bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectrums of thought in gesture
Authors: Stevens Michael Paul , Harrison Simon
Published: February 2019

This study examines the form and function of gestural depictions that develop over extended stretches of concept explanation by a philosopher. Building onStreeck’s (2009)explorations of depiction by gesture, we examine how this speaker’s process of exposition involves sequences of multimodal, analogical depiction by which the philosophical concepts are not only expressed through gesture forms, but also dynamically analyzed and construed through gestural activity. Drawing on perspectives of gesture as active meaning making (Müller 2014,2016,Streeck 2009), we argue that the build-up of gestures in depiction sequences, activated through a multimodal metaphor (Müller & Cienki 2009), engages the wider philosophical standpoint of the speaker. Using video analysis supported by interview data, we demonstrate how examination of gestures within and across discourse can lead to understanding of how dynamic, embodied, and subjective processes of conceptualization contribute to philosophical theorizing.
Cognitive processing of scalar implicatures with Chinese gradable adjectives
Authors: Liu Si , Yang Yi
Published: February 2019

In previous research comparing the Context-driven Model with the Default Model
of meaning processing, the former was preferred. It predicts that contexts play an exclusively decisive role in meaning
processing, whereas the latter holds that the inference of literal meaning generally goes through, unless it is subsequently
defaulted or cancelled by the context it is associated with. The Standardization Model, which we added to our
experiments, highlights that implicatures are figured out from standardized forms typically based on the mutual background belief
and speaker’s intention. We tested whether Chinese people’s processing of the gradable adjective scale
conformed more to the Context-driven Model, the Default Model, or the Standardization
Model. The results demonstrated that the Standardization Model is the most acceptable among the
three. The findings of this study, which is the first study using the experimental paradigm on Chinese gradable adjectives,
highlighted a need for further studies to investigate the same questions with different languages and cultures.
It’s got some meaning but I am not sure…
Authors: Gintsburg Sarali
Published: February 2019

In this research I aim to contribute to a better understanding of transitionality in poetic language by applying for the first time the hypotheses recently developed by pioneers in the emerging field of cognitive poetics to a living tradition. The benefits of working with a living tradition are tremendous: it is easy to establish the literacy level of the authors and the mode of recording of poetic text is also easy to elicit or, when necessary, to control. I chose a living poetic tradition originating from the Jbala (Morocco). Although it is not epic and local poets create only relatively short poetic texts, memorisation is also used; it has been demonstrated that oral improvisation and the use of memory are not mutually exclusive. This suggests that research on the living Jebli tradition holds promise for our understanding of oral poetry, and for revisiting the intriguing question of formulaic language.
Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis
Authors: Mentrup Torben , Theodorou Kosta , Cabrera-Cabrera Florencia , Helbig Andreas O. , Happ Kathrin , Gijbels Marion , Gradtke Ann-Christine , Rabe Björn , Fukumori Akio , Steiner Harald , Tholey Andreas , Fluhrer Regina , Donners Marjo , Schröder Bernd
Published: February 2019

The lectin-like oxidized LDL receptor 1 (LOX-1) is a key player in the development of atherosclerosis. LOX-1 promotes endothelial activation and dysfunction by mediating uptake of oxidized LDL and inducing pro-atherogenic signaling. However, little is known about modulators of LOX-1–mediated responses. Here, we show that the function of LOX-1 is controlled proteolytically. Ectodomain shedding by the metalloprotease ADAM10 and lysosomal degradation generate membrane-bound N-terminal fragments (NTFs), which we identified as novel substrates of the intramembrane proteases signal peptide peptidase–like 2a and b (SPPL2a/b). SPPL2a/b control cellular LOX-1 NTF levels which, following self-association via their transmembrane domain, can activate MAP kinases in a ligand-independent manner. This leads to an up-regulation of several pro-atherogenic and pro-fibrotic targets including ICAM-1 and the connective tissue growth factor CTGF. Consequently, SPPL2a/b-deficient mice, which accumulate LOX-1 NTFs, develop larger and more advanced atherosclerotic plaques than controls. This identifies intramembrane proteolysis by SPPL2a/b as a novel atheroprotective mechanism via negative regulation of LOX-1 signaling.
Modelling tiller growth and mortality as a sink-driven process using Ecomeristem: implications for biomass sorghum ideotyping
Authors: Larue Florian , Fumey Damien , Rouan Lauriane , Soulié Jean-Christophe , Roques Sandrine , Beurier Grégory , Luquet Delphine
Published: February 2019

Background and Aims

Plant modelling can efficiently support ideotype conception, particularly in multi-criteria selection contexts. This is the case for biomass sorghum, implying the need to consider traits related to biomass production and quality. This study evaluated three modelling approaches for their ability to predict tiller growth, mortality and their impact, together with other morphological and physiological traits, on biomass sorghum ideotype prediction.

Methods

Three Ecomeristem model versions were compared to evaluate whether tillering cessation and mortality were source (access to light) or sink (age-based hierarchical access to C supply) driven. They were tested using a field data set considering two biomass sorghum genotypes at two planting densities. An additional data set comparing eight genotypes was used to validate the best approach for its ability to predict the genotypic and environmental control of biomass production. A sensitivity analysis was performed to explore the impact of key genotypic parameters and define optimal parameter combinations depending on planting density and targeted production (sugar and fibre).

Key Results

The sink-driven control of tillering cessation and mortality was the most accurate, and represented the phenotypic variability of studied sorghum genotypes in terms of biomass production and partitioning between structural and non-structural carbohydrates. Model sensitivity analysis revealed that light conversion efficiency and stem diameter are key traits to target for improving sorghum biomass within existing genetic diversity. Tillering contribution to biomass production appeared highly genotype and environment dependent, making it a challenging trait for designing ideotypes.

