A sensitive LC-MS/MS assay to quantitate free payload Aur0101 from ADC PYX-201 in rat and monkey plasma.

Aim: Aur0101 is a cytotoxic and small-molecule microtubule depolymerizing agent, and is the payload conjugated to antibody-drug conjugate PYX-201. Developing and validating a sensitive bioanalytical method to quantitate Aur0101 was novel and crucial in preclinical PYX-201 studies. Materials & methods: Reference standard Aur0101 and its stable isotope labelled internal standard Aur0101-d8 were used in this LC-MS/MS method. Results: This sensitive assay was validated at a lower limit of quantitation of 15 pg/ml and successfully applied to support preclinical rat and monkey toxicology studies. Preclinical plasma toxicokinetic parameters were presented. Conclusion: A sensitive and robust LC-MS/MS assay was validated for Aur0101 in rat and monkey plasma.

Quantitation of total antibody (tAb) from antibody drug conjugate (ADC) PYX-201 in rat and monkey plasma using an enzyme-linked immunosorbent assay (ELISA) and its application in preclinical studies.

PYX-201 is an investigative ADC oncology drug composed of a monoclonal human immunoglobulin G (IgG) antibody targeting the extra domain B splice variant of fibronectin (EDB + FN) conjugated to an auristatin payload through a cleavable linker. Effective measurement of PYX-201 tAb is the key to ADC drug PYX-201 preclinical pharmacokinetics (PK) assessment. PYX-201 monoclonal antibody (mAb) was used as the reference standard, goat anti-human IgG polyclonal antibody (pAb) or rabbit anti-human Kappa light chain mAb was employed as the capture antibody, and mouse mAb or goat pAb anti-human IgG the crystallizable fragment (Fc) (horseradish peroxidase (HRP)) was utilized as the detection antibody in this ELISA. This assay was validated with a dynamic range 250 - 10,000 ng/mL and 250 - 6000 ng/mL in rat and monkey K2EDTA plasma, respectively. PYX-201 tAb bioanalytical ELISA assay was reported for the first time in any biological matrix. This is the first time for a bioanalytical method to be validated for a tAb from an ADC drug targeting EDB + FN in any biological matrix.

Quantification of antibody-drug conjugate PYX-201 in rat and monkey plasma via ELISA and its application in preclinical studies.

Aim: PYX-201 is a novel antibody-drug conjugate targeting the extra domain B splice variant of fibronectin in the tumor microenvironment. Accurate quantification of PYX-201 is critical for PYX-201 pharmacokinetics profiling in preclinical studies. Materials & methods: ELISA was performed using reference standard PYX-201, mouse monoclonal anti-monomethyl auristatin E antibody, mouse IgG1, mouse monoclonal anti-human IgG horseradish peroxidase and donkey anti-human IgG horseradish peroxidase. Results: This assay was validated at 50.0-10,000 ng/ml in rat dipotassium EDTA plasma and 250-10,000 ng/ml in monkey dipotassium EDTA plasma. Conclusion: This is the first time for a PYX-201 bioanalytical assay in any matrix to be reported.

COVID-19 Vaccination Delivery in Long-Term-Care using the CARD (Comfort Ask Relax Distract) System: Mixed Methods study of Implementation Drivers.

Objectives: CARD (comfort, ask, relax, distract) is a vaccine delivery framework that includes interventions to improve the patient's experience. CARD has not been previously implemented in long-term care (LTC) settings. This study evaluated drivers to implementation for COVID-19 vaccinations in an LTC facility. Methods: Postimplementation interpretive evaluation including qualitative interviews and quantitative surveys with eight participants. The Consolidated Framework for Implementation Research (CFIR) was used for analysis. Adverse reactions to vaccinations and CARD interventions, including local reactogenicity and systemic reactions, were abstracted from medical charts of residents. Results: Eight CFIR constructs emerged. Staff perceived CARD was complex because it added steps to vaccination delivery. Motivated to meet residents' needs, a receptive implementation climate of support among staff led to using strategies within CARD, such as administering topical anesthetics and omitting alcohol skin antisepsis prior to injections. Having an effective network like the residents council positively influenced implementation by allowing residents to voice their opinions. Facilitators to implementation included staff knowledge and beliefs and staff's commitment to their organization, which was focused on person-centered care. Barriers included lack of available resources (inadequate staffing), insufficient communication between management and staff and lack of awareness of CARD, and external policies not aligned with CARD. Chart reviews conducted for 93 vaccinated residents corroborated perceptions of vaccination and CARD intervention safety, revealing a low rate of local and systemic adverse reactions and no cases of skin infection. Discussion: We identified positive and negative implementation drivers. Future research is recommended to expand the strategies employed and involve residents more directly.

Objectifs: Le système CARD (confort, aide, relaxation, distraction) est un cadre d'administration de vaccins qui comprend des interventions pour amèliorer l'expérience du patient. Le système CARD n'a pas été mis en œuvre précédemment dans les établissements de soins de longue durée. Cette étude a évalué les facteurs de sa mise en œuvre pour la vaccination contre la COVID-19 dans un établissement de soins de longue durée.Méthodes: Évaluation interprétative après la mise en œuvre, y compris des entretiens qualitatifs et des enquêtes quantitatives auprès de huit participants. Le Cadre consolidé pour la recherche sur la mise en œuvre (CFIR) a été utilisé pour l'analyse. Les effets indésirables à la vaccination et aux interventions CARD, y compris la réactogénicité locale et les réactions systémiques, ont été extraites des dossiers médicaux des résidentsRésultats: Huit construits du CFIR ont émergé. Le personnel a perçu que le système CARD était complexe car il ajoutait des étapes à la vaccination. Motivé à répondre aux besoins des résidents, un climat de mise en œuvre réceptif suscitant le soutien du personnel a conduit à l'utilisation de stratégies propres au système CARD, telles que l'administration d'anesthésiques topiques et l'omission de l'antisepsie cutanée à l'alcool avant les injections. Le fait d'avoir un réseau efficace comme le conseil des résidents a influencé positivement la mise en œuvre en permettant à ces derniers d'exprimer leurs opinions. Les facilitateurs de la mise en œuvre comprenaient les connaissances et les croyances du personnel et l'engagement de celui-ci envers l'organisation, qui mettait l'accent sur les soins centrés sur la personne. Les obstacles comprenaient le manque de disponibilité des ressources (effectifs insuffisants), l'insuffisance de la communication entre la direction et le personnel et le manque de connaissances au sujet de CARD, de même que les politiques externes non alignées avec le système CARD. Un examen des dossiers effectué pour 93 résidents vaccinés a corroboré les perceptions de la sécurité de la vaccination et de l'intervention CARD tout en révélant un faible taux d'effets indésirables locaux et systémiques et aucun cas d'infection cutanée.Discussion: Nous avons identifié des facteurs de mise en œuvre positifs et négatifs. Des recherches futures sont recommandées pour élargir les stratégies utilisées et impliquer plus directement les résidents.

Complexity of Nurse Practitioners' Role in Facilitating a Dignified Death for Long-Term Care Home Residents during the COVID-19 Pandemic.

Due to the interplay of multiple complex and interrelated factors, long-term care (LTC) home residents are increasingly vulnerable to sustaining poor outcomes in crisis situations such as the COVID-19 pandemic. While death is considered an unavoidable end for LTC home residents, the importance of facilitating a good death is one of the primary goals of palliative and end-of-life care. Nurse practitioners (NPs) are well-situated to optimize the palliative and end-of-life care needs of LTC home residents. This study explores the role of NPs in facilitating a dignified death for LTC home residents while also facing increased pressures related to the COVID-19 pandemic. The current exploratory qualitative study employed a phenomenological approach. A purposive sample of 14 NPs working in LTC homes was recruited. Data were generated using semi-structured interviews and examined using thematic analysis. Three categories were derived: (a) advance care planning and goals of care discussions; (b) pain and symptom management at the end-of-life; and (c) care after death. The findings suggest that further implementation of the NP role in LTC homes in collaboration with LTC home team and external partners will promote a good death and optimize the experiences of residents and their care partners during the end-of-life journey.

