bluuebunny/crossref_metadata_2025 huggingface dataset:
Promoting Resilience: Breaking the Intergenerational Cycle of Adverse Childhood Experiences
Authors: Woods-Jaeger Briana A. , Cho Bridget , Sexton Chris C. , Slagel Lauren , Goggin Kathy
Published: February 2018

Adverse childhood experiences (ACEs), including trauma exposure, parent mental health problems, and family dysfunction, put children at risk for disrupted brain development and increased risk for later health problems and mortality. These negative effects may be prevented by resilience promoting environments that include protective caregiving relationships. We sought to understand (1) parents’ experiences of ACEs, (2) the perceived impact on parenting, (3) protective factors that buffer ACEs potential negative impact, and (4) supports and services that can reduce the number and severity of ACEs and promote resilience among children exposed to early adversity. We conducted in-depth qualitative interviews with 11 low-income, urban parents of young children who had experienced ACEs. Interviews were analyzed for emergent themes and shared with parents from the community to ensure relevance and proper interpretation. Themes from these interviews describe the potential intergenerational cycle of ACEs and key factors that can break that cycle, including parent aspirations to make children’s lives better and parent nurturance and support. Parents’ suggestions for intervention are also presented. Our findings illuminate protective factors and family strengths that are important to build upon when developing and implementing interventions to promote resilience among parents and children exposed to early adversity. This study benefits from highly ecologically valid data obtained from low–socioeconomic status, racial/ethnic minority parents through one-on-one in-depth interviews and interpreted with the aid of community stakeholders through a community-based participatory research approach.
Seasonal Masculinities: The Seasonal Contingencies of Doing Gender
Authors: Leap Braden
Published: February 2018

Researchers continue to stress interactions between humans and nonhuman animals, plants, and materials inform how gender is done. A number of works also emphasize gender is done differently depending on the time of day or year. However, how nonhumans and temporality dovetail to inform gender has not been considered. The author utilizes data from twenty months of fieldwork in a rural Missouri community to illustrate how men did masculinities differently in the spring, summer, fall, and winter through interactions with a range of (non)human things, beings, and institutions. These findings suggest we can better understand how gender is done by simultaneously considering (non)human interactions and temporal seasons.
Regression Discontinuity and Beyond
Authors: Wing Coady , Bello-Gomez Ricardo A.
Published: February 2018

Treatment effect estimates from a regression discontinuity design (RDD) have high internal validity. However, the arguments that support the design apply to a subpopulation that is narrower and usually different from the population of substantive interest in evaluation research. The disconnect between RDD population and the evaluation population of interest suggests that RDD evaluations lack external validity. New methodological research offer strategies for studying and sometimes improving external validity in RDDs. This article examines four techniques: comparative RDD, covariate matching RDD, treatment effect derivatives, and statistical tests for local selection bias. The goal of the article is to help evaluators understand the logic, assumptions, data requirements, and reach of the new methods.
Analytical model for flexural damping responses of CFRP cantilever beams in the low-frequency vibration
Authors: Yang Mo , Hu Yefa , Zhang Jinguang , Ding Guoping , Song Chunsheng
Published: February 2018

In this paper, an analytical model for the flexural vibration damping of Carbon Fiber Reinforced Plastics (CFRP) cantilever beams was proposed, which is based on the Lamination Theory and Euler–Bernoulli Beam Theory. By using a finite element analysis and an analytical model, four sets of specific damping capacity with different pavement schemes were predicted, and flexural vibration test and damping analysis were carried out. Comparing the analytical model, finite element analysis, and test results, it could be found that the analytical model had relatively good accuracy in predicting the first-order natural frequency and specific damping capacity of the bending vibration of CFRP beams. The maximum error of the first-order natural frequency between the analysis result and the experimental result was 7.05%; the maximum specific damping capacity error was only 5.65%. Comparing the finite element analysis method and the experiment results, the maximum error of the first-order natural frequency was 7.8%, the error of the specific damping capacity was bigger, and the [±30°]5S specimen was as high as 18.7%. However, there was a significant error when the analytical model was used to predict the second-order natural frequency and the specific damping capacity of CFRP beam’s flexural vibration.
Calculation of sound pressure level of marine propeller in low frequency
Authors: Gorji Mohsen , Ghassemi Hassan , Mohamadi Jalal
Published: February 2018

The research performed in this paper is carried out to calculate the sound pressure level of the marine propeller by Reynolds-Averaged Navier–Stokes solver in low frequencies band. Noise is generated by the induced trailing vortex wake and induced pressure pulses. The two-step Fflowcs Williams and Hawkings equations are used to calculate hydrodynamic pressure and its performance as well as sound pressure level at various points around the propeller. The directivity patterns of this propeller and accurate explanation of component propeller noise are discussed. Comparison of the numerical results shows good agreement with the experimental data.
The prisoner’s dilemma: How male prisoners experience and respond to penal threat while incarcerated
Authors: Maier Katharina H , Ricciardelli Rosemary
Published: February 2018

