bluuebunny/crossref_metadata_2025 huggingface dataset:
Building Capacity for Collective Action to Address Population Health Improvement Through Communities of Practice: A Distance-Based Education Pilot
Authors: Welter Christina R. , Jacobs Beth-Anne , Jarpe-Ratner Elizabeth , Naji Sophie , Gruss Kelsey
Published: May 2017

Improving population health requires a comprehensive array of interventions across individual, organizational, and community levels. Integrating primary care and public health strategies through partnerships is one type of intervention. Workforce development can facilitate this type of integration; however, models and modalities of workforce training primarily focus on individual skill building and may not build the capacity needed for collective action. A collaborative and strategic learning approach, communities of practice, fosters primary care and public health integration to address population health. A Health Resources and Services Administration–funded multistate regional Public Health Training Center (PHTC), the Great Lakes PHTC, undertook an action learning process to develop and pilot a workforce development initiative to promote ongoing learning toward shared goals. Great Lakes PHTC facilitated 11 discussions throughout the region with a total of 100 participants from primary care and governmental public health communities to better understand perceptions, gaps, barriers, and opportunities for integration and training. Findings indicated that a regional, coordinated model to workforce development provided a process for improved, ongoing learning that uncovered gaps in adapting distance-based approaches that can be addressed in future programming efforts. In addition, the process revealed that addressing population health issues through integrated partnerships requires training beyond content and discipline that incorporates multiple modalities and models.
Building the Plane While Flying It: Lessons Learned in the Development of the North Carolina Local Performance Site for the HRSA Region IV Public Health Training Center
Authors: Smith Stephanie D. , Matney Katelyn G. , Reel Justine J. , Miner Nathaniel P. , Cottrell Randall R. , Hardy Charles J. , Surles Megan K.
Published: May 2017

Developing a public health training center has provided a unique opportunity to meet the training needs of the public health workforce across North Carolina. Furthermore, the training center has fostered collaborations with community partners and other universities in the state. This article describes some lessons learned while building a local performance site that may help inform and shape expectations about what it takes to build a public health training center. Recommendations for successfully creating a local performance site within the Regional Public Health Training Center model are included.
Cervical Cancer Attitudes and Knowledge in Somali Refugees in Nebraska
Authors: Grimm Brandon , Alnaji Nada , Watanabe-Galloway Shinobu , Leypoldt Melissa
Published: May 2017

The state of Nebraska has a growing number of refugees with diverse backgrounds and health needs. To address these needs, a collaborative project was developed by the local performance site of the Midwestern Public Health Training Center at the University of Nebraska Medical Center, College of Public Health, and the Nebraska Department of Health and Human Services, Division of Public Health, Office of Women’s and Men’s Health. The purpose of this 2-year project is to improve the quality of services offered by the Office of Women’s and Men’s Health by assessing risk, knowledge, and preventive screening practices in refugee populations and provide recommendations to increase cancer-screening rates. The focus of the project was on cervical cancer prevention of Somali women refugees in Nebraska. In Year 1 of the project (2015-2016), a Refugee Screening Collaborative was created to provide input and recommendations throughout the project; focus groups and a literature review were completed to explore the knowledge, attitudes, and beliefs of cervical cancer screening and human papillomavirus vaccine among refugees and health care providers; and recommendations were made for the development and implementation of curricula and interventions that address the unique cultural and literacy needs of the population. This project demonstrates the importance of the Public Health Training Center program for building mutually beneficial partnerships between academia and practice.
Dying From Cancer
Authors: Cripe Larry D , Frankel Richard M
Published: May 2017

Medical oncologists and patients with advanced cancer struggle to discuss prognosis, goals, options, and values in a timely fashion. As a consequence, many patients die receiving aggressive treatment potentially inconsistent with their fully informed preferences and experience increased symptom burden and distress. The goals of patient - oncologist communication include exchanging information, building relationship, and engaging in shared decisions. Empathy is perhaps especially essential to effective patient - oncologist communication when the end of life is approaching. We speculate that, in addition to being a skilled response to a patient’s negative emotions, empathy is an emergent property of the relationship that allows the patient and oncologist to imagine what it will be like to navigate the transition from living with to dying from cancer; and to prepare for the transition. We propose that effective empathy: 1) requires an attentive, curious and imaginative physician; 2) acknowledges the complex and shifting goals as the end of life approaches; and 3) begins with a willingness of physicians to check in and find out what she may have misunderstood or misperceived. Empathy in end of life conversations cultivates the shared experiences necessary to co-create the new goals of care that underlie excellent end of life care.
Policy entrepreneurs and problem framing: The case of climate change
Authors: Mintrom Michael , Luetjens Joannah
Published: May 2017

Policy entrepreneurs are energetic actors who work with others in and around policymaking venues to promote significant policy change. After several decades of study, we know a lot about what policy entrepreneurs do, and how to assess their effectiveness in given policymaking contexts. Here, we review common practices of policy entrepreneurs, emphasising their problem framing activities and their role in catalysing large-scale behavioural change related to climate change. We then review what policy entrepreneurs operating in various locations and at different levels of government have begun doing to tackle the climate change challenge. Like others, we contend that policy entrepreneurs will play a vital role in future efforts to address climate change. We conclude by discussing opportunities for new research on policy entrepreneurship, policymaking processes and the diffusion of policy innovations relating to climate change.
Ecological Footprints and Appropriated Carrying Capacity: What Urban Economics Leaves Out
Authors: Rees William E.
Published: May 2017

