Accurate estimation of the normalized mutual information of multidimensional data.

While the linear Pearson correlation coefficient represents a well-established normalized measure to quantify the inter-relation of two stochastic variables X and Y, it fails for multidimensional variables, such as Cartesian coordinates. Avoiding any assumption about the underlying data, the mutual information I(X, Y) does account for multidimensional correlations. However, unlike the normalized Pearson correlation, it has no upper bound (I ∈ [0, ∞)), i.e., it is not clear if say, I = 0.4 corresponds to a low or a high correlation. Moreover, the mutual information (MI) involves the estimation of high-dimensional probability densities (e.g., six-dimensional for Cartesian coordinates), which requires a k nearest-neighbor algorithm, such as the estimator by Kraskov et al. [Phys. Rev. E 69, 066138 (2004)]. As existing methods to normalize the MI cannot be used in connection with this estimator, a new approach is presented, which uses an entropy estimation method that is invariant under variable transformations. The algorithm is numerically efficient and does not require more effort than the calculation of the (un-normalized) MI. After validating the method by applying it to various toy models, the normalized MI between the Cα-coordinates of T4 lysozyme is considered and compared to a correlation analysis of inter-residue contacts.

Exploring experiential learning within interprofessional practice education initiatives for pre-licensure healthcare students: a scoping review.

BACKGROUND: Interprofessional collaborative team-based approaches to care in health service delivery has been identified as important to health care reform around the world. Many academic institutions have integrated interprofessional education (IPE) into curricula for pre-licensure students in healthcare disciplines, but few provide formal initiatives for interprofessional practice (IPP). It is recognized that experiential learning (EL) can play a significant role supporting IPP education initiatives; however, little is known of how EL is used within education for IPP in healthcare settings. METHODS: We conducted a scoping review to map peer-reviewed literature describing IPP education initiatives involving EL for pre-licensure students in healthcare disciplines. A literature search was executed in MEDLINE, CINAHL, EMBASE, ERIC, PsycINFO, Scopus, and Social Services Abstracts. After deduplication, two independent reviewers screened titles and abstracts of 5664 records and then 252 full-text articles that yielded 100 articles for data extraction. Data was extracted using an Excel template, and results synthesized for presentation in narrative and tabular formats. RESULTS: The 100 included articles represented 12 countries and IPP education initiatives were described in three main typologies of literature - primary research, program descriptions, and program evaluations. Forty-three articles used a theory, framework, or model for design of their initiatives with only eight specific to EL. A variety of teaching and learning strategies were employed, such as small interprofessional groups of students, team huddles, direct provision of care, and reflective activities, but few initiatives utilized a full EL cycle. A range of perspectives and outcomes were evaluated such as student learning outcomes, including competencies associated with IPP, impacts and perceptions of the IPP initiatives, and others such as client satisfaction. CONCLUSION: Few educational frameworks specific to EL have been used to inform EL teaching and learning strategies to consolidate IPE learning and prepare students for IPP in healthcare settings. Further development and evaluation of existing EL frameworks and models would be beneficial in supporting robust IPP educational initiatives for students in healthcare disciplines. Intentional, thoughtful, and comprehensive use of EL informed by theory can contribute important advances in IPP educational approaches and the preparation of a future health care workforce.

'Snapshot in time': a cross-sectional study exploring stakeholder experiences with environmental scans in health services delivery research.

