Impact of motivational feedback on levels of physical activity and quality of life by activity monitoring following knee arthroplasty surgery-protocol for a randomized controlled trial nested in a prospective cohort (Knee-Activity).

BACKGROUND: Evidence on how to improve daily physical activity (PA) levels following total knee arthroplasty (TKA) or medial uni-compartmental knee arthroplasty (mUKA) by motivational feedback is lacking. Moreover, it is unknown whether a focus on increased PA after discharge from the hospital improves rehabilitation, physical function, and quality of life. The aim of this randomized controlled trial (RCT) nested in a prospective cohort is (a) to investigate whether PA, physical function, and quality of life following knee replacement can be increased using an activity monitoring device including motivational feedback via a patient app in comparison with activity monitoring without feedback (care-as-usual), and (b) to investigate the potential predictive value of PA level prior to knee replacement for the length of stay, return to work, and quality of life. METHODS: The study is designed as a multicenter, parallel-group, superiority RCT with balanced randomization (1:1) and blinded outcome assessments. One hundred and fifty patients scheduled for knee replacement (TKA or mUKA) will be recruited through Odense University Hospital, Denmark, Vejle Hospital, Denmark and Herlev/Gentofte Sygehus, Denmark. Patients will be randomized to either 12 weeks of activity monitoring and motivational feedback via a patient app by gamification or 'care-as-usual,' including activity monitoring without motivational feedback. The primary outcome is the between-group change score from baseline to 12-week follow-up of cumulative daily accelerometer counts, which is a valid proxy for average objectively assessed daily PA. DISCUSSION: Improving PA through motivational feedback following knee replacement surgery might improve post-surgical function, health-related quality of life, and participation in everyday life. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT06005623. Registered on 2023-08-22. TRIAL STATUS: Recruiting.

Adult Patients' Experiences of Closed Reduction Treatment for Distal Radius Fracture in the Emergency Department -A Qualitative Descriptive Study.

INTRODUCTION: Distal radius fractures are common injuries managed frequently in emergency departments. While numerous studies focus on the surgical treatment of distal radius fractures, there is a lack of research about non-surgically treated patients' early experiences post-injury. The objective of this study was to explore adult patients' initial experiences following closed reduction treatment of distal radius fracture in the emergency department. METHODS: This qualitative study involved semi-structured telephone interviews with 21 patients who underwent closed-reduction treatment at 2 hospitals in Southern Denmark. Interviews were conducted within the first week following ED treatment and analyzed thematically. RESULTS: Patients were aged 42 to 91, and 3 were men. Three major themes emerged: (1) Pain Management: Patients reported significant pain during waiting periods and treatment, indicating a need for improved pain management strategies; (2) Information Dissemination: Participants expressed a need for clearer, continuous communication about their treatment and recovery expectations; and (3) Beyond the fracture: Patients were anxious about future functional abilities, especially those with dominant hand fractures, underscoring the need for holistic patient care that addresses psychological and social dimensions. DISCUSSION: Effective pain management, both pharmacological and non-pharmacological, as well as comprehensive, clear communication, is crucial in the initial treatment phase of distal radius fracture. Acknowledging patients' broader concerns can enhance the quality of care and support improved recovery outcomes. These findings imply that future emergency nursing practice should prioritize swift and effective pain management, clear and empathetic communication, and a holistic approach to patient care to optimize recovery outcomes.

The patient's perspective on rehabilitation with wireless accelerometers, activity tracking and motivational feedback following knee replacement: A qualitative study prior to a randomised controlled trial (KneeActivity).