This article uses the concepts of human carrying capacity and natural capital to develop a framework to evaluate a city’s ‘ecological footprint’. It argues that prevailing economic assumptions regarding urbanisation and the sustainability of cities must be revised in light of global ecological change.
Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis
Authors: Smith Catherine C. , Paguirigan Amy , Jeschke Grace R. , Lin Kimberly C. , Massi Evan , Tarver Theodore , Chin Chen-Shan , Asthana Saurabh , Olshen Adam , Travers Kevin J. , Wang Susana , Levis Mark J. , Perl Alexander E. , Radich Jerald P. , Shah Neil P.
Published: May 2017

Key Points

Polyclonal mechanisms of resistance, demonstrated by single-cell analysis, occur in the majority of AML patients who relapse on quizartinib.
Mouse RUNX1C regulates premegakaryocytic/erythroid output and maintains survival of megakaryocyte progenitors
Authors: Draper Julia E. , Sroczynska Patrycja , Leong Hui Sun , Fadlullah Muhammad Z. H. , Miller Crispin , Kouskoff Valerie , Lacaud Georges
Published: May 2017

Key Points

Absence of RUNX1C in knock-in adult mice causes defective megakaryopoiesis and thrombocytopenia. Unlike total RUNX1 deficiency absence of RUNX1C does not alter megakaryocyte maturation but increases apoptosis in megakaryocyte progenitors.
Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma
Authors: Zinzani Pier Luigi , Ribrag Vincent , Moskowitz Craig H. , Michot Jean-Marie , Kuruvilla John , Balakumaran Arun , Zhang Yayan , Chlosta Sabine , Shipp Margaret A. , Armand Philippe
Published: May 2017

Key Points

Treatment options for relapsed/refractory PMBCL are limited, and prognosis is generally poor. Pembrolizumab had a manageable safety profile and promising antitumor activity in heavily pretreated rrPMBCL patients.
An endpoint associated with clinical benefit after initial treatment of chronic graft-versus-host disease
Authors: Martin Paul J. , Storer Barry E. , Inamoto Yoshihiro , Flowers Mary E. D. , Carpenter Paul A. , Pidala Joseph , Palmer Jeanne , Arora Mukta , Jagasia Madan , Arai Sally , Cutler Corey S. , Lee Stephanie J.
Published: May 2017

Key Points

Complete or partial response at 1 year without secondary systemic treatment provides clinical benefit in patients with chronic GVHD. Success defined by this endpoint is currently observed in fewer than 20% of patients after initial systemic treatment of chronic GVHD.
Effect of sitagliptin on the echocardiographic parameters of left ventricular diastolic function in patients with type 2 diabetes: a subgroup analysis of the PROLOGUE study
Authors: Yamada Hirotsugu , Tanaka Atsushi , Kusunose Kenya , Amano Rie , Matsuhisa Munehide , Daida Hiroyuki , Ito Masaaki , Tsutsui Hiroyuki , Nanasato Mamoru , Kamiya Haruo , Bando Yasuko K. , Odawara Masato , Yoshida Hisako , Murohara Toyoaki , Sata Masataka , Node Koichi ,   for the PROLOGUE Study Investigators
Published: May 2017

Background

Diabetes is associated closely with an increased risk of cardiovascular events, including diastolic dysfunction and heart failure that leads to a shortening of life expectancy. It is therefore extremely valuable to evaluate the impact of antidiabetic agents on cardiac function. However, the influence of dipeptidyl peptidase 4 inhibitors on cardiac function is controversial and a major matter of clinical concern. We therefore evaluated the effect of sitagliptin on echocardiographic parameters of diastolic function in patients with type 2 diabetes as a sub-analysis of the PROLOGUE study.

Methods

Patients in the PROLOGUE study were assigned randomly to either add-on sitagliptin treatment or conventional antidiabetic treatment. Of the 463 patients in the overall study, 115 patients (55 in the sitagliptin group and 60 in the conventional group) who had complete echocardiographic data of the ratio of peak early diastolic transmitral flow velocity (E) to peak early diastolic mitral annular velocity (e′) at baseline and after 12 and 24 months were included in this study. The primary endpoint of this post hoc sub-analysis was a comparison of the changes in the ratio of E to e′ (E/e′) between the two groups from baseline to 24 months.

Results

The baseline-adjusted change in E/e′ during 24 months was significantly lower in the sitagliptin group than in the conventional group (−0.18 ± 0.55 vs. 1.91 ± 0.53, p = 0.008), irrespective of a higher E/e′ value at baseline in the sitagliptin group. In analysis of covariance, sitagliptin treatment was significantly associated with change in E/e′ over 24 months (β = −9.959, p = 0.001), independent of other clinical variables at baseline such as blood pressure, HbA1c, and medications for diabetes. Changes in other clinical variables including blood pressure and glycemic parameters, and echocardiographic parameters, such as cardiac structure and systolic function, were comparable between the two groups. There was also no significant difference in the serum levels of N-terminal-pro brain natriuretic peptide and high-sensitive C-reactive protein between the two groups during the study period.

Conclusions

Adding sitagliptin to conventional antidiabetic regimens in patients with T2DM for 24 months attenuated the annual exacerbation in the echocardiographic parameter of diastolic dysfunction (E/e′) independent of other clinical variables such as blood pressure and glycemic control.

