The genomic and evolutionary landscapes of anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Interprofessional Teamwork: A Qualitative Study on Adapting Central Policies to Local Conditions in a Labour and Delivery Unit.

OBJECTIVES: We record the experiences of staff in a labour, delivery, and obstetric services (LD-OBS) unit in Alberta's largest quaternary medical centre-the Foothills Medical Centre (FMC)-as they navigated hospital policies during the COVID-19 pandemic. We examine how unit leadership applied these policies to better align with care delivery realities while staying true to the interprofessional nature of the unit. METHODS: A total of 12 semi-structured qualitative interviews were conducted with LD-OBS unit staff. Snowball and purposive sampling strategies were used to capture experiences from key informants. Interview transcripts underwent inductive coding. The themes identified through this process were discussed with members of the authorial team until a consensus was reached. RESULTS: FMC LD-OBS team members used 'interprofessional' as a value through which to interpret, adapt, and implement centrally developed COVID-19 policies. These were applied at 3 key moments: reconfiguring the unit, triaging, and rerouting patients, and contesting central personal protective equipment policies. LD-OBS leaders championed the importance of interprofessional collaboration and teamwork in the unit and worked to uphold it as a practice and value. CONCLUSION: The COVID-19 pandemic experience of the FMC LD-OBS unit illustrates the importance of considering interprofessionalism as a core value as policy was developed and implemented. Health authorities, hospitals, and other LD-OBS units may wish to consider how interprofessional work affects policy interpretation among health care teams, and how this may be leveraged to successfully adapt policies to local units, under both pandemic and 'normal' conditions.

Doing primary care integration: a qualitative study of meso-level collaborative practices.

BACKGROUND: The integration of Primary Care (PC) into broader health systems has been a goal in jurisdictions around the world. Efforts to achieve integration at the meso-level have drawn particular attention, but there are few actionable recommendations for how to enact a 'pro-integration culture' amongst government and PC governance bodies. This paper describes pragmatic integration activity undertaken by meso-level participants in Alberta, Canada, and suggests ways this activity may be generalizable to other health systems. METHODS: 11 semi-structured interviews with nine key informants from meso-level organizations were selected from a larger qualitative study examining healthcare policy development and implementation during the COVID-19 pandemic. Selected interviews focused on participants' experiences and efforts to 'do' integration as they responded to Alberta's first wave of the Omicron variant in September 2021. An interpretive descriptive approach was used to identify repeating cycles in the integration context, and pragmatic integration activities. RESULTS: As Omicron arrived in Alberta, integration and relations between meso-level PC and central health system participants were tense, but efforts to improve the situation were successfully made. In this context of cycling relationships, staffing changes made in reaction to exogenous shocks and political pressures were clear influences on integration. However, participants also engaged in specific behaviours that advanced a pro-integration culture. They did so by: signaling value through staffing and resource choices; speaking and enacting personal and group commitments to collaboration; persevering; and practicing bi-directional communication through formal and informal channels. CONCLUSIONS: Achieving PC integration involves not just the reactive work of responding to exogenous factors, but also the proactive work of enacting cultural, relationship, and communication behaviors. These behaviors may support integration regardless of the shocks, staff turnover, and relational freeze-thaw cycles experienced by any health system.

Quality of life for men with metastatic castrate-resistant prostate cancer participating in an aerobic and resistance exercise pilot intervention.