BACKGROUND: As healthcare systems evolve, individuals are expected to be more involved in managing their health and rehabilitation. A wireless medical accelerometer (SENS motion®) has been developed to collect objective data on physical activity. The number of patients requiring knee replacement is rising, but the motivational effect of medical accelerometers in the rehabilitation after knee replacement remains unexplored. This study aims to employ a user-driven approach to tailor the SENS motion® technology for patients undergoing knee replacement prior to testing the refined technology in a randomised controlled trial. METHODS: The study used a Participatory Design research methodology, emphasising collaboration and user involvement. It was carried out in three sessions, each aimed at refining the SENS motion® system toward the needs of the patient group in focus. The first session involved six healthcare professionals who provided written feed-back. The second and third sessions included testing and subsequent interviews of patients (n = 10). After each session, conducted in iterative processes (plan, act, observe, reflect), SENS motion® system revisions were implemented according to the patient's wishes. The data collected were then analysed using qualitative content analysis. RESULTS: Prior to patient testing, healthcare professionals identified functional and technical errors that required modifications. Patient interviews revealed that (1) there were positive attitudes towards the SENS motion® system, (2) patients were motivated by daily step counts and geographical locations, especially when they were familiar with landmarks, and (3) active involvement of family members was found to be feasible, which contributed to a sense of solidarity during the rehabilitation process. CONCLUSION: This study applied a user-driven approach to customise health technology for postoperative rehabilitation in knee replacement patients. Initially, the technology had both technical and functional problems, but system revisions based on patient feedback improved its acceptance. The refined technology is undergoing testing in a randomised design.

Protocol to achieve high-resolution single-cell transcriptomics of cardiomyocytes in multiple species.

Single-cell RNA sequencing (scRNA-seq) remains state-of-the-art for transcriptomic cell-mapping. Here, we provide a protocol to generate high-resolution scRNA-seq of rare cardiomyocyte populations (e.g., regenerating/dividing, etc.) from mouse and zebrafish hearts as well as induced pluripotent stem cells, collected in time to achieve detailed transcriptomic insight. We describe the serial steps of viability staining, methanol fixation, storage, and cell sorting to preserve RNA integrity suited for scRNA-seq as well as the quality assessment of the data as shown by examples. For complete details on the use and execution of this protocol, please refer to Bak et al.1.

Participatory design in telehealth research: Practical case examples.

Participatory design (PD) is a methodology that emphasizes user participation in the design of new technologies to leverage change within organizations and services. PD originated in the computer science field in the 1970s and 1980s when new programs and technologies were developed to empower workers, by involving them in decisions that affected them. PD in health research has been proven to change clinical practice. Genuine user involvement that includes all stakeholders, and robust collaborations across sciences, sectors, and disciplines are basic elements of successful research to change clinical practice and to implement novel technical and organizational approaches. This paper summarizes seven case studies involving the use of PD in telehealth research. All cases presented promoted organizational changes supported by health information and communications technology, and have been implemented at either international, national, regional, or local levels. We describe how PD can be applied in health sciences and used to facilitate organizational changes, new perspectives, and new communications methods. The relevance and suitability of PD as a research design in health science is explained, and recommendations for conducting PD studies in telehealth research are presented. In PD, mutual learning and co-creation is facilitated. Consequently, learning from users, rather than studying them, corroborates our understanding and the emergence of new knowledge.

Cervical cancer screening integrated in routine clinical care of women with HIV.

OBJECTIVE: To evaluate if integrated cervical cancer screening (CCS) for women with HIV (WWH) in routine HIV care resulted in increased adherence to screening, and to describe the prevalence of human papillomavirus (HPV)-specific genotypes and the incidence of cellular abnormalities. DESIGN: Cohort study. METHODS: WWH who accepted the offer of combined CCS and HIV care (group 1), WWH who declined the offer (group 2), and WWH not offered CCS within HIV care (group 3) between 2013 and 2019 were included. Data was collected from The Danish HIV Cohort Study and The Danish Pathology Data Bank. Adherence to the CCS program was defined as fulfilled if WWH were screened annually. RESULTS: A total of 804 WWH were included. WWH who accepted CCS within HIV care (group 1; n  = 218) had significantly higher adherence to screening in all study years 22-99% compared with the WWH who declined CCS (group 2; n  = 232) 10-16% and WWH who were not invited for CCS (group 3; n  = 354) 11-25%. There was no significant difference in the prevalence of HPV-specific genotypes and incidence of cellular abnormalities among the three groups. CONCLUSION: Integrating CCS for WWH in routine HIV care resulted in higher adherence to the CCS guidelines. Combined services thereby represent an opportunity to engage WWH in HIV care into preventive services.

A Single Injection of ADRCs Does Not Prevent AAA Formation in Rats in a Randomized Blinded Design.

