Angiotensin-(1-5) is a Potent Endogenous Angiotensin AT 2 -Receptor Agonist.

Background: The renin-angiotensin system involves many more enzymes, receptors and biologically active peptides than originally thought. With this study, we investigated whether angiotensin-(1-5) [Ang-(1-5)], a 5-amino acid fragment of angiotensin II, has biological activity, and through which receptor it elicits effects. Methods: The effect of Ang-(1-5) (1µM) on nitric oxide release was measured by DAF-FM staining in human aortic endothelial cells (HAEC), or Chinese Hamster Ovary (CHO) cells stably transfected with the angiotensin AT 2 -receptor (AT 2 R) or the receptor Mas. A potential vasodilatory effect of Ang-(1-5) was tested in mouse mesenteric and human renal arteries by wire myography; the effect on blood pressure was evaluated in normotensive C57BL/6 mice by Millar catheter. These experiments were performed in the presence or absence of a range of antagonists or inhibitors or in AT 2 R-knockout mice. Binding of Ang-(1-5) to the AT 2 R was confirmed and the preferred conformations determined by in silico docking simulations. The signaling network of Ang-(1-5) was mapped by quantitative phosphoproteomics. Results: Key findings included: (1) Ang-(1-5) induced activation of eNOS by changes in phosphorylation at Ser1177 eNOS and Tyr657 eNOS and thereby (2) increased NO release from HAEC and AT 2 R-transfected CHO cells, but not from Mas-transfected or non-transfected CHO cells. (3) Ang-(1-5) induced relaxation of preconstricted mouse mesenteric and human renal arteries and (4) lowered blood pressure in normotensive mice - effects which were respectively absent in arteries from AT 2 R-KO or in PD123319-treated mice and which were more potent than effects of the established AT 2 R-agonist C21. (5) According to in silico modelling, Ang-(1-5) binds to the AT 2 R in two preferred conformations, one differing substantially from where the first five amino acids within angiotensin II bind to the AT 2 R. (6) Ang-(1-5) modifies signaling pathways in a protective RAS-typical way and with relevance for endothelial cell physiology and disease. Conclusions: Ang-(1-5) is a potent, endogenous AT 2 R-agonist.

COVID-19 Pandemic Quarantines and Mental Health Among Adolescents in Norway.

Importance: Adolescence is a critical developmental phase when mental health disorders, such as anxiety and depression, often emerge. Stringent public health measures and quarantine mandates during the COVID-19 pandemic could threaten adolescent mental health. Objective: To investigate the associations of public health measures and quarantine experiences with mental distress among Norwegian adolescents and to explore if certain vulnerability factors moderate these associations. Design, Setting, and Participants: This longitudinal cohort study used repeated measures to capture variations in mental distress explained by the stringency of public health measures and quarantine experiences. Data from the Norwegian Mother, Father, and Child cohort study were linked to national health registries and a national stringency index from April 1, 2020, to February 17, 2021. Participant included 7787 Norwegian adolescents aged 16 to 18 years. Data were analyzed from October 2022 to October 2023. Exposures: Stringency index of public health measures and quarantine experiences including recent quarantine (within the last 2 weeks) and quarantine frequency (cumulative number of quarantine episodes). Main Outcome and Measures: Mental distress was measured using the Hopkins Symptom Checklist across 6 data collection waves. Results: In this study, 7787 participants were included in the analysis (4473 female [57%]; mean [SD] age, 17.0 [0.6] years). Stringent public health measures (ß = 0.18; SE, 0.02; P < .001), recent quarantine (ß = 0.11; SE, 0.02; P < .001), and frequent quarantine (ß = 0.08; SE, 0.01; P < .001) were associated with higher levels of mental distress. The associations between public health measures and mental distress were not moderated by sex, age, prepandemic anxiety or depression, or genetic liability for mental health conditions. Frequency of quarantine appeared to be more strongly associated with mental distress among younger adolescents (ß = -0.04; SE, 0.01; P = .008), those with parents with lower education (ß = -0.04; SE, 0.01; P = .007), and those with lower genetic risk for depression (ß = -0.03; SE, 0.01; P = .006). Conclusions and Relevance: In this study, younger adolescents, those with parents with lower education, or those with low genetic liability for depression appeared more vulnerable when being quarantined several times. These findings emphasize the need for targeted support strategies to better protect adolescent well-being during future crises. Adolescents who experienced increased mental distress during the COVID-19 pandemic may be at risk of continued mental health problems and in need of ongoing support.

