bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation Between White Matter Injury Identified by Neonatal Diffusion Tensor Imaging and Neurodevelopmental Outcomes Following Term Neonatal Asphyxia and Therapeutic Hypothermia: An Exploratory Pilot Study
Authors: Gerner Gwendolyn J. , Newman Eric I. , Burton V. Joanna , Roman Brenton , Cristofalo Elizabeth A. , Leppert Mary , Johnston Michael V. , Northington Frances J. , Huisman Thierry A.G.M. , Poretti Andrea
Published: May 2019

Aim:

Hypoxic-ischemic encephalopathy is associated with damage to deep gray matter; however, white matter involvement has become recognized. This study explored differences between patients and clinical controls on diffusion tensor imaging, and relationships between diffusion tensor imaging and neurodevelopmental outcomes.

Method:

Diffusion tensor imaging was obtained for 31 neonates after hypoxic-ischemic encephalopathy treated with therapeutic hypothermia and 10 clinical controls. A subgroup of patients with hypoxic-ischemic encephalopathy (n = 14) had neurodevelopmental outcomes correlated with diffusion tensor imaging scalars.

Results:

Group differences in diffusion tensor imaging scalars were observed in the putamen, anterior and posterior centrum semiovale, and the splenium of the corpus callosum. Differences in these regions of interest were correlated with neurodevelopmental outcomes between ages 20 and 32 months.

Conclusion:

Therapeutic hypothermia may not be a complete intervention for hypoxic-ischemic encephalopathy, as neonatal white matter changes may continue to be evident, but further research is warranted. Patterns of white matter change on neonatal diffusion tensor imaging correlated with neurodevelopmental outcomes in this exploratory pilot study.
Intimate Partner Violence in Adolescence: Associations With Perpetration Trauma, Rumination, and Posttraumatic Stress
Authors: Mozley Michaela M. , Modrowski Crosby A. , Kerig Patricia K.
Published: May 2019

Engagement in intimate partner violence (IPV) is related to a host of negative outcomes for youth, including posttraumatic stress symptoms (PTSS). Moreover, research indicates that the perpetration of violence may constitute a traumatic experience, termed perpetration trauma (PT), which, in turn, is related to elevated levels of PTSS. Little research to date, however, has illuminated the underlying processes that may link IPV perpetration, PT, and PTSS. One potential contributor to this association is rumination on negative emotions. In particular, for youth who report PT and rumination, engaging in IPV may be associated with elevations in PTSS. To investigate this hypothesis, data were gathered from a sample of 235 justice-involved youth (184 boys, 51 girls) who completed self-report measures of IPV perpetration and victimization, PT, sadness and anger rumination, and PTSS. Results of moderated mediational analyses indicated that IPV perpetration was related to PTSS through sadness rumination, and that these effects were stronger when youth endorsed PT. In turn, IPV perpetration was related to PTSS through anger rumination only when youth did not endorse PT. In addition, tests of alternative models indicated that these results were specific to IPV perpetration, given that IPV victimization was not related to PTSS through anger or sadness rumination when youth endorsed PT. These results suggest that the combination of rumination on sadness and endorsement of PT may put youth who perpetrate IPV at the greatest risk of PTSS. Therefore, interventions seeking to interrupt the cycle of IPV perpetration may benefit from targeting perpetrators’ sadness rumination, PT, and PTSS.
Parameter optimization and texture evolution in single point incremental sheet forming process
Authors: Basak Shamik , Prasad K Sajun , Mehto Amarjeet , Bagchi Joy , Ganesh Y Shiva , Mohanty Saurav , Sidpara Ajay M , Panda Sushanta Kumar
Published: May 2019

Prototyping through incremental sheet forming is emerging as a latest trend in the manufacturing industries for fabricating personalized components according to customer requirement. In this study, a laboratory scale single-point incremental forming test setup was designed and fabricated to deform AA6061 sheet metal plastically. In addition, response surface methodology with Box–Behnken design technique was used to establish different regression models correlating input process parameters with mechanical responses such as angle of failure, part depth per unit time and surface roughness. Correspondingly, the regression models were implemented to optimize the input process parameters, and the predicted responses were successfully validated at the optimal conditions. It was observed that the predicted absolute error for angle of failure, part depth per unit time and surface roughness responses was approximately 0.9%, 4.4% and 6.3%, respectively, for the optimum parametric combination. Furthermore, the post-deformation responses from an optimized single point incremental forming truncated cone were correlated with microstructural evolution. It was observed that the peak hardness and highest areal surface roughness of 158 ± 9 HV and 1.943 μm, respectively, were found near to the pole of single-point incremental forming truncated cone, and the highest major plastic strain at this region was 0.80. During incremental forming, a significant increase in microhardness occurred due to grain refinement, whereas a substantial increase in the Brass and S texture component was responsible for the increase in the surface roughness.
Fuel consumption reduction by introducing best-mode controller for hybrid electric vehicles
Authors: Mashadi Behrooz , Khadem Nahvi Mahdi
Published: May 2019