Drawing on interview data with 56 former prisoners in Canada, we examine how male prisoners understand, experience, and respond to threat while incarcerated. We show that prisoners face a variety of different and often competing threats, resulting from prisoner interactions (e.g. threat of physical violence for being a “snitch”) on the one side, and institutional powers and procedures on the other side (e.g. threat of delayed release from prison). These threats are competing insofar as countering a prisoner threat opens the door to threat on the institutional level (i.e. administrative uncertainties) and vice versa. As a consequence, we show how feeling threatened for prisoners becomes paramount and in many cases unavoidable as the different threats in prison are difficult, if not impossible, to handle in unison. However, in an effort to stay physically safe and work toward their release, prisoners must find viable strategies to navigate different prison environments, particularly as they move between prisons of differing security classifications. We draw on Giddens' notion of “ontological insecurity” to draw attention to prisoners' feelings of perpetual vulnerability and insecurity. In addition, we build on Luhmann's conceptualization of risk and danger to explain how male prisoners experience and respond to moments of “danger” when they are faced with competing threats and must decide how to best navigate them.
The movement to promote an ethnic language in American schools: The Korean community in the New York–New Jersey area
Authors: Min Pyong Gap
Published: February 2018

This paper examines a New York Korean immigrants’ movement to promote the Korean language in American schools. This movement includes the efforts of Korean community leaders to include the Korean language in the SAT II tests and to promote it to public schools as a foreign language in the New York–New Jersey area. This movement involves lobbying the College Board, school administrators and school board members, and collecting donations from Korean immigrants and the Korean government to cover expenses for the College Board’s creation of the Korean-language test and public schools’ adoption of the Korean language. Korean-language leaders have depended upon many different organizations and groups, such as Korean parents, Korean churches, Korean-language teachers, the Korean Cultural Center, Samsung, and Korean government agencies for the movement. This paper is significant because no previous study has shown a similar example of an immigrant group’s movement to promote its language in American public schools. It also contributes to transnational studies by documenting the emigrant state’s financial and technical support of its emigrants’ effort to promote the language and culture in a settlement country.
Differentiation of isomeric haloanilines by tosylation in combination with electrospray ionization mass spectrometry
Authors: Wang Shanshan , Cheng Yuanyuan , Chen Mengmeng , Jiang Kezhi
Published: February 2018

Differentiation of the isomeric haloanilines still remains a challenging and necessary analytic task due to their identical retention time in chromatography and similar mass spectra. In this work, p-tosylation of haloanilines by reaction of haloanilines with p-toluenesulfonyl chloride resulted in the corresponding N-tosyl haloanilines. Fragmentation of protonated N-tosyl haloanilines in electrospray ionization tandem mass spectrometry (ESI-MS/MS) mainly resulted in tosyl cation, haloaniline radical cation, and halohydroxyaniline radical cation. The MS/MS of the three group isomeric derivatives showed significant difference in abundance distribution of these product ions, respectively. Theoretical calculations showed that the stability of the ion-neutral complex (INC) is a key factor influencing the relative intensity of the product ions. The three group isomeric derivatives were also separated by high performance liquid chromatograph (HPLC) at conventional conditions. p-Tosylation combined tandem MS (or HPLC) technique were carried out to realize the differentiation of isomeric haloanilines.
Connect, Refresh, and Energize: Enabling Organizational Innovation Capacities Through Self-Determination Theory
Authors: Sipe Lori J.
Published: February 2018

The Problem

In the past decade, consumer spending on unique experiences (like vacations and concerts) relative to consumer spending on material goods (like vehicles and clothing) has increased dramatically. This has prompted renewed interest in studying the workplace practices of firms that place the co-created customer experience at the heart of their innovation efforts. In this industry context, innovation is collective, incremental, and ongoing. An updated perspective on developing and maintaining organizational capacities for continuous innovation in the experience economy is needed.

The Solution

A research-based model of organizational capacities for experience innovation is presented. The author discusses how the dimensions labeled Connect, Refresh, and Energize are consistent with key concepts of basic psychological needs and optimal motivation perspectives. This article helps make the business case for self-determination theory from the perspective of senior managers in the field.