Evaluation of Validity and Reliability of a German General and Sports Nutrition Knowledge Questionnaire for Athletes and Coaches (GSNKQ-AC).

Despite the availability of nutritional recommendations, studies have reported inadequate nutrition in athletes. The existing literature highlights the importance of the nutritional knowledge of both athletes and coaches in influencing athletes' food choices and behavior, as well as its direct and indirect impact on athletes' performance and health. To adequately assess nutritional knowledge, monitoring via valid and reliable questionnaires is required. As no questionnaire tailored to German-speaking athletes and coaches exists, this study aimed at developing a new General and Sports Nutritional Knowledge Questionnaire for Athletes and Coaches (GSNKQ-AC). The development followed a literature-based, ten-step validation approach. The initial questionnaire (63 items) was revised and reduced to 29 items in the final version after conducting construct verification in the target group (n = 84 athletes and coaches), evaluating content validity by a panel of nutrition experts (n = 8), verifying face validity by think-out-loud interviews in the target group (n = 7), and conducting classical test theory for item reduction analysis (n = 53). For the final GSNKQ-AC, internal consistency, calculated as Cronbach's alpha, was 0.87. Students with a focus on sports nutrition (n = 31) scored significantly higher than athletes and coaches (n = 53), revealing good construct validity (77% vs. 62%, p < 0.001). Test-retest reliability (n = 42, matched pairs) showed a Spearman's correlation coefficient of r = 0.61 (p < 0.01). The brief GSNKQ-AC can be used for status quo or longitudinal assessment of nutritional knowledge among athletes and coaches to reveal gaps and ensure purposeful planning of educational interventions.

Disturbed bone marrow adiposity in patients with Cushing's syndrome and glucocorticoid- and postmenopausal- induced osteoporosis.

Background: Skeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including hormonal signalling. Glucocorticoids (GC) are corticosteroid hormones that promote adipogenic differentiation and are endogenously increased in patients with Cushing´s syndrome (CS). Here, we investigate bone marrow adiposity changes in response to endogenous or exogenous GC increases. For that, we characterize bone biopsies from patients with CS and post-menopausal women with glucocorticoid-induced osteoporosis (GC-O), compared to age-matched controls, including postmenopausal osteoporotic patients (PM-O). Methods: Transiliac crest bone biopsies from CS patients and healthy controls, and from postmenopausal women with GC-O and matched controls were analysed; an additional cohort included biopsies from women with PM-O. Plastic-embedded biopsies were sectioned for histomorphometric characterization and quantification of adipocytes. The fraction of adipocyte area per tissue (Ad.Ar/T.Ar) and marrow area (Ad.Ar/Ma.Ar), mean adipocyte profile area (Ad.Pf.Ar) and adipocyte profile density (N.Ad.Pf/Ma.Ar) were determined and correlated to steroid levels. Furthermore, the spatial distribution of adipocytes in relation to trabecular bone was characterized and correlations between bone marrow adiposity and bone remodeling parameters investigated. Results: Biopsies from patients with CS and GC-O presented increased Ad.Ar/Ma.Ar, along with adipocyte hypertrophy and hyperplasia. In patients with CS, both Ad.Ar/Ma.Ar and Ad.Pf.Ar significantly correlated with serum cortisol levels. Spatial distribution analyses revealed that, in CS, the increase in Ad.Ar/Ma.Ar near to trabecular bone (<100 µm) was mediated by both adipocyte hypertrophy and hyperplasia, while N.Ad.Pf/Ma.Ar further into the marrow (>100 µm) remained unchanged. In contrast, patients with GC-O only presented increased Ad.Ar/Ma.Ar and mean Ad.Pf.Ar>100 µm from trabecular bone surface, highlighting the differential effect of increased endogenous steroid accumulation. Finally, the Ad.Ar/Ma.Ar and Ad.Ar/T.Ar correlated with the canopy coverage above remodeling events. Conclusion: Increased cortisol production in patients with CS induces increased bone marrow adiposity, primarily mediated by adipocyte hypertrophy. This adiposity is particularly evident near trabecular bone surfaces, where hyperplasia also occurs. The differential pattern of adiposity in patients with CS and GC-O highlights that bone marrow adipocytes and their progenitors may respond differently in these two GC-mediated bone diseases.