Conclusions

By modelling tiller growth and mortality as sink-driven processes, Ecomeristem could predict and explore the genotypic and environmental variability of biomass sorghum production. Its application to larger sorghum genetic diversity considering water deficit regulations and its coupling to a genetic model will make it a powerful tool to assist ideotyping for current and future climatic scenario.
Local and Volume-Conducted Contributions to Cortical Field Potentials
Authors: Torres Daniel , Makarova Julia , Ortuño Tania , Benito Nuria , Makarov Valeri A , Herreras Oscar
Published: February 2019

Brain field potentials (FPs) can reach far from their sources, making difficult to know which waves come from where. We show that modern algorithms efficiently segregate the local and remote contributions to cortical FPs by recovering the generator-specific spatial voltage profiles. We investigated experimentally and numerically the local and remote origin of FPs in different cortical areas in anesthetized rats. All cortices examined show significant state, layer, and region dependent contribution of remote activity, while the voltage profiles help identify their subcortical or remote cortical origin. Co-activation of different cortical modules can be discriminated by the distinctive spatial features of the corresponding profiles. All frequency bands contain remote activity, thus influencing the FP time course, in cases drastically. The reach of different FP patterns is boosted by spatial coherence and curved geometry of the sources. For instance, slow cortical oscillations reached the entire brain, while hippocampal theta reached only some portions of the cortex. In anterior cortices, most alpha oscillations have a remote origin, while in the visual cortex the remote theta and gamma even surpass the local contribution. The quantitative approach to local and distant FP contributions helps to refine functional connectivity among cortical regions, and their relation to behavior.
Toll-like receptor 7 deficiency promotes survival and reduces adverse left ventricular remodelling after myocardial infarction
Authors: de Kleijn Dominique P V , Chong Suet Yen , Wang Xiaoyuan , Yatim Siti Maryam J M , Fairhurst Anna-Marie , Vernooij Flora , Zharkova Olga , Chan Mark Y , Foo Roger S Y , Timmers Leo , Lam Carolyn S P , Wang Jiong-Wei
Published: February 2019

Aims

The Toll-like receptor 7 (TLR7) is an intracellular innate immune receptor activated by nucleic acids shed from dying cells leading to activation of the innate immune system. Since innate immune system activation is involved in the response to myocardial infarction (MI), this study aims to identify if TLR7 is involved in post-MI ischaemic injury and adverse remodelling after MI.

Methods and results

TLR7 involvement in MI was investigated in human tissue from patients with ischaemic heart failure, as well as in a mouse model of permanent left anterior descending artery occlusion in C57BL/6J wild type and TLR7 deficient (TLR7−/−) mice. TLR7 expression was up-regulated in human and mouse ischaemic myocardium after MI. Compared to wild type mice, TLR7−/− mice had less acute cardiac rupture associated with blunted activation of matrix metalloproteinase 2, increased expression of tissue inhibitor of metalloproteinase 1, recruitment of more myofibroblasts, and the formation of a myocardial scar with higher collagen fibre density. Furthermore, inflammatory cell influx and inflammatory cytokine expression post-MI were reduced in the TLR7−/− heart. During a 28-day follow-up after MI, TLR7 deficiency resulted in less chronic adverse left ventricular remodelling and better cardiac function. Bone marrow (BM) transplantation experiments showed that TLR7 deficiency in BM-derived cells preserved cardiac function after MI.

Conclusions

In acute MI, TLR7 mediates the response to acute cardiac injury and chronic remodelling probably via modulation of post-MI scar formation and BM-derived inflammatory infiltration of the myocardium.
New World Slave Traders and the Problem of Trade Goods: Brazil, Barbados, Cuba and North America in Comparative Perspective
Authors: Kelley Sean M
Published: February 2019

This article examines the phenomenon of New World-based slave trading, which encompasses slave-trading voyages that embarked from ports in the Americas. Much of the existing literature takes a European-based ‘triangular trade’ as the norm in the slave trade, but it is now clear that almost 40 per cent of all transatlantic slaving voyages sailed from ports in the New World. Slave traders based in the Americas needed to find appropriate and economical trade goods, which was difficult since European and Asian manufactures dominated African markets for captives. A comparative examination of the four largest American slave-trading polities (Barbados, Brazil, Cuba and British North America/the United States) reveals that all of them succeeded in converting plantation produce—sugar, molasses and tobacco—into African trade goods. However, all of these powers also sought to acquire the more valuable textiles and manufactures in order to improve their ‘assortments’. This finding is significant because it forces historians to consider the slave trade not merely as a ‘triangular’ trade between Europe, Africa and the Americas, but as a truly global system of exchange.
Epidemiology of acute kidney injury among paediatric patients after repair of anomalous origin of the left coronary artery from the pulmonary artery
Authors: Wang Chunrong , Fu Peng , Wang Yuefu , Yang Keming , Peng Yong G , Li Jun , Gong Junsong , Wang Jianhui , Luo Qipeng , Gao Yuchen , Wang Sudena , Tian Yu , Yan Fuxia
Published: February 2019

OBJECTIVES

Acute kidney injury (AKI) is a prevalent complication after the surgical repair of paediatric cardiac defects and is associated with poor outcomes. Insufficient renal perfusion secondary to severe myocardial dysfunction in neonates is most likely an independent risk factor in patients undergoing repair for anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). We retrospectively investigated the epidemiology and outcomes of children with ALCAPA who developed AKI after repair.