The Stakeholders

The specific leadership practices are measurable and can be practically applied by managers and human resource development (HRD) scholar-practitioners in their own organizations.
Planting Seeds to Grow Healthy Children: Strategic Community Partnerships
Authors: Alicea-Planas Jessica , Sullivan Kelly , Tran Hang , Cruz Anna
Published: February 2018

More than one third of U.S adults are considered obese, and childhood obesity has more than doubled in the past 30 years. Food security can influence obesity, in particular, within inner cities where access to healthy food is often limited. The use of a mobile food truck program (with refrigeration) was implemented in two large inner cities in Connecticut as part of an initiative aimed at helping low-income families with young children gain access to healthy food and nutrition education. Collaborating with community child care centers was used. The experiences of the families who participated in the program were assessed via focus groups. Main ideas derived from the focus groups were participant satisfaction with money saving suggestions, ideas for how to make healthier choices, and excitement about opportunities to receive foods that they would not normally buy. This innovative mobile food truck program demonstrated the value of strategic community partnerships to influence health.
Lawmaker Age, Issue Salience, and Senior Representation in Congress
Authors: Curry James M. , Haydon Matthew R.
Published: February 2018

Political scientists have demonstrated the importance of lawmakers’ identities, showing that race, gender, socioeconomic status, and sexual orientation affect legislative and representational behavior. Is the same true for age? We argue it is, but the effect is conditioned by the salience of different “senior issues.” Analyzing the bill introductions by members of Congress during the 109th and 110th Congresses, we show that older lawmakers are more likely to introduce legislation addressing lower salience senior issues than their younger colleagues. In contrast, sizeable senior constituencies in a district influence lawmaker attention to higher salience senior issues, regardless of a lawmaker’s age. These findings have implications for our understanding of senior power and personal roots of representation in the United States.
Ultrasound-Assisted Catheter-Directed Thrombolysis for Submassive Pulmonary Embolism
Authors: Mohan Prasoon P. , Manov John J. , Contreras Francisco , Langston Michael E. , Doshi Mehul H. , Narayanan Govindarajan
Published: February 2018

Purpose:

Catheter-directed thrombolysis (CDT) is a relatively new therapy for pulmonary embolism that achieves the superior clot resolution compared to systemic thrombolysis while avoiding the high bleeding risk intrinsically associated with that therapy. In order to examine the efficacy and safety of CDT, we conducted a retrospective cohort study of patients undergoing ultrasound-assisted CDT at our institution.

Methods:

The charts of 30 consecutive patients who underwent CDT as a treatment of pulmonary embolism at our institution were reviewed. Risk factors for bleeding during thrombolysis were noted. Indicators of the right heart strain on computed tomography and echocardiogram, as well as the degree of pulmonary vascular obstruction, were recorded before and after CDT. Thirty-day mortality and occurrence of bleeding events were recorded.

Results:

Nine (30%) patients had 3 or more minor contraindications to thrombolysis and 14 (47%) had major surgery in the month prior to CDT. Right ventricular systolic pressure and vascular obstruction decreased significantly after CDT. There was a significant decrease in the proportion of patients with right ventricular dilation or hypokinesis. Decrease in pulmonary vascular obstruction was associated with nadir of fibrinogen level. No patients experienced major or moderate bleeding attributed to CDT.

Conclusion:

Catheter-directed thrombolysis is an effective therapy in rapidly alleviating the right heart strain that is associated with increased mortality and long-term morbidity in patients with pulmonary embolism with minimal bleeding risk. Catheter-directed thrombolysis is a safe alternative to systemic thrombolysis in patients with risk factors for bleeding such as prior surgery. Future studies should examine the safety of CDT in patients with contraindications to systemic thrombolysis.
Commissioning new applications on processing machines: Part II – implementation
Authors: Troll Clemens , Schebitz Benno , Majschak Jens-Peter , Döring Michael , Holowenko Olaf , Ihlenfeldt Steffen
Published: February 2018

The subject of this splitted article is the commissioning of a new application that may be part of a processing machine. At the example of the intermittent transport of small sized goods, for example, chocolate bars, ideas for increasing the maximum machine performance are discussed. Therefore, optimal process motion profiles are synthesised with the help of a computer simulation. In the first part of the paper, the modelling of the process was shown. This second part focusses on implementing the simulated motion approaches on an experimental test rig, whereby the new motion approach is compared to the conventional approach. Hence, the increasing of the performance can be proven. Eventually, possibilities for an online process control are observed which are necessary to prevent unstable process conditions.
Jordanian adolescents’ health behaviour and school climate
Authors: Nassar Omayyah , Shaheen Abeer Mohammed , Jarrah Samiha S , Norton Mary E , Khalaf Inaam A , Mohammad Hamdan Khaldoun
Published: February 2018

Aim

This study was conducted to assess the occurrence of physical activity, nutritional habits, tooth brushing and seat belt use behaviour among adolescent school students in Jordan, and to examine the effect of psychosocial aspects of school on these behaviours.

Method

A cross-sectional descriptive correlational design was used to draw a sample of in-school adolescents aged between 11 and 15 years. The final sample included 1166 adolescents from five public and two private schools. Study participants filled in a translated version of the health behaviour in school aged children questionnaire. Descriptive statistics, correlational (point biserial), and bivariate analyses (chi-square tests) were used to analyse the data.