Contact with primary care physicians among adults with pre-existing common mental health problems during the COVID-19 pandemic: a registry-based study from Norway.

BACKGROUND: During the COVID-19 pandemic, individuals with pre-existing mental health problems may have experienced additional stress, which could worsen symptoms or trigger relapse. Thus, this study aimed to investigate if the number of consultations with general practitioners (GPs) among individuals with a pre-existing common mental health problem during the pandemic differed from pre-pandemic years. METHODS: Data on consultations with GPs among 18-65-year-olds registered with common mental health problems in 2017-2021 were retrieved from the Norwegian Control and Payment of Health Reimbursements Database. Based on data from the pre-pandemic years (2017-2019), we predicted the number of consultations per week for depression, anxiety disorder, phobia/obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and eating disorders during the pandemic (March 2020-December 2021) among individuals with pre-existing mental health problems. The forecasted and observed trends in GP consultations per week during the pandemic were stratified by diagnosis, gender, and age groups. RESULTS: The observed number of consultations for anxiety disorder, PTSD, and eating disorders were significantly higher than forecasted during extended periods of the two pandemic years. The differences were largest for PTSD (on average 37% higher in men and 47% higher in women during the pandemic), and for eating disorders among women (on average 87% higher during the pandemic). There were only minor differences between the predicted and observed number of consultations for depression and phobia/OCD. CONCLUSIONS: During the pandemic, individuals with a recent history of mental health problems were more likely to seek help for anxiety disorder, PTSD, and eating disorders, as compared to pre-pandemic years.

Orthopaedic patients' experiences of their sleep during hospitalisation and suggestions for improvements.

PURPOSE: To describe orthopaedic patients' perspectives on their sleep quality and their suggestions for improvement initiatives to achieve better sleep quality during hospitalisation. METHODS: In a qualitative design, 265 (50%) of 533 patients from a questionnaire survey responded to two free-text questions. Data were analysed based on a phenomenological-hermeneutic approach inspired by Paul Ricoeur's theory of narrative and interpretation. RESULTS: Three themes emerged: 1) Sleeping environment and preferences tailored to the individual patient, 2) The link between orthopaedic surgery care and sleeping, and 3) Noise challenged a good night's sleep. Good sleep was related to nurses' professional behaviour and the physical environment, such as quality beds and sleeping aids. Single and shared rooms, room lighting, and fresh air all influenced sleep quality. Unfamiliar and uncomfortable sleeping positions posed a challenge for orthopaedic patients but aids such as pillows, and duvets could provide more comfort at night. Offset circadian rhythms could affect sleep quality, as could nausea and vomiting. Pain and lack of pain relief were associated with poor sleep quality. Noise from both nurses and other patients affected sleep quality. Therefore, unnecessary care activities should be kept to a minimum, and a "night noise level" was suggested. CONCLUSION: Patients' sleep disturbance following orthopaedic surgery needs to be addressed by both nurses and hospital management. Patients' involvement is essential to create a sleep environment tailored to individual needs and to provide strategies patients use at home for addressing sleeping problems.

Incidence rates of treated mental disorders before and during the COVID-19 pandemic-a nationwide study comparing trends in the period 2015 to 2021.

BACKGROUND: There is a concern that exposure to psychosocial stressors during the COVID-19 pandemic may have led to a higher incidence of mental disorders. Thus, this study aimed to compare trends in incidence rates of depressive disorder, anxiety disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and eating disorders in primary- and specialist health care before (2015-2019) and during the COVID-19 pandemic (2020-2021). METHODS: We used aggregated population registry data to calculate incidence rates of mental disorders from primary- (The Norwegian Control and Payment of Health Reimbursements Registry (KUHR)) and specialist (The Norwegian Patient Registry (NPR)) health care. The analyses included all Norwegian residents aged 18-65 during the study period. Incident cases were defined as having no previous registration with the same mental disorder in KUHR (from 2006) or NPR (from 2008). We used linear prediction models and mean models to compare incidence rates and test trends before and during the pandemic. RESULTS: During the pandemic, the incidence rates among women were higher or as predicted for OCD in specialist health care and for eating disorders in both primary- and specialist health care. These findings were strongest among women aged 18-24 years. Incidence rates for depression and phobia/OCD among both genders in primary health care and phobic anxiety disorders among both genders in specialist health care were lower or as predicted. CONCLUSION: The COVID-19 pandemic may have led to more women needing treatment for OCD and eating disorders in the Norwegian population. The decreased incidence rates for some disorders might indicate that some individuals either avoided seeking help or had improved mental health during the pandemic.

