bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining Australia: The Activities of Four Examiners of the Associated Board for the Royal Schools of Music in 1923
Authors: Southcott Jane
Published: May 2017

In the mid-nineteenth century, a system of music examinations was initiated in Britain that came to encompass the far-flung reaches of the British Empire. These examinations offered an internationally recognized system of professional and musical standards. For the next several decades the Associated Board of the Royal Schools of Music (ABRSM) and Trinity College London (TCL) maintained this extensive system of graded instrumental and vocal examinations across large parts of the globe, principally those countries that were part of the British Empire (later the Commonwealth). Both the ABRSM and TCL continued examining for many years and this article discusses the work of four examiners appointed by the ABRSM to travel throughout the Empire, with a particular focus on Australia. The year selected is 1923. This is for several reasons. By 1923 the system of traveling expert examiners undertaking examinations across the country was well established; the vicissitudes and hardships of World War I and the influenza pandemic had passed; the practice of examiners traveling long distances by boat and train had resumed. At this time the British examinations were at their height despite the establishment of a rival Australian system, the Australian Music Examinations Board. The examiners not only undertook all the examinations across the country but also were influential public figures who spoke about music education and modern music in Britain. They gave concerts and public lectures and their activities were influential because of repeated reporting in the popular press. As a historian I am interested in the history of the commonplace—those well-established and pervasive activities that are taken for granted. Learning a musical instrument and taking annual graded practical and theoretical examinations was and continues to be a commonplace occurrence in Australia.
Effectiveness of Telementoring in Surgery Compared With On-site Mentoring: A Systematic Review
Authors: Bilgic Elif , Turkdogan Sena , Watanabe Yusuke , Madani Amin , Landry Tara , Lavigne Daniel , Feldman Liane S. , Vassiliou Melina C.
Published: May 2017

Background. Mentorship is important but may not be feasible for distance learning. To bridge this gap, telementoring has emerged. The purpose of this systematic review was to evaluate the effectiveness of telementoring compared with on-site mentoring. Methods. A search was done up to March 2015. Studies were included if they used telementoring between surgeons during a clinical encounter and if they compared on-site mentoring and telementoring. Results. A total of 11 studies were included. All reported no difference in complication rates, and 9 (82%) reported similar operative times; 4 (36%) reported technical issues, which was 3% of the total number of cases in the 11 studies. No study reported on higher levels of evidence for effectiveness of telementoring as an educational intervention. Conclusion. Studies reported that telementoring is associated with similar complication rates and operative times compared with on-site mentoring. However, the level of evidence to support the effectiveness of telementoring as a training tool is limited. There is a need for studies that provide evidence for the equivalence of the effectiveness of telementoring as an educational intervention in comparison with on-site mentoring.
Physicians’ perceptions towards brand medicine and its effect on prescribing: A narrative review
Authors: Murshid Mohsen Ali , Mohaidin Zurina
Published: May 2017

Objective

The purpose of this paper is to examine existing literature on physicians’ perceptions towards brand medicines, to examine the extent to which brands influence drug prescription and whether pharmaceutical industry influences the prescription of brands, as well as to examine the loyalty of physicians to a brand when prescribing drugs or willingness to switch to generic drugs.

Methods

Related articles published in different online databases from 2000 to 2017 were surveyed; 38 scientific articles indexed in Google Scholar, Science Direct, and PubMed were selected for review. Articles focused on physicians’ perceptions towards brand drugs and its effect on prescribing were extracted. The experimental design and quantitative and qualitative methods used in the studies were analyzed. The deductions made in each study were examined in tandem with the objective of the review.

Findings

The studies showed that physicians from high-income countries are inclined to prescribe generic drugs more than brand, whereas those from low-income countries heavily prescribe the brand drugs. The studies also revealed that brand influences the prescribing behavior of physicians. Five studies reported that marketing endeavors encourage the physicians to prescribe brand medicines, while three studies stated that physicians have a high loyalty toward brand medicines irrespective of country’s income. Other studies provided evidence that physicians are disposed to switching from brand to generic medicines under certain conditions. Marked differences in the prescribing generic drugs use by physicians among different age were observed. General physicians and pediatrics were more likely to suggest switching from the brand to generic drugs. The majority of physicians were familiar with biosimilars drugs.