Trial registration UMIN000004490 (University Hospital Medical Information Network Clinical Trials). https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000005356; registered November 1, 2010
RETRACTED ARTICLE: A new application of boundary integral behaviors of harmonic functions to the least harmonic majorant
Authors: Han Minghua , Sun Jianguo , Xue Gaoying
Published: May 2017

Our main aim in this paper is to obtain a new type of boundary integral behaviors of harmonic functions in a smooth cone. As an application, the least harmonic majorant of a nonnegative subharmonic function is also given.
Improved subsalt images with least-squares reverse time migration
Authors: Wang Ping , Huang Shouting , Wang Ming
Published: May 2017

Complex overburdens often distort reservoir images in terms of structural positioning, stratigraphic resolution, and amplitude fidelity. One prime example of a complex overburden is in the deepwater Gulf of Mexico, where thick and irregular layers of remobilized (i.e., allochthonous) salt are situated above prospective reservoir intervals. The highly variant salt layers create large lateral velocity variations that distort wave propagation and the illumination of deeper reservoir targets. In subsalt imaging, tools such as reflection tomography, full-waveform inversion, and detailed salt interpretation are needed to derive a high-resolution velocity model that captures the lateral velocity variations. Once a velocity field is obtained, reverse time migration (RTM) can be applied to restore structural positioning of events below and around the salt. However, RTM by nature is unable to fully recover the reflectivity for desired amplitudes and resolution. This shortcoming is well-recognized by the imaging community, and it has propelled the emergence of least-squares RTM (LSRTM) in recent years. We have investigated how current LSRTM methods perform on subsalt images. First, we compared the formulation of data-domain versus image-domain least-squares migration, as well as methods using single-iteration approximation versus iterative inversion. Then, we examined the resulting subsalt images of several LSRTM methods applied on the synthetic and field data. Among our tests, we found that image-domain single-iteration LSRTM methods, including an extension of an approximate inverse Hessian method in the curvelet domain, not only compensated for amplitude loss due to poor illumination caused by complex salt bodies, but it also produced subsalt images with fewer migration artifacts in the field data. In contrast, an iterative inversion method showed its potential for broadening the bandwidth in the subsalt, but it was less effective in reducing migration artifacts and noise. Based on our understanding, we evaluated the current state of LSRTM for subsalt imaging.
Aggressive care at the end-of-life for younger patients with cancer: Impact of ASCO's Choosing Wisely campaign.
Authors: Chen Ronald C. , Falchook Aaron David , Tian Fang , Basak Ramsankar , Hanson Laura , Selvam Nandini , Dusetzina Stacie
Published: May 2017

LBA10033

Background: Aggressive medical care at the end of life is widely recognized to be harmful to cancer patients. This includes cancer-directed procedures and therapies; emergency room and ICU admissions; and in-hospital deaths. Prevalence of its use in patients younger than 65 has not been previously examined. We evaluated use of aggressive care within the last 30 days of life from before to after ASCO’s 2012 Choosing Wisely campaign aimed at reducing aggressive end-of-life care. Methods: Claims data from the HealthCore Integrated Research Database were analyzed, which overall includes ~60 million individuals enrolled in Blue Cross and/or Blue Shield licensed plans across 14 states. Patients aged ≤ 65 who died between 2007-2014 and who had diagnoses for metastatic lung, colorectal, breast, pancreatic, and prostate cancers were included. Poisson multivariable regression models assessed the associations between age group, geographic region, gender, and regional education and income measures with aggressive care. Results: 28,731 patients were analyzed. 71-76% of patients across different cancers received aggressive care within the last 30 days of life (Table), including 30-35% of patients who died in the hospital. Rates of aggressive care use between early 2012 before Choosing Wisely vs. 2014 were unchanged in patients with colorectal and breast cancers; and increased in lung, pancreatic and prostate cancers. On the other hand, hospice use ranged from 14-18% across cancers. Multivariable models showed regional variations in aggressive care and hospice use. Conclusions: There is substantial overuse of aggressive end-of-life care among younger patients with incurable cancers. Aggressive care did not decrease following the 2012 ASCO Choosing Wisely recommendations. [Table: see text]
Targeted therapy for advanced solid tumors based on molecular profiles: Early results from MyPathway, an open-label, phase IIa umbrella basket study.
Authors: Hainsworth John D. , Meric-Bernstam Funda , Swanton Charles , Hurwitz Herbert , Spigel David R. , Sweeney Christopher , Burris Howard A. , Bose Ron , Guo Shuangli , Bernaards Coen , Beattie Mary Stanley , Stein Alisha , Brammer Melissa , Kurzrock Razelle
Published: May 2017