In this paper, a power management system for hybrid electric vehicles is developed and shown to improve the vehicle fuel consumption in various working conditions. A best-mode concept is defined based on the results of the dynamic programming global optimization strategy. It is shown that the use of exclusive control relations for each working mode improves fuel saving. The working state of the engine and one electric motor is used to determine the best-mode of powertrain operation. The best-mode classification also considers the battery state of charge. This enables the controller to specify near optimal working points in a wide range of state of charge. The control rule for each different work-mode is developed based on the dynamic programming results and applying the particle swarm optimization algorithm. The results show that the best-mode controller is capable of achieving fuel consumptions around 97% of that of the offline dynamic programming.
Child Protective Service Referrals Involving Exposure to Domestic Violence: Prevalence, Associated Maltreatment Types, and Likelihood of Formal Case Openings
Authors: Victor Bryan G. , Henry Colleen , Gilbert Terri Ticknor , Ryan Joseph P. , Perron Brian E.
Published: May 2019

Childhood exposure to domestic violence (CEDV) is widely understood as potentially harmful to children. Accordingly, many child welfare systems in the United States construe CEDV as maltreatment when the exposure results in harm or threatened harm to the child. The purpose of the current study was to investigate substantiated child welfare referrals directly related to CEDV to better understand the prevalence and patterns of CEDV-related maltreatment and how child welfare workers respond under the “harm or threatened harm” standard. Data were drawn from 23,704 substantiated referrals between 2009 and 2013 in a large Midwestern child welfare system. Approximately 20% of substantiated referrals were CEDV related. A plurality of CEDV-related referrals included both a male caregiver and female caregiver who were co-substantiated for maltreatment. The most common maltreatment types substantiated for these referrals were neglect based rather than abuse based, and just under a quarter (23%) of CEDV-related referrals were formally opened for services. Referrals involving co-occurring substance abuse were most likely to be opened for services based on predicted probabilities derived from multilevel modeling. Implications for policy and practice are considered.
Fibrinolytic Shutdown Is Associated With Intraoperative Thrombosis and Hemorrhage During Visceral Transplant
Authors: Raveh Yehuda , Souki Fouad , Livingstone Joshua , Beduschi Thiago , Vianna Rodrigo , Rodriguez Yiliam , Nicolau-Raducu Ramona
Published: May 2019

Background and Objective. End-stage liver disease is characterized by a precarious imbalance of hemostasis. Detrimental consequences of hypofibrinolysis, also known as fibrinolytic shutdown, have been recently demonstrated, and its significance in visceral (ie, an allograft that contains the intestine) transplant remains unknown. Design and Setting. To fill this gap, following institutional review board approval, this retrospective study included 49 adult recipients of visceral allografts (14 “visceral allograft without the liver” and 35 “multivisceral” with the liver) transplanted between 2010 and 2018 in a single university hospital, and for whom pre-incisional thromboelastography was available. Based on percent clot lysis 30 minutes after maximal amplitude, patients were stratified into 3 fibrinolysis phenotypes: fibrinolytic shutdown, physiologic fibrinolysis, and hyperfibrinolysis. Results. Fibrinolytic shutdown occurred in 57% of patients, with higher incidence in recipients of multivisceral transplant (69%) compared with visceral allograft without liver (29%) allografts ( P = .04). Fibrinolytic shutdown was associated with an increase in both intraoperative thrombosis and hemorrhage. Intraoperative thrombosis (18%) occurred only with multivisceral transplant, and accounted for 36% of in-hospital mortality. A clinically meaningful reduction in incidence of intraoperative thrombosis was noted in recipients who received intravenous heparin thromboprophylaxis. Logistic regression identified pretransplant platelet count as a risk factor for fibrinolytic shutdown (odds ratio = 0.992, 95% confidence interval = [0.984-0.998]; χ2 = 7.8, P = .005). Conclusions. This study highlights fibrinolytic shutdown as a dominant and clinically important feature of the hemostatic imbalance in recipients undergoing visceral transplantation.
Trichophyton species and Microsporum gypseum infection and fomite carriage in cats from three animal shelters: a retrospective case series
Authors: Moriello Karen A , Stuntebeck Rebecca , Mullen Laura
Published: May 2019

Objectives

The goal of this retrospective case series was to report on the clinical aspects of confirmed Trichophyton species and Microsporum gypseum infections in cats from three animal shelters

Methods

This was an observational retrospective study. Fungal culture and treatment data from three animal shelters was retrospectively reviewed to identify cats with dermatophytosis caused by Trichophyton species or M gypseum.

Results

Among the three shelters only four cats were diagnosed with M gypseum dermatophytosis. With respect to Trichophyton species infections, there were six cases identified and treated in a 1 year period in one shelter, 13 cases over 13 years in the second shelter and 27 cases over 5 years in the third shelter. Four cases of M gypseum dermatophytosis were treated in the third shelter. Young cats were most commonly infected and the disease was most commonly diagnosed in the fall and winter months. Lesions were inflammatory and found predominantly on the head and neck. There was a rapid response to treatment in all cases; mean (n = 20) and median (n = 17) days to mycological cure were calculated from available data. Fungal culture data revealed fomite carriage without clinical evidence of infection for Trichophyton species (n = 43) cats and M gypseum (n = 37) cats.