Implementation of ultrasound-guided carpal tunnel release.

INTRODUCTION: Ultra-minimally invasive ultrasound-guided carpal tunnel release is a surgical procedure for treatment of carpal tunnel syndrome that is associated with less surgery-related morbidity and faster recovery than open surgery. The objectives of this study were to describe how the surgical technique may be acquired and to report the results obtained after implementation in a clinical setting. METHODS: The study consisted of two parts: 1) description of the surgical skills needed to perform the procedure, and 2) evaluation of the procedure in the first ten consecutively operated patients after 12-month follow-up using questionnaires and magnetic resonance imaging (MRI). RESULTS: The procedure was performed on 29 cadaveric arms and assessed regarding surgical release success and signs of iatrogenic damage. Subsequently, the procedure was performed on ten patients with carpal tunnel syndrome. The results of the six-item Carpal Tunnel Symptoms Scale (1-5) improved from 3.3 ± 0.9 (mean ± standard deviation) preoperatively to 1.2 ± 0.3, p = 0.002, after 12 months. Quick Disabilities of the Arm, Shoulder and Hand (DASH) (0-100) results improved from 33.4 ± 14.8 to 2.3 ± 4.0, p = 0.002. There were no infections or iatrogenic damage to nerves or blood vessels. CONCLUSIONS: This study presents a way to safely acquire the skills needed to perform the procedure and implement it in an out-patient setting. The results were comparable to previous findings regarding both effectiveness and safety. MRI documented the surgical gap in the transverse carpal ligament, release length, cross-sectional area changes in the carpal tunnel and median nerve, and reactive changes in the carpal tunnel. FUNDING: None. TRIAL REGISTRATION: Not relevant.

T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy.

A key phenomenon in cancer is the establishment of a highly immunosuppressive tumour microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumour recognition and hence hereof tumour eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumour is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signalling pathway has been considered an attractive target, as it is a potent trigger of pro-inflammatory cytokines and types I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggests a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4+ T cells (T-EVs), sensitizes macrophages to elevate STING activation, mediated by IFNγ carried on the T-EVs. Our work support that T-EVs can disrupt the immune suppressive environment in the tumour by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.

'Why doesn't anyone ask me'? Patients' experiences of receiving, performing and practices of oral care in an acute Orthopaedic Department.

AIMS AND OBJECTIVES: Oral care is an integrated part of everyday life. Within nursing, barriers related to providing oral care often lead to unmet caring needs. Poor oral care is associated with a risk of respiratory and cardiovascular complications during hospitalisation. Knowledge on patients' perspectives of maintaining or receiving oral care during admissions are limited. Following the Fundamentals of Care (FOC) framework, this study uses a person-centred approach to explore patients' perceptions and experiences of receiving or performing oral care, including the nursing staff's clinical practices. METHODOLOGICAL DESIGN AND JUSTIFICATION: A focussed ethnographic approach was used to explore patients' perspectives and clinical practices during acute admissions in an Orthopaedic Department. ETHICS ISSUES AND APPROVAL: The local Data Protection Agency and the Ethics Committee approved the study. RESEARCH METHODS, RESULTS AND CONCLUSIONS: Data were collected in an Orthopaedic ward at a Copenhagen University hospital, Hvidovre, and consisted of 14 days of field observations of clinical practices and 15 patient interviews. Data were analysed inductively using qualitative content analysis. Two themes were identified. The first, 'The purpose of oral care is defined by the eye of the beholder', describes the social implications for the patients and how patients reject the assumption of oral care being a transgressive act. The second, 'The unspoken need', focus on the lack of dialogue, including the limited provision of oral care and how the nursing staff assesses patients' ability to perform oral care (in)dependently without including the patients. CONCLUSION: Oral care is related to the patient's psychological and physical well-being and affects social appearance. When oral care is provided respectfully, patients do not experience oral care as a transgressive act. Nursing staff's self-assessments of the patients' (in)dependency to perform oral care risk leading to incorrect care. Developing and implementing interventions applicable to the clinical practice is needed.