METHODS

Eighty-nine children underwent left coronary reimplantation. The paediatric-modified risk, injury, failure, loss and end-stage (p-RIFLE) criteria were used to diagnose AKI.

RESULTS

The incidence of AKI was 67.4% (60/89) in our study. Among the patient cohort with AKI, 23 (38.3%) were diagnosed with acute kidney injury/failure (I/F) (20 with acute kidney injury and 3 with acute kidney failure). Poor cardiac function (left ventricular ejection fraction < 35%) prior to surgery was a significant contributing factor associated with the onset of AKI [odds ratio (OR) 5.55, 95% confidential interval (CI) 1.39–22.13; P = 0.015], while a longer duration from diagnosis to surgical repair (OR 0.97, 95% CI 0.95–1.00; P = 0.049) and a higher preoperative albumin level (OR 0.83, 95% CI 0.70–0.99; P = 0.041) were found to lower the risk of AKI. Neither the severity of preoperative mitral regurgitation nor mitral annuloplasty was associated with the onset of AKI. After reimplantation, there was 1 death in the no-AKI group and 2 deaths in the AKI/F group (P = 0.356); the remaining patients survived until hospital discharge. The median follow-up time was 46.5 months (34.0–63.25). During follow-up, patients in the AKI cohort were seen more often by specialists and reassessed more often by echocardiography.

CONCLUSIONS

Paediatric AKI after ALCAPA repair occurs at a relatively higher incidence than that suggested by previous reports and is linked to poor clinical outcomes. Preoperative cardiac dysfunction (left ventricular ejection fraction < 35%) is strongly associated with AKI. The beneficial effect of delaying surgery seen in some of our cases warrants further investigation, as it is not concordant with standard teaching regarding the timing of surgery for ALCAPA.
Household dietary salt consumption and mortality from cardiovascular diseases: an ecological panel analysis in Japan
Authors: Li Tianyu , Hashimoto Hideki
Published: February 2019

Background

Epidemiological evidence has shown that lower salt intake reduces hypertension-related disease mortality. Japan has experienced a drastic decrease in cardiovascular mortality, although this varies across regions. This regional variation does not necessarily match the local patterns of reported average salt intake. In this study, we examined population-level risk factors for hypertension-related disease mortality, focussing on the average household dietary consumption of salt intake sources.

Methods

We prepared an ecological panel dataset, with prefecture as the unit of analysis, by referring to public statistics and market research data from 2012 to 2015. We collected prefectural averages of household dietary consumption related to salt intake and other nutrients that may affect hypertension control. We used demographic characteristics, medical care availability and local economy indices as covariates. Panel data analysis with fixed-effects modelling was performed, regressing prefectural-level mortality from ischaemic heart diseases, subarachnoid and intracerebral haemorrhage and cerebral infarction on dietary consumption and the selected covariates.

Results

We confirmed the average household consumption of salt equivalents of discretional salt intake sources to be positively but only weakly associated with mortality from ischaemic heart diseases and cerebral infarction. Household expenditure on processed foods was positively associated with ischaemic heart disease mortality.

Conclusions

These findings may suggest that the reduction of salt in processed foods, in addition to individual behavioural change, could be useful for decreasing mortality from ischaemic heart diseases in the Japanese population. Ecological factors related to decreasing cerebrovascular disease mortality in the context of the ageing Japanese population require further investigation.
Mastery and Longevity in Spousal Caregivers of Persons with Dementia
Authors: Savla Jyoti , Wang Zhe , Zhu Jiafeng , Brossoie Nancy , Roberto Karen A , Blieszner Rosemary
Published: February 2019

Objective

Researchers have consistently shown that providing care in a gradually deteriorating situation, such as dementia, can be stressful and detrimental to the caregiver’s (CG) health. Although stressor appraisal is important in understanding variability in CG outcomes, the role of personal mastery, a coping resource, in shaping CG’s health outcomes has not been considered. The primary goal of this paper was to determine whether personal mastery is associated with a survival advantage for spousal CGs of persons with dementia.

Methods

This study assessed the association of CG burden and personal mastery with longevity over a 10-year period in 71 spousal CGs of persons initially diagnosed with mild cognitive impairment.

Results

Over the 10 years, 16 of 71 CGs (23%) died. Cox regression models with right censoring of CGs’ time to death showed that after adjusting for the health of family CG, spousal CGs who reported high levels of burden had an 83% reduced risk of death when they also reported high personal mastery (hazard ratio [HR] = 0.17, 95% confidence interval [CI] 0.04, 0.65).

Conclusions

Findings have implications for support programs that help build personal mastery.
Female obesity is negatively associated with live birth rate following IVF: a systematic review and meta-analysis
Authors: Sermondade Nathalie , Huberlant Stéphanie , Bourhis-Lefebvre Vanessa , Arbo Elisangela , Gallot Vanessa , Colombani Marina , Fréour Thomas
Published: February 2019

BACKGROUND

A worldwide increase in the prevalence of obesity has been observed in the past three decades, particularly in women of reproductive age. Female obesity has been clearly associated with impaired spontaneous fertility, as well as adverse pregnancy outcomes. Increasing evidence in the literature shows that obesity also contributes to adverse clinical outcomes following in vitro fertilization (IVF) procedures. However, the heterogeneity of the available studies in terms of populations, group definition and outcomes prevents drawing firm conclusions. A previous meta-analysis published in 2011 identified a marginal but significant negative effect of increased female body mass index (BMI) on IVF results, but numerous studies have been published since then, including large cohort studies from national registries, highlighting the need for an updated review and meta-analysis.