BACKGROUND: Following a prostate cancer diagnosis, disease and treatment-related symptoms may result in diminished quality of life (QoL). Whether exercise improves QoL in men with metastatic castrate-resistant prostate cancer (mCRPC) is not fully understood. METHODS: We conducted a 3-arm pilot randomized controlled trial to assess the feasibility, acceptability, safety, and efficacy of a 12-week remotely monitored exercise program among men with mCRPC. Here we report qualitative changes in QoL, consistent with the guidelines for pilot trials. Men were randomized to control, aerobic exercise, or resistance exercise. Exercise prescriptions were based on baseline cardiorespiratory and strength assessments. QoL outcomes were evaluated using self-reported questionnaires (e.g., QLQ-C30, PROMIS Fatigue, Pittsburgh Sleep Quality Index (PSQI), EPIC-26) collected at baseline and 12 weeks. RESULTS: A total of 25 men were randomized (10 control, 8 aerobic, 7 resistance). Men were predominately white (76%) with a median age of 71 years (range: 51-84) and 10.5 years (range: 0.9-26.3) post prostate cancer diagnosis. The men reported poor sleep quality and high levels of fatigue at enrollment. Other baseline QoL metrics were relatively high. Compared to the controls at 12 weeks, the resistance arm reported some improvements in social function and urinary irritative/obstruction symptoms while the aerobic arm reported some improvements in social function and urinary incontinence, yet worsening nausea/vomiting. Compared to the resistance arm, the aerobic arm reported worse urinary irritative/obstruction symptoms and self-rated QoL, yet some improvements in emotional function, insomnia, and diarrhea. CONCLUSIONS: The 3-month exercise intervention pilot appeared to have modest effects on QoL among mCRPC survivors on ADT. Given the feasibility, acceptability, and safety demonstrated in prior analyses, evaluation of the effect of the intervention on QoL in a larger sample and for extended duration may still be warranted.

Considering context: Adaptive elements of a simulation program to improve primary care safety during the COVID-19 pandemic in Alberta, Canada.

BACKGROUND: Globally, primary care (PC) has been central to the COVID-19 response. The pandemic has strained PC systems and introduced novel infection prevention and control (IPC) risks to the provision of safe, accessible in-person care. Specifically, the implementation of IPC guidance developed outside of PC into its operational context has proved challenging. METHODS: Our team of "action researchers" developed an innovative virtual tabletop simulations (TTS) intervention which assisted PC teams as they adapted, implemented, and integrated IPC guidance into their specific clinical contexts. While we have detailed the "technical" elements of the TTS program elsewhere, this paper examines the specific "adaptive" elements that made this intervention successful in the high-income country context of Alberta, Canada. RESULTS: Multiple factors influenced the uptake of this program in our Albertan setting, including: cultural geography; approach to financing and delivering PC; and policies and cultural norms supporting PC integration, medical education and research, and egalitarian teamwork. CONCLUSIONS: Virtual TTS may provide substantial benefits to IPC and safety improvements in PC settings globally. However, the specific technical and adaptive elements of our Albertan TTS program might, or might not, make these a viable IPC intervention for adapting, spreading, and scaling to other settings.

Improving Conversations With COVID-19 Vaccine Hesitant Patients: Action Research to Support Family Physicians.

Vaccination delivery and efforts to counter vaccine hesitancy have become focal issues for family medicine teams as the COVID-19 pandemic has evolved. Conducting action research, our team developed an interactive web-based guide to improve clinical conversations around a broad range of vaccine hesitancies presented by patients. The paper presents a step-by-step account of the guide being codesigned with family physicians-its targeted end users-in a process that included validation interviews; role-play interviews; and user-tested design. The validation interviews sought to understand the pragmatic realities of vaccine hesitancy in family medicine clinical practice relative to relevant psychological theories. The role-play interviews drew out conversational strategies and advice from family physicians. The principles of motivational interviewing-an evidence-based approach to vaccine hesitancy conversations that supplements information deficit approaches-were used to codesign the content and layout of the guide. User counts, stakeholder engagement, and web-based analytics indicate the guide is being used extensively. Formal evaluation of the guide is presently underway.Originally published as Annals "Online First" article.

Introduction and expression of PIK3CAE545K in a papillary thyroid cancer BRAFV600E cell line leads to a dedifferentiated aggressive phenotype.

