bluuebunny/crossref_metadata_2025_split huggingface dataset:
How can evidence-based interventions give the best value for users in social services? Balance between adherence and adaptations: a study protocol
Authors: Hasson Henna , Gröndal Hedvig , Rundgren Åsa Hedberg , Avby Gunilla , Uvhagen Håkan , von Thiele Schwarz Ulrica 
Published: February 2020

Abstract
Background
Using evidence-based interventions (EBIs) is a basic premise of contemporary social services (e.g., child and family social services). However, EBIs seldom fit seamlessly into a specific setting but often need to be adapted. Although some adaptions might be necessary, they can cause interventions to be less effective or even unsafe. The challenge of balancing adherence and adaptations when using EBIs is often referred to as the adherence and adaptation dilemma. Although the current literature identifies professionals’ management of this dilemma as problematic, it offers little practical guidance for professionals. This research aims to investigate how the adherence and adaptation dilemma is handled in social services and to explore how structured decision support can impact the management of the dilemma.

Methods
The design is a prospective, longitudinal intervention with a focus on the feasibility and usefulness of the structured decision support. The project is a collaboration between academic researchers, embedded researchers at three research and development units, and social service organizations. A multi-method data collection will be employed. Initially, a scoping review will be performed, and the results will be used in the development of a structured decision support. The decision support will be further developed and tested during a series of workshops with social service professionals. Different forms of data—focus group interviews, questionnaires, and documentation—will be used on several occasions to evaluate the impact of the structured decision support. Qualitative and quantitative analysis will be performed and usefulness for practice prioritized throughout the study.

Discussion
The study will contribute with knowledge on how the adherence and adaption dilemma is handled and experienced by social service professionals. Most importantly, the study will generate rich empirical data on how a structured decision support impacts professionals’ management of adherence and adaptions. The goal is to produce more strategic and context-sensitive implementation of EBIs in social service, which will increase value for service users.
Development of a theory-driven implementation strategy for cancer management guidelines in sub-Saharan Africa
Authors: DeBoer Rebecca J. , Ndumbalo Jerry , Meena Stephen , Ngoma Mamsau T. , Mvungi Nanzoke , Siu Sadiq , Selekwa Msiba , Nyagabona Sarah K. , Luhar Rohan , Buckle Geoffrey , Lin Tracy Kuo , Breithaupt Lindsay , Kennell-Heiling Stephanie , Mushi Beatrice , Philipo Godfrey Sama , Mmbaga Elia J. , Mwaiselage Julius , Van Loon Katherine 
Published: February 2020

Abstract
Background
Despite recent international efforts to develop resource-stratified clinical practice guidelines for cancer, there has been little research to evaluate the best strategies for dissemination and implementation in low- and middle-income countries (LMICs). Guideline publication alone is insufficient. Extensive research has shown that structured, multifaceted implementation strategies that target barriers to guideline use are most likely to improve adherence; however, most of this research has been conducted in high-income countries. There is a pressing need to develop and evaluate guideline implementation strategies for cancer management in LMICs in order to address stark disparities in cancer outcomes.

Methods
In preparation for the launch of Tanzania’s first National Cancer Treatment Guidelines, we developed a theory-driven implementation strategy for guideline-based practice at Ocean Road Cancer Institute (ORCI). Here, we use the Intervention Mapping framework to provide a detailed stepwise description of our process. First, we conducted a needs assessment to identify barriers and facilitators to guideline-based practice at ORCI. Second, we defined both proximal and performance objectives for our implementation strategy. Third, we used the Capability, Opportunity, Motivation and Behavior/Behavior Change Wheel (COM-B/BCW) framework to categorize the barriers and facilitators, choose behavior change techniques most likely to overcome targeted barriers and leverage facilitators, and select a feasible mode of delivery for each technique. Fourth, we organized these modes of delivery into a phased implementation strategy. Fifth, we operationalized each component of the strategy. Sixth, we identified the indicators of the process, outcome, and impact of our intervention and developed an evaluation plan to measure them using a mixed methods approach.