Context matters when implementing patient centred rehabilitation models for persons with cognitive impairment: a case study.

BACKGROUND: There is a growing number of older adults with cognitive impairment (CI) that require inpatient rehabilitation, and as such patient centred rehabilitation models have been developed. However, implementing evidence-based models without attending to the fit of the model to the new context could lead to an unsuccessful outcome. Researchers collaborated with administrators and staff in one rural site to adapt a patient centred rehabilitation model of care in the Canadian province of Ontario. This paper reports on the contextual factors that influenced the implementation of the model of care. METHODS: The study takes a case study approach. One rural facility was purposefully selected for its interest in offering rehabilitation to persons with CI. Four focus group discussions were conducted to explore healthcare professionals' perceptions on the contextual factors that could affect the implementation of the rehabilitation model of care in the facility. Twenty-seven professionals with various backgrounds were purposively sampled using a maximum diversity sampling strategy. A hybrid inductive-deductive approach was used to analyze the data using the Context and Implementation of Complex Interventions (CICI) Framework. RESULTS: Across the domains of the CICI framework, three domains (political, epidemiological, and geographical) and seven corresponding sub-domains of the context were found to have a major influence on the implementation process. Key elements within the political domain included effective teamwork, facilitation, adequate resources, effective communication strategies, and a vision for change. Within the epidemiological domain, a key element was knowing how to tailor rehabilitation approaches for persons with CI. Infrastructure, an aspect of the geographical domain, focused on the facility's physical layout that required attention. CONCLUSIONS: The CICI framework was a useful guide to identify key factors within the context that existed and were required to fully support the implementation of the model of care in a new environment. The findings suggest that when implementing a new program of care, strong consideration should be paid to the political, epidemiological, and geographical domains of the context and how they interact and influence one another.

Healthcare professionals' perspectives on rehabilitating persons with cognitive impairment.

BACKGROUND AND OBJECTIVES: Despite emerging evidence that persons with cognitive impairment (CI) (including dementia and/or delirium) can be rehabilitated post-hip fracture surgery, there still remains a paucity of research on best practice rehabilitation strategies that help healthcare providers effectively rehabilitate persons with CI. Therefore, this qualitative study explores healthcare professionals' (HCPs) perspectives who have been successfully providing rehabilitation for people with CI. RESEARCH DESIGN AND METHODS: Sixteen HCPs with a specialty in rehabilitating persons with CI from one inpatient rehabilitation facility with various professional backgrounds were purposively sampled using a maximum diversity sampling strategy. Three focus group discussions were conducted to explore their experiences of providing rehabilitation to persons with CI. A hybrid inductive-deductive approach was used to analyze the data. FINDINGS: HCPs acknowledged that older adults with CI deserved the opportunity for inpatient rehabilitation and that good outcomes were achievable; however, their knowledge, skills, and attitudes required reframing. The analysis identified three essential components to rehabilitation: (1) staff education and support, (2) tailored rehabilitation approaches, and (3) care partner involvement and support. DISCUSSION AND IMPLICATIONS: Rehabilitation of persons with CI post-hip fracture surgery is achievable, and HCPs can learn to modify their practices to achieve positive patient outcomes. The attitudes of the healthcare team members had to be shifted to embrace the belief that persons with CI can be rehabilitated. However, it takes a steep learning curve, creativity, ingenuity, and tailored approaches to rehabilitate persons with CI successfully. This involves knowing the individual, maintaining routines, and learning the best ways to engage and motivate the person. As well, care partners' knowledge and understanding of the individual improved the chances of a successful rehabilitation stay and discharge. Essential to the success of rehabilitation of persons with CI includes a supportive management team to help create the processes to enable their staff to succeed.