Anaplastic thyroid cancer (ATC) is a rare, aggressive form of undifferentiated thyroid cancer, which exhibits rapid progression and is almost universally fatal. At least a subset of ATC is thought to arise from pre-existing well-differentiated thyroid cancer, most frequently papillary thyroid cancer (PTC). While PIK3CA mutations are rare in PTC, they are common in ATC and tend to co-occur with BRAF mutations. This provided the rationale for our study to identify the potential role of PIK3CA mutations in the progression from well-differentiated to undifferentiated thyroid cancer. We introduced PIK3CAE545K into the LAM1 PTC cell line, which carries a BRAFV600E mutation. In culture, the engineered cell line (LAM1:PIK3CAE545K) proliferated faster and demonstrated increased clonogenic potential relative to the parental line carrying an empty vector (LAM1EV). Both the LAM1EV and LAM1:PIK3CAE545K edited lines were implanted into hind flanks of athymic nude mice for in vivo determination of disease progression. While tumour weights and volumes were not significantly higher in LAM1:PIK3CAE545K mice, there was a decrease in expression of thyroid differentiation markers TTF-1, thyroglobulin, PAX8 and B-catenin, suggesting that introduction of PIK3CAE545K led to dedifferentiation in vivo. Collectively, this study provides evidence of a role for PIK3CAE545K in driving disease progression from a well-differentiated to an undifferentiated thyroid cancer; however, over-expression was not a determinant of an accelerated growth phenotype in ATC.

A "Shock Test" to Primary Care Integration: COVID-19 Lessons from Alberta.

The COVID-19 pandemic exposed primary care (PC), and policies aimed at integrating it into provincial health systems, to a "shock test." This paper draws on documentary analysis and qualitative interviews with PC and health system stakeholders to examine shifts in Alberta's pre-pandemic PC integration model during the first nine months of the pandemic. We begin with an account of three elements of the province's pre-pandemic model: finance, health authority activity and community activity. We describe these elements as they shifted, focusing on two indicators of change: novel virtual care billing codes and personal protective equipment (PPE) distribution channels. We draw out policy planning lessons for improving PC integration under normal and future pandemic conditions, namely, by facilitating rapid updates of virtual care billing codes, analyses of the impact of care delivery and backstopping of PPE markets and supply chains for PC.

Achieving Resilience in Primary Care during the COVID-19 Pandemic: Competing Visions and Lessons from Alberta.

The COVID-19 pandemic has tested the resilience of health systems broadly and primary care (PC) specifically. This paper begins by distinguishing the technical and political aspects of resilience and then draws on a documentary analysis and qualitative interviews with health system and PC stakeholders to examine competing resilience-focused responses to the pandemic in Alberta, Canada. We describe the pre-existing linkages between the province's central service delivery agency and its independent PC clinics. Together, these central and independent elements make up Alberta's broader health system, with the focus of this paper being on PC's particular vision of how resilience ought to be achieved. We describe two specific, pandemic-affected areas of activity by showing how competing visions of resilience emerged in the central service delivery agency and independent PC responses as they met at the system's points of linkage. At the first point of linkage, we describe the centralized activation of an incident management system and the replies made by independent PC stakeholders. At the second point of linkage, we describe central efforts to disseminate infection prevention and control guidance to PC clinics and the improvisational efforts of staff at those independent clinics to operationalize the guidance and ensure continuity of operations. We identify gaps between the resilience visions of the central agency and independent PC, drawing broadly applicable policy lessons for improving responses in present and future public health emergencies. Finding ways to include PC in centralized resilience policy planning is a priority.

Feasibility, safety, and acceptability of a remotely monitored exercise pilot CHAMP: A Clinical trial of High-intensity Aerobic and resistance exercise for Metastatic castrate-resistant Prostate cancer.

BACKGROUND: Exercise may improve clinical and quality of life outcomes for men with prostate cancer. No randomized controlled trials (RCTs) have examined the feasibility, safety, and acceptability of remote exercise training in men with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: We conducted a pilot RCT (1:1:1 aerobic or resistance exercise 3x/week or usual care) to determine the feasibility, safety, and acceptability of remotely monitored exercise over 12 weeks in 25 men with mCRPC. A prescribed exercise program was based on baseline testing including high- and moderate-intensity aerobic exercise or resistance exercise completed at a local exercise facility. Feasibility was based on attendance, adherence, and tolerance; safety on adverse events; and acceptability on participant interviews. RESULTS: Between March 2016 and March 2020, 25 patients were randomized (8 aerobic, 7 resistance, and 10 control). Twenty-three men (82%) completed the 12-week study. Men who completed the remote intervention attempted 90% and 96% of prescribed aerobic and resistance training sessions, respectively, and 86% and 88% of attempted sessions were completed as or more than prescribed. We observed changes in performance tests that corresponded with the exercise prescription. No safety concerns were identified. Ninety percent of participants interviewed were satisfied with the program and would recommend it to others. CONCLUSIONS: Remotely monitored exercise training is feasible, safe, and acceptable in men with mCRPC; there was no difference in these outcomes by mode of exercise. Through this research, we provide direction and rationale for future studies of exercise and clinical outcomes in patients with metastatic prostate cancer.