Results

Among the study sample 34.5% of the adolescents practised exercise outside school hours once a week or less frequently, and only 53.1% of them brushed their teeth more than once a day. Regarding seat belt use, 44.7% of the adolescents used them rarely or never. Concerning carbonated sugary drinks and sweets consumption, about 64% and 83.3% of the adolescents, respectively, consumed them once a day or more often. The percentages of adolescents who never drank low fat or whole fat milk were 43.1% and 38.2%, respectively.

Conclusions

The study concluded that school adolescents do engage in unhealthy behaviour. Psychosocial aspect of schools were associated with students’ physical activity, nutritional habits, tooth brushing and seat belt use behaviours.
Addressing a region? The Arab imagined audience and newsworthiness in the production of Al Jazeera Arabic
Authors: Matthews Julian , Al Habsi Maiya
Published: February 2018

Based on a production study of Al Jazeera Arabic, this article examines news professionals’ visualisation of the Arab news audience and its importance for their ideas about newsworthiness and an ideal news agenda. In applying the concept of the imagined audience to Al Jazeera, it uncovers a view of Arab news consumers as constructed as (i) heterogeneous in character and origin and as sharing (ii) a ‘mindset’ and an experience of (iii) voicelessness. Further, it shows that these understandings help to grasp the specifics of journalists’ news-making practices, including their efforts to prioritize potential stories for an ideal news agenda that demonstrate relevance for, or interest to, these imagined news consumers in addition to those stories that address their perceived ‘powerlessness’ in the Arab region. The article concludes that these ideas mark clear boundaries around the countries and the issues that Al Jazzera seeks to report on.
The language of digital constitutionalism and the role of national parliaments
Authors: Santaniello Mauro , Palladino Nicola , Catone Maria Carmela , Diana Paolo
Published: February 2018

Attempts to establish constitutional provisions for the Internet have been promoted since the late 1990s, mainly by the global civil society and intergovernmental organisations. More recently, a new wave of digital constitutionalism has emerged from the nation-state level, and particularly from national parliaments. In order to better understand this process, the article seeks to investigate, from both a theoretical and an empirical perspective, whether and to what extent parliamentary initiatives exhibit specific political features compared to constitutional attempts emerging from other kinds of sources. Further, the study aims to assess if drafting initiatives overlap or, rather, respond in different ways to different constitutional concerns.
Synthesis and substrate properties towards HIV-1 reverse transcriptase of new diphosphate analogues of 9-[(2-phosphonomethoxy)ethyl]adenine
Authors: Laux Wolfgang HG , Priet Stéphane , Alvarez Karine , Peyrottes Suzanne , Périgaud Christian
Published: February 2018

Background

The replacement of β,γ-pyrophosphate by β,γ-phosphonate moieties within the triphosphate chain of 5′-triphosphate nucleoside analogues was previously studied for various antiviral nucleoside analogues such as AZT and 2′,3′-dideoxynucleosides. Thus, it has been shown that these chemical modifications could preserve, in some cases, the terminating substrate properties of the triphosphate analogue for HIV-RT. Herein, we aimed to study such 5′-triphosphate mimics based on the scaffold of the well-known antiviral agent 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA, Adefovir).

Methods

Synthesis involved coupling of a morpholidate derivative of PMEA with appropriate pyrophosphoryl analogues. The relative efficiencies of incorporation of the studied diphosphate phosphonates were measured using subtype B WT HIV-1 RT in an in vitro susceptibility assay, in comparison to the parent nucleotide analogue (PMEApp).

Results

Searching for nucleoside 5′-triphosphate mimics, we have synthesized and studied a series of diphosphate analogues of PMEA bearing non hydrolysable bonds between the and phosphorus atoms. We also examined their relative inhibitory capacity towards HIV-1 reverse transcriptase in comparison to the parent nucleotide analogue (PMEApp). Only one of them appeared as a weak inhibitor (IC50 = 403.0 ± 75.5 µM) and proved to be less effective than PMEApp (IC50 = 6.4 ± 0.8 µM).