OBJECTIVE AND RATIONALE

Our systematic review and meta-analysis of the available literature aims to evaluate the association of female obesity with the probability of live birth following IVF. Subgroup analyses according to ovulatory status, oocyte origin, fresh or frozen-embryo transfer and cycle rank were performed.

SEARCH METHODS

A systematic review was performed using the following key words: (‘obesity’, ‘body mass index’, ‘live birth’, ‘IVF’, ‘ICSI’). Searches were conducted in MEDLINE, EMBASE, Cochrane Library, Eudract and clinicaltrial.gov from 01 January 2007 to 30 November 2017. Study selection was based on title and abstract. Full texts of potentially relevant articles were retrieved and assessed for inclusion by two reviewers. Subsequently, quality was assessed using the Newcastle-Ottawa Quality Assessment Scales for patient selection, comparability and assessment of outcomes. Two independent reviewers carried out study selection and data extraction according to Cochrane methods. Random-effect meta-analysis was performed using Review Manager software on all data (overall analysis), followed by subgroup analyses.

OUTCOMES

A total of 21 studies were included in the meta-analysis. A decreased probability of live birth following IVF was observed in obese (BMI ≥ 30 kg/m2) women when compared with normal weight (BMI 18.5–24.9 kg/m2) women: risk ratio (RR) (95% CI) 0.85 (0.82–0.87). Subgroups analyses demonstrated that prognosis was poorer when obesity was associated with polycystic ovary syndrome, while the oocyte origin (donor or non-donor) did not modify the overall interpretation.

WIDER IMPLICATIONS

Our meta-analysis clearly demonstrates that female obesity negatively and significantly impacts live birth rates following IVF. Whether weight loss can reverse this deleterious effect through lifestyle modifications or bariatric surgery should be further evaluated.
Micro-geographic population genetic structure within Arctic cod (Boreogadus saida) in Beaufort Sea of Alaska
Authors: Wilson Robert E , Sage George K , Wedemeyer Kate , Sonsthagen Sarah A , Menning Damian M , Gravley Megan C , Sexson Matthew G , Nelson R John , Talbot Sandra L
Published: February 2019

Many marine organisms show significant levels of genetic heterogeneity on local spatial scales despite exhibiting limited genetic structure at large geographic scales which can be produced through a variety of mechanisms. The Arctic cod (Boreogadus saida) is a circumpolar species and is a vital species in Arctic food webs. To examine population genetic structure of Arctic cod at macro- and micro-geographic scales, we characterized variation at mitochondrial DNA (mtDNA) and microsatellite loci among Arctic cod located in the Chukchi and Beaufort seas in Alaska. We found two distinct mtDNA haplotype clusters, although there was no underlying geographic pattern (FST = −0.001). Congruent with this finding, microsatellite loci suggested a panmictic population (FST = 0.001) across northern Alaskan marine waters at a large spatial scale. However, we found slight but significant micro-geographic partitioning of genetic variation in the southern shelf of the Beaufort Sea that appeared to be associated with the western reaches of the Mackenzie River plume. This fine-scale spatial pattern was not associated with kin-associated groups, suggesting larvae cohorts are not remaining together throughout development. We hypothesize that this pattern reflects the intermixing of Pacific and Arctic origin lineages of Arctic cod.
Immunogenicity and Safety of a Measles-Mumps-Rubella Vaccine Administered as a First Dose to Children Aged 12 to 15 Months: A Phase III, Randomized, Noninferiority, Lot-to-Lot Consistency Study
Authors: Klein Nicola P , Abu-Elyazeed Remon , Povey Michael , Macias Parra Mercedes , Diez-Domingo Javier , Ahonen Anitta , Korhonen Tiina , Tinoco Juan-Carlos , Weiner Leonard , Marshall Gary S , Silas Peter E , Sarpong Kwabena O , Ramsey Keith P , Fling John A , Speicher David , Campos Maribel , Munjal Iona , Peltier Christopher , Vesikari Timo , Baccarini Carmen , Caplanusi Adrian , Gillard Paul , Carryn Stephane , Henry Ouzama
Published: February 2019

Background

MMR II (M-M-R II [Merck & Co, Inc.]) is currently the only measles, mumps, and rubella (MMR) vaccine licensed in the United States. A second MMR vaccine would mitigate the potential risk of vaccine supply shortage or delay. In this study, we assessed the immunogenicity and safety of another MMR vaccine (MMR-RIT [Priorix, GlaxoSmithKline]) compared with those of the MMR II in 12- to 15-month-old children who received it as a first dose.

Methods

In this phase III, observer-blinded, noninferiority, lot-to-lot consistency clinical trial (ClinicalTrials.gov identifier NCT01702428), 5003 healthy children were randomly assigned to receive 1 dose of MMR-RIT (1 of 3 production lots) or MMR II along with other age-recommended routine vaccines. We evaluated the immunogenicity of all vaccines in terms of antibody concentrations (by using an enzyme-linked immunosorbent assay or electrochemiluminescence assay) and/or seroresponse rates 43 days after vaccination. We also assessed the reactogenicity and safety of the vaccines.

Results

Immunoresponses after vaccination with MMR-RIT were robust and noninferior to those after vaccination with the MMR II. Immunogenicity of the 3 production lots of MMR-RIT was consistent; more than 97% of the children had a seroresponse to MMR components. The coadministered vaccines elicited similar immunoresponses in the MMR-RIT and MMR II groups. Both MMR vaccines resulted in comparable reactogenicity profiles, and no safety concerns were detected.