There is a pressing need for alternative medical treatments for abdominal aortic aneurysms (AAAs). Mesenchymal regenerative cells derived from adipose tissue (ADRCs) have shown potential in modulating the inflammation and immune responses that drive AAA progression. We hypothesized that ADRCs could reduce inflammation and preserve vascular integrity, potentially slowing the progression of AAA. In our study, subcutaneous adipose tissue was harvested from male Sprague Dawley rats, from which ADRCs were isolated. AAA was induced in these rats using intraluminal porcine pancreatic elastase, followed by intravenous administration of either ADRCs (106 cells) or saline (0.1 mL). We monitored the progression of AAA through weekly ultrasound, and the rats were sacrificed on day 28 for histological analysis. Our results showed no significant difference in the inner abdominal aortic diameter at day 28 between the control group (172% ± 73%, n = 17) and the ADRC-treated group (181% ± 75%, n = 15). Histological analyses of AAA cross-sections also revealed no significant difference in the infiltration of neutrophils or macrophages between the two groups. Furthermore, the integrity and content of elastin in the tunica media were similar between groups. These findings indicate that a single injection of ADRCs does not inhibit the development of AAA in rats in a randomized blinded study.

No Clinical Efficacy of Adipose-Derived Regenerative Cells and Lipotransfer in Breast Cancer-Related Lymphedema: A double-blinded placebo-controlled phase-II trial.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a debilitating sequela affecting up to one in three breast cancer survivors. Current treatments are palliative and does not address the underlying lymphatic injury. Recently, preclinical and non-randomized studies have shown promising results using Adipose-Derived Regenerative Cells (ADRCs) and lipotransfer in alleviating BCRL through regeneration of lymphatic tissue. However no randomized controlled trial has been performed in an attempt to eliminate a placebo effect. METHODS: This randomized, double-blinded, placebo-controlled trial included patients with no-option, persistent disabling unilateral BCRL. Patients were randomly assigned in a 1:1 ratio to receive either autologous ADRCs (4.20x10 7±1.75x10 7 cells) and 30cc lipotransfer or placebo (saline) to the axilla. The primary outcome was a change in BCRL volume one year after treatment. Secondary outcomes included changes in the quality of life, indocyanine green lymphangiography stage, bioimpedance, and safety. RESULTS: Eighty patients were included, of which 39 were allocated to ADRCs and lipotransfer treatment and 41 to placebo treatment. Baseline characteristics were similar in both groups. One year after treatment, no objective improvements were observed in the treatment or placebo groups. In contrast, significant subjective improvements were noted for both the treatment and placebo groups. CONCLUSION: This trial failed to confirm a benefit of ADRCs and lipotransfer in the treatment of BCRL. These non-confirmatory results suggest that ADRC and lipotransfer should not be recommended for alleviating BCRL at this time. However, we cannot exclude that repeated treatments or higher doses of ADRCs or lipotransfer could yield a clinical effect.

Epistemological aspects of participatory design studies conducted in the field of health science.

AIM(S): To discuss the methodological aspects of participatory design, arguing for a three-phase approach and the suitability of situating participatory design within a phenomenological-hermeneutical tradition in health science. DESIGN AND METHODS: Methodological discussion based on participatory design theory, epistemology and research studies. RESULTS: The epistemological and methodological discussions show how the core values and key elements of participatory design align with the phenomenological-hermeneutical approach. In addition, examples of participatory design studies are provided to illustrate how it can be conducted in health science. CONCLUSION: Participatory design is a flexible framework based on genuine participation, defined by three core values: having a say, mutual learning and democratization. The iterative processes allow for adjustments in alignment with the core values and the scientific stance that defines the choice of methods, tools and techniques. A phenomenological-hermeneutic approach in participatory design studies is relevant and aligned with the core values of participatory design. Thus, this paper argues for a close integration between the participatory design methodology and the phenomenological-hermeneutic scientific approach within health science. IMPLICATIONS FOR THE PROFESSION: Participatory design is a powerful methodology with core values that can co-design sustainable health technologies with potential to impact patient care and the clinical practice of nurses. When combined with qualitative research methods, patients' lived experiences serve as the foundation for improving clinical nursing practice. Discussing the epistemological aspects of participatory design provides nurse researchers with a coherent methodological understanding, essential for the continual development of nursing research. IMPACT: This paper discusses the research methodology of participatory design within health sciences. It aims to address the lack of understanding of the methodology, particularly within a specific scientific stance. The main finding is the elaboration on participatory design and the relevance of a phenomenological-hermeneutical approach. The paper has the potential to impact researchers, master's and PhD students, as well as others engaged in participatory design or other methodologies related to user involvement within health science. REPORTING METHOD: No available EQUATOR guidelines were applicable to this methodological paper, as no new data were created or analysed. PATIENT OR PUBLIC CONTRIBUTION: There was no direct patient or public contribution, as this is a methodological paper.