OBJECTIVE: To describe stakeholder characteristics and perspectives about experiences, challenges and information needs related to the use of environmental scans (ESs). DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: A web-based survey platform was used to disseminate an online survey to stakeholders who had experience with conducting ESs in a health services delivery context (eg, researchers, policy makers, practitioners). Participants were recruited through purposive and snowball sampling. The survey was disseminated internationally, was available in English and French, and remained open for 6 weeks (15 October to 30 November 2022). ANALYSIS: Descriptive statistics were used to describe the characteristics and experiences of stakeholders. Thematic analysis was used to analyse the open-text questions. RESULTS: Of 47 participants who responded to the survey, 94% were from Canada, 4% from the USA and 2% from Australia. Respondents represented academic institutions (57%), health agency/government (32%) and non-government organisations or agencies (11%). Three themes were identified: (a) having a sense of value and utility; (b) experiencing uncertainty and confusion; and (c) seeking guidance. The data suggest stakeholders found value and utility in ESs and conducted them for varied purposes including to: (a) enhance knowledge, understanding and learning about the current landscape or state of various features of health services delivery (eg, programmes, practices, policies, services, best practices); (b) expose needs, service barriers, challenges, gaps, threats, opportunities; (c) help guide action for planning, policy and programme development; and (d) inform recommendations and decision-making. Stakeholders also experienced conceptual, methodological and practical barriers when conducting ESs, and expressed a need for methodological guidance delivered through published guidelines, checklists and other means. CONCLUSION: ESs have value and utility for addressing health services delivery concerns, but conceptual and methodological challenges exist. Further research is needed to help advance the ES as a distinct design that provides a systematic approach to planning and conducting ESs.

Toward a Benchmark for Markov State Models: The Folding of HP35.

Adopting a 300 µs long MD trajectory of the folding of villin headpiece (HP35) by D. E. Shaw Research, we recently constructed a Markov state model (MSM) based on inter-residue contacts. The model reproduces the folding time and predicts that the native basin and unfolded region consist of metastable substates that are structurally well-characterized. Recognizing the need to establish well-defined benchmark problems, we study to what extent and in what sense this MSM can be employed as a reference model. Hence, we test the robustness of the MSM by comparing it to models that use alternative combinations of features, dimensionality reduction methods, and clustering schemes. The study suggests some main characteristics of the folding of HP35 that should be reproduced by other competitive models. Moreover, the discussion reveals which parts of the MSM workflow matter most for the considered problem and illustrates the promises and pitfalls of state-based models for the interpretation of biomolecular simulations.

Selecting Features for Markov Modeling: A Case Study on HP35.

Markov state models represent a popular means to interpret molecular dynamics trajectories in terms of memoryless transitions between metastable conformational states. To provide a mechanistic understanding of the considered biomolecular process, these states should reflect structurally distinct conformations and ensure a time scale separation between fast intrastate and slow interstate dynamics. Adopting the folding of villin headpiece (HP35) as a well-established model problem, here we discuss the selection of suitable input coordinates or "features", such as backbone dihedral angles and interresidue distances. We show that dihedral angles account accurately for the structure of the native energy basin of HP35, while the unfolded region of the free energy landscape and the folding process are best described by tertiary contacts of the protein. To construct a contact-based model, we consider various ways to define and select contact distances and introduce a low-pass filtering of the feature trajectory as well as a correlation-based characterization of states. Relying on input data that faithfully account for the mechanistic origin of the studied process, the states of the resulting Markov model are clearly discriminated by the features, describe consistently the hierarchical structure of the free energy landscape, and─as a consequence─correctly reproduce the slow time scales of the process.

Understanding Student-Run Health Initiatives in the Context of Community-Based Services: A Concept Analysis and Proposed Definitions.

BACKGROUND: Student-run health initiatives in the community setting have been utilized to provide practical experience for undergraduate students to develop professional competencies, gain exposure to diverse populations, and to engage in activities of social accountability. There is much literature on student-run health initiatives; however, there is no consensus on a definition of this concept or a comprehensive synthesis of the literature that describes student-run health initiatives offered by students in pre-licensure healthcare education programs. PURPOSE: To provide a concept analysis of, and propose a definition for, student-run health initiatives that provide community-based services for students during pre-licensure health discipline education. METHODS: A systematic literature search and review process was used to identify and synthesize peer-reviewed articles from 7 academic databases covering a range of pre-licensure health disciplines and education. Walker and Avant's framework for concept analysis was used to guide exploration of attributes, antecedents and consequences of student-run initiatives, and to inform development of a definition for this concept. RESULTS: The review yielded 222 articles for data extraction and represented 17 distinct pre-licensure health disciplines, 18 health-related disciplines, and a range of other baccalaureate and graduate programs. Our analysis revealed 16 definitions, 5 attributes, 6 antecedents, and consequences identified for student-run health initiatives. Attributes were Provision of Service, Service is Free, Target Clientele, Volunteerism, and Student Governance. Antecedents included Purpose/Rationale, Affiliation with Academic Unit, Location and Partnerships, Funding and Resources, Professional Oversight, and Preparation for Student Role. Consequences were improved access to services and outcomes for clients; competency development, personal gains and interprofessional learning for students; and positive outcomes for broader systems, such as decrease of service utilization and cost/benefit. CONCLUSIONS: There was no clear conceptual definition for student-run health initiatives, but many defining characteristics and well-described exemplars in the literature. Given the variations in purpose and scope of these initiatives, particularly to distinguish degree of students' roles in operations and the involvement of academic institutions, we propose 3 distinct conceptual definitions: student-run, student-led, and student-infused health initiatives.