LBA11511

Background: The MyPathway study (NCT02091141) evaluates agents targeting the HER2, BRAF, Hedgehog (Hh), or EGFR pathways in non-indicated tumors with relevant genetic abnormalities. Early results from MyPathway merit pre-planned tumor-cohort expansion. Methods: Eligible pts had advanced solid tumors with no curative therapy and molecular alterations in HER2, BRAF, Hh, or EGFR. Pts received standard doses of trastuzumab + pertuzumab (for the HER2 pathway), vemurafenib (BRAF), vismodegib (Hh), or erlotinib (EGFR) based on alteration. The primary endpoint is investigator-evaluated response rate within a tumor-pathway cohort (RECIST 1.1). Cohort size and expansion is determined by Simon’s two-stage design criteria. Results: By December 14, 2015, MyPathway included 129 pts with available baseline assessments and alterations in HER2 (n = 82; 53 amplifications, 23 mutations, 5 both, 1 RBMS-NRG1 fusion), BRAF (n = 33; 18 V600E, 15 other), Hh (n = 8; 7 PTCH1, 1 SMO), or EGFR (n = 6). Pts had a median of 3 (range, 0–10) prior lines of therapy. Best responses (n = 118) are shown below; 11 pts had insufficient follow-up for reevaluation and were not analyzed. 22 pts had PR/CR (1 CR); current response durations were up to 11 months. Conclusions: Targeted therapy produced responses in pts with 9 different tumor types outside of current drug indications. As enrollment increases for all tumor-pathway cohorts, analyses of tumor responses based on specific alterations (eg, HER2 amplifications vs. mutations) are planned. The HER2 amplified colorectal, bladder, and biliary, and the BRAF lung cohorts will be expanded based on observed activity. Clinical trial information: NCT02091141. [Table: see text]
The Metastatic Breast Cancer Project: A national direct-to-patient initiative to accelerate genomics research.
Authors: Wagle Nikhil , Painter Corrie , Krevalin Max , Oh Coyin , Anderka Kristin , Larkin Katie , Lennon Niall , Dillon Deborah , Frank Elizabeth , Winer Eric P. , Lander Eric , Golub Todd
Published: May 2017

LBA1519

Background: The challenge in studying tumors from patients (pts) with metastatic breast cancer (MBC) has been that most tumors are not available for research, largely because most pts are cared for in community settings where genomics studies are not conducted. To address this, we launched a nationwide study, The Metastatic Breast Cancer Project, which seeks to empower patients to accelerate research by sharing their samples and clinical information. Methods: In collaboration with pts and advocacy groups, we developed a website to allow MBC pts to participate across the U.S. Enrolled pts are sent a saliva kit and asked to mail back a saliva sample, which is used to extract germline DNA. We contact participants’ medical providers and obtain medical records and part of their tumor biopsy. Whole exome and transcriptome sequencing is performed on tumor and germline. Clinically annotated genomic data are used to identify mechanisms of response and resistance to therapies. The database is shared widely with researchers. Study updates and discoveries are shared with participants regularly. Results: In the first 3 months, 1227 MBC pts enrolled. 1178 (96%) completed the 16-question survey about their cancer and treatments. Median age was 54 years (yrs) (range 25-91). Median time between initial diagnosis (dx) of breast cancer and MBC was 2 yrs; 424 pts were dx’d with de novo MBC. 1022 (87%) reported having a biopsy at or following their dx of MBC. Median time since MBC dx was 3 yrs; 87 reported having MBC >10 yrs. 436 (37%) reported being on a therapy for >2 yrs; 672 (57%) reported an “extraordinary response” to a therapy. For example, 77 reported long and/or extraordinary responses to capecitabine ; 44 to platinums, and 20 to everolimus. Initial medical records, saliva, and tumors have been received. Conclusions: A direct-to-patient approach enabled rapid identification of large numbers of MBC pts willing to share tumors, saliva, and medical records. This includes many with rare phenotypes, a group that has been challenging to identify with traditional approaches. Genomic analysis of pts with extraordinary responses and with de novo MBC are underway. Pt reported data has also identified unanticipated research questions.
FAST: An international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without IMAB362, a first-in-class anti-CLDN18.2 antibody, as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Al-Batran Salah-Eddin , Schuler Martin H. , Zvirbule Zanete , Manikhas Georgiy , Lordick Florian , Rusyn Andriy , Vynnyk Yuriy , Vynnychenko Ihor , Fadeeva Natalia , Nechaeva Marina , Dudov Assen , Gotovkin Evgeny , Pecheniy Alexander , Bazin Igor , Bondarenko Igor , Melichar Bohuslav , Mueller Christian , Huber Christoph , Tureci Oezlem , Sahin Ugur
Published: May 2017

LBA4001

Background:
Claudin18.2 (CLDN18.2) is a tight junction protein expressed by several cancers including gastric and GEJ adenocarcinoma. IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activation of immune effector mechanisms. IMAB362 has demonstrated single-agent activity and was safe and tolerable in patients (pts) with pretreated gastric cancer.
Methods:
Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by IHC (validated CLAUDETECT18.2 Kit). Eligible pts had a CLDN18.2 expression of ≥ 2+ in ≥ 40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts were randomized 1:1 to first-line EOX (epirubicin 50 mg/m
2
and oxaliplatin 130 mg/m
2
d1, and capecitabine 625 mg/m
2
bid, d1–21; qd22) with or without IMAB362 (loading dose 800 mg/m
2
, then 600 mg/m
2
d1, qd21). The study was extended by an exploratory Arm3 (N = 85) to investigate a high dose IMAB362 (1000 mg/m
2
) plus EOX, (not subject here). The primary study endpoint was PFS (Arm 1 v 2, 70% power, HR 0.72, 1-sided p = 0.1).
Results:
730 pts were consented, of whom 352 pts (48%) were tested CLDN18.2+ per protocol criteria. Of those, 161 pts (median age, 58 yrs; male 64%; gastric, 80%; GEJ, 16%; esophageal, 4%) were randomized into Arms1 and 2. The study met its endpoints. IMAB362 plus EOX improved PFS (median 5.7 v 7.9 mon; HR 0.5; 95% CI 0.35–0.78, 1-sided p = 0.001) and OS (median 8.7 v 12.5 mon; HR 0.5, 95% CI 0.28–0.73) compared to EOX alone. In the subpopulation with very high CLDN18.2 expression ( ≥ 2+ intensity in ≥ 70% tumor cells), efficacy was more pronounced (PFS, 6.1 vs 9.1 mon; HR 0.46; OS, 9.3 v 16.6 mon; HR 0.44). Most common IMAB362-related adverse events included vomiting, neutropenia, and anemia, which were mostly of NCI-CTC grade 1/2. Grade 3/4 events were not significantly increased by IMAB362.
Conclusions:
IMAB362 combined with first-line chemotherapy exhibited a clinically relevant benefit in PFS and OS and a favorable risk/benefit profile.
Clinical trial information: NCT01630083.
OV21/PETROC: A randomized Gynecologic Cancer Intergroup (GCIG) phase II study of intraperitoneal (IP) versus intravenous (IV) chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer (EOC).
Authors: Mackay Helen , Gallagher Christopher J. , Parulekar Wendy R. , Ledermann Jonathan A. , Armstrong Deborah Kay , Gourley Charlie , Romero Ignacio , Feeney Amanda , Bessette Paul , Hall Marcia , Weberpals Johanne Ingrid , Hall Geoff , Lau Susie K , Gauthier Philippe , Fung-Kee-Fung Michael , Eisenhauer Elizabeth A. , Winch Chad , Tu Dongsheng , Provencher Diane M.
Published: May 2017