A Critical Role of the Bone Marrow Envelope in Human Bone Remodeling.

Proper bone remodeling depends not only on a team of bone-resorbing osteoclasts and bone-forming osteoblasts. It also depends on the site-specific delivery of a large amount of osteoblast lineage cells to the bone remodeling site. How this delivery occurs is poorly known. Here, we gained insight into this mechanism by analyzing the distribution of markers of osteoblastogenesis on bone surfaces and in their bone marrow neighborhood in human cancellous bone. We found a CD271-positive/PDGFß-R-positive cell layer surrounding the bone marrow that provides osteoblastogenic potential along all bone surfaces, whether quiescent or remodeling. This bone marrow envelope cell layer takes the appearance of a canopy above remodeling sites, where it then also shows an upregulation of the proliferation marker Ki67, smooth muscle actin (SMA), tenascin C, fibronectin, and MMP13. This indicates that the canopy is a region of the bone marrow envelope where early markers of osteoblastogenesis are activated concurrently with initiation of bone remodeling. Importantly, the high proliferation index in the canopy is not associated with increasing cell densities at the canopy level, but it is at the bone surface level, thereby supporting delivery of cells from the canopy to the bone surface. This delivery route explains why lack of canopies was previously found to coincide with lack of bone formation, and fits current knowledge on the canopies as a target for regulators of bone remodeling. We conclude that the coordination of bone marrow envelope activities and bone surface activities allows integrating osteoblastogenesis and bone remodeling into the same functional unit, and propose that the bone marrow envelope is critical for preserving bone health. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer's disease neurons.

Alzheimer's disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied amyloid beta (Aß) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD phenotypes, such as increased Aß secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in various in vivo and in vitro complementary disease models, which can be exacerbated via additional risk variants in SORL1.

Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson's disease GBA-N370S dopamine neurons.

Variants at the GBA locus, encoding glucocerebrosidase, are the strongest common genetic risk factor for Parkinson's disease (PD). To understand GBA-related disease mechanisms, we use a multi-part-enrichment proteomics and post-translational modification (PTM) workflow, identifying large numbers of dysregulated proteins and PTMs in heterozygous GBA-N370S PD patient induced pluripotent stem cell (iPSC) dopamine neurons. Alterations in glycosylation status show disturbances in the autophagy-lysosomal pathway, which concur with upstream perturbations in mammalian target of rapamycin (mTOR) activation in GBA-PD neurons. Several native and modified proteins encoded by PD-associated genes are dysregulated in GBA-PD neurons. Integrated pathway analysis reveals impaired neuritogenesis in GBA-PD neurons and identify tau as a key pathway mediator. Functional assays confirm neurite outgrowth deficits and identify impaired mitochondrial movement in GBA-PD neurons. Furthermore, pharmacological rescue of glucocerebrosidase activity in GBA-PD neurons improves the neurite outgrowth deficit. Overall, this study demonstrates the potential of PTMomics to elucidate neurodegeneration-associated pathways and potential drug targets in complex disease models.

Estimated glomerular filtration rate based on creatinine, cystatin C, ß-trace protein and ß2 microglobulin in patients undergoing nontraumatic lower extremity amputation.