Conclusion

Generally, the studies showed that physicians tend to have mixed views regarding prescribing brand medicines. The perceptions of physicians towards the brand drugs were found to differ in relation to the nature of healthcare system and level of development.
A review of research on professional learning communities in mainland China (2006–2015)
Authors: Qiao Xuefeng , Yu Shulin , Zhang Limin
Published: May 2017

In the last decade, there has been growing interest in professional learning communities (PLCs) outside mainstream Western contexts. In this paper, we provide a narrative synthesis of empirical studies of PLCs in kindergarten to 12th grade educational systems in mainland China published between 2006 and 2015. The review reveals five major emerging themes in the published literature: PLC characteristics; PLC practices in different regions; teacher collaboration in PLCs; the roles of university researchers; and educational leadership in PLCs. Significant progress has been identified in the enhancement of social harmony in teaching research groups, structural teacher collaboration, the construction of transregional PLCs and the complex roles of university researchers and school leaders. However, compared with the literature on PLCs in Western contexts, research on these communities in mainland China is still far from mature. The authors highlight the need for more empirically solid research on the development of sustainable PLCs in mainland China.
The Interpersonal Functions of Empathy: A Relational Perspective
Authors: Main Alexandra , Walle Eric A. , Kho Carmen , Halpern Jodi
Published: May 2017

Empathy is an extensively studied construct, but operationalization of effective empathy is routinely debated in popular culture, theory, and empirical research. This article offers a process-focused approach emphasizing the relational functions of empathy in interpersonal contexts. We argue that this perspective offers advantages over more traditional conceptualizations that focus on primarily intrapsychic features (i.e., within the individual). Our aim is to enrich current conceptualizations and empirical approaches to the study of empathy by drawing on psychological, philosophical, medical, linguistic, and anthropological perspectives. In doing so, we highlight the various functions of empathy in social interaction, underscore some underemphasized components in empirical studies of empathy, and make recommendations for future research on this important area in the study of emotion.
Cross-cultural adaptation and psychometric properties of the Nigerian (IGBO) version of the Disabilities of the Arm, Shoulder and Hand questionnaire (I-DASH)
Authors: Ibikunle PO , Odole AC , Akosile CO , Ezeakunne AC
Published: May 2017

Introduction

The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire is a self-administered region-specific outcome questionnaire developed to measure upper extremity disability and symptoms. The aim of this study was to translate, culturally adapt and validate the Igbo version of the DASH in order to enhance its use in the Igbo-speaking population.

Method

This cross-sectional survey involved 100 participants (56 males, 44 females) with upper extremity musculoskeletal disorders, in the South-Eastern part of Nigeria. Participants completed both English and Igbo versions of the DASH on two occasions. Internal consistency was evaluated with Cronbach’s alpha. Test–retest reliability was analysed by intraclass coefficient (ICC) and the Bland and Altman method. Construct validity was investigated with the Spearman rank correlation coefficient, and a principal component analysis was performed. Alpha was set at 0.05.

Results

Test–retest reliability was excellent (ICC = 0.99). The Cronbach’s alpha coefficient was high (0.979) for the entire items on the scale. There was a significant strong correlation (r = 0.994; p = 0.001) between the scores obtained on the English and Igbo versions of the DASH indicating excellent construct validity. Thirty linear components were identified within the data set. The communalities were above 0.4.

Conclusion

Principal component analysis of the Igbo DASH revealed a two-factor structure, having fulfilled all necessary conditions. The Igbo version of the DASH questionnaire is a valid and reliable outcome measure for individuals with upper extremity musculoskeletal disabilities.
Alternative Routes for a Proposed Nigerian Superhighway to Limit Damage to Rare Ecosystems and Wildlife
Authors: Mahmoud Mahmoud I. , Sloan Sean , Campbell Mason J. , Alamgir Mohammed , Imong Inaoyom , Odigha Odigha , Chapman Hazel M. , Dunn Andrew , Laurance William F.
Published: May 2017

The Cross River State Government in Nigeria is proposing to construct a “Cross River Superhighway” that would bisect critical remaining areas of tropical rainforest in south eastern Nigeria. We offer and evaluate two alternative routes to the superhighway that would be less damaging to forests, protected areas, and biological diversity. The first alternative we identified avoids intact forests entirely while seeking to benefit agriculture and existing settlements. The second alternative also avoids intact forests while incorporating existing paved and unpaved roads to limit construction costs. As currently proposed, the superhighway would be 260 km long, would intersect 115 km of intact forests or protected areas, and would cost an estimated ∼US$2.5 billion to construct. Alternative Routes 1 and 2 are only slightly longer (∼290 and ∼353 km, respectively) and have markedly lower estimated construction costs (∼US$0.92 billion). Furthermore, the alternative routes would have negligible impacts on forests and protected areas and would be better aligned to benefit local communities and agriculture. We argue that alternative routings such as those we examined here could markedly reduce the economic and environmental costs, and potentially increase the socioeconomic benefits, for the proposed Cross River Superhighway.
Monitoring Pressure Augmentation in Patients With Ischemic Penumbra Using Continuous Electroencephalogram: Three Cases and a Review of the Literature
Authors: Newey Christopher R. , Gupta Vikas , Ardelt Agnieszka A.
Published: May 2017

Background:

Continuous electroencephalography (CEEG) is a sensitive, noninvasive surrogate monitor of cerebral blood flow (CBF). Changes in CBF can be seen as changes in the frequencies on the CEEG. This case series suggests that increase in CEEG frequencies may be used to detect improved CBF following pressure augmentation such as with treatment of vasospasm from subarachnoid hemorrhage (SAH) or acute thrombosis from ischemic stroke. The application of this observation to clinical decision-making has not been clearly defined and requires further study.