Discussion
We developed a robust, multifaceted guideline implementation strategy derived from a prominent behavior change theory for use in Tanzania. The barriers and strategies we generated are consistent with those well established in the literature, enhancing the validity and generalizability of our process and results. Through our rigorous evaluation plan and systematic account of modifications and adaptations, we will characterize the transferability of “proven” guideline implementation strategies to LMICs. We hope that by describing our process in detail, others may endeavor to replicate it, meeting a widespread need for dedicated efforts to implement cancer guidelines in LMICs.
Improving the implementation and sustainment of evidence-based practices in community mental health organizations: a study protocol for a matched-pair cluster randomized pilot study of the Collaborative Organizational Approach to Selecting and Tailoring Implementation Strategies (COAST-IS)
Authors: Powell Byron J. , Haley Amber D. , Patel Sheila V. , Amaya-Jackson Lisa , Glienke Beverly , Blythe Mellicent , Lengnick-Hall Rebecca , McCrary Stacey , Beidas Rinad S. , Lewis Cara C. , Aarons Gregory A. , Wells Kenneth B. , Saldana Lisa , McKay Mary M. , Weinberger Morris 
Published: February 2020

Abstract
Background
Implementing and sustaining evidence-based programs with fidelity may require multiple implementation strategies tailored to address multi-level, context-specific barriers and facilitators. Ideally, selecting and tailoring implementation strategies should be guided by theory, evidence, and input from relevant stakeholders; however, methods to guide the selection and tailoring of strategies are not well-developed. There is a need for more rigorous methods for assessing and prioritizing implementation determinants (barriers and facilitators) and linking implementation strategies to determinants. The Collaborative Organizational Approach to Selecting and Tailoring Implementation Strategies (COAST-IS) is an intervention designed to increase the effectiveness of evidence-based practice implementation and sustainment. COAST-IS will enable organizational leaders and clinicians to use Intervention Mapping to select and tailor implementation strategies to address their site-specific needs. Intervention Mapping is a multi-step process that incorporates theory, evidence, and stakeholder perspectives to ensure that implementation strategies effectively address key determinants of change.

Methods
COAST-IS will be piloted with community mental health organizations that are working to address the needs of children and youth who experience trauma-related emotional or behavioral difficulties by engaging in a learning collaborative to implement an evidence-based psychosocial intervention (trauma-focused cognitive behavioral therapy). Organizations will be matched and then randomized to participate in the learning collaborative only (control) or to receive additional support through COAST-IS. The primary aims of this study are to (1) assess the acceptability, appropriateness, feasibility, and perceived utility of COAST-IS; (2) evaluate the organizational stakeholders’ fidelity to the core elements of COAST-IS; and (3) demonstrate the feasibility of testing COAST-IS in a larger effectiveness trial.

Discussion
COAST-IS is a systematic method that integrates theory, evidence, and stakeholder perspectives to improve the effectiveness and precision of implementation strategies. If effective, COAST-IS has the potential to improve the implementation and sustainment of a wide range of evidence-based practices in mental health and other sectors.

Trial registration
This study was registered in ClinicalTrials.gov (NCT03799432) on January 10, 2019 (last updated August 5, 2019).
Effectiveness of confidential reports to physicians on their prescribing of antipsychotic medications in nursing homes
Authors: Ivers Noah M. , Taljaard Monica , Giannakeas Vasily , Reis Catherine , Mulhall Cara L. , Lam Jonathan M.C. , Burchell Ann N. , Lebovic Gerald , Bronskill Susan E. 
Published: February 2020

Abstract
Background
Antipsychotic medication use in nursing homes is associated with potential for harms. In Ontario, Canada, an agency of the provincial government offers nursing home physicians quarterly audit and feedback on their antipsychotic prescribing. We compared the characteristics of physicians who did and did not engage with the intervention, and assessed early changes in prescribing.