Conclusions

If licensed, the MMR-RIT could provide a valid option for the prevention of measles, mumps, and rubella in children in the United States and would reduce potential risks of a vaccine shortage.
Pressure Ulcer Prevalence by Level of Paralysis in Patients With Spinal Cord Injury in Long-term Care
Authors: Cowan Linda J. , Ahn Hyochol , Flores Micah , Yarrow Joshua , Barks Lelia S. , Garvan Cyndi , Weaver Michael T. , Stechmiller Joyce
Published: February 2019

OBJECTIVE:

Scientific literature suggests pressure ulcer (PU) risk increases as immobility increases, indicating that more extensive paralysis confers a greater risk of PU. Yet the specific level of paralysis (ie, hemiplegia vs paraplegia vs quadriplegia), apart from neurodegenerative diagnoses, has never been examined in the long-term care (LTC) population. This study examined the prevalence of PU among LTC residents with different paralysis levels.

METHODS:

The authors conducted a secondary data analysis of the 2012 US Minimum Data Set of LTC facilities (n = 51,664 residents). Measures included PU stage, level of paralysis, functional impairments, comorbidities, and sociodemographic factors. After removing residents with neurodegenerative disease, comatose patients, and those with hip fractures from the analysis, logistic regressions were used to examine the association of risk factors and sociodemographic characteristics with the presence of PU.

MAIN RESULTS:

The sample included 7,540 patients with quadriplegia, 11,614 patients with paraplegia, and 32,510 patients with hemiplegia in LTC facilities. The PU prevalence in the sample (stages 2, 3, and 4; suspected deep-tissue injury; and unstageable PUs) was 33.9% for patients with quadriplegia, 47.4% for patients with paraplegia, and 9.6% for patients with hemiplegia.

CONCLUSIONS:

Within paralysis groups (quadriplegic, paraplegic, hemiplegic), risk factors for PU differed in type and magnitude. The PU rates associated with quadriplegia and paraplegia are much higher than LTC residents without paralysis, and PU prevalence for hemiplegia is similar to the rate in LTC residents without paralysis. When the risk factor of paraplegia versus quadriplegia was isolated, PU prevalence for patients with paraplegia was significantly higher.
Diabetes
Authors: Faminu Femi
Published: February 2019

Implementing lifestyle changes can be a substantial challenge for patients with diabetes. This article offers nursing strategies to help patients set and meet glycemic goals and manage their own therapy.
Developing a Training Program to Diversify the Biomedical Research Workforce
Authors: Rubio Doris M. , Hamm Megan E. , Mayowski Colleen A. , Nouraie Seyed Mehdi , Quarshie Alexander , Seto Todd , Shaheen Magda , Soto de Laurido Lourdes E. , Norman Marie K.
Published: February 2019

The National Institutes of Health has made considerable investments to diversify the biomedical research workforce. Towards this goal, the authors partnered with representatives from several minority-serving institutions (MSIs) to develop training for the next generation of researchers. To ensure the most effective training program, the authors conducted a needs assessment with junior and senior investigators from the partnering MSIs. In 2016, the authors conducted focus groups and interviews with 23 junior investigators as well as in-depth interviews with 6 senior investigators from the partnering institutions with the goal of identifying specific areas of training and support that would help junior investigators at MSIs develop and sustain research careers. The data were transcribed and coded, and thematic analysis was conducted. The authors determined four areas in which training and support were needed: training in the “informal curriculum” (skills not covered in traditional clinical research courses), protected time for research training, opportunities to create career-advancing work products, and networking opportunities. The themes that were identified informed the development of the LEADS (Leading Emerging and Diverse Scientists to Success) program. The program consists of 10 instructor-led online modules each lasting approximately one month in duration with weekly synchronous sessions. Scholars are expected to be able to devote at least 20% of their time to the program.
Inter-Rater Reliability of the Modified Radiographic Union Score for Diaphyseal Tibial Fractures With Bone Defects
Authors: Mitchell Stuart L. , Obremskey William T. , Luly Jason , Bosse Michael J. , Frey Katherine P. , Hsu Joseph R. , MacKenzie Ellen J. , Morshed Saam , O'Toole Robert V. , Scharfstein Daniel O. , Tornetta Paul ,   the Major Extremity Trauma Rehabilitation Consortium (METRC)
Published: February 2019

Objectives:

To evaluate inter-rater reliability of the modified Radiographic Union Score for Tibial (mRUST) fractures among patients with open, diaphyseal tibia fractures with a bone defect treated with intramedullary nails (IMNs), plates, or definitive external fixation (ex-fix).

Design:

Retrospective cohort study.

Setting:

Fifteen-level one civilian trauma centers; 2 military treatment facilities.

Patients/Participants:

Patients ≥18 years old with open, diaphyseal tibia fractures with a bone defect ≥1 cm surgically treated between 2007 and 2012.

Intervention:

Three of 6 orthopedic traumatologists reviewed and applied mRUST scoring criteria to radiographs from the last clinical visit within 13 months of injury.

Main Outcome Measurements:

Inter-rater reliability was assessed using Krippendorff's alpha (KA) statistic; intraclass correlation coefficient (ICC) is presented for comparison with previous publications.