LBA5503

Background: The aim of this 2 stage randomized trial was to evaluate whether women undergoing neoadjuvant IV chemotherapy followed by delayed debulking surgery benefit from the addition of IP/IV treatment after surgery. Methods: Stage 1 was a randomized 3-arm design including 2 IP platinum regimens: 153 women who received 3-4 courses of IV platinum-based chemo for stage IIB-III (IV pleural effusion only) EOC followed by optimal debulking surgery ( < 1 cm) were randomized to: ARM1 D1 IV paclitaxel (pacli) 135mg/m2 + IV Carboplatin AUC 5/6 with d8 pacli IV 60 mg/m2 Q 21d X3; ARM 2 D1 IV pacli 135mg/m2 + IP cisplatin (Cis) 75 mg/m2 and d8 IP pacli 60 mg/m2 Q21d X3; or ARM 3 d1 IV pacli 135mg/m2+ IP Carboplatin AUC 5/6 and d8 IP pacli 60mg/m2 Q21dX3. A planned DSMC review confirmed dropping ARM2 (IP cis) and continuing study as an expanded phase II comparing 200 patients randomized to ARMs 1 and 3, which has 80% power to detect a 19% difference in progression rate at 9 mo (PD9, primary endpoint), 2-sided α = 0.05. Progression free survival (PFS) and overall survival (OS) are secondary efficacy endpoints. Results: Between 2009 and May 2015, 275 patients were accrued: n = 101 Arm 1, 72 Arm 2, 102 Arm 3. Median age was 62; 81.8%s had stage 3 C disease; 12.7% stage IV. Baseline characteristics were balanced between arms. Median number of cycles was 3 all arms; completion rates Arm 1, 93.7% and Arm 3, 84.8%. Intention to treat PD9 rates: Arm 1: 38.6% (95% CI 29.1%- 48.8%) and Arm 3: 24.5% (95% CI 16.5%-34.0%); p = 0.065 stratified; p = 0.03 unstratified. Per protocol (eligible, received > one dose of protocol therapy) PD9 rates: Arm 1: 42.2% (95% CI 31.9%- 53.1%), Arm 3: 23.3% (95% CI 15.1%-33.4%); p = 0.03 stratified; p = 0.01 unstratified. Median PFS 11.3 mo (Arm1) and 12.5 mo (Arm 3); HR 0.82 (95% CI 0.57 - 1.17); p = 0.27. Median OS: 38.1 mo (Arm 1) and 59.3 mo (Arm 3); HR 0.80 (95% CI 0.47-1.35) p = 0.40. Adverse events > Gr 3 rates: 23% (Arm 1) and 16% (Arm 3) (p = 0.24). Conclusions: The IP carboplatin based regimen, post neoadjuvant chemotherapy and debulking surgery, is well tolerated and associated with a lower PD9 rate compared to IV therapy. Clinical trial information: NCT00993655.
Global differences in cancer drug prices: A comparative analysis.
Authors: Goldstein Daniel A. , Clark Jonathon , Tu Yifan , Zhang Jie , Fang Fenqi , Goldstein Robert Michael , Stemmer Salomon M. , Rosenbaum Eli
Published: May 2017

LBA6500

Background: Cancer drug prices are different in every country in the world, however, little is known about the magnitude of these differences. The primary objective of this study was to describe the differences in prices globally. The secondary objective was to understand ability to pay, using gross domestic product per capita at purchasing power parity (GDPcap), as a surrogate. Methods: We calculated monthly drug doses for 23 cancer drugs, 15 of which are available generically. We then calculated monthly drug prices from 6 countries on 5 different continents: Australia (AUS), China (CHI), India (IND), South Africa (SA), United Kingdom (UK), and United States (US). Given the lack of availability of discounted prices, we used list prices in order to make appropriate comparisons. Prices were obtained from locally and nationally recognized institutions. The monthly cost was converted to US$ at the exchange rate ruling on 19 January 2016. We obtained GDPcap data for each country from the International Monetary Fund, in order to estimate the monthly drug price as a percentage of GDPcap. Results: Results are displayed in the table. The median monthly patented drug price ranged from US$1515 (IND) to $8694 (US). The median monthly generic drug price ranged from US$120 (SA) to $654 (US). The median monthly % of GDPcap for patented drugs ranged from 71% (AUS) to 313% (IND). The median monthly % of GDPcap for generic drugs ranged from 3% (AUS) to 48% (CHI). Detailed information regarding specific drugs will be presented. Conclusions: There is a wide variation in drug prices globally. Despite lower prices in poorer countries, both generic and patented drugs appear to be less affordable in poorer countries. Price differences likely have some impact on access to care within individual countries. [Table: see text]
Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC).
Authors: Rudin Charles M. , Pietanza Maria Catherine , Bauer Todd Michael , Spigel David R. , Ready Neal , Morgensztern Daniel , Glisson Bonnie S. , Byers Lauren Averett , Johnson Melissa Lynne , Burris Howard A. , Robert Francisco , Strickland Donald K , Zayed Hany , Govindan Ramaswamy , Dylla Scott , Peng Stanford L.
Published: May 2017