Methods
This population-level, retrospective cohort study used linked administrative databases to track prescribing practices in nursing homes pre-intervention (baseline), immediately post-initiative (3 months), and at follow-up (6 months). Exposure variables identified whether a physician signed up to participate (or not) or viewed the feedback following sign up (or not). Differences in the proportion of days that residents received antipsychotic medications at 6 months compared to baseline by exposure(s) were assessed using a linear mixed effects regression analysis to adjust for a range of resident, physician, and nursing home factors. Benzodiazepine and statin prescribing were assessed as a balance and tracer measures, respectively.

Results
Of 944 eligible physicians, 210 (22.3%) signed up to recieve the feedback report and 132 (13.9%) viewed their feedback. Physicians who signed up for feedback were more likely to have graduated from a Canadian medical school, work in urban nursing homes, and care for a larger number of residents. The clinical and functional characteristics of residents were similar across physician exposure groups. At 6 months, antipsychotic prescribing had decreased in all exposure groups. Those who viewed their feedback report had a signicantly greater reduction in antipsychotic prescribing than those who did not sign up (0.94% patient-days exposed; 95% CI 0.35 to 1.54%, p = 0.002). Trends in prescribing patterns across exposure groups for benzodiazepines and statins were not statistically significant.

Interpretation
Almost a quarter of eligible physicians engaged early in a voluntary audit and feedback intervention related to antipsychotic prescribing in nursing homes. Those who viewed their feedback achieved a small but statistically significant change in prescribing, equivalent to approximately 14,000 fewer days that nursing home residents received antipsychotic medications over 6 months. This study adds to the literature regarding the role of audit and feedback interventions to improve quality of care.
Welcome to Implementation Science Communications
Authors: Armstrong Rebecca , Sales Anne 
Published: February 2020

AbstractImplementation research in health is a rapidly growing field. Fourteen years after the launch of Implementation Science, submissions to the journal have grown exponentially, and the journal now uses a high bar for assessing submitted manuscripts. The field of implementation research in health, however, is growing largely through entry of junior researchers with keen interest in the field whose funding histories and research experience are still developing. We consider it essential to support newer entrants to the field and boundary-spanning work that may consist of smaller, pilot studies, as well as those that contribute primarily descriptive findings.As a companion journal to Implementation Science, Implementation Science Communications will accept a broad and diverse range of article types, and provide an important platform for smaller scale or more descriptive research. As with Implementation Science, no specific discipline, research design, or paradigm will be favoured.
Exploring Integrative Analysis Using the BioMedical Evidence Graph
Authors: Struck Adam , Walsh Brian , Buchanan Alexander , Lee Jordan A. , Spangler Ryan , Stuart Joshua M. , Ellrott Kyle 
Published: February 2020

PURPOSE The analysis of cancer biology data involves extremely heterogeneous data sets, including information from RNA sequencing, genome-wide copy number, DNA methylation data reporting on epigenetic regulation, somatic mutations from whole-exome or whole-genome analyses, pathology estimates from imaging sections or subtyping, drug response or other treatment outcomes, and various other clinical and phenotypic measurements. Bringing these different resources into a common framework, with a data model that allows for complex relationships as well as dense vectors of features, will unlock integrated data set analysis. METHODS We introduce the BioMedical Evidence Graph (BMEG), a graph database and query engine for discovery and analysis of cancer biology. The BMEG is unique from other biologic data graphs in that sample-level molecular and clinical information is connected to reference knowledge bases. It combines gene expression and mutation data with drug-response experiments, pathway information databases, and literature-derived associations. RESULTS The construction of the BMEG has resulted in a graph containing > 41 million vertices and 57 million edges. The BMEG system provides a graph query–based application programming interface to enable analysis, with client code available for Python, Javascript, and R, and a server online at bmeg.io. Using this system, we have demonstrated several forms of cross–data set analysis to show the utility of the system. CONCLUSION The BMEG is an evolving resource dedicated to enabling integrative analysis. We have demonstrated queries on the system that illustrate mutation significance analysis, drug-response machine learning, patient-level knowledge-base queries, and pathway level analysis. We have compared the resulting graph to other available integrated graph systems and demonstrated the former is unique in the scale of the graph and the type of data it makes available.
TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial)
Authors: Tung Nadine , Arun Banu , Hacker Michele R. , Hofstatter Erin , Toppmeyer Deborah L. , Isakoff Steven J. , Borges Virginia , Legare Robert D. , Isaacs Claudine , Wolff Antonio C. , Marcom Paul Kelly , Mayer Erica L. , Lange Paulina B. , Goss Andrew J. , Jenkins Colby , Krop Ian E. , Winer Eric P. , Schnitt Stuart J. , Garber Judy E. 
Published: February 2020