Detection of Circulating Tumor DNA in Patients with Thyroid Nodules.

OBJECTIVE: Detection of circulating tumor DNA (ctDNA) in cancer patients can potentially serve as a noninvasive, sensitive test of disease status. The purpose of this study was to determine the ability to detect BRAF (V600E) mutations in the plasma of patients with thyroid nodules, with the goal of distinguishing between benign and malignant nodules. METHODS: Consecutive patients with thyroid nodules who consented for surgery were recruited. Plasma samples were obtained preoperatively and one month postoperatively. Quantitative PCR was used to determine the levels of the BRAF (V600E) mutation preoperatively and postoperatively. RESULTS: A total of 109 patients were recruited. On final pathology, 38 (32.8%) patients had benign thyroid nodules, 45 (38.8%) had classical papillary thyroid cancer (PTC), 23 (19.8%) had nonclassical PTC, and 3 (2.6%) had follicular thyroid cancer. 15/109 patients had detectable BRAF (V600E) ctDNA in their preoperative samples-all of them having classical PTC. Higher T-stage and extrathyroidal extension in PTC were associated with positive BRAF (V600E) ctDNA (p < 0.05). Eighty-eight pairs of preoperative and postoperative plasma samples were collected and analyzed. Of these eighty-eight paired samples, a total of 13/88 (14.8%) patients had detectable BRAF (V600E) ctDNA in their preoperative samples-all of them having classical PTC. 12 of these 13 patients had no detectable BRAF (V600E) postoperatively, while one remaining patient had a significant decline in his levels (p < 0.05). CONCLUSION: BRAF (V600E) circulating thyroid tumor DNA can be detected in plasma and is correlated with a final diagnosis of the classical variant of PTC. Given that a postoperative drop in BRAF (V600E) ctDNA levels was observed in all cases suggests its utility as a tumor marker.

Virtual tabletop simulations for primary care pandemic preparedness and response.

INTRODUCTION: The COVID-19 pandemic prompted widescale use of clinical simulations to improve procedures and practices. We outline our deployment of a virtual tabletop simulation (TTS) method in primary care (PC) clinics across Alberta, Canada. We summarise the quality and safety improvements from this method and report end users' perspectives on key elements. METHODS: Our virtual TTS used teleconferencing software alongside digital whiteboards to walk clinic stakeholders through patient scenarios. Participants reviewed and rehearsed their workflows and care practices. The goal was for staff to take ownership over gaps and codesigned solutions. After simulation sessions, follow-up interviews were conducted to collect feedback. RESULTS: These sessions helped PC staff identify and codesign solutions for clinical hazards and threats. These included the flow of patients through clinics, communications, redesignation of physical spaces, and adaptation of guidance for cleaning and personal protective equipment use. End users reported sessions provided neutral spaces to discuss practice changes and built confidence in delivering safe care during the pandemic. DISCUSSION: TTS has not been extensively deployed to improve clinical practice in outpatient environments. We show how virtual TTS can bridge gaps between knowledge and practice by offering a guided space to rehearse clinical changes. We show that virtual TTS can be used in multiple contexts to help identify hazards, improve safety and build confidence in professional teams adapting to rapid changes in both policies and practices. While our sessions were conducted in Alberta, our results suggest this method may be deployed in other contexts, including low-resource settings.

Feasibility and Acceptability of an Asthma App to Monitor Medication Adherence: Mixed Methods Study.