LBA8505

Background: SCLC remains among the most deadly of malignancies. Rovalpituzumab tesirine is a first-in-class ADC comprised of a humanized monoclonal antibody against DLL3, a dipeptide linker, and a pyrrolobenzodiazepine (PBD) dimer toxin. DLL3 is highly expressed in neuroendocrine tumors, including approximately 80% of SCLC. The emerging results of the SCLC patients (pts) in a first-in-human study (NCT01901653) are reported here. Methods: Pts with progressive SCLC after at least 1 previous systemic therapy were eligible. Efficacy was assessed by the investigator via RECIST v1.1, and toxicity graded per CTCAE v4.03. When available, archived tumor tissue was assessed retrospectively for DLL3 expression by immunohistochemistry. Results: Seventy-four (74) pts were enrolled at dose levels ranging from 0.05 to 0.8 mg/kg at either q3w or q6w. Among evaluable pts treated at doses of 0.2-0.4 mg/kg, 15/61 (25%; 95% CI 15-37%) achieved a best response of PR or CR, and 44/61 (72%; 95% CI 59-83%) achieved clinical benefit (best response of at least SD). Among pts with available archive tissue specimens and ≥ 50% of cells expressing DLL3 (DLL3hi, an intended companion diagnostic cutoff), 12/22 (55%; 95% CI 32-76%) achieved a best response of PR or CR, and 20/22 (91%; 95% CI 71-99%) achieved clinical benefit, with a median overall survival of 8 (range 1-18+) months. In 3rd line DLL3hi pts (n = 10), where no approved therapy currently exists, the ORR and CBR were 70% and 90%, respectively, with at least 4 evaluable pts achieving OS of > 6 (8, 15, 18 and 18) months. Among responders treated at the phase 2 dose of 0.3 mg/kg, the median duration of response was 6 (range 1-8+) months. Among all SCLC pts, the most common grade 3+ toxicities considered study drug-related have included serosal effusions (14%), thrombocytopenia (12%) and skin reactions (8%). Conclusions: With manageable toxicity, rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity and durability in recurrent or refractory SCLC. A single-arm pivotal study in 3rd line DLL3-expressing SCLC has been initiated. Clinical trial information: NCT01901653.
Pooled Analysis of Individual Patient Data on Concurrent Chemoradiotherapy for Stage III Non–Small-Cell Lung Cancer in Elderly Patients Compared With Younger Patients Who Participated in US National Cancer Institute Cooperative Group Studies
Authors: Stinchcombe Thomas E. , Zhang Ying , Vokes Everett E. , Schiller Joan H. , Bradley Jeffrey D. , Kelly Karen , Curran Walter J. , Schild Steven E. , Movsas Benjamin , Clamon Gerald , Govindan Ramaswamy , Blumenschein George R. , Socinski Mark A. , Ready Neal E. , Akerley Wallace L. , Cohen Harvey J. , Pang Herbert H. , Wang Xiaofei
Published: May 2017

Purpose

Concurrent chemoradiotherapy is standard treatment for patients with stage III non–small-cell lung cancer. Elderly patients may experience increased rates of adverse events (AEs) or less benefit from concurrent chemoradiotherapy.

Patients and Methods

Individual patient data were collected from 16 phase II or III trials conducted by US National Cancer Institute–supported cooperative groups of concurrent chemoradiotherapy alone or with consolidation or induction chemotherapy for stage III non–small-cell lung cancer from 1990 to 2012. Overall survival (OS), progression-free survival, and AEs were compared between patients age ≥ 70 (elderly) and those younger than 70 years (younger). Unadjusted and adjusted hazard ratios (HRs) for survival time and CIs were estimated by single-predictor and multivariable frailty Cox models. Unadjusted and adjusted odds ratio (ORs) for AEs and CIs were obtained from single-predictor and multivariable generalized linear mixed-effect models.

Results

A total of 2,768 patients were classified as younger and 832 as elderly. In unadjusted and multivariable models, elderly patients had worse OS (HR, 1.20; 95% CI, 1.09 to 1.31 and HR, 1.17; 95% CI, 1.07 to 1.29, respectively). In unadjusted and multivariable models, elderly and younger patients had similar progression-free survival (HR, 1.01; 95% CI, 0.93 to 1.10 and HR, 1.00; 95% CI, 0.91 to 1.09, respectively). Elderly patients had a higher rate of grade ≥ 3 AEs in unadjusted and multivariable models (OR, 1.35; 95% CI, 1.07 to 1.70 and OR, 1.38; 95% CI, 1.10 to 1.74, respectively). Grade 5 AEs were significantly higher in elderly compared with younger patients (9% v 4%; P < .01). Fewer elderly compared with younger patients completed treatment (47% v 57%; P < .01), and more discontinued treatment because of AEs (20% v 13%; P < .01), died during treatment (7.8% v 2.9%; P < .01), and refused further treatment (5.8% v 3.9%; P = .02).