Conclusions and relevance

There is a paucity of clinical information about non- Microsporum canis dermatophytosis in shelter cats. This study data shows that Trichophyton species and M gypseum infections do occur but are uncommon. Based upon the rapid response to conventional treatment, these infections do not represent a treatment challenge, as most cats reached mycological cure within 3 weeks.
Neoliberal Governance, Education, and Roma in Romania
Authors: Voiculescu Cerasela
Published: May 2019

State education is neo/liberalism’s preeminent form of self-governance, included in programmes of governance, which aim at integrating into the structures of the state populations (e.g. Roma) whose cultural constituencies and forms of knowledge are not yet subjected to market rationality. Based on interviews and participant observation, the dialectical communication between Roma local forms of knowledge and state education is critically explored by looking at interactions between teachers, school mediators, and Roma adults. Cultural idiosyncrasies are further analysed in relation to the utopian character of European neoliberal programme of social integration for the Roma. The article argues for a constructive dialogue between state education and idiosyncratic Roma forms of knowledge and culture, which can engender authentic forms of empowerment.
Socioeconomic inequalities of suicide: Sociological and psychological intersections
Authors: Chandler Amy
Published: May 2019

Suicide is complex; yet suicide research is dominated by ‘psy’ disciplines which can falter when seeking to explain social patterning of suicide rates, and how this relates to individual actions. This article discusses a multidisciplinary report which aimed to advance understandings of socioeconomic inequalities in suicide rates in the UK. Contrasts are drawn between health psychology and sociology. Important intersections are highlighted, including a lack of attention to socioeconomic inequalities, and an emphasis on adverse life experiences and emotions to understand inequalities and suicide. There are also curious disconnects, both within and between relevant psychological and sociological perspectives. The article argues that there are significant gaps in existing theorization regarding suicide, which can only be addressed through meaningful inter-disciplinary collaborations between sociologists, psychologists and others. Current theorization in mainstream suicide research is limited by its failure to engage with enduring, yet vitally important sociological debates regarding structure and agency, nature and culture.
The contribution of smoking-related deaths to the gender gap in life expectancy in Sweden between 1997 and 2016
Authors: Östergren Olof , Martikainen Pekka
Published: May 2019

Aims: In recent decades, smoking-related mortality has declined among men and increased among women in Sweden. We estimate the contribution of smoking-related deaths to the narrowing of the gender gap in life expectancy in Sweden between 1997 and 2016. Methods: We extracted population data on deaths and population under risk on the entire Swedish population aged 25 years and over for the period 1997–2016. Smoking-related mortality was assessed using an indirect method based on lung cancer mortality. We then estimated the contribution of smoking to the gender gap in life expectancy by comparing the observed life expectancies to life expectancies excluding smoking-related deaths. Results: The gender gap in life expectancy was 5.0 years in 1997 and 3.4 years in 2016. The gender gap narrowed by 1.6 years, of which 0.6 years were attributable to smoking-related deaths. Conclusions: The combination of decreasing smoking-related mortality among men and increasing smoking-related mortality among women in Sweden accounted for almost 40% of the narrowing of the gender gap in life expectancy during the period 1997–2016.
‘Up close and in person’: United States and Australian political reporters’ changing conceptions of the value of campaign coverage
Authors: Brookes Stephanie
Published: May 2019

The way political reporters understand their own role in election campaigns is changing, signalling a deeper shift in journalistic self-conception. In traditional discourses of journalistic identity, campaign reporters are positioned as playing a unique democratic role enabling citizens to make informed voting decisions. This article asks, ‘How do campaign reporters understand and construct their own value and that of their work in an increasingly fragmented and crowded news environment?’ It offers new empirical insight through a two-country study that both considers journalist perspectives and situates these within relevant theoretical debates. It analyses interviews with political reporters in the United States and Australia in 2017, guided by two conceptual frameworks that consider the ways journalists actively construct their own identity and authority: interpretive communities and metajournalistic discourse. This allows insight into the way political reporters reconsider the need to cover campaigns from ‘on the bus’ and defend the enduring value of being there.
But her emails! How journalistic preferences shaped election coverage in 2016
Authors: Searles Kathleen , Banda Kevin K
Published: May 2019

While existing work explains how journalists use news values to select some stories over others, we know little about how stories that meet newsworthiness criteria are prioritized. Once stories are deemed newsworthy, how do journalists calculate their relative utility? Such an ordering of preferences is important as higher ranked stories receive more media attention. To better understand how stories are ordered once they are selected, we propose a model for rational journalistic preferences which describes how journalists rank stories by making cost-benefit analyses. When faced with competing newsworthy stories, such as in an election context, the model can generate expectations regarding news coverage patterns. To illustrate model utility, we draw on a unique case – the US 2016 presidential election – to explain how reporters order newsworthy stories (e.g. scandal and the horse race) by observing changes in the volume. Our content data captures coverage featuring Hillary Clinton or Donald Trump on major broadcast and cable networks over 31  weeks. We find that the rational journalistic preference model explains the imbalance of scandal coverage between the two candidates and the dominance of horse race coverage. In 2016, such preferences may have inadvertently contributed to a balance of news stories that favored Trump.
Habit as a central concept in marketing
Authors: Tadajewski Mark
Published: May 2019