Results:

Two hundred thirteen patients met inclusion criteria including 115 IMNs, 24 plates, 29 ex-fixes, and 45 cases that no longer had instrumentation at evaluation. All reviewers agreed on the pattern of scoreable cortices for 90.4% of IMNs, 88.9% of those without instrumentation, 44.8% of rings, and 20.8% of plates. Thirty-one (15%) cases, primarily plates and ex-fixes, did not contribute to KA and ICC estimates because <2 raters scored all cortices. The overall KA for the 85% that could be analyzed was 0.64 (ICC 0.71). For IMNs, plates, ex-fixes, and no instrumentation, KA (ICC) was 0.65 (0.75), 0.88 (0.90), 0.47 (0.62), and 0.48 (0.57), respectively.

Conclusions:

In tibia fractures with bone defects, the mRUST seems similarly reliable to previous work in patients treated with IMN but is less reliable in those with plates or ex-fixes, or after removal of instrumentation.
Declining Mortality in Patients With Acute Respiratory Distress Syndrome: An Analysis of the Acute Respiratory Distress Syndrome Network Trials
Authors: Zhang Zhongheng , Spieth Peter Markus , Chiumello Davide , Goyal Hemant , Torres ; Antoni , Laffey John G. , Hong Yucai
Published: February 2019

Objectives:

There has been multiple advances in the management of acute respiratory distress syndrome, but the temporal trends in acute respiratory distress syndrome–related mortality are not well known. This study aimed to investigate the trends in mortality in acute respiratory distress syndrome patients over time and to explore the roles of daily fluid balance and ventilation variables in those patients.

Design:

Secondary analysis of randomized controlled trials conducted by the Acute Respiratory Distress Syndrome Network from 1996 to 2013.

Setting:

Multicenter study involving Acute Respiratory Distress Syndrome Network trials.

Patients:

Patients with acute respiratory distress syndrome.

Interventions:

None.

Measures and Main Results:

Individual patient data from 5,159 acute respiratory distress syndrome patients (excluding the Late Steroid Rescue Study trial) were enrolled in this study. The crude mortality rate decreased from 35.4% (95% CI, 29.9–40.8%) in 1996 to 28.3% (95% CI, 22.0–34.7%) in 2013. By adjusting for the baseline Acute Physiology and Chronic Health Evaluation III, age, ICU type, and admission resource, patients enrolled from 2005 to 2010 (odds ratio, 0.61; 95% CI, 0.50–0.74) and those enrolled after 2010 (odds ratio, 0.73; 95% CI, 0.58–0.92) were associated with lower risk of death as compared to those enrolled before 2000. The effect of year on mortality decline disappeared after adjustment for daily fluid balance, positive end-expiratory pressure, tidal volume, and plateau pressure. There were significant trends of declines in daily fluid balance, tidal volume, and plateau pressure and an increase in positive end-expiratory pressure over the 17 years.

Conclusions:

Our study shows an improvement in the acute respiratory distress syndrome-related mortality rate in the critically ill patients enrolled in the Acute Respiratory Distress Syndrome Network trials. The effect was probably mediated via decreased tidal volume, plateau pressure, and daily fluid balance and increased positive end-expiratory pressure.
Prevalence of Axonal Sensory Neuropathy With IgM Binding to Trisulfated Heparin Disaccharide in Patients With Fibromyalgia
Authors: Malik Asma , Lopate Glenn , Hayat Ghazala , Jones Jacqueline , Atluri Rama , Malo Bassam , Pestronk Alan
Published: February 2019

Objective:

To assess the intraepidermal nerve fiber density in patients diagnosed with fibromyalgia (FM) and to evaluate the role of IgM binding to trisulfated heparin disaccharide (TS-HDS) in these patients.

Methods:

FM is a poorly understood pain disorder with several proposed pathophysiologic mechanisms. It is characterized by widespread pain, fatigue, and sleep abnormalities. Small fiber neuropathy (SFN) has been proposed as an underlying mechanism, and patients with FM have been shown to have a reduction in the intraepidermal nerve fiber density. An underlying inflammatory process that could be a result of autoimmune phenomena has also been suggested. Non–length-dependent SFN (NLDSFN) has been shown to have a higher incidence of autoimmune disease. Twenty-two patients with established diagnosis of FM underwent skin biopsy at 2 sites; 10 cm above the lateral malleolus and 10 cm above the patella. Serum IgM binding to TS-HDS was assayed using an ELISA method.

Results:

A total of 5/22 patients had positive TS-HDS antibodies; of these, 4 had NLDSFN (P = 0.0393). Comparison with a control group at Washington University showed no significant difference in percentage with TS-HDS antibodies (P = 0.41). When compared with Washington University database of skin biopsy, there was a trend for an increased percentage of NLDSFN in patients with FM (P = 0.06).

Conclusions:

This study further supports the hypothesis that a subgroup of patients with FM has SFN. We suggest a correlation between the presence of NLDSFN and TS-HDS antibodies.
Amifampridine Phosphate (Firdapse) Is Effective in a Confirmatory Phase 3 Clinical Trial in LEMS
Authors: Shieh Perry , Sharma Khema , Kohrman Bruce , Oh Shin J.
Published: February 2019

Objective:

To assess tolerability and efficacy of amifampridine phosphate versus placebo for symptomatic treatment of Lambert–Eaton Myasthenic Syndrome (LEMS).

Methods:

This phase 3 randomized, double-blind, placebo-controlled withdrawal trial in 26 adults with LEMS compared efficacy of amifampridine phosphate versus placebo over a 4-day period. The primary endpoints were quantitative myasthenia gravis score (QMG) and subject global impression, and the secondary endpoint was Clinical Global Impression–Improvement. The exploratory endpoints were 3TUG (timed up and go) test and QMG limb domain score. All participants had been receiving amifampridine phosphate (30–80 mg/d divided into 3 or 4 doses daily) in an expanded access protocol and had been titrated to the optimal dose and frequency for at least 1 week before randomization into the current study. After completion of assessments after 4 days of double-blind treatment, patients had the option to return to open-label amifampridine phosphate. The efficacy endpoints were mean changes from baseline in the various evaluation parameters.