Conclusion

PMEA diphosphoryl derivatives were designed as potential substrates and/or inhibitors of various viral polymerases. These modifications dramatically affect their ability to inhibit HIV-RT.
Line-Drawn Scenes Provide Sufficient Information for Discrimination of Threat and Mere Negativity
Authors: Boshyan Jasmine , Feldman Barrett Lisa , Betz Nicole , Adams Reginald B. , Kveraga Kestutis
Published: February 2018

Previous work using color photographic scenes has shown that human observers are keenly sensitive to different types of threatening and negative stimuli and reliably classify them by the presence, and spatial and temporal directions of threat. To test whether such distinctions can be extracted from impoverished visual information, we used 500 line drawings made by hand-tracing the original set of photographic scenes. Sixty participants rated the scenes on spatial and temporal dimensions of threat. Based on these ratings, trend analysis revealed five scene categories that were comparable to those identified for the matching color photographic scenes. Another 61 participants were randomly assigned to rate the valence or arousal evoked by the line drawings. The line drawings perceived to be the most negative were also perceived to be the most arousing, replicating the finding for color photographic scenes. We demonstrate here that humans are very sensitive to the spatial and temporal directions of threat even when they must extract this information from simple line drawings, and rate the line drawings very similarly to matched color photographs. The set of 500 hand-traced line-drawing scenes has been made freely available to the research community: http://www.kveragalab.org/threat.html .
You have got a (different) friend in me: Asymmetrical roles in gaming as potential ambassadors of computational and cooperative thinking
Authors: Gandolfi Enrico
Published: February 2018

This article aims to enlighten how individuals apply and develop cooperative and computational thinking in online collaborative challenges, and what ludic features support or discourage such approaches. Over n = 1400 subjects have been involved with a quantitative survey about three collaboration-based video games – i.e. Overwatch, For Honor, and Tom Clancy’s Rainbow Six: Siege. Results point to malleable factors in strengthening teamwork – i.e. asymmetrical roles, sharing information mechanics, broad game community – and provide empirical evidence of the correlation between cooperative and computational thinking. Implications for educational activities and cooperative learning interventions are outlined in terms of design strategies and concrete applications.
Accelerated collagen turnover in women with angina pectoris without obstructive coronary artery disease: An iPOWER substudy
Authors: Nielsen Signe H , Mygind Naja D , Michelsen Marie M , Bechsgaard Daria F , Suhrs Hannah E , Genovese Federica , Nielsen Henning B , Brix Susanne , Karsdal Morten , Prescott Eva , Kastrup Jens
Published: February 2018

Aim

Collagens are major cardiac extracellular matrix components, known to be actively remodelled and accumulated during diffuse myocardial fibrosis. We evaluated whether accelerated collagen turnover described by neo-epitope biomarkers reflecting collagen formation and degradation separates patients with diffuse myocardial fibrosis from asymptomatic controls.

Methods and results

Seventy-one women with angina pectoris without significant coronary artery disease assessed by invasive coronary angiogram were included. Competitive enzyme-linked immunosorbent assays (ELISAs) measuring circulating protein fragments in serum assessed the formation and degradation of collagen type III (Pro-C3, C3M and C3C), IV (P4NP7S and C4M), V (Pro-C5 and C5M) and VI (Pro-C6 and C6M), and degradation of collagen type I (C1M). Serum samples from 32 age-matched asymptomatic women were included as controls. Symptomatic women presented significantly elevated levels of Pro-C6, C3C, C3M, C4M and C8-C ( p < 0.0001–0.0058) and significantly decreased levels of Pro-C3, C5M and C6M ( p < 0.0001–0.041), reflecting accelerated collagen turnover and an imbalanced collagen formation and degradation compared to controls. Cardiac magnetic resonance T1 mapping was performed to determine extracellular volume fraction and thus diffuse myocardial fibrosis. A significant association was identified between C5M and extracellular volume fraction by cardiac magnetic resonance ( p = 0.01).

Conclusion

Women with angina pectoris, but without significant obstructive coronary artery disease, showed an imbalanced collagen turnover compared to asymptomatic controls. The examined biomarkers are tools to monitor active collagen remodelling in patients with angina pectoris, in risk of developing myocardial fibrosis.
Chinese Post80s Generational Resilience: Chengyu (成语) as Communicative Resources for Adaptation and Change
Authors: Long Ziyu , Buzzanell Patrice M. , Kuang Kai
Published: February 2018

The combined forces of China’s reforms, resurgent traditional values, and problematic labor market have led the Chinese Post80s generation to reconstruct their careers. Drawing on 33 in-depth interviews, this study examines how Post80s professionals communicatively constitute resilience as they utilize and transform meanings of chengyu (成语, Chinese four-word idiom encapsulating shared values). Guided by chengyu, Post80s construct resilience processes from temporal (past-present-future), relational (self-other-collective), and introspective perspectives (passion-practice). As discursive cultural resources of resilience, chengyu legitimize choices, frame actions, inspire ways of managing change and expectations, and offer comfort in difficult times. This study expands resilience research to a non-Western context and highlights how cultural and generational discourses can mobilize agency in the constitution of resilience. Findings offer practical implications in promoting and cultivating resilience.
A Relational Approach to Peacebuilding in the Korean Peninsula
Authors: Schluter Michael , Ive Jeremy
Published: February 2018