Conclusion

Elderly patients in concurrent chemoradiotherapy trials experienced worse OS, more toxicity, and had a higher rate of death during treatment than younger patients.
Systematic and general method for quantifying localization in microscopy images
Authors: Sheng Huanjie , Stauffer Weston , Lim Han N.
Published: May 2017

Quantifying the localization of molecules with respect to other molecules, cell structures and intracellular regions is essential to understanding their regulation and actions. However, measuring localization from microscopy images is often difficult with existing metrics. Here, we evaluate a metric for quantifying localization termed the threshold overlap score (TOS), and show it is simple to calculate, easy to interpret, able to be used to systematically characterize localization patterns, and generally applicable. TOS is calculated by: (i) measuring the overlap of pixels that are above the intensity thresholds for two signals; (ii) determining whether the overlap is more, less, or the same as expected by chance, i.e. colocalization, anti-colocalization, or non-colocalization; and (iii) rescaling to allow comparison at different thresholds. The above is repeated at multiple threshold combinations to generate a TOS matrix to systematically characterize the relationship between localization and signal intensities. TOS matrices were used to identify and distinguish localization patterns of different proteins in various simulations, cell types and organisms with greater specificity and sensitivity than common metrics. For all the above reasons, TOS is an excellent first line metric, particularly for cells with mixed localization patterns.
Strain-specific differences of the effects of stress on memory in Lymnaea
Authors: Hughes Emily , Shymansky Tamila , Swinton Erin , Lukowiak Kai S. , Swinton Cayley , Sunada Hiroshi , Protheroe Amy , Phillips Iain , Lukowiak Ken
Published: May 2017

Stress alters the ability to form, recall and maintain memory according to the Yerkes–Dodson/Hebb (YDH) law. The effects of environmentally relevant stressors, such as low environmental calcium and crowding, on learning and memory have previously been described in a laboratory-reared ‘average’ strain of Lymnaea stagnalis (i.e. the Dutch strain) as well as two strains of freshly collected L. stagnalis with enhanced memory formation abilities (i.e. ‘smart’ snails). Here, we use L. stagnalis to study the effects of other environmentally relevant stressors on memory formation in two other strains of freshly collected snails, one ‘smart’ and one ‘average’. The stressors we examined are thermal, resource restriction combined with food odour, predator detection and, for the first time, tissue injury (shell damage). We show that the same stressor has significantly different effects on memory formation depending on whether snails are ‘smart’ or ‘average’. Specifically, our data suggest that a stressor or a combination of stressors act to enhance memory in ‘average’ snails but obstruct memory formation in ‘smart’ snails. These results are consistent with the YDH law and our hypothesis that ‘smart’ snails are more easily stressed than ‘average’ snails.
Intertidal oysters reach their physiological limit in a future high-CO2 world
Authors: Scanes Elliot , Parker Laura M. , O'Connor Wayne A. , Stapp Laura S. , Ross Pauline M.
Published: May 2017

Sessile marine molluscs living in the intertidal zone experience periods of internal acidosis when exposed to air (emersion) during low tide. Relative to other marine organisms, molluscs have been identified as vulnerable to future ocean acidification; however, paradoxically it has also been shown that molluscs exposed to high CO2 environments are more resilient compared with those molluscs naive to CO2 exposure. Two competing hypotheses were tested using a novel experimental design incorporating tidal simulations to predict the future intertidal limit of oysters in a high-CO2 world; either high-shore oysters will be more tolerant of elevated PCO2 because of their regular acidosis, or elevated PCO2 will cause high-shore oysters to reach their limit. Sydney rock oysters, Saccostrea glomerata, were collected from the high-intertidal and subtidal areas of the shore and exposed in an orthogonal design to either an intertidal or a subtidal treatment at ambient or elevated PCO2, and physiological variables were measured. The combined treatment of tidal emersion and elevated PCO2 interacted synergistically to reduce the haemolymph pH (pHe) of oysters, and increase the PCO2 in the haemolymph (Pe,CO2) and standard metabolic rate. Oysters in the intertidal treatment also had lower condition and growth. Oysters showed a high degree of plasticity, and little evidence was found that intertidal oysters were more resilient than subtidal oysters. It is concluded that in a high-CO2 world the upper vertical limit of oyster distribution on the shore may be reduced. These results suggest that previous studies on intertidal organisms that lacked tidal simulations may have underestimated the effects of elevated PCO2.
Polyadenylation is the key aspect of GLD-2 function in C. elegans
Authors: Nousch Marco , Minasaki Ryuji , Eckmann Christian R.
Published: May 2017