PURPOSE Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers ( BRCA carriers). Limited data exist for estrogen receptor (ER)–positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC. PATIENTS AND METHODS BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review. RESULTS A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities. CONCLUSION pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.
End of phase I results of ZUMA-3, a phase 1/2 study of KTE-X19, anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in adult patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).
Authors: Shah Bijal D. , Bishop Michael Russell , Oluwole Olalekan O. , Logan Aaron , Baer Maria R. , Donnellan William Bruce , Carr-O'Dwyer Kristen Marie , Holmes Houston , Arellano Martha Lucia , Ghobadi Armin , Pagel John M. , Lin Yi , Cassaday Ryan Daniel , Park Jae Hong , Mardiros Armen , Shen Tong , Goyal Lovely , Vezan Remus , Jain Rajul K. , Wierda William G. 
Published: February 2020

7006 Background: KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for adult R/R ALL. In an interim analysis of Phase 1 of ZUMA-3, we reported manageable safety and encouraging efficacy of KTE-X19; 72% of pts achieved a complete remission (CR) or CR with incomplete bone marrow (BM) recovery (CRi; Wierda et al, ASH 2018. #897). Here, we present end of Phase 1 results. Methods: Adults with R/R B cell ALL, > 5% BM blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 KTE-X19 cells/kg after conditioning chemotherapy. Revised adverse event management (rAE mgmt) was implemented for additional pts in a 1 × 106 dose cohort: corticosteroids were given earlier at onset of Grade ≥ 2 neurologic events (NEs) and tocilizumab was used only for active toxicity. The primary endpoint was the dose-limiting toxicity (DLT) rate. Key additional endpoints were KTE-X19 levels, incidence of AEs, minimal residual disease (MRD), and CR/CRi rate. Results: As of 9/27/18, 45 pts had received KTE-X19 (median follow-up [f/u], 16 mo). The median age was 46 y (range, 18–77); 30 pts (66%) had ≥ 3 prior therapies and the median pre-conditioning BM blasts was 70% (range, 0–97). Six, 23, and 16 pts received 2, 1, and 0.5 × 106 cells/kg, respectively. There were no DLTs in the DLT-evaluable pts. The most common Grade ≥ 3 AEs were hypotension (38%), pyrexia (38%) and thrombocytopenia (31%). There were 2 previously reported KTE-X19–related Grade 5 AEs of cerebral infarction and multiorgan failure, both in the context of CRS. Grade ≥ 3 CRS and NEs occurred in 13 (29%) and 17 (38%) pts, respectively. Of 41 pts with ≥ 2 mo of f/u, 68% had CR/CRi, and 73% had undetectable MRD. Of 19 pts with ≥ 2 mo of f/u treated with 1 × 106 cells/kg, 16 (84%) had a CR/CRi and the median event-free survival was 15 mo. In 9 pts treated with 1 × 106 cells/kg and rAE mgmt, 2 (22%) had Grade 3 CRS and 1 (11%) had Grade 3 NE with no Grade 4/5 events. Conclusions: KTE-X19 dosing and safety mgmt have been successfully refined by testing 3 cell doses and evaluating a new AE mgmt guideline with altered corticosteroids/tocilizumab use for NE/CRS. Pivotal Phase 2 is ongoing at the 1 × 106 dose with rAE mgmt. Clinical trial information: NCT02614066.
Effective targeted antitumor activity of the antimicrobial agent taurolidine against relapsed/refractory neuroblastoma: Cytotoxicity, target modulation and tumor xenograft studies.
Authors: Swift Lucy , Zhang Chunfen , Pfaffle Antony , Chew Paul , Kovalchuk Olga , Trippett Tanya Maria , Narendran Aru 
Published: February 2020

