated by the particle size and the magnitude of the zeta potential, is advanced. The mechanism is completely generic, describing nanoparticles ranging from quantum dots, gold and silica nanoparticles, nanoceria, and single‐walled carbon nanotubes (SWNTs). In addition, the use of imaging flow cytometry to investigate the influence of protoplasts' morphological characteristics on nanoparticle uptake efficiency is demonstrated. Using DNA‐wrapped SWNTs as model nanoparticles, it is found that glycerolipids, the predominant lipids in chloroplast membranes, exhibit stronger lipid–nanoparticle interaction than phospholipids, the major constituent in protoplast membrane. This work can guide the rational design of nanoparticles for targeted delivery into specific compartments within plant cells without the use of chemical or mechanical aid, potentially enabling various plant engineering applications.
Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms
Authors: Yehuda Rachel , Lehrner Amy
Published: September 2018

This paper reviews the research evidence concerning the intergenerational transmission of trauma effects and the possible role of epigenetic mechanisms in this transmission. Two broad categories of epigenetically mediated effects are highlighted. The first involves developmentally programmed effects. These can result from the influence of the offspring's early environmental exposures, including postnatal maternal care as well as in utero exposure reflecting maternal stress during pregnancy. The second includes epigenetic changes associated with a preconception trauma in parents that may affect the germline, and impact fetoplacental interactions. Several factors, such as sex‐specific epigenetic effects following trauma exposure and parental developmental stage at the time of exposure, explain different effects of maternal and paternal trauma. The most compelling work to date has been done in animal models, where the opportunity for controlled designs enables clear interpretations of transmissible effects. Given the paucity of human studies and the methodological challenges in conducting such studies, it is not possible to attribute intergenerational effects in humans to a single set of biological or other determinants at this time. Elucidating the role of epigenetic mechanisms in intergenerational effects through prospective, multi‐generational studies may ultimately yield a cogent understanding of how individual, cultural and societal experiences permeate our biology.
Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis
Authors: Carbon Maren , Kane John M. , Leucht Stefan , Correll Christoph U.
Published: September 2018

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second‐generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first‐generation antipsychotics, FGAs). As some reports questioned this notion, we meta‐analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head‐to‐head RCTs, including 32 FGA and 86 SGA arms, were meta‐analyzed, yielding 32 FGA‐SGA pairs and 35 SGA‐SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3‐7.8%) vs. 2.6% (95% CI: 2.0‐3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39‐0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28‐0.45, p<0.0001, number‐needed‐to‐treat, NNT=20). Meta‐regression showed no FGA dose effect on FGA‐SGA comparisons (Z=−1.03, p=0.30). FGA‐SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non‐clozapine SGAs in exploratory pairwise comparisons. SGA‐SGA comparisons confirmed the olanzapine advantage vs. non‐clozapine SGAs (RaR=0.66, 95% CI: 0.49‐0.88, p=0.006, k=17, NNT=100). This meta‐analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.
Alternative Facts, Misinformation, and Fake News
Authors: Hendricks Vincent F. , Vestergaard Mads
Published: September 2018

Some very specific topics stole the show the day Trump was inaugurated as president on January 20, 2017. The limelight topics are related to simple questions about the facts of the day: Did the sun shine or not during the inauguration speech? How large was the crowd? Was this crowd larger or smaller than the one present at President Obama’s first inauguration? It seemed clear from available photos and video footage that the sun did not shine at any point during Trump’s speech. Nonetheless, Trump claimed otherwise later that same day during his speech at Langley Air Force Base:
Interpretations of the Term “Actionable” when Discussing Genetic Test Results: What you Mean Is Not What I Heard
Authors: Gornick Michele C. , Ryan Kerry A. , Scherer Aaron M. , Scott Roberts J. , De Vries Raymond G. , Uhlmann Wendy R.
Published: September 2018