Methods:

Case series and imaging.

Results:

We present 3 patients with ischemic penumbras either from vasospasm from SAH or thrombosis from acute ischemic stroke. All patients were monitored on CEEG and found to have lateralized slowing. During pressure augmentation, the lateralized slowing improved in frequency, which corresponded with improvement in the patients’ neurological examinations.

Conclusion:

Continuous electroencephalography may be used as a noninvasive monitor to allow for individualization of pressure augmentation in cases of vasospasm from SAH or in cases of acute ischemic strokes. This customized approach may allow for less morbidity associated with pressure augmentation in patients who otherwise may have dysfunction of their intracerebral autoregulation.
Using Care Bundles to Improve Surgical Outcomes and Reduce Variation in Care for Fragility Hip Fracture Patients
Authors: Bandara Stephanie , Lynch Genni , Cooke Cameron , Varghese Paul , Ward Nicola
Published: May 2017

Introduction:

Fragility hip fractures constitute a large proportion of orthogeriatric admissions to orthopedic wards. This study looked at reducing variation in care in fragility hip fracture patients using a novel approach with care bundles. The care bundle comprises 5 elements targeted at providing adequate analgesia, early mobilization, improving recognition of delirium, and decreasing rates of urinary infections.

Methods:

A total of 198 patients who sustained a fragility hip fracture during the intervention period were included in the study. The primary outcome measure was compliance in applying the bundle to the study population, and secondary outcome measures were in-hospital mortality, acute length of stay, delirium and duration of delirium, and urinary tract infections.

Results:

During the 12-month intervention period, compliance to the bundle of care was 47% (n = 92) based on the “all-or-none” approach. This was 28% higher than the preintervention rate. Overall, there was an increased rate of compliance across all individual elements of the bundle in the intervention group when compared to the preintervention group ( P = .01). The most significant clinical result was a 10.5% reduction in “in-hospital mortality” in the intervention group ( P < .001).

Conclusion:

This study demonstrated that the implementation of specific care bundle in patients with fragility hip fracture significantly reduces variation in care.
Efficacy of Paraprofessional-Implemented Video Prompting to Teach Vocational Skills to Students With Autism Spectrum Disorder
Authors: Seaman Rachel L. , Cannella-Malone Helen I. , Brock Matthew E. , Dueker Scott A.
Published: May 2017

Researchers have previously shown that video prompting can promote vocational skill acquisition for students with autism, and in a prior study, we demonstrated a model to train a paraprofessional to implement this practice. In this study, we evaluated (a) the degree to which the paraprofessional generalized implementation to new students and situations, and (b) the degree to which his implementation resulted in participants acquiring a vocational skill. The paraprofessional implemented the video prompting procedure with high fidelity without any additional training, and all three participants mastered the photocopying skill and generalized their implementation. These results suggest that focused coaching on video prompting implementation with one student may enable paraprofessionals to effectively generalize implementation when targeting similar skills with other students.
Establishment of Lawyers’ Academy to Promote Legal Education— The Need of the Day
Authors: Mohanty Madhubrata
Published: May 2017

The imparting of legal education has passed through a number of phases throughout its development, but it is still in need of more promotion regarding its various perspectives. People from different strata of the society still consider the legal profession as a last resort, sometimes due to lack of awareness and sometimes due to lack of proper education. The poor performance of the institutions imparting legal education can also be considered as an additional factor to this issue. At such a juncture, it is high time to establish such an institution that would work for the promotion of legal education as well as to train the budding lawyers of the country regarding the sanctity of legal profession so as to make this profession the most alluring one amongst the law graduates. Only establishment of a lawyers’ academy will not suffice; it should get the patronization of senior advocates, judges and academicians of high repute. ‘Law’ has always acquired a distinct position in the mythology and history of Indian culture, be in one form or other, and people have often been punished for ignorance of law. Still no remarkable development has been made in the imparting of legal education, and now it is high time to think of the matter seriously, and instead of promoting for legal process outsourcing by our legal professionals for foreign countries, let more and more opportunities be created by our own country to accommodate these professionals to serve our own country.
Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth
Authors: Michael James V. , Wurtzel Jeremy G. T. , Mao Guang Fen , Rao A. Koneti , Kolpakov Mikhail A. , Sabri Abdelkarim , Hoffman Nicholas E. , Rajan Sudarsan , Tomar Dhanendra , Madesh Muniswamy , Nieman Marvin T. , Yu Johnny , Edelstein Leonard C. , Rowley Jesse W. , Weyrich Andrew S. , Goldfinger Lawrence E.
Published: May 2017