AIMS: The study's aim is to compare current and new equations for estimating glomerular filtration rate (GFR) based on creatinine, cystatin C, ß-trace protein (BTP) and ß2 microglobulin (B2M) among patients undergoing major amputation. METHODS: This is a secondary analysis of data from a prospective cohort study investigating patients undergoing nontraumatic lower extremity amputation. Estimated GFR (eGFR) was calculated using equations based on creatinine (eGFRcre[2009] and eGFRcre[2021]), cystatin C (eGFRcys), the combination of creatinine and cystatin C (eGFRcomb[2012] and eGFRcomb[2021]) or a panel of all 4 filtration markers (eGFRpanel). Primary outcome was changed in eGFR across amputation according to each equation. Two case studies of prior amputation with GFR measured by 99mTc-DTPA clearance are described to illustrate the relative accuracies of each eGFR equation. RESULTS: Analysis of the primary outcome included 29 patients (median age 75 years, 31% female). Amputation was associated with a significant decrease in creatinine concentration (-0.09 mg/dL, P = 0.004), corresponding to a significant increase in eGFRcre[2009] (+6.1 mL/min, P = 0.006) and eGFRcre[2021] (+6.3 mL/min, P = 0.006). Change across amputation was not significant for cystatin C, BTP, B2M or equations incorporating these markers (all P > 0.05). In both case studies, eGFRcre[2021] yielded the largest positive bias, eGFRcys yielded the largest negative bias and eGFRcomb[2012] and eGFRcomb[2021] yielded the smallest absolute bias. CONCLUSION: Creatinine-based estimates were substantially higher than cystatin C-based estimates before amputation and significantly increased across amputation. Estimates combining creatinine and cystatin were stable across amputation, while the addition of BTP and B2M is unlikely to be clinically relevant.

Ceruloplasmin-deficient mice show changes in PTM profiles of proteins involved in messenger RNA processing and neuronal projections and synaptic processes.

Ceruloplasmin (Cp) is a multicopper oxidase with ferroxidase properties being of importance to the mobilisation and export of iron from cells and its ability to bind copper. In ageing humans, Cp deficiency is known to result in aceruloplasminemia, which among other is characterised by neurological symptoms. To obtain novel information about the functions of Cp in the central nervous system (CNS) we compared the brain proteome in forebrains from asymptomatic 4-6-month-old Cp-deficient (B6N(Cg)-Cptm1b(KOMP)Wtsi /J) and wild-type mice. Of more than 5600 quantified proteins, 23 proteins, were regulated, whereas more than 1200 proteins had regulated post-translational modifications (PTMs). The genes of the regulated proteins, glycoproteins and phosphoproteins appeared mostly to be located to neurons and oligodendrocyte precursor cells. Cp deficiency especially affected the function of proteins involved in the extension of neuronal projections, synaptic signalling and cellular mRNA processing and affected the expression of proteins involved in neurodegenerative disease and diabetes. Iron concentration and transferrin saturation were reduced in the blood of even younger, 3- to 5-month-old, Cp-deficient mice. Iron act as cofactor in many enzymatic processes and reactions. Changes in iron availability and oxidation as consequence of Cp deficiency could therefore affect the synthesis of proteins and lipids. This proteomic characterisation is to our knowledge the first to document the changes taking place in the CNS-proteome and its phosphorylation and glycosylation state in Cp-deficient mice.

Quantitative Phosphoproteomics and Acetylomics of Safranal Anticancer Effects in Triple-Negative Breast Cancer Cells.

Safranal, as an aroma in saffron, is one of the cytotoxic compounds in saffron that causes cell death in triple-negative breast cancer cells. Our recent research reported the anti-cancer effects of safranal, which further demonstrated its impact on protein translation, mitochondrial dysfunction, and DNA fragmentation. To better understand the underlying mechanisms, we identified acetylated and phosphorylated peptides in safranal-treated cancer cells. We conducted a comprehensive phosphoproteomics and acetylomics analysis of safranal-treated MDA-MB-231 cells by using a combination of TMT labeling and enrichment methods including titanium dioxide and immunoprecipitation. We provide a wide range of phosphoproteome regulation in different signaling pathways that are disrupted by safranal treatment. Safranal influences the phosphorylation level on proteins involved in DNA replication and repair, translation, and EGFR activation/accumulation, which can lead the cells into apoptosis. Safranal causes DNA damage which is followed by the activation of cell cycle checkpoints for DNA repair. Over time, checkpoints and DNA repair are inhibited and cells are under a mitotic catastrophe. Moreover, safranal prevents repair by the hypo-acetylation of H4 and facilitates the transcription of proapoptotic genes by hyper-acetylation of H3, which push the cells to the brink of death.

Artificial intelligence assisted compositional analyses of human abdominal aortic aneurysms ex vivo.