This article reorients the conceptual architecture of marketing theory. It is proposed that marketing is the dynamic force that economists and sociologists seek to explain the centrality of habit in everyday life. Questioning the arguments proffered by these twin disciplines, we submit that these processes of habit formation are not ‘undesigned’ or ‘hidden’, but perfectly visible and articulated by theorists and practitioners alike. These debates are complex. We outline their ‘strategic logic’, tracking the constitutive function of the discourse of habit. We unravel the theorized processes of habit formation as these are emplaced at the subconscious level and conceptualized via the ‘subconscious self’. Theoretically, we account for these power relations by uniting the concepts of biopolitics and anatomo-politics in terms of ‘bio-anatomopolitics’. Marketing, therefore, must be considered a disciplinary vehicle oriented towards habit creation and the destabilization of inertia.
Interaction between tele-nurses and callers with an evolving myocardial infarction: Consequences for level of directed care
Authors: Ericsson Maria , Ängerud Karin H , Brännström Margareta , Lawesson Sofia S , Strömberg Anna , Thylén Ingela
Published: May 2019

Background:

Rapid contact with emergency medical services is imperative to save the lives of acute myocardial infarction patients. However, many patients turn to a telehealth advisory nurse instead, where the delivery of urgent and safe care largely depends on how the interaction in the call is established.

Purpose:

The purpose of this study was to explore the interaction between tele-nurses and callers with an evolving myocardial infarction after contacting a national telehealth advisory service number as their first medical contact.

Method:

Twenty men and 10 women (aged 46–89 years) were included. Authentic calls were analysed using inductive content analysis.

Findings:

One overall category, Movement towards directed level of care, labelled the whole interaction between the tele-nurse and the caller. Four categories conceptualised the different interactions: a distinct, reasoning, indecisive or irrational interaction. The interactions described how tele-nurses and callers assessed and elaborated on symptoms, context and actions. The interaction was pivotal for progress in the dialogue and affected the achievement of mutual understanding in the communicative process. An indecisive or irrational interaction could increase the risk of failing to recommend or call for acute care.

Conclusion:

The interaction in the communication could either lead or mislead the level of care directed in the call. This study adds new perspectives to the communicative process in the acute setting in order to identify a myocardial infarction and the level of urgency from both individuals experiencing myocardial infarction and professionals in the health system.
Astrocyte Receptor Rebirth
Authors: Salvati Kathryn , Beenhakker Mark
Published: May 2019

[Box: see text]
The opportunity cost of intrastate violence and the out-of-sample validity of commodity price shocks
Authors: Dorsey Spencer
Published: May 2019

Recent work in economics and political science has identified a positive correlation between commodity prices and violence—which are theoretically linked through an opportunity cost mechanism. The findings have important implications for the academic understanding of violence and for policy makers working to anticipate and prevent it. Despite the importance of the findings, they are based on in-sample validation and aggressively aggregated data. There is a growing understanding, both within this literature and in the broader social science literature, that out-of-sample validation should be considered essential before any policy recommendations are made based on academic research. I find that while coffee price shocks are still correlated with intrastate violence in a higher resolution test (district-month), they fail to be useful out-of-sample. These results should prompt a reevaluation of scholarly work based on the relationship between commodity prices and violence and of any policies that have been crafted based on it.
A retrospective analysis of inpatient cardiac arrests over one year at a tertiary heart attack and cardiothoracic centre identifying potential candidates for an inpatient extracorporeal cardiopulmonary resuscitation service
Authors: Harrogate Suzanne , Stretch Benjamin , Seatter Rosie , Finney Simon , Singer Ben
Published: May 2019

Introduction

Extracorporeal cardiopulmonary resuscitation (ECPR) is an internationally recognised treatment for refractory cardiac arrest, with evidence of improved outcomes in selected patient groups from cohort studies and case series. In order to establish the clinical need for an in-hospital extracorporeal cardiopulmonary resuscitation service at a tertiary cardiac centre, we analysed the inpatient cardiac arrest database for the previous 12 months.

Methods

Evidence-based inclusion criteria were used to retrospectively identify the number of patients potentially eligible for extracorporeal cardiopulmonary resuscitation over a 12-month period.

Results

A total of 261 inpatient cardiac arrests were analysed with 21 potential extracorporeal cardiopulmonary resuscitation candidates meeting the inclusion criteria (1.75 patients per month, or 8% of inpatient cardiac arrests (21/261)). The majority (71%) of these cardiac arrests occurred outside of normal working hours. Survival-to-discharge within this sub-group with conventional cardiopulmonary resuscitation was 19% (4/21).