Key Points

Platelet MPs infiltrate solid tumors and transfer platelet-derived miRNAs to tumor cells within solid tumors in vivo. Transfer of platelet miRNAs to tumor cells results in downregulation of tumor cell genes and inhibition of solid tumor growth.
CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies
Authors: Al Sayed Mohamad F. , Ruckstuhl Carla A. , Hilmenyuk Tamara , Claus Christina , Bourquin Jean-Pierre , Bornhauser Beat C. , Radpour Ramin , Riether Carsten , Ochsenbein Adrian F.
Published: May 2017

Key Points

CD27 expression on malignant B cells triggers CD70 reverse signaling in NK cells and improves lymphoma immunosurveillance. CD70 reverse signaling in NK cells is mediated via the AKT signaling pathway and enhances survival and effector function.
JAK2 inhibitors for myeloproliferative neoplasms: what is next?
Authors: Bose Prithviraj , Verstovsek Srdan
Published: May 2017

Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.
Incidence of non-pulmonary cancer and lung cancer by amount of emphysema and airway wall thickness: a community-based cohort
Authors: Aamli Gagnat Ane , Gjerdevik Miriam , Gallefoss Frode , Coxson Harvey O. , Gulsvik Amund , Bakke Per
Published: May 2017

There is limited knowledge about the prognostic value of quantitative computed tomography (CT) measures of emphysema and airway wall thickness in cancer.

The aim of this study was to investigate if using CT to quantitatively assess the amount of emphysema and airway wall thickness independently predicts the subsequent incidence of non-pulmonary cancer and lung cancer.

In the GenKOLS study of 2003–2005, 947 ever-smokers performed spirometry and underwent CT examination. The main predictors were the amount of emphysema measured by the percentage of low attenuation areas (%LAA) on CT and standardised measures of airway wall thickness (AWT-PI10). Cancer data from 2003–2013 were obtained from the Norwegian Cancer Register. The hazard ratio associated with emphysema and airway wall thickness was assessed using Cox proportional hazards regression for cancer diagnoses.

During 10 years of follow-up, non-pulmonary cancer was diagnosed in 11% of the subjects with LAA <3%, in 19% of subjects with LAA 3–10%, and in 17% of subjects with LAA ≥10%. Corresponding numbers for lung cancer were 2%, 3% and 11%, respectively. After adjustment, the baseline amount of emphysema remained a significant predictor of the incidence of non-pulmonary cancer and lung cancer. Airway wall thickness did not predict cancer independently.

This study offers a strong argument that emphysema is an independent risk factor for both non-pulmonary cancer and lung cancer.
Target organ damage and incident type 2 diabetes mellitus: the Strong Heart Study
Authors: de Simone Giovanni , Wang Wenyu , Best Lyle G. , Yeh Fawn , Izzo Raffaele , Mancusi Costantino , Roman Mary J. , Lee Elisa T. , Howard Barbara V. , Devereux Richard B.
Published: May 2017

Background

Recent analyses in a registry of hypertensive patients suggested that preceding left ventricular (LV) hypertrophy (LVH) and/or carotid atherosclerosis are associated with incident type 2 diabetes, independent of confounders. We assess the relation between prevalent cardio-renal target organ damage (TOD) and subsequent incident type 2 diabetes in a population-based study with high prevalence of obesity.

Methods

We selected 2887 non-diabetic participants from two cohorts of the Strong Heart Study (SHS). Clinical exam, laboratory tests and echocardiograms were performed. Adjudicated TODs were LVH, left atrium (LA) dilatation, and high urine albumin/creatinine ratio (UACR). Multivariable logistic regression models were used to identify variables responsible for the association between initial TODs and incident diabetes at 4-year follow-up (FU).

Results

After 4 years, 297 new cases of diabetes (10%) were identified, 216 of whom exhibited baseline impaired fasting glucose (IFG, 73%, p < 0.0001). Participants developing type 2 diabetes exhibited higher inflammatory markers, fat-free mass and adipose mass and higher prevalence of initial LVH and LA dilatation than those without (both p < 0.04). In multivariable logistic regression, controlling for age, sex, family relatedness, presence of arterial hypertension and IFG, all three indicators of TOD predicted incident diabetes (all p < 0.01). However, the effects of TOD was offset when body fat and inflammatory markers were introduced into the model.

Conclusions

In this population-based study with high prevalence of obesity, TOD precedes clinical appearance of type 2 diabetes and is related to the preceding metabolic status, body composition and inflammatory status.