For North and South Korea to come together in partnership or as one nation will require a shared vision acceptable to both societies. Prioritizing harmony and proximity in personal and organizational relationships across society and the economy can provide a framework that is in keeping with Korea’s social traditions, as well as with biblical social design. A “Track Two” process for building consensus based on a relational framework through a program of consultations contributed to ending apartheid in South Africa and ending civil war in Sudan. Such an approach could now be applied in the Korean Peninsula.
Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI
Authors: Montague Samantha J. , Delierneux Céline , Lecut Christelle , Layios Nathalie , Dinsdale Robert J. , Lee Christine S.-M. , Poulter Natalie S. , Andrews Robert K. , Hampson Peter , Wearn Christopher M. , Maes Nathalie , Bishop Jonathan , Bamford Amy , Gardiner Chris , Lee Woei Ming , Iqbal Tariq , Moiemen Naiem , Watson Steve P. , Oury Cécile , Harrison Paul , Gardiner Elizabeth E.
Published: February 2018

Key Points

Soluble GPVI is elevated in patients with thermal injury with sepsis, and sGPVI levels augment severity score prediction of mortality. The GPVI ligand, fibrin, induces GPVI shedding without requirement for platelet activation or signaling
The immunoglobulin heavy chain 3′ regulatory region superenhancer controls mouse B1 B-cell fate and late VDJ repertoire diversity
Authors: Ghazzaui Nour , Issaoui Hussein , Saintamand Alexis , Oblet Christelle , Carrion Claire , Denizot Yves
Published: February 2018

Key Points

Similar to B2 B cells, the IgH 3′RR superenhancer controls μ-chain transcription and cell fate in B1 B cells. In contrast to B2 B cells, deletion of the IgH 3′RR superenhancer affects B1 B-cell late repertoire diversity.
Multiple-therapy-resistant major depressive disorder: a clinically important concept
Authors: McAllister-Williams R. H. , Christmas D. M. B. , Cleare A. J. , Currie A. , Gledhill J. , Insole L. , Malizia A. L. , McGeever M. , Morriss R. , Robinson L. J. , Scott M. , Stokes P. R. A. , Talbot P. S. , Young A. H.
Published: February 2018

Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such ‘non-standard’ interventions. This analysis proposes a framework to aid this decision.

Declaration of interest

In the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.

In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.
Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors
Authors: Luke Jason J. , Lemons Jeffrey M. , Karrison Theodore G. , Pitroda Sean P. , Melotek James M. , Zha Yuanyuan , Al-Hallaq Hania A. , Arina Ainhoa , Khodarev Nikolai N. , Janisch Linda , Chang Paul , Patel Jyoti D. , Fleming Gini F. , Moroney John , Sharma Manish R. , White Julia R. , Ratain Mark J. , Gajewski Thomas F. , Weichselbaum Ralph R. , Chmura Steven J.
Published: February 2018

Purpose

Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1–treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors.

Patients and Methods

Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-γ–induced gene expression.

Results

A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-γ–associated genes from post–SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response.

Conclusion

Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1–directed immunotherapy are warranted.
Genomic Profiling of T-Cell Neoplasms Reveals Frequent JAK1 and JAK3 Mutations With Clonal Evasion From Targeted Therapies
Authors: Greenplate Allison , Wang Kai , Tripathi Rati M. , Palma Norma , Ali Siraj M. , Stephens Phil J. , Miller Vincent A. , Shyr Yu , Guo Yan , Reddy Nishitha M. , Kozhaya Lina , Unutmaz Derya , Chen Xueyan , Irish Jonathan M. , Davé Utpal P.
Published: February 2018

Purpose

The promise of precision oncology is that identification of genomic alterations will direct the rational use of molecularly targeted therapy. This approach is particularly applicable to neoplasms that are resistant to standard cytotoxic chemotherapy, like T-cell leukemias and lymphomas. In this study, we tested the feasibility of targeted next-generation sequencing in profiles of diverse T-cell neoplasms and focused on the therapeutic utility of targeting activated JAK1 and JAK3 in an index case.

Patients and Methods

Using Foundation One and Foundation One Heme assays, we performed genomic profiling on 91 consecutive T-cell neoplasms for alterations in 405 genes. The samples were sequenced to high uniform coverage with an Illumina HiSeq and averaged a coverage depth of greater than 500× for DNA and more than 8M total pairs for RNA. An index case of T-cell prolymphocytic leukemia (T-PLL), which was analyzed by targeted next-generation sequencing, is presented. T-PLL cells were analyzed by RNA-seq, in vitro drug testing, mass cytometry, and phospho-flow.