The role of many enzymes extends beyond their dedicated catalytic activity by fulfilling important cellular functions in a catalysis-independent fashion. In this aspect, little is known about 3′-end RNA-modifying enzymes that belong to the class of nucleotidyl transferases. Among these are noncanonical poly(A) polymerases, a group of evolutionarily conserved enzymes that are critical for gene expression regulation, by adding adenosines to the 3′-end of RNA targets. In this study, we investigate whether the functions of the cytoplasmic poly(A) polymerase (cytoPAP) GLD-2 in C. elegans germ cells exclusively depend on its catalytic activity. To this end, we analyzed a specific missense mutation affecting a conserved amino acid in the catalytic region of GLD-2 cytoPAP. Although this mutated protein is expressed to wild-type levels and incorporated into cytoPAP complexes, we found that it cannot elongate mRNA poly(A) tails efficiently or promote GLD-2 target mRNA abundance. Furthermore, germ cell defects in animals expressing this mutant protein strongly resemble those lacking the GLD-2 protein altogether, arguing that only the polyadenylation activity of GLD-2 is essential for gametogenesis. In summary, we propose that all known molecular and biological functions of GLD-2 depend on its enzymatic activity, demonstrating that polyadenylation is the key mechanism of GLD-2 functionality. Our findings highlight the enzymatic importance of noncanonical poly(A) polymerases and emphasize the pivotal role of poly(A) tail-centered cytoplasmic mRNA regulation in germ cell biology.
A Matheuristic for the Multivehicle Inventory Routing Problem
Authors: Archetti Claudia , Boland Natashia , Grazia Speranza M.
Published: May 2017

We consider the inventory routing problem, in which a supplier has to replenish a set of customers by means of a limited fleet of capacitated vehicles over a discrete time horizon. The goal is to minimize the total cost of the distribution that comprises the inventory cost at the supplier and at the customers and the routing cost. We present a matheuristic that combines a tabu search and mathematical programming formulations. When compared with two exact methods on 640 small instances, the matheuristic finds 192 (48%) optima over the 402 instances with known optima and improves 125 upper bounds. Tested on 240 large instances (with up to 200 customers) for which no optimal solutions are known, it improves the best solution for 220 (92%) of the 240 instances.

The online supplement is available at https://doi.org/10.1287/ijoc.2016.0737 .
Greater Mutual Aggravation
Authors: Ebert Sebastian , Nocetti Diego C. , Schlesinger Harris
Published: May 2017

A large strand of research has identified when (i) a single risk is undesirable and (ii) two independent risks aggravate each other. We extend this line of inquiry by establishing when (iii) mutual aggravation is greater for greater risks. This natural property of greater mutual aggravation explains recent experimental findings on higher-order risk preferences, and can guide managerial behavior when risks in the decision environment become more severe.

The online appendix is available at https://doi.org/10.1287/mnsc.2017.2746 .

This paper was accepted by Han Bleichrodt, decision analysis.
Lower urinary tract infections in women
Authors: Davis Cathy , Rantell Angie
Published: May 2017

In her lifetime, a woman is highly likely to develop at least one lower urinary tract infection. Early detection and treatment are key. Being aware of predisposing factors for infection and understanding appropriate diagnosis and treatment regimens will help nurses in both primary and acute care manage these patients correctly. This will not only benefit patients but will also help prevent incorrect antimicrobial management and avoid unplanned admissions. This aim of this article is to provide nurses with the information they need to best advise both colleagues and patients on how to manage lower urinary tract infections in women.
Inferior results with unilateral compared with bilateral brace in Ponseti-treated clubfeet
Authors: Sætersdal C. , Fevang J. M. , Engesæter L. B.
Published: May 2017

Purpose

The Ponseti method for treating clubfoot was introduced in Norway in 2003, and a cohort of children has been followed for 8 to 11 years. In a previous study, we found good results after follow-up of two to five years, with 3% rate of extensive surgery (posterior release or posteromedial release). During 8 to 11 years of follow-up, the rate of extensive surgery increased to 11%. The children had been treated with a bilateral brace or a unilateral brace. In this multicentre study we aimed to compare these two post-corrective treatment methods.

Methods

In all, 94 children (133 feet) were initially treated according to the Ponseti method, and had post-corrective treatment with either a bilateral foot abduction brace or a unilateral above-the-knee brace. The children were examined at a mean age of 9.3 years (8 to 11) regarding flexibility and deformity of the foot and ankle. Information including type of brace, brace compliance and surgical procedures was ­obtained from the patient records. The parents answered questionnaires and radiographs were taken of the feet.

Results

Feet treated with a bilateral brace had better dorsal flexion (p = 0.008), plantar flexion (p = 0.02), external rotation (p = 0.001) and less forefoot adduction (p = 0.04) than feet treated with a unilateral brace. Children using a bilateral brace had a better Functional Rating System score (p = 0.005) and Disease Specific Instrument score (p = 0.02).

Conclusion

Children treated with a bilateral brace had better parent-reported outcomes and more flexible feet than children treated with a unilateral brace. Our results do not support the use of a unilateral foot abduction brace in clubfoot treatment.
AN ALGEBRAIC REPRESENTATION VIA DIFFERENTIAL EQUATIONS FOR PAIRWISE COMPARISONS OF AHP
Authors: Mizuno Takafumi
Published: May 2017

We propose a simple algebraic representation for pairwise comparisons of AHP. The representation is an associative relation between the importances of elements and consists of basic arithmetic operations. First, we define a ratio, which is estimated by decision makers by comparing the importances of elements, as a partial differentiation of importances (Section 2). Then, we construct systems of differential equations. Algebraic representations of the importances are derived as formal solutions of the equations. We analyze pairwise comparisons and the construction of the importances from them with the representations (Section 3). The validity of using eigenvectors and C.I. in AHP is illustrated by deriving a particular solution of the equations.https://doi.org/10.13022/ijahp2017.v9.is1.278