Trial registration Trial registration number: NCT00005134, Name of registry: Strong Heart Study, URL of registry: https://clinicaltrials.gov/ct2/show/NCT00005134, Date of registration: May 25, 2000, Date of enrolment of the first participant to the trial: September 1988
ASPECT: A Survey to Assess Student Perspective of Engagement in an Active-Learning Classroom
Authors: Wiggins Benjamin L. , Eddy Sarah L. , Wener-Fligner Leah , Freisem Karen , Grunspan Daniel Z. , Theobald Elli J. , Timbrook Jerry , Crowe Alison J.
Published: May 2017

The primary measure used to determine relative effectiveness of in-class activities has been student performance on pre/posttests. However, in today’s active-learning classrooms, learning is a social activity, requiring students to interact and learn from their peers. To develop effective active-learning exercises that engage students, it is important to gain a more holistic view of the student experience in an active-learning classroom. We have taken a mixed-methods approach to iteratively develop and validate a 16-item survey to measure multiple facets of the student experience during active-learning exercises. The instrument, which we call Assessing Student Perspective of Engagement in Class Tool (ASPECT), was administered to a large introductory biology class, and student responses were subjected to exploratory factor analysis. The 16 items loaded onto three factors that cumulatively explained 52% of the variation in student response: 1) value of activity, 2) personal effort, and 3) instructor contribution. ASPECT provides a rapid, easily administered means to measure student perception of engagement in an active-learning classroom. Gaining a better understanding of students’ level of engagement will help inform instructor best practices and provide an additional measure for comprehensively assessing the impact of different active-learning strategies.
How Should I Study for the Exam? Self-Regulated Learning Strategies and Achievement in Introductory Biology
Authors: Sebesta Amanda J. , Bray Speth Elena
Published: May 2017

In college introductory science courses, students are challenged with mastering large amounts of disciplinary content while developing as autonomous and effective learners. Self-regulated learning (SRL) is the process of setting learning goals, monitoring progress toward them, and applying appropriate study strategies. SRL characterizes successful, “expert” learners, and develops with time and practice. In a large, undergraduate introductory biology course, we investigated: 1) what SRL strategies students reported using the most when studying for exams, 2) which strategies were associated with higher achievement and with grade improvement on exams, and 3) what study approaches students proposed to use for future exams. Higher-achieving students, and students whose exam grades improved in the first half of the semester, reported using specific cognitive and metacognitive strategies significantly more frequently than their lower-achieving peers. Lower-achieving students more frequently reported that they did not implement their planned strategies or, if they did, still did not improve their outcomes. These results suggest that many students entering introductory biology have limited knowledge of SRL strategies and/or limited ability to implement them, which can impact their achievement. Course-specific interventions that promote SRL development should be considered as integral pedagogical tools, aimed at fostering development of students’ lifelong learning skills.
Metacognition in Upper-Division Biology Students: Awareness Does Not Always Lead to Control
Authors: Dye Kathryn Morris , Stanton Julie Dangremond
Published: May 2017

Students with awareness and control of their own thinking can learn more and perform better than students who are not metacognitive. Metacognitive regulation is how you control your thinking in order to learn. It includes the skill of evaluation, which is the ability to appraise your approaches to learning and then modify future plans based on those appraisals. We asked when, why, and how upper-division biology students evaluated their approaches to learning. We used self-evaluation assignments to identify students with potentially high metacognition and conducted semistructured interviews to collect rich qualitative data from them. Through content analysis, we found that students evaluated their approaches to learning when their courses presented novel challenges. Most students evaluated in response to an unsatisfactory grade. While evaluating study strategies, many students considered performance and learning simultaneously. We gained insights on the barriers students face when they try to change their approaches to learning based on their evaluations. A few students continued to use ineffective study strategies even though they were aware of the ineffectiveness of those strategies. A desire to avoid feeling uncomfortable was the primary reason they avoided strategies that they knew were more effective. We examined the behavioral change literature to help interpret these findings.
Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials
Authors: Lahuerta Juan-Jose , Paiva Bruno , Vidriales Maria-Belen , Cordón Lourdes , Cedena Maria-Teresa , Puig Noemi , Martinez-Lopez Joaquin , Rosiñol Laura , Gutierrez Norma C. , Martín-Ramos María-Luisa , Oriol Albert , Teruel Ana-Isabel , Echeveste María-Asunción , de Paz Raquel , de Arriba Felipe , Hernandez Miguel T. , Palomera Luis , Martinez Rafael , Martin Alejandro , Alegre Adrian , De la Rubia Javier , Orfao Alberto , Mateos María-Victoria , Blade Joan , San-Miguel Jesus F. ,   on behalf of the GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group
Published: May 2017

Purpose

To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM).

Patients and Methods

Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months.

Results

Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%.

Conclusion

Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.
Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas
Authors: Lee June-Koo , Lee Junehawk , Kim Sehui , Kim Soyeon , Youk Jeonghwan , Park Seongyeol , An Yohan , Keam Bhumsuk , Kim Dong-Wan , Heo Dae Seog , Kim Young Tae , Kim Jin-Soo , Kim Se Hyun , Lee Jong Seok , Lee Se-Hoon , Park Keunchil , Ku Ja-Lok , Jeon Yoon Kyung , Chung Doo Hyun , Park Peter J. , Kim Joon , Kim Tae Min , Ju Young Seok
Published: May 2017

Purpose

Histologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell lung cancer (SCLC) has been described as one of the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the molecular pathogenesis is still unclear.

Methods

We investigated 21 patients with advanced EGFR-mutant LADCs that were transformed into EGFR TKI–resistant SCLCs. Among them, whole genome sequencing was applied for nine tumors acquired at various time points from four patients to reconstruct their clonal evolutionary history and to detect genetic predictors for small-cell transformation. The findings were validated by immunohistochemistry in 210 lung cancer tissues.

Results

We identified that EGFR TKI–resistant LADCs and SCLCs share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. We extended the findings by immunohistochemistry in the early-stage LADC tissues of 75 patients treated with EGFR TKIs; inactivation of both Rb and p53 was strikingly more frequent in the small-cell–transformed group than in the nontransformed group (82% v 3%; odds ratio, 131; 95% CI, 19.9 to 859). Among patients registered in a predefined cohort (n = 65), an EGFR mutant LADC that harbored completely inactivated Rb and p53 had a 43× greater risk of small-cell transformation (relative risk, 42.8; 95% CI, 5.88 to 311). Branch-specific mutational signature analysis revealed that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)–induced hypermutation was frequent in the branches toward small-cell transformation.

Conclusion

EGFR TKI–resistant SCLCs are branched out early from the LADC clones that harbor completely inactivated RB1 and TP53. The evaluation of RB1 and TP53 status in EGFR TKI–treated LADCs is informative in predicting small-cell transformation.
The New Genomics: What Molecular Databases Can Tell Us About Human Population Variation and Endocrine Disease
Authors: Rotwein Peter
Published: May 2017

Major recent advances in genetics and genomics present unique opportunities for enhancing our understanding of human physiology and disease predisposition. Here I demonstrate how analysis of genomic information can provide new insights into endocrine systems, using the human growth hormone (GH) signaling pathway as an illustrative example. GH is essential for normal postnatal growth in children, and plays important roles in other biological processes throughout life. GH actions are mediated by the GH receptor, primarily via the JAK2 protein tyrosine kinase and the STAT5B transcription factor, and inactivating mutations in this pathway all lead to impaired somatic growth. Variation in GH signaling genes has been evaluated using DNA sequence data from the Exome Aggregation Consortium, a compendium of information from >60,000 individuals. Results reveal many potential missense and other alterations in the coding regions ofGH1,GHR,JAK2, andSTAT5B, with most changes being uncommon. The total number of different alleles per gene varied by ~threefold, from 101 forGH1 to 338 forJAK2. Several known disease-linked mutations inGH1,GHR, andJAK2 were present but infrequent in the population; however, three amino acid changes inGHR were sufficiently prevalent (~4% to 44% of chromosomes) to suggest that they are not disease causing. Collectively, these data provide new opportunities to understand how genetically driven variability in GH signaling and action may modify human physiology and disease.
Pancreas Atrophy and Islet Amyloid Deposition in Patients With Elderly-Onset Type 2 Diabetes
Authors: Xin An , Mizukami Hiroki , Inaba Wataru , Yoshida Taro , Takeuchi Yu-ki , Yagihashi Soroku
Published: May 2017

Context

With prolonged life expectancy, we often encounter patients with elderly-onset type 2 diabetes mellitus (eT2DM). Although the clinical features of eT2DM are suggested to be different from those in patients with middle-age–onset type 2 diabetes mellitus (mT2DM), the islet pathologic features in eT2DM have not been addressed.

Objective

We attempted to characterize the pancreatic pathology in eT2DM and sought its clinical implications.

Materials and Methods

Pancreata from 13 young nondiabetic (age, 20 to 29 years), 27 patients with mT2DM (age, 45 to 87 years), 22 middle-age subjects without T2DM, 15 subjects with eT2DM (age, 85 to 100 years), and 30 elderly subjects without T2DM were investigated. Together with conventional microscopic observations, morphometric analysis on the islet, islet endocrine cells, and amyloid deposition was conducted on immunostained sections.

Results

The estimated age of diabetes onset was 80.8 ± 1.4 years (mean ± standard error) in the eT2DM group and that of the mT2DM group was 48.3 ± 2.4 years. The pancreatic weight was nearly 50% less in the eT2DM group than in the other groups, showing duct obstruction with epithelial hyperplasia, marked acinar atrophy, fibrosis, and amyloid deposition in the islet. The islet mass was significantly reduced in the eT2DM group. The amyloid volume density correlated inversely with the β-cell volume density but not with the body mass index in the eT2DM group. Laboratory data showed mild elevation of serum amylase in the eT2DM group, although clinical signs and symptoms of pancreatitis were not apparent.

Conclusions

eT2DM is distinct from mT2DM and characterized by pancreas atrophy, ductal lesions, and amyloid deposition.
Parallel imaging of Drosophila embryos for quantitative analysis of genetic perturbations of the Ras pathway
Authors: Goyal Yogesh , Levario Thomas J. , Mattingly Henry H. , Holmes Susan , Shvartsman Stanislav Y. , Lu Hang
Published: May 2017

The Ras pathway patterns the poles of the Drosophila embryo by downregulating the levels and activity of a DNA-binding transcriptional repressor Capicua (Cic). We demonstrate that the spatiotemporal pattern of Cic during this signaling event can be harnessed for functional studies of the Ras-pathway mutations from human diseases. Our approach relies on a new microfluidic device that enables parallel imaging of Cic dynamics in dozens of live embryos. We found that although the pattern of Cic in early embryos is complex, it can be accurately approximated by a product of one spatial profile and one time-dependent amplitude. Analysis of these functions of space and time alone reveals the differential effects of mutations within the Ras pathway. Given the highly-conserved nature of Ras-dependent control of Cic, our approach opens a new way for functional analysis of multiple sequence variants from developmental abnormalities and cancers.
Early life experience drives short-term acclimation of metabolic and osmoregulatory traits in the leaf-eared mouse
Authors: Cavieres G. , Nuñez-Villegas M. , Bozinovic F. , Sabat P.
Published: May 2017

We studied the putative effect of early experience on the physiological flexibility of metabolic and osmoregulatory traits in the leaf-eared mouse Phyllotis darwini, an altricial rodent inhabiting seasonal mediterranean environments. Adult individuals were collected in central Chile and maintained in breeding pairs. Pups were isolated after weaning and acclimated to different temperature (cold or warm) and water availability (unrestricted and restricted) until adulthood. Subsequently, individuals were re-acclimated to the opposite treatment. Rodents reared in warm and subjected to water restriction had lower basal metabolic rate (BMR), lower total evaporative water loss (TEWL), and body mass (Mb) compared to those developing in the cold treatment; nevertheless, individuals subjected to warm temperatures had greater relative medullary thickness (RMT) and urine concentrating ability (UCA). Cold-reared rodents re-acclimated to warm conditions exhibited physiological flexibility of metabolic traits; however, their osmoregulatory attributes did not vary. Conversely, warm-reared rodents re-acclimated to cold had reduced RMT and UCA, but the metabolic traits of these individuals did not change; these results suggest a trade-off between metabolic performance and renal capabilities that might hinder physiological acclimation. Our results support the hypothesis of ontogenetic dependence of short-term acclimation in osmoregulatory and metabolic traits in Phyllotis darwini.
Sources of variance in immunological traits: evidence of congruent latitudinal trends across species
Authors: Meister Hendrik , Tammaru Toomas , Sandre Siiri-Lii , Freitak Dalial
Published: May 2017

Among-population differences in immunological traits allow to assess both evolutionary and plastic changes in organisms' resistance to pathogens. Such knowledge also provides information necessary to predict responses of such traits to environmental changes. Studies on latitudinal trends in insect immunity have so far yielded contradictory results, suggesting that multispecies approaches with highly standardised experimental conditions are needed. Here, we studied among-population differences of two parameters reflecting constitutive immunity – phenoloxidase (PO) and lytic activity – using common garden design on three distantly related moth species represented by populations ranging from northern Finland to Georgia (Caucasus). The larvae were reared at different temperatures and host plants under a crossed factors experimental design. Haemolymph samples to measure immune status were taken from the larvae strictly synchronously. Clear among-population differences could be shown only for PO activity in one species (elevated activity in the north). There was some indication that the cases of total absence of lytic activity are more common in southern populations. The effects of temperature, host and gender on the immunological traits studied remained highly species-specific. Some evidence was found that lytic activity may be involved in mediating trade-offs between immunity and larval growth performance. In contrast, PO did rarely covary with fitness-related traits, neither were the values of PO and lytic activity correlated with each other. The relatively inconsistent nature of the detected patterns suggests that studies on geographic differences in immunological traits should involve multiple species, and rely on several immunological indices if general trends are a point of interest.
Intestinal digestive enzyme modulation in house sparrow nestlings occurs within 24 hours of a change in diet composition
Authors: Rott Katherine H. , Caviedes-Vidal Enrique , Karasov William H.
Published: May 2017