Correlation-Based Feature Selection to Identify Functional Dynamics in Proteins.

To interpret molecular dynamics simulations of biomolecular systems, systematic dimensionality reduction methods are commonly employed. Among others, this includes principal component analysis (PCA) and time-lagged independent component analysis (TICA), which aim to maximize the variance and the time scale of the first components, respectively. A crucial first step of such an analysis is the identification of suitable and relevant input coordinates (the so-called features), such as backbone dihedral angles and interresidue distances. As typically only a small subset of those coordinates is involved in a specific biomolecular process, it is important to discard the remaining uncorrelated motions or weakly correlated noise coordinates. This is because they may exhibit large amplitudes or long time scales and therefore will be erroneously considered important by PCA and TICA, respectively. To discriminate collective motions underlying functional dynamics from uncorrelated motions, the correlation matrix of the input coordinates is block-diagonalized by a clustering method. This strategy avoids possible bias due to presumed functional observables and conformational states or variation principles that maximize variance or time scales. Considering several linear and nonlinear correlation measures and various clustering algorithms, it is shown that the combination of linear correlation and the Leiden community detection algorithm yields excellent results for all considered model systems. These include the functional motion of T4 lysozyme to demonstrate the successful identification of collective motion, as well as the folding of the villin headpiece to highlight the physical interpretation of the correlated motions in terms of a functional mechanism.

Use of environmental scans in health services delivery research: a scoping review.

OBJECTIVE: To examine the extent and nature of evidence on the use of the environmental scan (ES) in the health services delivery literature. DESIGN: Scoping review. METHODS: This scoping review followed the five-stage scoping review methodology outlined by Khalil et al. A Peer Review of Electronic Search Strategies was completed. Seven electronic databases and the grey literature were searched. Pairs of researchers independently performed two levels of screening and data extraction. Data were analysed using qualitative content and thematic analysis. RESULTS: Ninety-six studies were included in the scoping review. Researchers conducted ESs for many purposes, the most common being to examine the current state of programmes, services or policies. Recommendations were informed by ESs in 20% of studies. Most common data collection methods were literature review (71%), key informant or semistructured interviews (46%) and surveys (35%). Over half (53%) of the studies used a combination of passive (looking at information eg, literature, policies, guidelines) and active (looking for information eg, surveys, interviews) approaches to data collection. Person sources of data (eg, healthcare stakeholders, community representatives) and non-person sources of data (eg, documents, electronic databases, the web) were drawn on to a similar extent. The thematic analysis of the definitions/descriptions yielded several themes including instrument of discovery, knowledge synthesis, forward-looking and decision making. Research gaps identified included absence of a standard definition, inconsistencies in terminology and lack of guiding frameworks in the health services delivery context. CONCLUSION: ESs were conducted to gather evidence and to help inform decision making on a range of policy and health services delivery issues across the continuum of care. Consistency in terminology, a consensus definition and more guidance on ES design may help provide structure for researchers and other stakeholders, and ultimately advance ES as a methodological approach. A working definition of ES in a health services delivery context is presented.

Concept Analysis and Proposed Definition of Community Health Center.