Transitioning from hospital to home after a major lower extremity amputation: Interview study on patients' and relatives' perspectives.

INTRODUCTION: Patients often feel unprepared and concerned about their new life after a major lower extremity amputation (LEA). Therefore, we implemented an integrated care program, Safe Journey, to optimize the quality and continuity of care for patients with LEA due to vascular disease when transitioning from hospital to home. This study aims to illuminate and explore the experiences of patients with LEA and their relatives with the transition from hospital to home after implementing Safe Journey. MATERIAL AND METHODS: This qualitative, exploratory study individually interviewed six patients with a major LEA and four relatives and jointly interviewed eight patients with their relatives. RESULTS: The participants' experiences transitioning from hospital to home were centered around two major themes: (1) Going home: mixed emotions and confusion, and (2) bridging the gap. The main themes encompassed six subthemes: (1) simultaneously expectant and worried, (2) a lack of knowledge creating uncertainty, (3) an unexpressed but pending need for psychosocial support, (4) reassurance but safety comes at a price, (5) navigating the system, and (6) lack of involvement. CONCLUSION: Transitioning from hospital to home after a major LEA creates mixed emotions. Knowledge, feeling involved, and being prepared and cared for were highlighted as important during the transition. The Safe Journey program made patients and relatives feel physically reassured and safe, but all the home visits strained the families. The program's benefits are consistent with existing knowledge on patients with complex needs benefitting from integrated care models. However, a more individualized and person-centered approach is needed.

Use of Bladder-Related Medication in Non-Muscle Invasive Bladder Cancer Patients.

Repeated transurethral bladder resections (TURBs) and instillation treatments in non-muscle invasive bladder cancer (NMIBC) might influence bladder function and, therefore, quality of life. Bladder-related medication is a surrogate marker of compromised bladder function. The objective was to investigate whether TURBs and adjuvant instillation therapy are associated with the use of anticholinergics, ß3-agonists, and cystitis-relevant antibiotics. We divided all Danish patients diagnosed with primary NMIBC during 2002-2017 registered in the Danish National Patient Registry (DNPR) based on TURB-load within the first five years from diagnosis (1 TURB, 2-4 TURBs, ≥5 TURBs). Instillation therapy with either mitomycin C (MMC) or bacillus Calmette-Guerin vaccine (BCG) was independent exposure (yes or no). We included 17,774 patients; 76% men, median age: 70 years (IQR: 63, 77). Patients exposed to ≥5 TURBs had a higher risk of using bladder-relaxing medication than patients exposed to 1 TURB, HR = 4.01 [3.33; 4.83], and higher risk of cystitis, HR = 2.27 [2.05; 2.51]. BCG-exposed patients had a higher risk of bladder-relaxing medication use compared to non-exposed, HR = 1.92 [1.69; 2.18], and a higher risk of cystitis, HR = 1.39 [1.31; 1.48]. Repeated TURBs have the highest impact on bladder function. Adjuvant instillation therapy is also associated with the use of bladder-related medication.

An investigation of trachoma vaccine regimens by the chlamydia vaccine CTH522 administered with cationic liposomes in healthy adults (CHLM-02): a phase 1, double-blind trial.

BACKGROUND: There is no vaccine against the major global pathogen Chlamydia trachomatis; its different serovars cause trachoma in the eye or chlamydia in the genital tract. We did a clinical trial administering CTH522, a recombinant version of the C trachomatis major outer membrane molecule, in different dose concentrations with and without adjuvant, to establish its safety and immunogenicity when administered intramuscularly, intradermally, and topically into the eye, in prime-boost regimens. METHODS: CHLM-02 was a phase 1, double-blind, randomised, placebo-controlled trial at the National Institute for Health Research Imperial Clinical Research Facility, London, UK. Participants were healthy men and non-pregnant women aged 18-45 years, without pre-existing C trachomatis genital infection. Participants were assigned into six groups by the electronic database in a pre-prepared randomisation list (A-F). Participants were randomly assigned (1:1:1:1:1) to each of the groups A-E (12 participants each) and 6 were randomly assigned to group F. Investigators were masked to treatment allocation. Groups A-E received investigational medicinal product and group F received placebo only. Two liposomal adjuvants were compared, CAF01 and CAF09b. The groups were intramuscular 85 µg CTH522-CAF01, or placebo on day 0 and two boosters or placebo at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (A); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional topical ocular administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (B); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional intradermal administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (C); intramuscular 15 µg CTH522-CAF01, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (D); intramuscular 85 µg CTH522-CAF09b, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (E); intramuscular placebo (F). The primary outcome was safety; the secondary outcome (humoral immunogenicity) was the percentage of trial participants achieving anti-CTH522 IgG seroconversion, defined as four-fold and ten-fold increase over baseline concentrations. Analyses were done as intention to treat and as per protocol. The trial is registered with ClinicalTrials.gov, NCT03926728, and is complete. FINDINGS: Between Feb 17, 2020 and Feb 22, 2022, of 154 participants screened, 65 were randomly assigned, and 60 completed the trial (34 [52%] of 65 women, 46 [71%] of 65 White, mean age 26·8 years). No serious adverse events occurred but one participant in group A2 discontinued dosing after having self-limiting adverse events after both placebo and investigational medicinal product doses. Study procedures were otherwise well tolerated; the majority of adverse events were mild to moderate, with only seven (1%) of 865 reported as grade 3 (severe). There was 100% four-fold seroconversion rate by day 42 in the active groups (A-E) and no seroconversion in the placebo group. Serum IgG anti-CTH522 titres were higher after 85 µg CTH522-CAF01 than 15 µg, although not significantly (intention-to-treat median IgG titre ratio groups A-C:D=5·6; p=0·062), with no difference after three injections of 85 µg CTH522-CAF01 compared with CTH522-CAF09b (group E). Intradermal CTH522 (group C) induced high titres of serum IgG anti-CTH522 neutralising antibodies against serovars B (trachoma) and D (urogenital). Topical ocular CTH522 (group B) at day 28 and 112 induced higher total ocular IgA compared with baseline (p<0·001). Participants in all active vaccine groups, particularly groups B and E, developed cell mediated immune responses against CTH522. INTERPRETATION: CTH522, adjuvanted with CAF01 or CAF09b, is safe and immunogenic, with 85 µg CTH522-CAF01 inducing robust serum IgG binding titres. Intradermal vaccination conferred systemic IgG neutralisation breadth, and topical ocular administration increased ocular IgA formation. These findings indicate CTH522 vaccine regimens against ocular trachoma and urogenital chlamydia for testing in phase 2, clinical trials. FUNDING: The EU Horizon Program TRACVAC.

Adult patients' experiences after a distal radius fracture - A qualitative systematic review.

BACKGROUND: Distal radius fractures are a common presentation in emergency departments. Synthesis of qualitative research of treatment, care and rehabilitation this fracture presents from the patient perspective could improve clinical practice and care. The purpose of this systematic review was to synthesize the qualitative literature on patient experiences after sustaining a distal radius fracture. METHODS: We searched Embase, MEDLINE, CINAHL, Psycinfo and CINAHL to identify qualitative studies published from database conception to May 2023. All studies were screened, extracted, analysed and quality assessed by two blinded reviewers. A thematic synthesis approach was used to analyse the findings from included studies. RESULTS: A total of 9 studies interviewing 160 unique patients were included. We identified 3 themes in relation to patient experiences after sustaining a distal radius fracture: 1) Concerns about dependency, 2) Fear and pain and 3) Motivators for recovery. The themes did not exist as sharply demarcated topics but were intertwined with patients reflecting that more information and knowledge could assist in managing expectations and the recovery period. CONCLUSION: Our synthesis highlighted that adult patients with DRF experience a lack of information about the care and treatment inhibiting independence and successful management of expectations due to pain, fear and lack of motivation. Our findings can inform orthopaedic units and assist in tailoring information to patient needs.

Biomedical laboratory scientists and technicians in digital pathology - Is there a need for professional development?

Objective: Digital pathology (DP) is moving into Danish pathology departments at high pace. Conventionally, biomedical laboratory scientists (BLS) and technicians have prepared tissue sections for light microscopy, but workflow alterations are required for the new digital era with whole slide imaging (WSI); digitally assisted image analysis (DAIA) and artificial intelligence (AI). We aim to explore the role of BLS in DP and assess a potential need for professional development. Methods: We investigated the roles of BLS in the new digital era through qualitative interviews at Danish Pathology Departments in 2019/2020 before DP implementation (supported by a questionnaire); and in 2022 after DP implementation. Additionally, senior lecturers from three Danish University Colleges reported on how DP was integrated into the 2023 bachelor's degree educational curricula for BLS students. Results: At some Danish pathology departments, BLS were involved in the implementation process of DP and their greatest concerns were lack of physical laboratory requirements (69%) and implementation strategies (63%). BLS were generally positive towards working with DP, however, some expressed concern about extended working hours for scanning. Work-task transfers from pathologists were generally greeted positively from both management and pathologists; however, at follow-up interviews after DP implementation, job transfers had not been effectuated. At Danish university colleges, DP had been integrated systematically in the curricula for BLS students, especially WSI. Conclusion: Involving BLS in DP implementation and development may benefit the process, as BLS have a hands-on workflow perspective with a focus on quality assurance. Several new work opportunities for BLS may occur with DP including WSI, DAIA and AI, and therefore new qualifications are warranted, which must be considered in future undergraduate programmes for BLS students or postgraduate programmes for BLS.

Usability and Evaluation of a Health Information System in the Emergency Department: Mixed Methods Study.

BACKGROUND: A lack of information during an emergency visit leads to the experience of powerlessness for patients and their family members, who may also feel unprepared to cope with acute symptoms. The ever-changing nature and fast-paced workflow in the emergency department (ED) often affect how health care professionals can tailor information and communication to the needs of the patient. OBJECTIVE: This study aimed to evaluate the usability and experience of a newly developed information system. The system was developed together with patients and their family members to help provide the information needed in the ED. METHODS: We conducted a mixed methods study consisting of quantitative data obtained from the System Usability Scale questionnaire and qualitative interview data obtained from purposively selected participants included in the quantitative part of the study. RESULTS: A total of 106 patients and 14 family members (N=120) answered the questionnaire. A total of 10 patients and 3 family members participated in the interviews. Based on the System Usability Scale score, the information system was rated close to excellent, with a mean score of 83.6 (SD 12.8). Most of the participants found the information system easy to use and would like to use it again. The participants reported that the system helped them feel in control, and the information was useful. Simplifications were needed to improve the user experience for the older individuals. CONCLUSIONS: This study demonstrates that the usability of the information system is rated close to excellent. It was perceived to be useful as it enabled understanding and predictability of the patient's trajectory in the ED. Areas for improvement include making the system more usable by older individuals. The study provides an example of how a technological solution can be used to diminish the information gap in an ED context.

Pericardial delta like non-canonical NOTCH ligand 1 (Dlk1) augments fibrosis in the heart through epithelial to mesenchymal transition.

BACKGROUND: Heart failure due to myocardial infarction (MI) involves fibrosis driven by epicardium-derived cells (EPDCs) and cardiac fibroblasts, but strategies to inhibit and provide cardio-protection remains poor. The imprinted gene, non-canonical NOTCH ligand 1 (Dlk1), has previously been shown to mediate fibrosis in the skin, lung and liver, but very little is known on its effect in the heart. METHODS: Herein, human pericardial fluid/plasma and tissue biopsies were assessed for DLK1, whereas the spatiotemporal expression of Dlk1 was determined in mouse hearts. The Dlk1 heart phenotype in normal and MI hearts was assessed in transgenic mice either lacking or overexpressing Dlk1. Finally, in/ex vivo cell studies provided knowledge on the molecular mechanism. RESULTS: Dlk1 was demonstrated in non-myocytes of the developing human myocardium but exhibited a restricted pericardial expression in adulthood. Soluble DLK1 was twofold higher in pericardial fluid (median 45.7 [34.7 (IQR)) µg/L] from cardiovascular patients (n = 127) than in plasma (median 26.1 µg/L [11.1 (IQR)]. The spatial and temporal expression pattern of Dlk1 was recapitulated in mouse and rat hearts. Similar to humans lacking Dlk1, adult Dlk1-/- mice exhibited a relatively mild developmental, although consistent cardiac phenotype with some abnormalities in heart size, shape, thorax orientation and non-myocyte number, but were functionally normal. However, after MI, scar size was substantially reduced in Dlk1-/- hearts as compared with Dlk1+/+ littermates. In line, high levels of Dlk1 in transgenic mice Dlk1fl/fl xWT1GFPCre and Dlk1fl/fl xαMHCCre/+Tam increased scar size following MI. Further mechanistic and cellular insight demonstrated that pericardial Dlk1 mediates cardiac fibrosis through epithelial to mesenchymal transition (EMT) of the EPDC lineage by maintaining Integrin ß8 (Itgb8), a major activator of transforming growth factor ß and EMT. CONCLUSIONS: Our results suggest that pericardial Dlk1 embraces a, so far, unnoticed role in the heart augmenting cardiac fibrosis through EMT. Monitoring DLK1 levels as well as targeting pericardial DLK1 may thus offer new venues for cardio-protection.

Validation of PRE-DELIRIC and E-PRE-DELIRIC in a Danish population of intensive care unit patients-A prospective observational multicenter study.

BACKGROUND: Delirium is a clinical condition characterized by an acute change in brain function and is frequently observed in critically ill patients. The condition has been associated with negative outcomes, making it crucial to identify patients who are at risk. Two recent prediction models have been developed to estimate the risk of delirium in intensive care unit (ICU) patients; the prediction model for delirium (PRE-DELIRIC) and the early prediction model for delirium (E-PRE-DELIRIC). We aimed to perform an external validation of these models in a Danish cohort of critically ill patients. METHODS: We conducted a prospective, observational multicenter study to validate the PRE-DELIRIC and E-PRE-DELIRIC models in a population of patients admitted to four general ICUs in the Zealand Region of Denmark. From January 2022 to January 2023 all adult patients acutely admitted to the participating ICUs were assessed for eligibility. Patients had to be admitted to the ICU for >24 h to be included in the study. Included patients were screened with E-PRE-DELIRIC upon ICU admission and PRE-DELIRIC after 24 h of admission and followed throughout their ICU stay with CAM-ICU delirium assessments. Our primary outcomes were the prognostic accuracy measured by Area Under the Receiver Operating Characteristics (AUROC) and the calibration plot for the E-PRE-DELIRIC and PRE-DELIRIC prediction models. RESULTS: We included 660 patients, of whom 660 were assessed with E-PRE-DELIRIC, and 622 were assessed with PRE-DELIRIC. PRE-DELIRIC showed acceptable discrimination with AUROC of 0.70 (95% CI 0.66 to 0.74) and good calibration. E-PRE-DELIRIC had inadequate discrimination AUROC of 0.63 (95% CI 0.58 to 0.67) and poor calibration. CONCLUSION: In a Danish cohort, we found that the PRE-DELIRIC model demonstrated acceptable performance and E-PRE-DELIRIC demonstrated poor performance. In critically ill adult patients PRE-DELIRIC may be useful in identifying patients at high risk of delirium.

Burnout Among Nursing Home Care Aides and the Effects on Resident Outcomes.

While burnout among health care workers has been well studied, little is known about the extent to which burnout among health care workers impacts the outcomes of their care recipients. To test this, we used a multi-year (2014-2020) survey of care aides working in approximately 90 nursing homes (NHs); the survey focused on work-life measures, including the Maslach Burnout Inventory (MBI) and work-unit identifier. Resident Assessment Instrument Minimum Data Set (RAI-MDS 2.0) data were obtained on all residents in the sampled NHs during this time and included a unit identifier for each resident. We used multi-level models to test associations between the MBI emotional exhaustion and cynicism sub-scales reported by care aides and the resident outcomes of antipsychotics without indication, depressive symptoms, and responsive behaviors among residents on units. In 2019/2020, our sample included 3,547 care aides and 10,117 residents in 282 units. The mean frequency of emotional exhaustion and cynicism across units was 43% and 50%, respectively. While residents frequently experienced antipsychotics without indication 1,852 (18.3%), depressive symptoms 2,089 (20.7%), and responsive behaviors 3,891 (38.5%), none were found to be associated with either emotional exhaustion or cynicism among care aides.

Evaluating drug-drug interaction risk associated with peptide analogues using advanced in vitro systems.

Drug-drug interaction (DDI) assessment of therapeutic peptides is an evolving area. The industry generally follows DDI guidelines for small molecules, but the translation of data generated with commonly used in vitro systems to in vivo is sparse. In the current study, we investigated the ability of advanced human hepatocyte in vitro systems namely HepatoPac, spheroids, and Liver-on-a-chip to assess potential changes in regulation of CYP1A2, CYP2B6, CYP3A4, SLCO1B1 and ABCC2 in the presence of selected therapeutic peptides, proteins, and small molecules. The peptide NN1177, a glucagon and GLP-1 receptor co-agonist, did not suppress mRNA expression or activity of CYP1A2, CYP2B6, and CYP3A4 in HepatoPac, spheroids, or Liver-on-a-chip; these findings were in contrast to the data obtained in sandwich cultured hepatocytes. No effect of NN1177 on SLCO1B1 and ABCC2 mRNA was observed in any of the complex systems. The induction magnitude differed across the systems (e.g., rifampicin induction of CYP3A4 mRNA ranged from 2.8-fold in spheroids to 81.2-fold in Liver-on-a-chip). Small molecules, obeticholic acid and abemaciclib, showed varying responses in HepatoPac, spheroids and Liver-on-a-chip, indicating a need for EC50 determinations to fully assess translatability data. HepatoPac, the most extensively investigated in this study (3 donors), showed high potential to investigate DDIs associated with CYP regulation by therapeutic peptides. Spheroids and Liver-on-a-chip were only assessed in one hepatocyte donor and further evaluations are required to confirm their potential. This study establishes an excellent foundation towards the establishment of more clinically-relevant in vitro tools for evaluation of potential DDIs with therapeutic peptides. Significance Statement At present, there are no guidelines for drug-drug interaction (DDI) assessment of therapeutic peptides. Existing in vitro methods recommended for assessing small molecule DDIs do not appear to translate well for peptide drugs, complicating drug development for these moieties. Here, we establish evidence that complex cellular systems have potential to be used as more clinically-relevant tools for the in vitro DDI evaluation of therapeutic peptides.

What is long-term survival in patients with peritoneal metastasis from gastric, pancreatic, or colorectal cancer? A study of patients treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: A definition of long-term survival (LTS) in patients with peritoneal metastasis (PM) from gastric cancer (GC), pancreatic cancer (PC) or colorectal cancer (CRC) treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) is lacking. We aimed to define LTS and investigate characteristics and treatment response in patients who reached LTS in data from two prospective trials. Methods: Retrospective study of patients with GC-, PC-, or CRC-PM from the prospective PIPAC-OPC1 and PIPAC-OPC2 studies. The definition of LTS was based on published systematic reviews and randomized controlled trials. LTS was defined at the time point where 25 % of the patients were alive in these studies. Histology based response was evaluated by the mean Peritoneal Regression Grading Score (PRGS) using biopsies obtained prior to PIPAC 3, and defined by a mean PRGS of ≤2.0 or a decrease of mean PRGS of ≥1, compared to baseline. Results: LTS was defined at 21 (GC), 15 (PC), and 24 (CRC) months. Fifty-one (47.2 %) patients (nine GC, 17 PC, 25 CRC) reached LTS calculated from the date of PM diagnosis. All but one received palliative chemotherapy before PIPAC, and 37 % received bidirectional treatment. More than 90 % of the LTS patients had response according to PRGS. The mOS from PIPAC 1 was 23.3, 12.4, and 28.5 months for GC, PC, and CRC LTS patients. Conclusions: Patients with PM from GC, PC, and CRC treated with systemic chemotherapy and PIPAC can reach LTS and most show histological response. Causality must be further investigated.