e21502 Background: Neuroblastoma (NB) is the most common extracranial solid tumor and one of the most complex and difficult to treat diseases in pediatrics. Currently, even with highly aggressive treatment protocols, the prognosis for patients with high-risk and relapsed NB remains poor. Hence, there is a clear need to identify new agents and novel therapeutic strategies for the treatment of these children. Taurolidine (TRD) is derived from the aminosulfoacid taurine and has known anti-microbial and anti-inflammatory properties. TRD has demonstrated anti-neoplastic activity against a range of aggressive human tumors. We present mechanistic evidence and supportive preclinical data from in vitro and animal models of refractory NB for the development of an early phase clinical trial incorporating TRD. Methods: For in vitro activity studies, a panel of cell lines derived from patients with relapsed NB (n = 6) and normal control cells were treated with increasing concentrations of TRD and cell viability was measured by alamar blue assay. Phase-contrast light microscopy, western blotting, time-lapse video microscopy and analysis of global gene expression by RNA-Seq were used to evaluate target modulation and induction of cell death pathways. Bioluminescence imaging of mice bearing NB xenografts treated with TRD was used to investigate the efficacy of TRD in vivo. Results: Cell survival data showed that TRD is cytotoxic against NB cell lines in vitro (mean IC50 value 100 µM, range 65-135 µM). Phase-contrast and time-lapse video microscopy confirmed the antitumor effects of TRD. Western blot analyses identified that TRD induced target modulation and an effective apoptotic cascade, resulting in PARP cleavage. Gene expression analyses and signaling pathway activation scores indicated alterations in the Notch, MAPK and IL-10 signaling pathways. Xenograft studies further validated the in vivo activity of TRD with decreased tumor burden in treated mice and a measurable improvement in survival. Conclusions: Our study provides key pre-clinical data on the activity and mechanism of action of TRD against NB. The findings support the rationale for further evaluation of TRD for the treatment of relapsed/refractory NB patients in an early phase clinical trial.
Histone variant dictates fate biasing of neural crest cells to melanocyte lineage
Authors: Raja Desingu Ayyappa , Subramaniam Yogaspoorthi , Aggarwal Ayush , Gotherwal Vishvabandhu , Babu Aswini , Tanwar Jyoti , Motiani Rajender K. , Sivasubbu Sridhar , Gokhale Rajesh S. , Natarajan Vivek T. 
Published: February 2020

ABSTRACT
In the neural crest lineage, progressive fate restriction and stem cell assignment are crucial for both development and regeneration. Whereas fate commitment events have distinct transcriptional footprints, fate biasing is often transitory and metastable, and is thought to be moulded by epigenetic programmes. Therefore, the molecular basis of specification is difficult to define. In this study, we established a role for a histone variant, H2a.z.2, in specification of the melanocyte lineage from multipotent neural crest cells. H2a.z.2 silencing reduces the number of melanocyte precursors in developing zebrafish embryos and from mouse embryonic stem cells in vitro. We demonstrate that this histone variant occupies nucleosomes in the promoter of the key melanocyte determinant mitf, and enhances its induction. CRISPR/Cas9-based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby, our study establishes the role of a histone variant upstream of the core gene regulatory network in the neural crest lineage. This epigenetic mark is a key determinant of cell fate and facilitates gene activation by external instructive signals, thereby establishing melanocyte fate identity.