BACKGROUND: Poor medication adherence is a major challenge in asthma, and objective assessment of inhaler adherence is needed. The InspirerMundi app aims to monitor adherence while providing a positive experience through gamification and social support. OBJECTIVE: This study aimed to evaluate the feasibility and acceptability of the InspirerMundi app to monitor medication adherence in adolescents and adults with persistent asthma (treated with daily inhaled medication). METHODS: A 1-month mixed method multicenter observational study was conducted in 26 secondary care centers from Portugal and Spain. During an initial face-to-face visit, physicians reported patients' asthma therapeutic plan in a structured questionnaire. During the visits, patients were invited to use the app daily to register their asthma medication intakes. A scheduled intake was considered taken when patients registered the intake (inhaler, blister, or other drug formulation) by using the image-based medication detection tool. At 1 month, patients were interviewed by phone, and app satisfaction was assessed on a 1 (low) to 5 (high) scale. Patients were also asked to point out the most and least preferred app features and make suggestions for future app improvements. RESULTS: A total of 107 patients (median 27 [P25-P75 14-40] years) were invited, 92.5% (99/107) installed the app, and 73.8% (79/107) completed the 1-month interview. Patients interacted with the app a median of 9 (P25-P75 1-24) days. At least one medication was registered in the app by 78% (77/99) of patients. A total of 53% (52/99) of participants registered all prescribed inhalers, and 34% (34/99) registered the complete asthma therapeutic plan. Median medication adherence was 75% (P25-P75 25%-90%) for inhalers and 82% (P25-P75 50%-94%) for other drug formulations. Patients were globally satisfied with the app, with 75% (59/79) scoring ≥4,; adherence monitoring, symptom monitoring, and gamification features being the most highly scored components; and the medication detection tool among the lowest scored. A total of 53% (42/79) of the patients stated that the app had motivated them to improve adherence to inhaled medication and 77% (61/79) would recommend the app to other patients. Patient feedback was reflected in 4 major themes: medication-related features (67/79, 85%), gamification and social network (33/79, 42%), symptom monitoring and physician communication (21/79, 27%), and other aspects (16/79, 20%). CONCLUSIONS: The InspirerMundi app was feasible and acceptable to monitor medication adherence in patients with asthma. Based on patient feedback and to increase the registering of medications, the therapeutic plan registration and medication detection tool were redesigned. Our results highlight the importance of patient participation to produce a patient-centered and engaging mHealth asthma app.

Autotrasplante Dental Utilizando Simulación Virtual y un Prototipo de Modelo de Impresión 3D

RESUMEN: La técnica de autotrasplante dental se ideó como opción terapéutica ante la pérdida o ausencia de dientes por traumatismos, caries, agenesias, exfoliación temprana, iatrogenias, u otros factores. Consiste en extraer un diente desde su posición original para implantarlo en un solo acto quirúrgico en una zona edéntula, sea ésta un alveolo postextracción o alveolo confeccionado quirúrgicamente. Un resultado exitoso, requiere una meticulosa selección de candidatos, para esto, se debe considerar la ausencia de patologías y condiciones de orden local o sistémico que dificulten una adecuada cicatrización de heridas y reparación tisular. Nuevas herramientas para facilitar éxito clínico, como la planificación y simulación virtual, junto con la impresión de prototipos en tres dimensiones (3D), permitirían optimizar posibles osteotomías y una implantación del diente donante de manera fácil y en tiempos quirúrgicos mínimos, favoreciendo la disminución de la complejidad quirúrgica, además de la reparación y regeneración de tejidos pulpares y periodontales. El objetivo de este artículo es reunir una serie de consideraciones para optimizar la técnica de autotrasplante dental.