Quantification of histological information from excised human abdominal aortic aneurysm (AAA) specimens may provide essential information on the degree of infiltration of inflammatory cells in different regions of the AAA. Such information will support mechanistic insight in AAA pathology and can be linked to clinical measures for further development of AAA treatment regimens. We hypothesize that artificial intelligence can support high throughput analyses of histological sections of excised human AAA. We present an analysis framework based on supervised machine learning. We used TensorFlow and QuPath to determine the overall architecture of the AAA: thrombus, arterial wall, and adventitial loose connective tissue. Within the wall and adventitial zones, the content of collagen, elastin, and specific inflammatory cells was quantified. A deep neural network (DNN) was trained on manually annotated, Weigert stained, tissue sections (14 patients) and validated on images from two other patients. Finally, we applied the method on 95 new patient samples. The DNN was able to segment the sections according to the overall wall architecture with Jaccard coefficients after 65 epocs of 92% for the training and 88% for the validation data set, respectively. Precision and recall both reached 92%. The zone areas were highly variable between patients, as were the outputs on total cell count and elastin/collagen fiber content. The number of specific cells or stained area per zone was deterministically determined. However, combining the masks based on the Weigert stainings, with images of immunostained serial sections requires addition of landmark recognition to the analysis path. The combination of digital pathology, the DNN we developed, and landmark registration will provide a strong tool for future analyses of the histology of excised human AAA. In combination with biomechanical testing and microstructurally motivated mathematical models of AAA remodeling, the method has the potential to be a strong tool to provide mechanistic insight in the disease. In combination with each patients' demographic and clinical profile, the method can be an interesting tool to in supportof a better treatment regime for the patients.

Dialogue is a prerequisite for the nurse-patient relationship in nutritional care: A secondary analysis using the fundamentals of care framework.

BACKGROUND: Providing good nutritional care is complex as it goes beyond assessing and ensuring the patients' dietary needs. So far, nutritional research has mainly focused on establishing evidence for the nutritional treatment, while less attention has been on the complexity of providing nutritional care. The Fundamentals of Care (FoC) describes five elements (focus, knowledge, anticipate, evaluate and trust) essential for establishing a nurse-patient relationship as a foundation for quality care. By studying how these elements shape nutritional care and dialogue, we can explore and describe the complexity of nutritional care. AIM: By using the FoC framework as an analytic framework, this study explores how the nurse-patient relationship shapes the nutritional care of orthopaedic patients. METHOD: This study is a secondary analysis using deductive content analysis of interviews with patients undergoing major orthopaedic surgery, nursing staff and observations of interactions between nursing staff and patients. The core dimension of the FoC framework, 'Establishment of relationship,' was used as an analytic framework. RESULT: The nurses perceived serving meals and providing nutritional supplements as an essential part of the nutritional care. Still, the nutritional care was organised as a routine task to be less time-consuming. Appropriate care was initiated when the nursing staff explored patients´ food preferences. When the nursing staff failed to familiarise themselves with the patient's preferences, the patients interpreted nutritional care as unrelated to their needs, resulting in a lack of trust. CONCLUSION: The need for efficiency within nutritional care must not compromise the patients' need for dialogue with the nurse. Establishing a trusting relationship between nurses and patients prevents nutritional care from becoming a routine task unrelated to the patients' needs.

Coping, Social Support and Loneliness during the COVID-19 Pandemic and Their Effect on Depression and Anxiety: Patients' Experiences in Community Mental Health Centers in Norway.

Background: Little is known about psychiatric patients' experiences during the COVID-19 pandemic. The purpose of this study was to investigate associations of coping strategies, social support and loneliness with mental health symptoms among these patients. Methods: We recruited 164 patients from Community Mental Health Centers in June-July 2020. Participants responded to an online questionnaire on corona-related questions, Brief Coping Orientation to Problems Experience, Crisis Support Scale, a 3-item Loneliness Scale, and Hopkins Symptom Checklist-25. We used linear regression models to investigate associations between these and symptoms of depression and anxiety. Results: Almost 51% were aged 31-50 years and 77% were females. Forty-six (28%) participants reported worsened overall mental health due to the pandemic. The reported rates of clinical depression and anxiety were 84% and 76%, respectively. Maladaptive coping was independently associated with both depression and anxiety symptoms. Loneliness was independently associated with depression symptoms. Conclusions: Patients in Community Mental Health Centers in Norway reported high rates of depression and anxiety symptoms. Many of them reported worsening of their mental health due to the pandemic, even at a time when COVID-19 infections and restrictive measures were relatively low. Maladaptive coping strategies and loneliness may be possible explanations for more distress.