Results:

Amifampridine phosphate (n = 13) demonstrated significant benefit in QMG and subject global impression compared with placebo (n = 13) at 4 days. Other measures of efficacy, including Clinical Global Impression–Improvement, 3TUG, and QMG limb domain score were also improved. The most common “adverse events” in the placebo group were muscle weakness (n = 5) and fatigue (n = 4), as expected from withdrawal of amifampridine phosphate, whereas only back pain (n = 1), pain in extremity (n = 1), and headache (n = 1) were reported in amifampridine phosphate group.

Conclusions:

This phase 3 randomized, double-blind, placebo-controlled withdrawal trial in adults with LEMS provided class I evidence of efficacy of amifampridine phosphate as symptomatic treatment in LEMS.
Retrospective Balance Study for Individuals With Chronic Obstructive Pulmonary Disease: Evaluating the Effect of a 1-Month Physical Therapy Program
Authors: Champion Tiffany , Sanford Kathleen , Byrd Rebecca
Published: February 2019

Purpose:

To determine whether a 1-month physical therapy (PT) program that includes a balance component improves balance impairments and fear of falling in individuals with chronic obstructive pulmonary disease (COPD), and to evaluate the utility of the Four Square Step Test (FSST) and Functional Reach Test (FRT) in this population.

Methods:

A retrospective analysis of participants with COPD in a PT program between May 2015 and December 2015. Assessments performed before and after therapy were the Berg Balance Scale (BBS), FRT, FSST, and Activities Balance Confidence Scale (ABC) questionnaire. Statistical analysis used Pearson product–moment coefficient of correlation, 1-tailed T test, and Independent T test.

Results:

Twenty-five individuals with COPD completed the PT program. Individuals at high risk of falls experienced significant improvements on the BBS (6.6 points, P = .0097), FSST (6.75 seconds, P = .001), and FRT (5.63 cm, P = .01333). The BBS and FSST were correlated with each other (r = 0.70) at baseline. Improvements in the ABC were not statistically significant (P = .071). Use of supplemental oxygen was not correlated with any assessment tool.

Conclusions:

People with greater balance deficits had significant improvements in balance after a 1-month PT program. The FSST should be investigated further in patients with COPD.
A further assessment of a role for Toll-like receptor 4 in the reinforcing and reinstating effects of opioids
Authors: Yue Kai , Tanda Gianluigi , Katz Jonathan L. , Zanettini Claudio
Published: February 2019

The Toll-like receptor 4 (TLR4) antagonists, (+)-naloxone and (+)-naltrexone, have been reported to decrease self-administration of opioids in rats and to reduce other preclinical indicators of abuse potential. However, under the self-administration conditions studied, the effects of TLR4 antagonists were not reinforcer selective, questioning the involvement of those receptors and their mediated inflammatory response specifically in opioid abuse. The objectives of the current study were to further characterize the reinforcer specificity of TLR4 antagonism in opioid self-administration and to explore its effects in a preclinical model of craving/relapse. The TLR4 antagonist (+)-naltrexone decreased responding in rats trained to self-administer the µ-opioid receptor agonist remifentanil, but with a potency that was not significantly different from that observed in another group of subjects in which responding was maintained by food reinforcement. Responding reinstated by heroin injection was decreased by (+)-naltrexone; however, a similar reduction was not reproduced with the administration of another TLR4 antagonist, lipopolysaccharide from Rhodobacter sphaeroides, administered into the NAcc shell. Thus, TLR4 antagonists lacked reinforcer selectivity in reducing opioid self-administration and were not uniformly effective in a model of craving/relapse, suggesting limitations on the development of (+)-naltrexone or TLR4 antagonists as treatments for opioid abuse.
ALDH2 Activation Inhibited Cardiac Fibroblast-to-Myofibroblast Transformation Via the TGF-β1/Smad Signaling Pathway
Authors: Yuan Qiuhuan , Cao Shengchuan , Dong Qianqian , Wang Zheng , Xu Youshun , Han Qi , Ma Jingjing , Wei Shujian , Pang Jiaojiao , Yang Feihong , Zhang Rui , Liu Baoshan , Dai Shuai , Xue Li , Wang Jiali , Xue Mengyang , Xu Tonghui , Zheng Wen , Xu Feng , Chen Yuguo , Guo Ping
Published: February 2019

Pathological stimulus–triggered differentiation of cardiac fibroblasts plays a major role in the development of myocardial fibrosis. Aldehyde dehydrogenase 2 (ALDH2) was reported to exert a protective role in cardiovascular disease, and whether ALDH2 is involved in cardiac fibroblast differentiation remains unclear. In this study, we used transforming growth factor-β1 (TGF-β1) to induce the differentiation of human cardiac fibroblasts (HCFs) and adopted ALDH2 activator Alda-1 to verify the influence of ALDH2 on HCF differentiation. Results showed that ALDH2 activity was obviously impaired when treating HCFs with TGF-β1. Activation of ALDH2 with Alda-1 inhibited the transformation of HCFs into myofibroblasts, demonstrated by the decreased smooth muscle actin (α-actin) and periostin expression, reduced HCF-derived myofibroblast proliferation, collagen production, and contractility. Moreover, application of Smad2/3 inhibitor alleviated TGF-β1–induced HCF differentiation and improved ALDH2 activity, which was reversed by the application of ALDH2 inhibitor daidzin. Finally, Alda-1–induced HCF alterations alleviated neonatal rat cardiomyocyte hypertrophy, supported by the immunostaining of α-actin. To summarize, activation of ALDH2 enzymatic activity inhibited the differentiation of cardiac fibroblasts via the TGF-β1/Smad signaling pathway, which might be a promising strategy to relieve myocardial fibrosis of various causes.
Validity of a Submaximal 6-min Recumbent Stepper Test for Cardiac Rehabilitation
Authors: Donaldson Seth , Wright Lanecia , Day Amanda , Weiford Brian
Published: February 2019