ABSTRACT: The dental autotransplantation technique was devised as a therapeutic option for the loss or absence of teeth due to trauma, caries, agenesis, early exfoliation, iatrogenesis, or other factors. It consists of extracting a tooth from its original position to implant it in a single surgical act in an edentulous area, be it a post-extraction socket or a surgically made socket. A successful result requires meticulous selection of candidates, for this, the absence of pathologies and local or systemic conditions that hinder adequate wound healing and tissue repair must be considered. New tools to facilitate clinical success,such as planning and virtual simulation, together with the printing of prototypes in three dimensions (3D), would allow possible osteotomies and an implantation of the donor tooth in an easy way and in minimal surgical times, favoring the decrease of surgical complexity, in addition to the repair and regeneration of pulp and periodontal tissues. The objective of this article is to gather a series of considerations to optimize the dental autotransplantation technique.

Rapid conversion of an in-patient hospital unit to accommodate COVID-19: An interdisciplinary human factors, ethnography, and infection prevention and control approach.

BACKGROUND: In response to the Coronavirus disease-19 (COVID-19) pandemic, in-patient units in hospitals around the world have altered their patient care routines and Infection Prevention and Control (IPC) practices. Our interdisciplinary team of applied Human Factors (HF), ethnography, and IPC experts assisted one Unit, normally serving general surgical and orthopedic patients, as it rapidly converted to deliver COVID-19-specific care. This paper describes the conversion experience of the Unit, and outlines broader lessons for other acute care teams faced with similar issues. METHODS: We deployed walkthroughs, simulations, and ethnography to identify important safety gaps in care delivery processes on the Unit. These interventions were undertaken using interdisciplinary theories of implementation that combined systems-level HF perspectives, ethnographic approaches, and individual-level IPC perspectives. Timely recommendations were developed and delivered to Unit staff for feedback and implementation. RESULTS: We describe three interventions on the Unit: 1) the de-cluttering and re-organization of personal protective equipment (PPE); 2) the reconfiguring of designated 'dirty' tray tables and supplies; and 3) the redesign of handling pathways for 'dirty' linens and laundry. Each of these interventions was implemented to varying degrees, but all contributed to discussions of safety and IPC implementation that extended beyond the Unit and into the operations of the broader hospital. CONCLUSIONS: Leveraging our team's interdisciplinary expertise and blended approaches to implementation, the interventions assisted in the Unit's rapid conversion towards providing COVID-19-specific care. The deployment and implementation of the interventions highlight the potential of collaboration between HF, ethnography, and IPC experts to support frontline healthcare delivery under pandemic conditions in an effort to minimize nosocomial transmission potential in the acute healthcare setting.

Monitoring Adherence to Asthma Inhalers Using the InspirerMundi App: Analysis of Real-World, Medium-Term Feasibility Studies.

Background: Poor medication adherence is a major challenge in asthma and objective assessment of inhaler adherence is needed. InspirerMundi app aims to monitor inhaler adherence while turning it into a positive experience through gamification and social support. Objective: We assessed the medium-term feasibility of the InspirerMundi app to monitor inhaler adherence in real-world patients with persistent asthma (treated with daily inhaled medication). In addition, we attempted to identify the characteristics of the patients related to higher app use. Methods: Two real-world multicenter observational studies, with one initial face-to-face visit and a 4-month telephone interview, were conducted in 29 secondary care centers from Portugal. During an initial face-to-face visit, patients were invited to use the app daily to register their asthma medication intakes. A scheduled intake was considered taken when patients took a photo of the medication (inhaler, blister, or others) using the image-based medication detection tool. Medication adherence was calculated as the number of doses taken as a percentage of the number scheduled. Interacting with the app ≥30 days was used as the cut-off for higher app use. Results: A total of 114 patients {median 20 [percentile 25 to percentile 75 (P25-P75) 16-36] years, 62% adults} were invited, 107 (94%) installed the app and 83 (73%) completed the 4-month interview. Patients interacted with the app for a median of 18 [3-45] days, translated on a median use rate of 15 [3-38]%. Median inhaler adherence assessed through the app was 34 [4-73]% when considering all scheduled inhalations for the study period. Inhaler adherence assessed was not significantly correlated with self-reported estimates. Median adherence for oral and other medication was 41 [6-83]% and 43 [3-73]%, respectively. Patients with higher app use were slightly older (p = 0.012), more frequently taking medication for other health conditions (p = 0.040), and more frequently prescribed long-acting muscarinic antagonists (LAMA, p = 0.024). After 4 months, Control of Allergic Rhinitis and Asthma Test (CARAT) scores improved (p < 0.001), but no differences between patients interacting with the app for 30 days or less were seen. Conclusions: The InspirerMundi app was feasible to monitor inhaler adherence in patients with persistent asthma. The persistent use of this mHealth technology varies widely. A better understanding of characteristics related to higher app use is still needed before effectiveness studies are undertaken.