In genomic medicine, the familiarity and inexactness of the term “actionable” can lead to multiple interpretations and mistaken beliefs about realistic treatment options. As part of a larger study focusing on public attitudes toward policies for the return of secondary genomic results, we looked at how members of the lay public interpret the term “medically actionable” in the context of genetic testing. We also surveyed a convenience sample of oncologists as part of a separate study and asked them to define the term “medically actionable.” After being provided with a definition of the term, 21 out of 60 (35%) layperson respondents wrote an additional action not specified in the provided definition (12 mentioned “cure” and 9 mentioned environment or behavioral change) and 17 (28%) indicated “something can be done” with no action specified. In contrast, 52 surveyed oncologists did not mention environment, behavioral change, or cure. Based on our findings, we propose that rather than using the term “actionable” alone, providers should also say “what they mean” to reduce miscommunication and confusion that could negatively impact medical decision‐making. Lastly, to guide clinicians during patient‐ provider discussion about genetic test results, we provide examples of phrasing to facilitate clearer communication and understanding of the term “actionable.”
Bone Mineral Density Among Individuals With Residual Lower Limb Weakness After Polio
Authors: Grill Beth , Levangie Pamela K. , Cole Maria , Rosenberg Darren , Jensen Leah
Published: September 2018

Background

Literature indicates that individuals with long‐term residual lower extremity (LE) weakness after polio have decreased bone mineral density (BMD) related to muscle weakness. Where weakness is asymmetrical, bone densitometry measured only on the stronger LE may misclassify BMD.

Objective

To determine (1) whether femoral neck BMD differed from side to side in individuals with asymmetrical LE muscle weakness, and (2) the proportion of individuals at risk for underdiagnosis of low bone density or osteoporosis given unilateral assessment of the femoral neck.

Design

Retrospective study.

Setting

Outpatient postpolio center.

Participants

Patients >18 years old with complete relevant data.

Main Outcome Measures

Bone densitometry T scores, BMD categories based on standard T‐score ranges, and side of LE weakness determined by a strength score.

Results

Forty‐three patients had at least 1 femoral neck T score and bilateral LE strength scores. Fourteen (32.5%) had bone densitometry only on their weaker LE and 14 (32.5%) had bone densitometry only on their stronger LE. Of the 15 patients with bone densitometry done on both femoral necks, T scores (mean [SD]) were lower in the weaker LE (−1.73 [1.09]) than the stronger LE (−0.88 [1.0]) (P = .001). Classification of low bone density or osteoporosis was more frequent based on T scores taken on a weaker LE (48.3% and 24.1%, respectively) than from T scores from a stronger LE (41.4% and 6.9%, respectively).

Conclusions

In this small sample, using strong‐limb T scores resulted in fewer individuals categorized as having low bone density or osteoporosis than when weak‐limb T scores were used. Underestimating BMD loss may lead to undertreatment and increased risk of morbidity, mortality, and costs associated with femoral neck fractures in this high‐fall‐risk group.

Level of Evidence

III
Snow Storms and Vulnerable Populations: Local Public Health Activities in Response to the 2014-2015 Severe Winter Weather
Authors: Bernard Dorothy , Konate Souleymane , Savoia Elena
Published: September 2018

The Northeastern United States experienced some of its coldest and snowiest conditions ever recorded during the winter of 2014-2015. The snowfall and extreme temperatures created significant challenges for local health departments attempting to continue critical services and respond to storm-related needs of the community. This report from the field aims to describe the impact of the severe weather on local health departments’ operations, to examine the disruption to public health services, and to document public health support provided to vulnerable populations during the 2014-2015 winter season. Our findings show that the severe weather exposed major challenges in continuity of public health operations across health departments of various sizes and highlighted some key issues as well as effective strategies, such as collaborations with community-based organizations, to identify and address the needs of the most vulnerable during the winter storms. (Disaster Med Public Health Preparedness. 2019;13:647-649)
Red Dirt Education Leaders ‘Caught in the Middle’: Priorities for Local and Nonlocal Leaders in Remote Schools
Authors: Guenther John , Osborne Samuel
Published: September 2018

Schooling for Aboriginal and Torres Strait Islander students in remote or ‘Red Dirt’ communities has been cast as ‘problematic’, and ‘failing’. The solutions to deficit understandings of remote schooling are often presented as simple. But for those who work in Red Dirt schools, the solutions are not simple, and for education leaders positioned between the local Red Dirt school and upward accountability to departments of education, they are complex. Between 2011 and 2016, the Cooperative Research Centre for Remote Economic Participation's (CRC-REP) Remote Education Systems project explored how education could better meet the needs of those living in remote communities. More than 1000 people with interests in remote education contributed to the research. Education leaders were identified as one stakeholder group. These leaders included school-based leaders, bureaucrats, community-based leaders and teacher educators preparing university graduates for Red Dirt schools. This paper focusses on what Red Dirt education leaders think is important for schooling. The findings show school leaders as ‘caught in the middle’ (Gonzalez & Firestone, 2013) between expectations from communities, and of system stakeholders who drive policy, funding and accountability measures. The paper concludes with some implications for policy and practice that follow on from the findings.
Visualising Primary Health Care: World Health Organization Representations of Community Health Workers, 1970–89
Authors: Medcalf Alexander , Nunes João
Published: September 2018