Results

One third of the samples had genomic aberrations in the JAK-STAT pathway, most often composed of JAK1 and JAK3 gain-of-function mutations. We present an index case of a patient with T-PLL with a clonal JAK1 V658F mutation that responded to ruxolitinib therapy. After relapse developed, an expanded clone that harbored mutant JAK3 M511I and downregulation of the phosphatase, CD45, was identified. We demonstrate that the JAK missense mutations were activating, caused pathway hyperactivation, and conferred cytokine hypersensitivity.

Conclusion

These results underscore the utility of profiling occurrences of resistance to standard regimens and support JAK enzymes as rational therapeutic targets for T-cell leukemias and lymphomas.
Hypoxic-Ischemic Encephalopathy and Other Neonatal Encephalopathies
Authors: Glass Hannah C.
Published: February 2018

PURPOSE OF REVIEW

Neonatal encephalopathy is the most common condition in neonates encountered by child neurologists. The etiology is most often global hypoxia-ischemia due to failure of cerebral perfusion to the fetus caused by uterine, placental, or umbilical cord compromise prior to or during delivery. Other etiologies of neonatal encephalopathy include ischemic stroke and intracranial hemorrhage, infection, developmental anomalies, and inborn errors of metabolism.

RECENT FINDINGS

Therapeutic hypothermia is standard of care for the treatment of neonatal encephalopathy presumed to be caused by hypoxia-ischemia. The number needed to treat is approximately 6 to 7 to prevent one child from either death or disability at age 18 to 22 months. EEG monitoring and MRI are important tools in determining the etiology of encephalopathy and prognosis of the infant.

Neonatal encephalopathy is a heterogeneous disorder that is characterized by alterations in mental status, hypotonia, seizures, and abnormalities in feeding and respiration. The most common cause of neonatal encephalopathy is hypoxic-ischemic encephalopathy, for which treatment with 72 hours of therapeutic hypothermia is associated with reduced death or disability.
Nervous System Malformations
Authors: Gaitanis John , Tarui Tomo
Published: February 2018

PURPOSE OF REVIEW

This article provides an overview of the most common nervous system malformations and serves as a reference for the latest advances in diagnosis and treatment.

RECENT FINDINGS

Major advances have occurred in recognizing the genetic basis of nervous system malformations. Environmental causes of nervous system malformations, such as perinatal infections including Zika virus, are also reviewed. Treatment for nervous system malformations begins prior to birth with prevention. Folic acid supplementation reduces the risk of neural tube defects and is an important part of health maintenance for pregnant women. Fetal surgery is now available for prenatal repair of myelomeningocele and has been demonstrated to improve outcomes.

Each type of nervous system malformation is relatively uncommon, but, collectively, they constitute a large population of neurologic patients. The diagnosis of nervous system malformations begins with radiographic characterization. Genetic studies, including chromosomal microarray, targeted gene sequencing, and next-generation sequencing, are increasingly important aspects of the assessment. A genetic diagnosis may identify an associated medical condition and is necessary for family planning. Treatment consists primarily of supportive therapies for developmental delays and epilepsy, but prenatal surgery for myelomeningocele offers a glimpse of future possibilities. Prognosis depends on multiple clinical factors, including the examination findings, imaging characteristics, and genetic results. Treatment is best conducted in a multidisciplinary setting with neurology, neurosurgery, developmental pediatrics, and genetics working together as a comprehensive team.
Neurocutaneous Disorders
Authors: Rosser Tena
Published: February 2018

PURPOSE OF REVIEW

This article presents an up-to-date summary of the genetic etiology, diagnostic criteria, clinical features, and current management recommendations for the most common neurocutaneous disorders encountered in clinical adult and pediatric neurology practices.

RECENT FINDINGS

The phakomatoses are a phenotypically and genetically diverse group of multisystem disorders that primarily affect the skin and central nervous system. A greater understanding of the genetic and biological underpinnings of numerous neurocutaneous disorders has led to better clinical characterization, more refined diagnostic criteria, and improved treatments in neurofibromatosis type 1, Legius syndrome, neurofibromatosis type 2, Noonan syndrome with multiple lentigines, tuberous sclerosis complex, Sturge-Weber syndrome, and incontinentia pigmenti.

Neurologists require a basic knowledge of and familiarity with a wide variety of neurocutaneous disorders because of the frequent involvement of the central and peripheral nervous systems. A simple routine skin examination can often open a broad differential diagnosis and lead to improved patient care.
Epilepsy Syndromes in Childhood
Authors: Pearl Phillip L.
Published: February 2018

PURPOSE OF REVIEW

Epilepsy syndromes are an important clinical construct in pediatric epilepsy, as they encompass recognizable patterns seen in patients with epilepsies, whether of the more benign variety or associated with encephalopathy.

RECENT FINDINGS

Syndromes may be organized by age of onset: neonatal, infantile, childhood, or adolescent. The assignment of a syndrome has specific implications for diagnosis, management, and prognostication. The 2010 revised classification of the epilepsies by the International League Against Epilepsy preserved the syndrome approach, while progress in genetics continues to advance our understanding of the pathophysiology and overlap of the epilepsy syndromes.