Conclusion

Sufficient numbers of refractory inpatient cardiac arrests occur to justify an extracorporeal cardiopulmonary resuscitation service, but a 24-h on-site extracorporeal membrane oxygenation team presents a significant financial and logistical challenge.
The Visual Analogue Scale for Pain: A Comparison of Scores Reported to Residents Versus an Attending Foot and Ankle Surgeon
Authors: Rushing Calvin J. , Spinner Steven M. , Hardigan Patrick
Published: May 2019

Background. Recent studies have raised concerns regarding the usefulness of the visual analogue scale (VAS) as an effective outpatient patient-reported outcome measure (PROM), with disparate scores reported during the same encounter to a nurse versus physician. The purpose of present study was to assess the VAS reported by new patient referrals to 2 different physicians of varying training levels (resident, attending), during the same initial outpatient encounter. Methods. One hundred and one patients treated by a single foot and ankle surgeon were included in the retrospective cohort. Each patient was asked to rate their pain intensity by a resident, and then by the attending surgeon using a standard horizontal VAS 0 to 10, from “no pain” to the “worst pain.” Differences in reported scores were analyzed. Results. Overall, the mean VAS reported to the residents (4.97 ± 2.75) and the attending surgeon (5.02 ± 2.71) were not significantly different ( P = .61). On the 11-point scale, the mean difference accounted for only 0.05 points. Conclusion. Taken into consideration with previous studies, the data suggest collection personnel may influence the reported VAS, possibly owing to patients’ preferences and perception of their care. Although the exact reasons remain unclear, our findings lend credence to the previous concerns expressed regarding the subjective nature of the VAS.

Levels of Evidence: Level III: Comparative study
Management of myelodysplastic syndromes after failure of response to hypomethylating agents
Authors: Gil-Perez Angela , Montalban-Bravo Guillermo
Published: May 2019

Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndrome (MDS). However, only around 50% of patients respond to these agents, and responses tend to be transient, with loss of response frequently happening within 2 years and being associated with very poor prognosis and limited therapeutic options. Identification of patients who will respond to HMAs is challenging. Mechanisms underlying resistance to HMAs are not clear yet. Recently, absence of response has been associated with increased cell-cycle quiescence among the hematopoietic progenitor cells. There are no standard-of-care options for patients after HMA failure. However, the increasing knowledge of MDS pathogenesis has led to the development of new potential therapies, including HMAs with longer half-life and exposure, inhibition of the antiapoptotic BCL2 protein with venetoclax or inhibition of immune-checkpoint regulatory proteins such as PD-1 or CTLA-4, innate immunity and targeting of CD33/CD3 with multiple monoclonal antibodies. In addition, multiple targeted agents are opening opportunities to treat subgroups of patients whose disease harbors mutations in TP53, IDH, FLT3, and genes involved in splicing machinery. Newer formulations of intensive chemotherapy and its different combinations may be considered a valid option in selected patients after HMA failure. Finally, decision making at the time of failure of response to HMAs should be personalized, taking into account that allogenic stem-cell transplantation remains the only therapeutic approach with curative potential in these patients. In the current review, we will focus on all the above aspects.
Can C7 Slope Be Used as a Substitute for T1 Slope? A Radiographic Analysis
Authors: Ye Ivan B. , Tang Ray , Cheung Zoe B. , White Samuel J. W. , Cho Samuel K.
Published: May 2019

Study Design:

Retrospective radiographic study.

Objectives:

T1 slope is an important parameter of sagittal spinal balance. However, the T1 superior endplate can be difficult to visualize on radiographs due to overlying anatomical structures. C7 slope has been proposed as a potential substitute for T1 slope when the T1 superior endplate is not well visualized. The objective of this study was 2-fold: (1) to assess the correlation between C7 and T1 slopes on upright cervical spine radiographs and (2) to evaluate the interrater reliability of C7 slope.

Methods:

Cervical spine radiographs taken between December 2017 and June 2018 at a single institution were reviewed. Two observers measured upper C7 slope, lower C7 slope, and T1 slope. The correlations between upper and lower C7 slope and T1 slope were evaluated, and linear regression analyses were performed. Interrater reliability of C7 slope was also assessed.

Results:

In this cohort of 152 patients, there was a strong correlation between upper C7 slope and T1 slope ( r = 0.91, P < .001), as well as between lower C7 slope and T1 slope ( r = 0.90, P < .001). T1 slope could be estimated from the linear regression equation, T1 slope = 0.87 × C7 slope + 7, with an overall model fit of R 2 = 0.8. There was strong interrater reliability for upper (intraclass correlation coefficient [ICC] = 0.95, P < .001) and lower C7 slope (ICC = 0.96, P < .001).

Conclusions:

Both the upper and lower C7 slope are strongly correlated with T1 slope and can be used as a substitute to estimate T1 slope when the superior endplate of T1 is not well visualized.
Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial
Authors: Ulrich Silvia , Saxer Stéphanie , Hasler Elisabeth D. , Schwarz Esther I. , Schneider Simon R. , Furian Michael , Bader Patrick R. , Lichtblau Mona , Bloch Konrad E.
Published: May 2019

Study question

We investigated whether domiciliary oxygen therapy (DOXT) increases exercise capacity and quality of life in patients with pulmonary arterial or distal chronic thromboembolic pulmonary hypertension (PAH/CTEPH) presenting with mild resting hypoxaemia and exercise-induced oxygen desaturation.

Materials and methods

30 patients with PAH/CTEPH, mean±sdage 60±15 years, pulmonary artery pressure 39±11 mmHg, resting arterial oxygen saturation measured by pulse oximetry (SpO2) ≥90%,SpO2drop during a 6-min walk test ≥4%, on pulmonary hypertension-targeted medication, were randomised in a double-blind crossover protocol to DOXT and placebo (ambient air) treatment, each over 5 weeks, at 3 L·min−1vianasal cannula overnight and when resting during the day. Treatment periods were separated by 2 weeks of washout. Co-primary outcomes were changes in 6-min walk distance (6MWD, breathing ambient air) and physical functioning scale of the 36-item short-form medical outcome questionnaire during treatment periods.

Results

DOXT increased the 6MWD from baseline 478±113 m by a mean (95% CI) of 19 (6–32) m, and physical functioning from 52±29 by 4 (0–8) points. Corresponding changes with placebo were 1 (−11–13) m in 6MWD and −2 (−6–2) points in physical functioning. Between-treatment differences in changes were 6MWD 18 (1–35) m (p=0.042) and physical functioning 6 (1–11) points (p=0.029). DOXT significantly improved the New York Heart Association functional classversusplacebo.

Answer to the question

This first randomised trial in PAH/CTEPH patients with exercise-induced hypoxaemia demonstrates that DOXT improves exercise capacity, quality of life and functional class. The results support large long-term randomised trials of DOXT in PAH/CTEPH.
Airway inflammation in COPD: progress to precision medicine
Authors: Brightling Christopher , Greening Neil
Published: May 2019

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide, and its prevalence is increasing. Airway inflammation is a consistent feature of COPD and is implicated in the pathogenesis and progression of COPD, but anti-inflammatory therapy is not first-line treatment. The inflammation has many guises and phenotyping this heterogeneity has revealed different patterns. Neutrophil-associated COPD with activation of the inflammasome, T1 and T17 immunity is the most common phenotype with eosinophil-associated T2-mediated immunity in a minority and autoimmunity observed in more severe disease. Biomarkers have enabled targeted anti-inflammatory strategies and revealed that corticosteroids are most effective in those with evidence of eosinophilic inflammation, whereas, in contrast to severe asthma, response to anti-interleukin-5 biologicals in COPD has been disappointing, with smaller benefits for the same intensity of eosinophilic inflammation questioning its role in COPD. Biological therapies beyond T2-mediated inflammation have not demonstrated benefit and in some cases increased risk of infection, suggesting that neutrophilic inflammation and inflammasome activation might be largely driven by bacterial colonisation and dysbiosis. Herein we describe current and future biomarker approaches to assess inflammation in COPD and how this might reveal tractable approaches to precision medicine and unmask important host–environment interactions leading to airway inflammation.
Discussion of “A Framework to Evaluate the Benefit of Seismic Upgrading”
Authors: Galanis Panagiotis , Broccardo Marco , Bodenmann Lukas , Stojadinović Božidar
Published: May 2019

Discussers (Michel et al.) address the paper “A Framework to Evaluate the Benefit of Seismic Upgrading” written by the coauthors of this response. Discussers present the compliance factor approach to evaluate existing structures and determine the need for a seismic upgrade implemented in the Swiss code SIA 269/8 and compare this approach to the one presented in the discussed paper. The approach proposed in the discussed paper combines elements of the Pacific Earthquake Engineering Research (PEER) Center Performance-Based Earthquake Engineering (PBEE) framework and the standard actuarial frequency-severity approach. Discussers criticize this approach as not being risk based and, consequently, consider it inappropriate for seismic evaluation of existing buildings. Coauthors welcome the comparison of different approaches for evaluation of existing buildings but disagree with the discussers’ characterization of the PEER PBEE framework and, by extension, the approach of the discussed paper.
Increases in Life-Safety Risks to Building Occupants from Induced Earthquakes in the Central United States
Authors: Liu Taojun , Luco Nicolas , Liel Abbie B.
Published: May 2019

Earthquake occurrence rates in some parts of the Central United States have been elevated for a number of years; this increase has been widely attributed to deep wastewater injection associated with oil and gas activities. This induced seismicity has caused damage to buildings and infrastructure and substantial public concern. In March 2016, the U.S. Geological Survey (USGS) published its first earthquake ground motion hazard model that accounts for the elevated seismicity, producing a one-year forecast encompassing both induced and natural earthquakes. To assess the potential impact of the elevated seismicity on buildings and the public, this paper quantifies forecasted risks of (1) building collapse and (2) the falling of nonstructural building components by combining the 2016 USGS hazard model with fragility curves for generic modern code-compliant buildings. The assessment shows significant increases in both types of risk compared to that caused by noninduced earthquakes alone; the magnitude of the increases varies from a few times to more than 100 times, depending on location, building period (which is correlated to building height), alternatives for the hazard model, and type of risk of interest. For exploratory purposes only, we also estimate revised values of the risk-targeted ground motion that are currently used for designing buildings.
The Mortality-to-Incidence Ratio Is Not a Valid Proxy for Cancer Survival
Authors: Ellis Libby , Belot Aurélien , Rachet Bernard , Coleman Michel P.
Published: May 2019

PURPOSE

The ratio of cancer mortality and cancer incidence rates in a population has conventionally been used as an indicator of the completeness of cancer registration. More recently, the complement of the mortality-to-incidence ratio (1-M/I) has increasingly been presented as a surrogate for cancer survival. We discuss why this is mistaken in principle and misleading in practice.

METHODS

We provide an empirical assessment of the extent to which trends in the 1-M/I ratio reflect trends in cancer survival. We used national cancer incidence, mortality and survival data in England to compare trends in both the 1-M/I ratio and net survival at 1, 5, and 10 years for 19 cancers in men and 20 cancers in women over the 29-year period from 1981 to 2009.