Nestling house sparrows near fledging age (12 days) were previously found to reversibly modulate the activity of their intestinal digestive enzymes in response to changes in diet composition. However, it is not known how quickly nestlings can adjust to new diets with different substrate compositions, nor is it known how early in life nestlings can modulate their enzyme activity in response to changes in diet. In the current study, 3-day-old nestlings were captured from the wild and fed and switched among contrasting diets – one high in protein and low in carbohydrate and another higher in carbohydrate and with lower but adequate protein – in order to determine (1) how quickly house sparrow nestlings could adjust to changes in diet composition, (2) how early in life nestlings could modulate their digestive enzyme activity in response to these changes, and (3) which digestive enzymes could be modulated in house sparrow nestlings earlier in life. We found that house sparrow nestlings as young as three days post-hatch were capable of modulating their intestinal disaccharidase activity within 24 hours of a change in diet composition, and nestlings gained the ability to modulate aminopeptidase-N by six or seven days of age. To our knowledge, this is the first evidence of digestive enzyme modulation completed within 24 hours of a change in diet in an avian species and the first study to show intestinal digestive enzyme modulation in response to changes in diet composition in any animal this early in development.
Kinematics of ram filter feeding and beat-glide swimming in the northern anchovy Engraulis mordax
Authors: Carey Nicholas , Goldbogen Jeremy A.
Published: May 2017

In the dense aquatic environment, the most adept swimmers are streamlined to reduce drag and increase the efficiency of locomotion. However, because they open their mouth to wide gape angles to deploy their filtering apparatus, ram filter feeders apparently switch between diametrically opposite swimming modes; highly efficient, streamlined 'beat-glide' swimming, and ram filter feeding, which has been hypothesized to be a high-cost feeding mode because of presumed increased drag. Ram filter feeding forage fish are thought to play an important role in the flux of nutrients and energy in upwelling ecosystems, however the biomechanics and energetics of this feeding mechanism remain poorly understood. We quantified the kinematics of an iconic forage fish, the northern anchovy, Engraulis mordax, during ram filter feeding and non-feeding, mouth-closed beat-glide swimming. Although many kinematic parameters between the two swimming modes were similar, we found that swimming speeds and tailbeat frequencies were significantly lower during ram feeding. Rather than maintain speed with the school, a speed which closely matches theoretical optimum filter feeding speeds was consistently observed. Beat-glide swimming was characterized by high variability in all kinematic parameters, but variance in kinematic parameters was much lower during ram filter feeding. Under this mode, body kinematics are substantially modified, and E. mordax swims more slowly, and with decreased lateral movement along the entire body, but most noticeably in the anterior. Our results suggest that hydrodynamic effects that come with deployment of the filtering anatomy may limit behavioral options during foraging and result in slower swimming speeds during ram filtration.
Transforming growth factor beta-1 (TGF-β1) stimulates collagen synthesis in cultured rainbow trout cardiac fibroblasts
Authors: Johnston Elizabeth F. , Gillis Todd E.
Published: May 2017

Cold acclimation of rainbow trout, Oncorhynchus mykiss, causes collagen to increase within the extracellular matrix (ECM) of the myocardium, while warm acclimation has the opposite effect. The mechanism responsible for this remodeling response is not known. In mammals, transforming growth factor beta-1 (TGF-β1) stimulates collagen deposition within the myocardial ECM. Therefore, we hypothesized that TGF-β1 regulates trout myocardial ECM turnover and predicted that TGF-β1 would induce collagen deposition in cultured rainbow trout cardiac fibroblasts. We found that treatment of trout cardiac fibroblasts with 15 ng · ml−1 human recombinant TGF-β1 caused an increase in total collagen at 48 h and 72 h and an increase in collagen type I protein after 7 d. We also found that TGF-β1 treatment caused an increase in the transcript abundance of tissue inhibitor of metalloproteinase 2 (timp-2) and matrix metalloproteinase 9 (mmp-9) at 24 h. Cells treated with TGF-β1 also had lower levels of the gene transcript for mmp-2 after 48 h and higher levels of the gene transcript for collagen type I α I (col1a1) after 72 h. These changes in gene expression suggest that the increase in collagen deposition is due to a decrease in the activity of matrix metalloproteinases and an increase in collagen synthesis. Together, these results indicate that TGF-β1 is a regulator of ECM composition in cultured trout cardiac fibroblasts and suggests that this cytokine may play a role in regulating collagen content in the trout heart during thermal acclimation.