Given that mutations of the same gene may cause both encephalopathic and relatively benign epilepsies, an understanding of the pediatric epilepsy syndromes remains vital to patient care.
Calcium signaling mediates five types of cell morphological changes to form neural rosettes
Authors: Hříbková Hana , Grabiec Marta , Klemová Dobromila , Slaninová Iva , Sun Yuh-Man
Published: February 2018

Neural rosette formation is a critical morphogenetic process during neural development, whereby neural stem cells are enclosed in rosette niches to equipoise proliferation and differentiation. How neural rosettes form and provide a regulatory micro-environment remains to be elucidated. We employed the human embryonic stem cell-based neural rosette system to investigate the structural development and function of neural rosettes. Our study shows that neural rosette formation consists of five types of morphological change: intercalation, constriction, polarization, elongation and lumen formation. Ca2+ signaling plays a pivotal role in the five steps by regulating the actions of the cytoskeletal complexes, actin, myosin II and tubulin during intercalation, constriction and elongation. These, in turn, control the polarizing elements, ZO-1, PARD3 and β-catenin during polarization and lumen production for neural rosette formation. We further demonstrate that the dismantlement of neural rosettes, mediated by the destruction of cytoskeletal elements, promotes neurogenesis and astrogenesis prematurely, indicating that an intact rosette structure is essential for orderly neural development.
Changes in Cycling and Incidence of Overweight and Obesity among Danish Men and Women
Authors: RASMUSSEN MARTIN GILLIES , OVERVAD KIM , TJØNNELAND ANNE , JENSEN MAJKEN K. , ØSTERGAARD LARS , GRØNTVED ANDERS
Published: February 2018

Purpose

Overweight and obesity are associated with increased risk of several noncommunicable diseases and are a growing public health issue. The primary purpose of the current study was to investigate incidence of overweight and obesity according to 5-yr cycling habits. The secondary purpose was to investigate incidence of remission from overweight and obesity according to 5-yr cycling habits.

Methods

We analyzed 9014 men and 8661 women without chronic disease who between 1993 and 2003 completed two assessments approximately 5 yr apart. At both assessments, participants reported habitual cycling habits. Also, body weight and waist circumference were measured by a laboratory technician at baseline and self-assessed at second examination. We computed multivariable adjusted odds ratios (OR) with 95% confidence intervals (CI) for development of and remission from abdominal and general overweight and obesity, according to 5-yr cycling habits.

Results

Continued cycling was associated with lower odds for incidence of abdominal (men, >102 cm; women, >88 cm) and incidence of general (body mass index ≥30 kg·m−2) obesity; compared with no cycling, OR (95% CI) values were 0.82 (0.74–0.91) and 0.74 (0.60–0.92) for abdominal and general obesity, respectively. Also, those who initiated cycling had lower odds for incidence of abdominal obesity; OR (95% CI) was 0.85 (0.73–1.00) relative to no cycling. Although we found no evidence of remission from abdominal and general overweight and obesity according to 5-yr cycling habits, those who continued cycling had significantly larger decreases in waist circumference relative to noncyclists (β coefficient (95% CI), −0.95 cm (−1.56 to −0.33 cm)).

Conclusions

Continued cycling compared with no cycling was associated with lower odds for abdominal and general obesity. Also, late-in-life initiation of cycling was associated with lower odds for abdominal obesity relative to no cycling.
Targeting tumour hypoxia: shifting focus from oxygen supply to demand
Authors: Coates James T , Skwarski Michael , Higgins Geoff S
Published: February 2018

Tumour hypoxia is a well-recognised barrier to anti-cancer therapy and represents one of the best validated targets in oncology. Previous attempts to tackle hypoxia have focussed primarily on increasing tumour oxygen supply; however, clinical studies using this approach have yielded only modest clinical benefit, with often significant toxicity and practical limitations. Therefore, there are currently no anti-hypoxia treatments in widespread clinical use. As an emerging alternative strategy, we discuss the relevance of inhibiting tumour oxygen metabolism to alleviate hypoxia and highlight recently initiated clinical trials using this approach.
Typification and reestablishment of the Linnaean name Dalechampiacolorata (Euphorbiaceae)
Authors: Pereira-Silva Rafaela Alves , Athiê-Souza Sarah Maria , Armbruster W. Scott , de Melo André Laurênio , de Salesi Margareth Ferreira
Published: February 2018

Revisionary studies of Dalechampia sect. Dalechampia have revealed the need to lectotypify D. colorata and that it represents a distinct species rather than a synonym of D. tiliifolia. Dalechampia karsteniana is interpreted to be a synonym of D. colorata.