A sensitive liquid chromatography-tandem mass spectrometry method for quantitative determination of dasotraline in human plasma and its clinical application.

This manuscript describes a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of dasotraline in human plasma. Dasotraline and the internal standard (IS) d4-13C4-dasotraline were extracted from the 0.500-mL plasma pre-mixed with 0.20-mL of 0.5 M sodium bicarbonate solution by a 3-mL of hexane containing 0.7 % sec-butyl alcohol. The organic extract, after dried down, was reconstituted in 150 µL acetonitrile containing 0.1 % formic acid. Forty (40) µL of the resulted sample was injected into LC-MS/MS for analysis. Chromatographic separation was on a Betasil Silica column. MS/MS detection was by monitoring m/z 275→159 and 283→160 for dasotraline and IS, respectively. Peak area ratio of analyte/IS was used for constructing calibration curve and calculating sample concentration. The retention time was ∼3.1 min for both dasotraline and IS. The validated linear range was 5-5000 pg/mL with correlation coefficient r ≥ 0.999. Intra-run precision and accuracy were ≤ 7.3 % CV (n = 6) and 94.4-101.0 % of nominals. Inter-run precision and accuracy were ≤ 4.7 % CV (n = 18) and 96.1-99.8 % of nominals. Plasma sample was confirmed stable for 8 cycles of freeze/thaw, 29 h on bench-top, and up to 977 days of storage at both -20 °C and -70 °C. This method was successfully applied to analyze pharmacokinetic (PK) samples from a single ascending dose (SAD) clinical study with healthy subjects. PK results indicated that dasotraline was slowly absorbed (tmax: 10-12 h) and slowly eliminated (terminal elimination half-life, i.e. t1/2: 47-77 h) with dose proportional Cmax but slightly greater than dose proportional AUC with increase of dosed amount.

Exploring a Common Data Element for International Research in Long-Term Care Homes: A Measure for Evaluating Nursing Supervisor Effectiveness.

The aim of this study is to recommend a common data element (CDE) to measure supervisory effectiveness of staff working in LTC homes that can be used in international research. Supervisory effectiveness can serve as a CDE in an effort to establish an international, person-centered LTC research infrastructure in accordance with the aims of the WE-THRIVE group (Worldwide Elements to Harmonize Research in Long Term Care Living Environments). A literature review was completed and then a panel of experts independently reviewed and prioritized appropriateness of the measures with mindfulness of their potential applications to international LTC settings. The selection of a recommended CDE measure was guided by the WE-THRIVE group's focus on capacity rather than deficits, the expected availability of internationally comparable data and the goal to provide a short, ecologically viable measurement, specifically for low- and middle-income countries. Two measures were considered as the CDE for supervisory effectiveness, Benjamin Rose Relationship Scale and the Supervisory Support Scale; however, given that the latter measure has been translated in Spanish and Chinese and has been tested with nursing assistants in both of these countries with good psychometric properties, our group recommends it as the CDE going forward.

Recommended Common Data Elements for International Research in Long-Term Care Homes: Exploring the Workforce and Staffing Concepts of Staff Retention and Turnover.

The aim of this review is to develop a common data element for the concept of staff retention and turnover within the domain of workforce and staffing. This domain is one of four core domains identified by the WE-THRIVE (Worldwide Elements to Harmonize Research in Long-Term Care Living Environments) group in an effort to establish an international, person-centered long-term care research infrastructure. A rapid review identified different measurement methods to assess either turnover or retention at facility level or intention to leave or stay at the individual staff level. The selection of a recommended measurement was guided by the WE-THRIVE group's focus on capacity rather than deficits, the expected availability of internationally comparable data, and the goal to provide a short, ecologically viable measurement. We therefore recommend to measure staff's intention to stay with a single item, at the individual staff level. This element, we argue, is an indicator of staff stability, which is important for reduced organizational cost and improved productivity, positive work environment, and better resident-staff relationships and quality of care.