Background: Community health centers (CHCs) have been used for delivery of health services since the 1920s and originally were intended to provide care to underserved populations. CHCs have become an integral part of healthcare systems in many countries; however, the term CHC is used synonymously with other concepts and there is no clear definition for CHC. The purpose of our concept analysis was to determine how CHCs are described in the literature and to develop a concept definition for CHC. Methods: Informed by the 8-step process described by Walker and Avant, we searched for literature spanning disciplines within health, business, and policy. We used a systematic review process to identify a range of peer-reviewed articles that help illustrate the attributes, antecedents, and consequences of CHCs. A total of 102 articles from 7 databases were included in our concept analysis. Results: We distinguished 6 attributes of a CHC: primary care; accessibility; preventative care; defined population; health promotion; and comprehensive and integrated care. About 4 antecedents fundamental to a CHC included: secure funding; vision and support; adequate human resources; and governance structure. Consequences of CHCs are improved health outcomes, efficiency, and cost-effective provision of healthcare services. Conclusions: Our concept analysis revealed core characteristics of CHCs that assisted us in synthesizing a concept definition for CHC. These characteristics and our proposed definition will help provide clarity on the concept of CHC to benefit evaluation, research, and policy development of CHCs.

Pilot of a community-based interprofessional "student-infused" pulmonary rehabilitation program in Saint John, New Brunswick.

Background: With the increasing prevalence of chronic pulmonary conditions in New Brunswick and Canada it is necessary to consider innovative interventions to improve access to rehabilitation and supportive care for affected clients. In Fall 2018 we piloted a pulmonary rehabilitation (PR) program for persons with moderate to severe chronic obstructive pulmonary disease (COPD) to demonstrate a novel approach of bridging interprofessional education of students in health care fields with provision of care in a community setting. Methods: An 8-week PR program was implemented and evaluated using a quasi-experimental design with pre- and post-testing to measure the effects of the program's exercise and educational interventions on persons with COPD. Participants were assessed using the 6-Minute Walk Test (6MWT), the St. George's Respiratory Questionnaire (SGRQ), and a custom questionnaire that rated the participants' activities of daily living and the PR program. Results: Seven participants completed our PR program. Following the intervention, participants' self-reported health demonstrated a statistically significant improvement. Even though changes on the 6MWT and SGRQ were not shown to be statistically significant, there was evidence of clinically meaningful improvements in those measures. On average, participants walked 25 m further postintervention and showed clinically meaningful improvements on the SGRQ. Conclusions: This pilot project demonstrated that a community-based PR program with active involvement of students from multiple health care programs can have positive outcomes for clients with COPD. It also illustrated how educational programs can provide an innovative means for increasing access to rehabilitation and supportive care for clients in the community.

MSMPathfinder: Identification of Pathways in Markov State Models.

Markov state models represent a popular means to interpret biomolecular processes in terms of memoryless transitions between metastable conformational states. To gain insight into the underlying mechanism, it is instructive to determine all relevant pathways between initial and final states of the process. Currently available methods, such as Markov chain Monte Carlo and transition path theory, are convenient for identifying the most frequented pathways. They are less suited to account for the typically huge amount of pathways with low probability which, though, may dominate the cumulative flux of the reaction. On the basis of a systematic construction of all possible pathways, the here proposed method MSMPathfinder is able to characterize the multitude of unique pathways (say, up to 1010) in a complex system and to quantitatively calculate their correct weights and associated waiting times with predefined accuracy. Adopting the chiral transitions of a peptide helix and the folding of the villin headpiece as model problems, mechanisms and associated waiting times of these processes are discussed using a kinetic network representation. The analysis reveals that the waiting time distribution may yield only little insight into the diversity of pathways, because the measured folding times do typically not reflect the most probable path lengths but rather the cumulative effect of many different pathways.

A concept analysis of children with complex health conditions: implications for research and practice.

BACKGROUND: This concept analysis aimed to clarify the meaning of "children with complex health conditions" and endorse a definition to inform future research, policy, and practice. METHODS: Using Walker and Avant's (2011)'s approach, we refined the search strategy with input from our team, including family representatives. We reviewed the published and grey literature. We also interviewed 84 health, social, and educational stakeholders involved in the care of children with complex health conditions about their use/understanding of the concept. RESULTS: We provided model, borderline, related, and contrary cases for clarification purposes. We identified defining attributes that nuance the concept: (1) conditions and needs' breadth; (2) uniqueness of each child/condition; (3) varying extent of severity over time; 4) developmental age; and (5) uniqueness of each family/context. Antecedents were chronic physical, mental, developmental, and/or behavioural condition(s). There were individual, family, and system consequences, including fragmented services. CONCLUSIONS: Building on previous definitions, we proposed an iteration that acknowledges the conditions' changing trajectories as involving one or more chronic condition(s), regardless of type(s), whose trajectories can change over time, requiring services across sectors/settings, oftentimes resulting in a lower quality of life. A strength of this paper is the integration of the stakeholders'/family's voices into the development of the definition.

The use of the environmental scan in health services delivery research: a scoping review protocol.

INTRODUCTION: The environmental scan has been described as an important tool to inform decision-making on policy, planning and programme development in the healthcare sector. Despite the wide adoption of environmental scans, there is no consensus on a working definition within the health services delivery context and methodological guidance on the design and implementation of this approach is lacking in the literature. The objectives of this study are to map the extent, range and nature of evidence that describe the definitions, characteristics, conceptualisations, theoretical underpinnings, study limitations and other features of the environmental scan in the health services delivery literature and to propose a working definition specific to this context. METHODS AND ANALYSIS: This protocol describes a scoping review based on the methodology outlined by Khalil and colleagues. A comprehensive search strategy was developed by experienced health science librarians in consultation with the research team. A Peer Review of Electronic Search Strategies (PRESS) was completed. Two reviewers will independently screen titles, abstracts and full-text articles and select studies meeting the inclusion criteria from seven electronic databases: Academic Search Premier, Canadian Business & Current Affairs (CBCA), CINAHL, ERIC, Embase, MEDLINE and PsycINFO. The grey literature and reference lists of included articles will also be searched. The data will be analysed and presented in tabular format, and will include a descriptive numerical summary as well as a qualitative thematic analysis. ETHICS AND DISSEMINATION: This protocol provides an audit trail for a scoping review that will advance understanding about the environmental scan and its application in the health services delivery context. The review will propose a working definition and will inform future research to explore the development of a conceptual framework in this context. Findings will be disseminated through a peer-reviewed journal and conference presentations. The scoping review does not require ethics approval.

Dynamical coring of Markov state models.

The accurate definition of suitable metastable conformational states is fundamental for the construction of a Markov state model describing biomolecular dynamics. Following the dimensionality reduction in a molecular dynamics trajectory, these microstates can be generated by a recently proposed density-based geometrical clustering algorithm [F. Sittel and G. Stock, J. Chem. Theory Comput. 12, 2426 (2016)], which by design cuts the resulting clusters at the energy barriers and allows for a data-based identification of all parameters. Nevertheless, projection artifacts due to the inevitable restriction to a low-dimensional space combined with insufficient sampling often leads to a misclassification of sampled points in the transition regions. This typically causes intrastate fluctuations to be mistaken as interstate transitions, which leads to artificially short life times of the metastable states. As a simple but effective remedy, dynamical coring requires that the trajectory spends a minimum time in the new state for the transition to be counted. Adopting molecular dynamics simulations of two well-established biomolecular systems (alanine dipeptide and villin headpiece), dynamical coring is shown to considerably improve the Markovianity of the resulting metastable states, which is demonstrated by Chapman-Kolmogorov tests and increased implied time scales of the Markov model. Providing high structural and temporal resolution, the combination of density-based clustering and dynamical coring is particularly suited to describe the complex structural dynamics of unfolded biomolecules.

Frameworks for evaluation of community health centers' services and outcomes: a scoping review protocol.

REVIEW OBJECTIVES/QUESTION: The objective of this scoping review is to identify and map the frameworks used to evaluate services and outcomes of community health centers within the broader context of primary health care.The primary question for this scoping review is: what are the frameworks used to evaluate services and outcomes of community health centers?Secondary questions for this review are.

Getting a Picture.

Delivery of care by nurses in virtual environments is rapidly increasing with uptake of digitally mediated technologies, such as remote patient monitoring (RPM). Knowing the person is a phenomenon in nursing practice deemed requisite to building relationships and informing clinical decisions, but it has not been studied in virtual environments. PURPOSE OF STUDY: The intent of this study was to explicate the processes of how nurses come to know the person using RPM, one form of telehealth technology used in a virtual environment. STUDY DESIGN AND METHOD: The study was informed by Charmaz's constructivist grounded theory and included 33 interviews and 5 observational experiences of nurses using RPM in 7 different settings. FINDINGS: Getting a Picture evolved as the core category to a theoretical conceptualization of nurses knowing the person through use of RPM and other technologies, such as telephone and electronic medical records. Getting a Picture reflected a dynamic flow and integration of seven processes, such as Connecting With the Person and Recording and Reflecting, to describe how nurses strove to attain a visualization of the person. CONCLUSIONS: While navigating disparate and disconnected information and communication technologies, Getting a Picture was important for providing safe, holistic, person-centered care.

Inhibition of Canonical NF-κB Signaling by a Small Molecule Targeting NEMO-Ubiquitin Interaction.

The IκB kinase (IKK) complex acts as the gatekeeper of canonical NF-κB signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKKα and IKKß and the regulatory subunit NEMO/IKKγ. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-κB activation in response to TNFα, but not IL-1ß stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin binding (iNUB). Using biochemical and NMR experiments we demonstrate that iNUB binds to NEMOUBAN and competes for interaction with methionine-1-linked linear ubiquitin chains. iNUB inhibited NF-κB activation upon UBAN-dependent TNFα and TCR/CD28, but not UBAN-independent IL-1ß stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-κB activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-κB signaling.

Conceptualizing Telehealth in Nursing Practice: Advancing a Conceptual Model to Fill a Virtual Gap.

Increasingly nurses use various telehealth technologies to deliver health care services; however, there has been a lag in research and generation of empirical knowledge to support nursing practice in this expanding field. One challenge to generating knowledge is a gap in development of a comprehensive conceptual model or theoretical framework to illustrate relationships of concepts and phenomena inherent to adoption of a broad range of telehealth technologies to holistic nursing practice. A review of the literature revealed eight published conceptual models, theoretical frameworks, or similar entities applicable to nursing practice. Many of these models focus exclusively on use of telephones and four were generated from qualitative studies, but none comprehensively reflect complexities of bridging nursing process and elements of nursing practice into use of telehealth. The purpose of this article is to present a review of existing conceptual models and frameworks, discuss predominant themes and features of these models, and present a comprehensive conceptual model for telehealth nursing practice synthesized from this literature for consideration and further development. This conceptual model illustrates characteristics of, and relationships between, dimensions of telehealth practice to guide research and knowledge development in provision of holistic person-centered care delivery to individuals by nurses through telehealth technologies.

Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma.

Survival of activated B cell-subtype (ABC) of diffuse large B cell lymphoma (DLBCL) is driven by chronic B cell receptor (BCR) signaling that activates the canonical NF-κB pathway. Inhibition of BTK by Ibrutinib has been shown to kill ABC DLBCL cells that carry activating mutations in the BCR adaptor CD79. However, mutations in BTK or in downstream components such as CARMA1/CARD11 can render lymphomas Ibrutinib resistant. Therefore, we assessed here the simultaneous inhibition of BTK and the protease MALT1 that acts downstream of CARMA1 and is essential for ABC DLBCL tumor growth. We show that in CD79 mutant cells BTK is a crucial upstream regulator of MALT1, but dispensable in CARMA1 mutant ABC DLBCL. Combined inhibition of BTK by Ibrutinib and MALT1 by S-Mepazine additively impaired MALT1 cleavage activity and expression of NF-κB pro-survival factors. Thereby, combinatorial Ibrutinib and S-Mepazine treatment enhanced killing of CD79 mutant ABC DLBCL cells. Moreover, while expression of oncogenic CARMA1 in CD79 mutant cells conferred Ibrutinib resistance, double mutant cells were still sensitive to MALT1 inhibition by S-Mepazine. Thus, based on the genetic background combinatorial BTK and MALT1 inhibition may improve effectiveness of therapeutic treatment and reduce the chances for the development of drug resistances.