GRADE Concept Paper 1: Validating the "F.A.C.E" instrument using stakeholder perceptions of feasibility, acceptability, cost, and equity in guideline implement.

BACKGROUND AND OBJECTIVE: To present a structured approach for assessing stakeholder perceptions and implementing the approach in guideline development. METHODS: This work was carried out by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Equity and Stakeholder Engagement Project Groups through brainstorming and iterative frameworks, stakeholder engagement, pilot testing, refinement of ideas, using input from workshops, and discussions at GRADE Working Group meetings to produce this document, which constitutes a GRADE conceptual article on implementation. RESULTS: We introduce the FACE implementation criteria, feasibility, acceptability, cost, and equity; priority; and "intent to implement" criterion. We outline the implementation importance of networks and approaches to patient and other stakeholder engagement. Implementation is often highly contextual and can benefit from stakeholder engagement and other assessments. Our FACE approach provides stakeholder questions and language to inform guideline implementation and tools. CONCLUSION: The FACE criteria propose a series of knowledge translation questions to guide the assessment of implementation for evidence-based guidelines. It is desirable for guideline developers to use a conceptual approach, such as FACE, to tailor implementation and inform end of guideline dissemination and knowledge translation activities.

Beyond COVID-19: Evidence-Based Consensus Statement on the Role of Physiotherapy in Pulmonary Rehabilitation in the Indian Context.

Post COVID-19 sequelae includes breathlessness, weakness, fatigue, decreased exercise tolerance and impaired quality of life. Physiotherapy based rehabilitation program is an essential component for post COVID-19 patients in facilitating maximum functional recovery. Expert consensus statements are available from the developed countries. There is a need for a guidelines to manage post COVID-19 sequelae in Indian context. The objective of this consensus statement is to provide evidence informed guidelines for post COVID-19 physiotherapy management as a component of pulmonary rehabilitation. This consensus statement was developed by expert panel across India. Published literatures were appraised and used to prepare the recommendations. This is the first of its kind of work providing preliminary guidelines for post COVID-19 physiotherapy.

Determinants of Implementation of a Clinical Practice Guideline for Homeless Health.

Clinical practice guidelines can improve the clinical and social care for marginalized populations, thereby improving health equity. The aim of this study is to identify determinants of guideline implementation from the perspective of patients and practitioner stakeholders for a homeless health guideline. We completed a mixed-method study to identify determinants of equitable implementation of homeless health guidelines, focusing on the Grading of Recommendations Assessment, Development and Evaluation Feasibility, Acceptability, Cost, and Equity Survey (GRADE-FACE) health equity implementation outcomes. The study included a survey and framework analysis. Eighty-eight stakeholders, including practitioners and 16 persons with lived experience of homelessness, participated in the study. Most participants favourably rated the drafted recommendations' priority status, feasibility, acceptability, cost, equity impact, and intent-to-implement. Qualitative analysis uncovered stakeholder concerns and perceptions regarding "fragmented services". Practitioners were reluctant to care for persons with lived experience of homelessness, suggesting that associated social stigma serves as a barrier for this population to access healthcare. Participants called for improved "training of practitioners" to increase knowledge of patient needs and preferences. We identified several knowledge translation strategies that may improve implementation of guidelines for marginalized populations. Such strategies should be considered by other guideline development groups who aim to improve health outcomes in the context of limited and fragmented resources, stigma, and need for advocacy.

TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma.

BACKGROUND: Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs). METHODS: Five unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance. RESULTS: Prolonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20-35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib. CONCLUSIONS: We have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients.