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.

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.

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.

Management of treatment-related sequelae following colorectal cancer.

AIM: Colorectal cancer survivors are one of the most rapidly growing groups of patients living with and beyond cancer. In a national multidisciplinary setting, we have examined the extent of late treatment-related sequelae in colorectal cancer survivors and present the scientific evidence for management of these conditions in this patient category with the aim of facilitating identification and treatment. METHOD: A systematic search for existing guidelines and relevant studies was performed across 16 and 4 databases, respectively, from inception to 2021. This yielded 13 guidelines and 886 abstracts, of which 188 were included in the finalized guideline (231 included for full text review). Secondarily, bibliographies were cross-referenced and 53 additional articles were included. RESULTS: Symptoms have been divided into overall categories including psychosocial, bowel-related, urinary, sexual (male and female), pain/neuropathy and fatigue symptoms or complaints that are examined individually. Merging and grading of data resulted in 22 recommendations and 42 management strategies across categories. Recommendations are of a more general character, whereas management strategies provide more practical advice suited for initiation on site before referral to specialized units. CONCLUSION: Treatment-related sequelae in colorectal cancer survivors are common and attention needs to be focused on identifying patients with unmet treatment needs and the development of evidence-based treatment algorithms.

Exploring nursing home resident and their care partner priorities for care using the Action-Project Method.

BACKGROUND: Nursing home (NH) residents' experiences are embedded within their relationships to others. Our objectives were to describe how residents and care partners (family or staff members) jointly construct, discuss, and act on care priorities. METHODS: We used Action-Project Method, a qualitative method focused on action within social context. We recruited 15 residents and 12 care partners (5 family and 7 staff members) from 3 urban NHs in Alberta, Canada. Residents and care partners participated in a video-recorded conversation about their experiences in the NH, then individually reviewed the video-recording to add context to the conversation. Following transcription, preliminary narrative construction, and participant feedback, the research team conducted in-depth analysis to identify participant actions, goals, and projects, including those jointly shared by dyad members. RESULTS: All participants' intentions could be broadly described as "making time in the NH as good as possible" and projects were grouped into five categories: resident identity, relationships (both presence and absence), advocacy, positivity, and respectful care. Participants often raised issues of short-staffing as a significant barrier to respectful care. Care partners, especially staff, used positivity to redirect residents from difficult topics. Joint projects could be identified in some, but not all, cases. CONCLUSIONS: We found that maintaining a sense of identity, fostering relationships, and receiving respectful care were important to residents but that short-staffing created barriers. Methods to capture these aspects of the resident experience are needed but should not be influenced by care partners' tendency towards positivity in resident interactions.

Danish general practitioners as gatekeepers for gynaecological patients in regions with different density of resident specialists in gynaecology: in which situations and to whom do they refer? A cross-sectional study.

BACKGROUND: There are large differences in the density of Resident Specialists in Gynaecology (RSG) in the various regions of Denmark. It is unknown if this inequality affects the General Practitioner (GP) referral patterns of gynaecological patients. OBJECTIVE: To investigate the GP referral patterns of gynaecological patients to the RSG or to the Hospital/Outpatient Clinic (HOC) in specific situations according to the regional density of RSGs. Moreover, to examine whether GPs prefer to refer to the HOC or to the RSG, or whether they were treated by the GP depending on the density of RSGs, specifically, in six benign gynaecological diagnoses. DESIGN: A cross-sectional questionnaire survey. SETTING: In Denmark, GPs serve as gatekeepers to secondary care, being responsible for referrals to resident specialists and in- and outpatient hospital care. SUBJECTS: Five hundred Danish GPs were randomly selected and invited to take part in the questionnaire study. Main outcome measurements: Referral patterns: Own treatment, RSG, or HOC. RESULTS: GPs prefer to refer their gynaecologic patients to RSGs rather than to HOCs. In addition, the study shows the higher the density of RSGs, the more gynaecological patients are referred to the RSG. This also applies to the six diagnoses examined. CONCLUSION: To allow patients' equal access to specialist care, the density of RSGs must be equal all over the country.

Differences in the referral process from general practice to resident specialists in gynaecology depending on density of specialists and patients' socioeconomic status.

BACKGROUND: There are significant differences in the densities of resident specialists in gynaecology (RSGs) in various regions of Denmark. It is unclear whether this disparity affects gynaecological patients' experience of the referral process and whether it differs in terms of their socioeconomic status (SES). OBJECTIVE: To examine gynaecological patients' experiences of the referral process to an RSG concerning RSG density and patients' SES. DESIGN: Cross-sectional questionnaire and registry-based study. SETTING: In Denmark, general practitioners (GPs) serve as gatekeepers of secondary care and are responsible for referrals to resident specialists as well as inpatient and outpatient hospital care. SUBJECTS: A total of 2917 patients who consulted an RSG participated in this study. MAIN OUTCOME MEASUREMENTS: Patients' experiences of referral to an RSG, waiting times, involvement, and how they experienced the referral process. RESULTS: Patients who lived in the highest density RSG region were referred to an RSG more promptly after the onset of symptoms, had to visit their GP less frequently to obtain a referral to the RSG, and rarely received a gynaecological examination by their GP compared with those living in regions with lower RSG densities. Moreover, their waiting times were shorter, and more often, the patients themselves proposed to be referred to an RSG. The findings show that RSG density had a greater impact on women's experiences than SES. CONCLUSION: To allow equal access to specialist care, RSG density must be equal across all regions in the country.

Cardiotocography combined with ST analysis versus cardiotocography combined with fetal blood sampling in deliveries with abnormal CTG: a randomized trial.

PURPOSE: The aim was to investigate if intrapartum monitoring with cardiotocography (CTG) in combination with ST analysis (STAN) results in an improved perinatal outcome. METHODS: We performed a two-center randomized trial. 1013 women with term fetuses in cephalic presentation entered the trial. If a CTG showed intermediate or pathological abnormalities, they were offered fetal blood sampling (FBS) and inclusion if the pH value was above 7.25. They were randomized to either CTG + FBS or CTG + STAN. The primary outcome was neonatal metabolic acidosis, defined as umbilical cord arterial blood pH below 7.05, and base excess equal to or below -10. The secondary outcomes included operative vaginal delivery for fetal distress. RESULTS: The rate of metabolic acidosis was 0.8% in the CTG + FBS group and 1.5% in women in the CTG + STAN (P = 0.338). More women in the CTG + STAN group delivered by operative vaginal delivery (25.6% vs 33.5%, P = 0.006). Significantly fewer women in the CTG + STAN group had three to five (28.8% vs 11.0%, P = < 0.001) and six to ten fetal blood samples taken (3.4% vs 0.4%, P = < 0.001). CONCLUSION: CTG + STAN did not reduce the incidence of neonatal metabolic acidosis compared to CTG + FBS. CTG + STAN was, however, associated with an increased risk of operative vaginal delivery and a reduced use of FBS. If STAN is used for fetal surveillance, we recommend that it is combined with other methods, such as FBS, for confirmation of the need for operative delivery. CLINICALTRIALS: gov ID: NCT01699646. Date of registration: October 4, 2012 (retrospectively registered). https://clinicaltrials.gov/ct2/show/NCT01699646?id=NCT01699646&draw=2&rank=1.

Translation and cultural adaption of the emergency department-consumer assessment of healthcare providers and systems (ED CAPHS)-A questionnaire to measure patient experience in Denmark.

AIM: The aim of this study was to translate and culturally adapt The Emergency Department-Consumer Assessment of Healthcare Providers and Systems (ED CAPHS) to the Danish ED context. BACKGROUND: In Denmark, a large number of patients attend emergency departments (ED) every year. During their ED visits, examinations, tests and encounters with different healthcare professionals occur frequently. Moreover, patients receive much information. Patients' direct experiences of care can provide valuable insights into what works and what does not in health care. The emergency department-consumer assessment of healthcare providers and systems (ED CAPHS) is a valid questionnaire designed to measure patients' experiences with ED care and is intended for patients discharged home following their ED visit. METHOD: The translation process was systematically planned and executed using the principles of good practice for the translation and cultural adaptation process for patient-reported outcomes (PRO) guidelines by the ISPOR. RESULTS: The translation and cultural adaption process were successfully conducted. Three items concerning language and race were omitted as they are not distinct in Danish ED context. Furthermore, a few conceptual factors and linguistic challenges were discussed and harmonised during the reconciliation and harmonisation process respectively. The Danish survey ED CAPHS DK containing 32 items was proofread and finalised. CONCLUSION: Overall, patients reported that the survey was relevant and comprehensive, as it focused on essential factors when discharged directly home after an ED admission. ED CAPHS DK is found to be content valid and ready for use. However, a future study testing the Danish version using confirmative factor analysis and internal consistency reliability is needed to ensure construct validity and reliability.

Dlk1 regulates quiescence in calcitonin receptor-mutant muscle stem cells.

Muscle stem cells, also called muscle satellite cells (MuSCs), are responsible for skeletal muscle regeneration and are sustained in an undifferentiated and quiescent state under steady conditions. The calcitonin receptor (CalcR)-protein kinase A (PKA)-Yes-associated protein 1 (Yap1) axis is one pathway that maintains quiescence in MuSCs. Although CalcR signaling in MuSCs has been identified, the critical CalcR signaling targets are incompletely understood. Here, we show the relevance between the ectopic expression of delta-like non-canonical Notch ligand 1 (Dlk1) and the impaired quiescent state in CalcR-conditional knockout (cKO) MuSCs. Dlk1 expression was rarely detected in both quiescent and proliferating MuSCs in control mice, whereas Dlk1 expression was remarkably increased in CalcR-cKO MuSCs at both the mRNA and protein levels. It is noteworthy that all Ki67+ non-quiescent CalcR-cKO MuSCs express Dlk1, and non-quiescent CalcR-cKO MuSCs are enriched in the Dlk1+ fraction by cell sorting. Using mutant mice, we demonstrated that PKA-activation or Yap1-depletion suppressed Dlk1 expression in CalcR-cKO MuSCs, which suggests that the CalcR-PKA-Yap1 axis inhibits the expression of Dlk1 in quiescent MuSCs. Moreover, the loss of Dlk1 rescued the quiescent state in CalcR-cKO MuSCs, which indicates that the ectopic expression of Dlk1 disturbs quiescence in CalcR-cKO. Collectively, our results suggest that ectopically expressed Dlk1 is responsible for the impaired quiescence in CalcR-cKO MuSCs.

On the Road to Digital Pathology in Denmark-National Survey and Interviews.

Digital pathology (DP) is changing pathology departments dramatically worldwide, yet globally, few departments are presently digitalized for the full diagnostic workflow. Denmark is also on the road to full digitalization countrywide, and this study aim to cover experiences during the implementation process in a national context. Thus, quantitative questionnaires were distributed to all pathology departments in Denmark (n = 13) and distributed to all professions including medical clinical directors, medical doctors (MD) and biomedical laboratory scientists (BLS). For a qualitative perspective, we interviewed four employees representing four professions. Data were collected in 2019-2020. From the questionnaire and interviews, we found strategies differed at the Danish departments with regards to ambitions, technological equipment, workflows, and involvement of type of professions. DP education was requested by personnel. Informants were in general positive toward the digital future but mainly had concerns regarding the political pressure to integrate DP before technological advances are sufficient for maintaining rational budgets, workflows, and for sustaining diagnostic quality. This study is a glance on the Danish implementation process in its early stages from personnel's point of view. It shows the complexity when large new workflow processes are to be implemented countrywide and with a large diversity of stakeholders like managers, MD, BLS, IT-professionals, and authorities. To ensure best technological and economical solutions and to maintain-or even optimize-diagnostic quality with DP and workflow alignment, we suggest superior inter- and intradepartmental communication. When implementing DP countrywide, a national working group is warranted with the variety of stakeholders represented.

Adipose-Derived Stem Cells from Type 2 Diabetic Rats Retain Positive Effects in a Rat Model of Erectile Dysfunction.

Erectile dysfunction is a common complication associated with type 2 diabetes mellitus (T2DM) and after prostatectomy in relation to cancer. The regenerative effect of cultured adipose-derived stem cells (ASCs) for ED therapy has been documented in multiple preclinical trials as well as in recent Pase 1 trials in humans. However, some studies indicate that diabetes negatively affects the mesenchymal stem cell pool, implying that ASCs from T2DM patients could have impaired regenerative capacity. Here, we directly compared ASCs from age-matched diabetic Goto-Kakizaki (ASCGK) and non-diabetic wild type rats (ASCWT) with regard to their phenotypes, proteomes and ability to rescue ED in normal rats. Despite ASCGK exhibiting a slightly lower proliferation rate, ASCGK and ASCWT proteomes were more or less identical, and after injections to corpus cavernosum they were equally efficient in restoring erectile function in a rat ED model entailing bilateral nerve crush injury. Moreover, molecular analysis of the corpus cavernosum tissue revealed that both ASCGK and ASCWT treated rats had increased induction of genes involved in recovering endothelial function. Thus, our finding argues that T2DM does not appear to be a limiting factor for autologous adipose stem cell therapy when correcting for ED.

Metronomic treatment of vinorelbine with oral capecitabine is tolerable in the randomized Phase 2 study XeNa including patients with HER2 non-amplified metastatic breast cancer.

BACKGROUND: Metronomic treatment is hypothesized to be less toxic and more effective as compared to standard maximal tolerable dosing treatment in metastatic cancer disease. MATERIAL AND METHODS: We tested the metronomic treatment principle with vinorelbine in a randomized phase 2 setting combined with standard capecitabine treatment in the XeNa trial with Clinical Trials.gov identifier number: NCT0141771. 120 patients with disseminated HER2 non-amplified breast cancer were included. Randomization was between Arm A: vinorelbine 60 mg/m2 day 1 + day 8 in the first cycle followed by 80 mg/m2 day 1 + day 8 in the following cycles or Arm B: vinorelbine 50 mg three times a week. Capecitabine 1000 mg/m2 twice a day for days 1-14 was administered in both arms. RESULTS: The treatment was generally well-tolerated. The response rate (RR) was 24% (arm A) versus 29% (arm B) (p = .67). The clinical benefit rate (CBR) 46.8% (arm A) versus 51.7% (arm B) (p = .72). We found a median progression-free survival (PFS) of 7.1 months (95% confidence interval [CI] 3.9-10.3) in arm A and 6.3 months (95% CI 4.1-8.5) in arm B (p = .25) whereas median overall survival (OS) was 23.3 months (95% CI 20.2-26.4) in arm A and 22.3 months (95% CI 14.3-30.3) in arm B (p = .76). CONCLUSIONS: We confirmed that the combination of vinorelbine and capecitabine was well tolerated. Metronomic treatment can be used with acceptable adverse events (AEs), but we did not find significant difference in the effect compared to the standard treatment.

MESP1 knock-down in human iPSC attenuates early vascular progenitor cell differentiation after completed primitive streak specification.

MESP1 is a key transcription factor in development of early cardiovascular tissue and it is required for induction of the cardiomyocyte (CM) gene expression program, but its role in vascular development is unclear. Here, we used inducible CRISPRi knock-down of MESP1 to analyze the molecular processes of the early differentiation stages of human induced pluripotent stem cells into mesoderm and subsequently vascular progenitor cells. We found that expression of the mesodermal marker, BRACHYURY (encoded by T) was unaffected in MESP1 knock-down cells as compared to wild type cells suggesting timely movement through the primitive streak whereas another mesodermal marker MIXL1 was slightly, but significantly decreased. In contrast, the expression of the vascular cell surface marker KDR was decreased and CD31 and CD34 expression were substantially reduced in MESP1 knock-down cells supporting inhibition or delay of vascular specification. In addition, mRNA microarray data revealed several other altered gene expressions including the EMT regulating transcription factors SNAI1 and TWIST1, which were both significantly decreased indicating that MESP1 knock-down cells are less likely to undergo EMT during vascular progenitor differentiation. Our study demonstrates that while leaving primitive streak markers unaffected, MESP1 expression is required for timely vascular progenitor specification. Thus, MESP1 expression is essential for the molecular features of early CM, EC and VSMC lineage specification.

Experiences with and perspectives on goal setting in spinal cord injury rehabilitation: a systematic review of qualitative studies.

STUDY DESIGN: Systematic review of qualitative studies. OBJECTIVE: To synthesise qualitative research exploring the experiences and perspectives of persons with spinal cord injury (SCI), relatives and health professionals concerning goal setting in SCI rehabilitation. METHODS: Five electronic databases were searched. A search strategy was constructed with key concepts identified using PICo (Population, phenomena of Interest and Context). Peer reviewed studies complying with the inclusion criteria were selected. Interpretive Description methodology guided analysis and synthesis of the findings. RESULTS: The search yielded 427 records. Of 12 full text studies assessed for eligibility, four were included describing goal setting in SCI rehabilitation from the perspective of persons with SCI and health professionals. Persons with SCI described a need for goal setting to be related to their everyday life, whereas the health professionals tended to use the hospital setting as their point of reference. Persons with SCI emphasised the importance of being self-directed and taking an active role in goal setting and rehabilitation. No studies presented the perspective of relatives. CONCLUSIONS: This review illuminates the divergence in the understanding of goal setting between persons with SCI and health professionals. Goal setting in SCI rehabilitation often directly reflects physical functioning goals set by the health professionals, which does not prepare persons with SCI for everyday life and emotional issues. There is lack of focus on goals addressing psychosocial components such as family issues and change of roles. A shared process with goal setting relevant to persons with SCI and their everyday life is needed.

Copenhagen Baby Heart Study: a population study of newborns with prenatal inclusion.

Congenital heart diseases (CHDs) are reported in 0.8% of newborns. Numerous factors influence cardiovascular development and CHD prevalence, and possibly also development of cardiovascular disease later in life. However, known factors explain the probable etiology in only a fraction of patients. Past large-scale population-based studies have made invaluable contributions to the understanding of cardiac disease, but none recruited participants prenatally and focused on the neonatal period. The Copenhagen Baby Heart Study (CBHS) is a population-based study of the prevalence, spectrum, and prognosis of structural and functional cardiac abnormalities. The CBHS will also establish normal values for neonatal cardiac parameters and biomarkers, and study prenatal and early childhood factors potentially affecting later cardiovascular disease risk. The CBHS is an ongoing multicenter, prospective study recruiting from second trimester pregnancy (gestational weeks 18-20) (expected n = 25,000). Information on parents, pregnancy, and delivery are collected. After birth, umbilical cord blood is collected for biochemical analysis, DNA purification, and biobank storage. An echocardiographic examination, electrocardiography, and post-ductal pulse oximetry are performed shortly after birth. Infants diagnosed with significant CHD are referred to a specialist or admitted to hospital, depending on CHD severity. CBHS participants will be followed prospectively as part of specific research projects or regular clinical follow-up for CHD. CBHS design and methodology are described. The CBHS aims to identify new mechanisms underlying cardiovascular disease development and new targets for prevention, early detection, and management of CHD and other cardiac diseases presenting at birth or developing later in life.

Screening and systematic follow-up for cardiopulmonary comorbidity in elective surgery for colorectal cancer: a randomised feasibility study.

BACKGROUND: One third of patients with colorectal cancer (CRC) have comorbidity, which impairs their postoperative outcomes. Scoring systems may predict mortality, but there is limited evidence of effective interventions in high-risk patients. Our aim was to test a trial setup to assess the effect of extra postoperative medical visits and follow-up on 1-year mortality and other outcomes in patients with cardiopulmonary risk factors undergoing elective surgery for colorectal tumours. METHODS: Patients preoperatively screened positive for cardiopulmonary comorbidity were eligible. On postoperative day 4, they were randomised to either routine follow-up (RFU) or RFU with one extra medical visit and additional visits to the Cardiology and Respiratory Medicine Clinics 1 and 3 months postoperatively. The primary outcome measure was 1-year mortality; secondary outcome measures were length of stay (LOS), complications, and readmissions. RESULTS: Of 673 screened patients 326 (48%) were found eligible, 108 declined participation, and 198 were randomised. Postoperative medical problems and/or need for intervention were found in 15-23% of the patients at the extra medical visits. The 90-day mortality was 0 and the 1-year mortality only 2.6% with no differences between the two groups. LOS and complication rates did not differ, but there were significantly fewer readmissions in the intervention group. CONCLUSIONS: The 1-year mortality after elective CRC surgery was low, even in the presence of cardiopulmonary risk factors. There was no evidence of reduced mortality with additional medical follow-up in these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02328365 registered 31 December 2014 (retrospectively registered).

Expression and Functional Analyses of Dlk1 in Muscle Stem Cells and Mesenchymal Progenitors during Muscle Regeneration.

Delta like non-canonical Notch ligand 1 (Dlk1) is a paternally expressed gene which is also known as preadipocyte factor 1 (Pref-1). The accumulation of adipocytes and expression of Dlk1 in regenerating muscle suggests a correlation between fat accumulation and Dlk1 expression in the muscle. Additionally, mice overexpressing Dlk1 show increased muscle weight, while Dlk1-null mice exhibit decreased body weight and muscle mass, indicating that Dlk1 is a critical factor in regulating skeletal muscle mass during development. The muscle regeneration process shares some features with muscle development. However, the role of Dlk1 in regeneration processes remains controversial. Here, we show that mesenchymal progenitors also known as adipocyte progenitors exclusively express Dlk1 during muscle regeneration. Eliminating developmental effects, we used conditional depletion models to examine the specific roles of Dlk1 in muscle stem cells or mesenchymal progenitors. Unexpectedly, deletion of Dlk1 in neither the muscle stem cells nor the mesenchymal progenitors affected the regenerative ability of skeletal muscle. In addition, fat accumulation was not increased by the loss of Dlk1. Collectively, Dlk1 plays essential roles in muscle development, but does not greatly impact regeneration processes and adipogenic differentiation in adult skeletal muscle regeneration.

Effects of genetic distance on heterosis in a Drosophila melanogaster model system.

Habitat fragmentation and small population sizes can lead to inbreeding and loss of genetic variation, which can potentially cause inbreeding depression and decrease the ability of populations to adapt to altered environmental conditions. One solution to these genetic problems is the implementation of genetic rescue, which re-establishes gene flow between separated populations. Similar techniques are being used in animal and plant breeding to produce superior production animals and plants. To optimize fitness benefits in genetic rescue programs and to secure high yielding domestic varieties in animal and plant breeding, knowledge on the genetic relatedness of populations being crossed is imperative. In this study, we conducted replicated crosses between isogenic Drosophila melanogaster lines from the Drosophila Genetic Reference Panel. We grouped lines in two genetic distance groups to study the effect of genetic divergence between populations on the expression of heterosis in two fitness components; starvation resistance and reproductive output. We further investigated the transgenerational effects of outcrossing by investigating the fitness consequences in both the F1- and the F3-generations. High fitness enhancements were observed in hybrid offspring compared to parental lines, especially for reproductive output. However, the level of heterosis declined from the F1- to the F3-generation. Generally, genetic distance did not have strong impact on the level of heterosis detected, although there were exceptions to this pattern. The best predictor of heterosis was performance of parental lines with poorly performing parental lines showing higher hybrid vigour when crossed, i.e. the potential for heterosis was proportional to the level of inbreeding depression. Overall, our results show that outcrossing can have very strong positive fitness consequences for genetically depauperate populations.

Human and Autologous Adipose-derived Stromal Cells Increase Flap Survival in Rats Independently of Host Immune Response.

INTRODUCTION: There is a rising interest in adipose-derived stromal cells for clinical use; however, it is unknown whether freshly isolated stromal cells (SVF) or culture-expanded cells (ASCs) are more efficacious. We therefore aimed to compare the 2 cellular therapies in an in vivo model of angiogenesis, the ischemic flap in rats, which induces acute ischemia. We also aimed to determine the importance of cell presence and the host immune response. METHODS: A total of 96 rats (n = 12 in each group) were used, and in each rat, a caudally based random flap measuring 2 × 7 cm was made. The study was conducted in 3 phases. First, each rat was treated with human SVF cells, human ASCs, or vehicle. Second, each rat was treated with human SVF, human SVF lysate, or vehicle. Finally, each rat was treated with rat (autologous) SVF cells or vehicle. Flap survival, vessel density, and stromal cell retention were evaluated after 7 days. RESULTS: The mean survival rates for SVF treatment regardless of human or autologous origin were significantly increased as compared with the control group. Adipose stem/stromal cell and SVF lysate injection did not increase flap survival. Vessel density was increased for human and rat SVF and human ASC but not for SVF lysate. Human cells were not detected in the flaps after 7 days. CONCLUSIONS: Flap survival increased with SVF treatment regardless of human or autologous origin, suggesting that increased flap survival is independent of the host immune response. All cell injections lead to increased vessel density, but it did not necessarily lead to increased flap survival. Further research should elaborate which molecular events make SVF treatment more efficacious than ASC.