Purpose:

Submaximal exercise tests, such as the 6-min walk test (6MWT), are used to assess and determine changes in cardiorespiratory fitness in cardiopulmonary rehabilitation (CR) programs. However, other modalities such as recumbent steppers are frequently utilized in rehabilitation settings and suit individuals of all ability levels; yet, no self-paced submaximal test has been developed for this exercise modality. The aim of this study was to produce a self-paced, submaximal 6-min recumbent stepper test (6MRST) that is comparable with the 6MWT and can be used as pre- and post-CR assessments.

Methods:

Seventy subjects participating in CR performed a 6WMT and a 6MRST at the beginning and end of their CR program. Distance exercised, blood pressure, heart rate, and perceived exertion were measured to determine whether the 6MRST was comparable with the 6MWT.

Results:

Significant correlations were found between the distance exercised in the 6MWT and the 6MRST during both pre- and post-CR testing (r = 0.540 and r = 0.700, respectively; P < .001). The distance for the 6MRST increased from 1599 to 2101 ft after CR. Heart rate and rating of perceived exertion showed strong correlations between the 6MWT and the 6MRST at both testing time points.

Conclusions:

The 6MRST was found to produce similar results to that of the 6MWT in a CR setting. The 6MRST could therefore serve as an alternative to the 6MWT in those patients who cannot adequately perform a 6MWT, in a facility where space may be too limited, and a walking track is not available or simply due to patient or staff preference.
An Examination of the Frequency of Paravascular Defects and Epiretinal Membranes in Eyes With Early Glaucoma Using En-face Slab OCT Images
Authors: Mavrommatis Maria A. , De Cuir Nicole , Reynaud Juan , De Moraes Carlos G. , Xin Daiyan , Rajshekhar Rashmi , Liebmann Jeffrey M. , Ritch Robert , Fortune Brad , Hood Donald C.
Published: February 2019

Purpose:

To examine the frequency of paravascular defects (PDs) and macular epiretinal membranes (ERMs) in eyes categorized as having mild glaucoma or glaucoma suspect using en-face slab analysis of optical coherence tomography (OCT) scans.

Materials and Methods:

Fifty-seven glaucomatous eyes, 44 low-risk suspect eyes, and 101 healthy control eyes were included in the study. The 101 glaucomatous and suspect eyes had a mean deviation better than −6 dB on the 24-2 visual field, and a spherical refractive error between±6 D or axial length <26.5 mm. Two OCT-graders masked to eye classification identified ERMs and PDs on en-face slab images of the macula and peripapillary retina using horizontal B-scans and derived vertical B-scans.

Results:

Glaucomatous eyes had a significantly higher number of PDs and ERMs than healthy controls (PD, P<0.001; ERM, P=0.046) and low-risk glaucoma suspects (PD, P=0.004; ERM, P=0.043). PDs and/or ERMs were present in 16 of 57 (28.1%) glaucomatous eyes, 2 of 44 (4.5%) suspect eyes, and 3 of 101 (3.0%) control eyes. Further, PDs were present in 11 of the 57 (19.3%) glaucomatous eyes, 1 of the 44 (2.3%) suspect eyes and 0 of the 101 (0%) control eyes, ERMs were seen in 7 of the 57 (12.3%) glaucomatous eyes, 1 of the 44 (2.3%) suspects, and 3 of the 101 (3.0%) control eyes.

Conclusions:

Eyes with early glaucoma have a higher frequency of PDs and ERMs than suspects or controls and exhibit PDs even in the absence of ERMs or high myopia.
Platelet-derived growth factor activates nociceptive neurons by inhibiting M-current and contributes to inflammatory pain
Authors: Barkai Omer , Puig Stephanie , Lev Shaya , Title Ben , Katz Ben , Eli-Berchoer Luba , Gutstein Howard B. , Binshtok Alexander M.
Published: February 2019

Endogenous inflammatory mediators contribute to the pathogenesis of pain by acting on nociceptors, specialized sensory neurons that detect noxious stimuli. Here, we describe a new factor mediating inflammatory pain. We show that platelet-derived growth factor (PDGF)-BB applied in vitro causes repetitive firing of dissociated nociceptor-like rat dorsal root ganglion neurons and decreased their threshold for action potential generation. Injection of PDGF-BB into the paw produced nocifensive behavior in rats and led to thermal and mechanical pain hypersensitivity. We further detailed the biophysical mechanisms of these PDGF-BB effects and show that PDGF receptor–induced inhibition of nociceptive M-current underlies PDGF-BB–mediated nociceptive hyperexcitability. Moreover, in vivo sequestration of PDGF or inhibition of the PDGF receptor attenuates acute formalin-induced inflammatory pain. Our discovery of a new pain-facilitating proinflammatory mediator, which by inhibiting M-current activates nociceptive neurons and thus contributes to inflammatory pain, improves our understanding of inflammatory pain pathophysiology and may have important clinical implications for pain treatment.