RESULTS

The absolute difference between the 1-M/I ratio and 5-year net survival for 2009 was less than 5% for only 12 of the 39 cancer/sex combinations examined. For an additional 12, the 1-M/I ratio differed from 5-year net survival by at least 15%. The comparison is also unstable over time; thus, even when differences were small for 2009, the difference between 5-year net survival and the 1-M/I ratio had changed dramatically for most cancers between 1981 and 2009.

CONCLUSION

The 1-M/I ratio lacks any theoretical basis as a proxy for cancer survival. It is not a valid proxy for cancer survival in practice, either, whether at 5 years or at any other time interval since diagnosis. It has none of the useful properties of a population-based survival estimate. It should not be used as a surrogate for cancer survival.
Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function
Authors: Fearnley Gareth W. , Abdul-Zani Izma , Latham Antony M. , Hollstein Monica C. , Ladbury John E. , Wheatcroft Stephen B. , Odell Adam F. , Ponnambalam Sreenivasan
Published: May 2019

New blood vessel sprouting (angiogenesis) and vascular physiology are fundamental features of metazoan species but we do not fully understand how signal transduction pathways regulate diverse vascular responses. The vascular endothelial growth factor (VEGF) family bind membrane-bound receptor tyrosine kinases (VEGFRs), which trigger multiple signal transduction pathways and diverse cellular responses. We evaluated whether the MAP3K family member and proto-oncoprotein Tpl2 (MAP3K8) regulates basal and VEGF-A-stimulated signal transduction in endothelial cells. Notably, stimulation with exogenous VEGF-A increased Tpl2 mRNA levels and consequently de novo protein synthesis. Depletion of Tpl2 levels reveals a role in both basal and VEGF-A-stimulated endothelial cell responses, including endothelial-leukocyte interactions, monolayer permeability, and new blood vessel formation. Under basal conditions, Tpl2 modulates a signal transduction cascade resulting in phosphorylation of a nuclear transcription factor (ATF-2) and altered endothelial gene expression, a pathway previously identified as crucial in VEGF-dependent vascular responses. Loss of Tpl2 expression or activity impairs signal transduction through Akt, eNOS and ATF-2, broadly impacting on endothelial function. Our study now provides a mechanism for Tpl2 as a central component of signal transduction pathways in the endothelium.
Meiosis in the scorpion Tityus silvestris: new insights into achiasmatic chromosomes
Authors: Almeida Bruno Rafael Ribeiro de , Noronha Renata Coelho Rodrigues , Costa Marlyson Jeremias Rodrigues da , Nagamachi Cleusa Yoshiko , Pieczarka Julio Cesar
Published: May 2019

Achiasmatic male meiosis in scorpions is characterized by a high frequency of gaps, asynaptic regions, and multivalent associations. Here, we performed an immunocytogenetic analysis to investigate recombination, and synapsis and chromatin-remodeling events during meiosis of the scorpion Tityus silvestris. Our results demonstrate that the synaptonemal complex (SC) begins its organization in the zygotene stage and persists until metaphase I. The advancement of the synaptic process is related to the epigenetic modification histone H3 lysine 27 trimethylation (H3K27m3). The distribution and dynamics patterns of variant γH2AX and recombinase Rad51 during achiasmatic meiosis suggests formation and repair of DNA double-strand breaks (DSBs) during early stages of prophase I. The epigenetic modifications, histone H3 lysine 4 trimethylation (H3K4m3) and histone H3 lysine 9 acetylation (H3K9ac), showed a dispersed distribution along the bivalents, suggesting that transcriptional activity is maintained constitutively during prophase I. However, H3K9ac modifications are absent in constitutive heterochromatin carrying the 45S rDNA in pachytene and post-pachytene stages. Collectively, our data demonstrate that T. silvestris exhibits adaptations to the achiasmatic mode, and suggest that epigenetic modifications may act in the regulation of these mechanisms to favor the normal continuation of meiosis in this scorpion.
Detection of changes in mitochondrial hydrogen sulfide i
n vivo in the fish model Poecilia mexicana (Poeciliidae)
Authors: Lau Gigi Y. , Barts Nicholas , Hartley Richard C. , Tobler Michael , Richards Jeffrey G. , Murphy Michael P. , Arndt Sabine
Published: May 2019

In this paper, we outline the use of a mitochondria-targeted ratiometric mass spectrometry probe, MitoA, to detect in vivo changes in mitochondrial hydrogen sulfide (H2S) in Poecilia mexicana (family Poeciliidae). MitoA is introduced via intraperitoneal injection into the animal and is taken up by mitochondria, where it reacts with H2S to form the product MitoN. The MitoN/MitoA ratio can be used to assess relative changes in the amounts of mitochondrial H2S produced over time. We describe the use of MitoA in the fish species P. mexicana to illustrate the steps for adopting the use of MitoA in a new organism, including extraction and purification of MitoA and MitoN from tissues followed by tandem mass spectrometry. In this proof-of-concept study we exposed H2S tolerant P. mexicana to 59 µM free H2S for 5 h, which resulted in increased MitoN/MitoA in brain and gills, but not in liver or muscle, demonstrating increased mitochondrial H2S levels in select tissues following whole-animal H2S exposure. This is the first time that accumulation of H2S has been observed in vivo during whole-animal exposure to free H2S using MitoA.