For the World Health Organization (WHO), the 1978 Alma-Ata Declaration marked a move away from the disease-specific and technologically-focused programmes of the 1950s and 1960s towards a reimagined strategy to provide ‘Health for All by the Year 2000’. This new approach was centred on primary health care, a vision based on acceptable methods and appropriate technologies, devised in collaboration with communities and dependent on their full participation. Since 1948, the WHO had used mass communications strategies to publicise its initiatives and shape public attitudes, and the policy shift in the 1970s required a new visual strategy. In this context, community health workers (CHWs) played a central role as key visual identifiers of Health for All. This article examines a period of picturing and public information work on the part of the WHO regarding CHWs. It sets out to understand how the visual politics of the WHO changed to accommodate PHC as a new priority programme from the 1970s onwards. The argument tracks attempts to define CHWs and examines the techniques employed by the WHO during the 1970s and early 1980s to promote the concept to different audiences around the world. It then moves to explore how the process was evaluated, as well as the difficulties in procuring fresh imagery. Finally, the article traces these representations through the 1980s, when community approaches came under sustained pressure from external and internal factors and imagery took on the supplementary role of defending the concept.
The Place of Post-Traumatic Amnesia in the Assessment of Blunt Head Trauma: The Epistemic, Professional and Material Factors Shaping British Neurology, circa 1920–40
Authors: Ross Ryan
Published: September 2018

The increase in road traffic accidents in twentieth-century Britain brought with it a rise in the number of patients admitted to hospital with blunt, non-penetrating head injuries. Patients who had suffered mild to moderate trauma typically complained of a variety of problems, including headaches, dizziness and giddiness. For the neurologists tasked with diagnosing and treating these patients, such symptoms proved difficult to assess and liable to obscure the clinical picture. This article focuses on why neurologists turned to time as a diagnostic-tool in helping to resolve these issues, specifically the measurement of post-traumatic amnesia (PTA). This article argues that PTA became so central to neurological diagnosis owing to a set of epistemic, professional and material factors in the decades prior to the Second World War. It concludes with a call for deeper appreciation of the range of issues that contribute to the shaping of medical theories of head trauma.
Palaeogeological hiatus surface mapping: a tool to visualize vertical motion of the continents
Authors: FRIEDRICH ANKE M.
Published: September 2018

Dynamic topography is a well-established consequence of global geodynamic models of mantle convection with horizontal dimensions of >1000 km and amplitudes up to 2 km. Such physical models guide the interpretation of geological records on equal dimensions. Continent-scale geological maps therefore serve as reference frames of choice to visualize erosion/non-deposition as a proxy for long-wavelength, low-amplitude vertical surface motion. At a resolution of systems or series, such maps display conformable and unconformable time boundaries traceable over hundreds to thousands of kilometres. Unconformable contact surfaces define the shape and size of time gap (hiatus) in millions of years based on the duration of time represented by the missing systems or series. Hiatus for a single system or series base datum diminishes laterally to locations (anchor points) where it is conformable at the mapped resolution; it is highly dependent upon scale. A comparison of hiatus area between two successive system or series boundaries yields changes in location, shape, size and duration, indicative of the transient nature of vertical surface motion. As a single-step technique, it serves as a quantitative proxy for palaeotopography that can be calibrated using other geological data. The tool magnifies the need for geological mapping at the temporal resolution of stages, matching process rates. The method has no resolving power within conformable regions (basins) but connects around them. When applied to marine seismic sections that relate to rock record, not to time, biostratigraphic and radiometric data from deep wells are needed before hiatus areas – that relate to time – can be mapped.
Collective Action and the Origins of the American Labor Movement
Authors: Schmick Ethan
Published: September 2018

This article examines the relationship between collective action and the size of worker and employer groups in the United States. It proposes and tests a theory of union formation and strikes. Using a new county-by-industry level dataset containing the location of unions, the location of strikes, average establishment size, and the number of establishments around the turn of the twentieth century, I find that unions were more likely to form and strikes were more likely to occur in counties with intermediate-sized worker groups and large employer groups.