This article has an associated First Person interview with the first author of the paper.
Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration
Authors: Xie Yufei , Tolmeijer Sofie , Oskam Jelle M. , Tonkens Tijs , Meijer Annemarie H. , Schaaf Marcel J. M.
Published: May 2019

Glucocorticoid drugs are widely used to treat immune-related diseases, but their use is limited by side effects and by resistance, which especially occurs in macrophage-dominated diseases. In order to improve glucocorticoid therapies, more research is required into the mechanisms of glucocorticoid action. In the present study, we have used a zebrafish model for inflammation to study glucocorticoid effects on the innate immune response. In zebrafish larvae, the migration of neutrophils towards a site of injury is inhibited upon glucocorticoid treatment, whereas migration of macrophages is glucocorticoid resistant. We show that wounding-induced increases in the expression of genes that encode neutrophil-specific chemoattractants (Il8 and Cxcl18b) are attenuated by the synthetic glucocorticoid beclomethasone, but that beclomethasone does not attenuate the induction of the genes encoding Ccl2 and Cxcl11aa, which are required for macrophage recruitment. RNA sequencing on FACS-sorted macrophages shows that the vast majority of the wounding-induced transcriptional changes in these cells are inhibited by beclomethasone, whereas only a small subset is glucocorticoid-insensitive. As a result, beclomethasone decreases the number of macrophages that differentiate towards a pro-inflammatory (M1) phenotype, which we demonstrated using a tnfa:eGFP-F reporter line and analysis of macrophage morphology. We conclude that differentiation and migration of macrophages are regulated independently, and that glucocorticoids leave the chemotactic migration of macrophages unaffected, but exert their anti-inflammatory effect on these cells by inhibiting their differentiation to an M1 phenotype. The resistance of macrophage-dominated diseases to glucocorticoid therapy can therefore not be attributed to an intrinsic insensitivity of macrophages to glucocorticoids.
Enhancer of Polycomb and the Tip60 complex repress hematological tumor initiation by negatively regulating JAK/STAT pathway activity
Authors: Bailetti Alessandro A. , Negrón-Piñeiro Lenny J. , Dhruva Vishal , Harsh Sneh , Lu Sean , Bosula Aisha , Bach Erika A.
Published: May 2019

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders that cause excessive production of myeloid cells. Most MPN patients have a point mutation in JAK2 (JAK2V617F), which encodes a dominant-active kinase that constitutively triggers JAK/STAT signaling. In Drosophila, this pathway is simplified, with a single JAK, Hopscotch (Hop), and a single STAT transcription factor, Stat92E. The hopTumorous-lethal [hopTum] allele encodes a dominant-active kinase that induces sustained Stat92E activation. Like MPN patients, hopTum mutants have significantly more myeloid cells, which form invasive tumors. Through an unbiased genetic screen, we found that heterozygosity for Enhancer of Polycomb [E(Pc)], a component of the Tip60 lysine acetyltransferase complex (also known as KAT5 in humans), significantly increased tumor burden in hopTum animals. Hematopoietic depletion of E(Pc) or other Tip60 components in an otherwise wild-type background also induced blood cell tumors. The E(Pc) tumor phenotype was dependent on JAK/STAT activity, as concomitant depletion of hop or Stat92E inhibited tumor formation. Stat92E target genes were significantly upregulated in E(Pc)-mutant myeloid cells, indicating that loss of E(Pc) activates JAK/STAT signaling. Neither the hop nor Stat92E gene was upregulated upon hematopoietic E(Pc) depletion, suggesting that the regulation of the JAK/STAT pathway by E(Pc) is dependent on substrates other than histones. Indeed, E(Pc) depletion significantly increased expression of Hop protein in myeloid cells. This study indicates that E(Pc) works as a tumor suppressor by attenuating Hop protein expression and ultimately JAK/STAT signaling. Since loss-of-function mutations in the human homologs of E(Pc) and Tip60 are frequently observed in cancer, our work could lead to new treatments for MPN patients.

This article has an associated First Person interview with the first author of the paper.
Gene Annotation Easy Viewer (GAEV): Integrating KEGG’s Gene Function Annotations and Associated Molecular Pathways
Authors: Huynh Trung , Xu Sen
Published: May 2019

We developed a Gene Annotation Easy Viewer (GAEV) that integrates the gene annotation data from the KEGG (Kyoto Encyclopedia of Genes and Genomes) Automatic Annotation Server. GAEV generates an easy-to-read table that summarizes the query gene name, the KO (KEGG Orthology) number, name of gene orthologs, functional definition of the ortholog, and the functional pathways that query gene has been mapped to. Via links to KEGG pathway maps, users can directly examine the interaction between gene products involved in the same molecular pathway. We provide a usage example by annotating the newly published freshwater microcrustacean Daphnia pulex genome. This gene-centered view of gene function and pathways will greatly facilitate the genome annotation of non-model species and metagenomics data. GAEV runs on a Windows or Linux system equipped with Python 3 and provides easy accessibility to users with no prior Unix command line experience.