Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases.

Fisetin, a flavonoid naturally occurring in plants, fruits, and vegetables, has recently gained attention for its potential role as a senotherapeutic agent for the treatment of age-related chronic diseases. Senotherapeutics target senescent cells, which accumulate with age and disease, in both circulating immune cell populations and solid organs and tissues. Senescent cells contribute to development of many chronic diseases, primarily by eliciting systemic chronic inflammation through their senescence-associated secretory phenotype. Here, we explore whether fisetin as a senotherapeutic can eliminate senescent cells, and thereby alleviate chronic diseases, by examining current evidence from in vitro studies and animal models that investigate fisetin's impact on age-related diseases, as well as from phase I/II trials in various patient populations. We discuss the application of fisetin in humans, including challenges and future directions. Our review of available data suggests that targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases, potentially transforming future healthcare for older and multimorbid patients. However, further studies are needed to establish the safety, pharmacokinetics, and efficacy of fisetin as a senotherapeutic, identify relevant and reliable outcome measures in human trials, optimize dosing, and better understand the possible limitations of fisetin as a senotherapeutic agent.

Patients with Non-Specific Complaints in Emergency Departments: A Growing Patient Safety Concern in an Aging Population with Multimorbidity.

In this opinion, we offer a new perspective on the important and persistent problem of diagnostic errors for patients with non-specific complaints (NSCs). As an increasing number of complex patients present clinicians with challenging diagnostic work in the time-pressured and high-volume contexts of EDs, we need to improve how clinicians and healthcare organizations can understand and perform safe diagnostics for patients with NSCs. The combination of a growing number of patients with NSCs and the ways in which clinicians use the categories 'non-specific complaints' and 'non-specific diagnosis' in diagnostic work in emergency departments presents a growing patient safety concern especially for older patients with multimorbidity that require the integration of clinical and organizational research. We argue why the growing numbers of patients with NSCs and clinicians' use of these categories have implications for patient safety both within and beyond the acute care context. We end by pointing to the importance of an interdisciplinary patient safety research agenda, ideally followed by the development of targeted usable protocols for older multimorbid patients with non-specific complaints.

Minimizing the Risk of Diagnostic Errors in Acute Care for Older Adults: An Interdisciplinary Patient Safety Challenge.

Modern healthcare systems are increasingly organized according to diagnosis-specific clinical pathways and treatment protocols. At the same time, the number of patients with complex problems and needs that do not fit the single-diagnosis approach is rising, contributing to a high prevalence of diagnostic errors. In this article, we focus on the risk of diagnostic errors arising from missed or incomplete diagnosis and assessment of older adult patients' care needs in the first hours of acute hospitalizations in EDs. This focus is important for improving patient safety, as clinical decisions made in EDs impact patient safety in the subsequent steps of the process, thereby potentially causing new risks to arise. Based on our discussion of clinical decision-making and diagnostic errors in the acute care context, we propose a more comprehensive interdisciplinary approach to improvements in patient safety that integrates organizational and clinical research and examines where, when, how, and why risks to patient safety arise in and across different clinical-organizational contexts.

Between acute medicine and municipal alcohol treatment: Cross-sectoral collaborations regarding patients with alcohol problems.

Aim: The aim was to examine cross-sectoral collaborations of a Danish emergency department (ED) and two municipal treatment centres in the uptake area regarding patients with alcohol problems. Methods: The study was a qualitative exploratory study. We conducted individual interviews with ED nurses and secretaries (n = 21) and group interviews (n = 2) in municipal alcohol treatment centres with three and four participants, respectively. Interviews were analysed, first with qualitative content analysis, then by applying the analytical concept "boundary object". Results: Three themes emerged: (1) Responsibilities in practice; (2) Professional contrasts; and (3) The social nurse in a unique position. Themes illuminated a low degree of collaboration characterising the intersectoral work. Blurred responsibilities, challenged communication and acute versus long-term focus were some of the factors not supporting cross-sector collaborations. However, the function of the social nurse was highly appreciated in both sectors and plays a central role. Nonetheless, implicit limitations of this function entail that not all patients with alcohol problems are referred and handled within an ED setting. Conclusions: Overall, we found a lack of collaborative work between healthcare professionals in ED and municipalities for patients with alcohol problems. However, the "social nurse" function was greatly valued in both sectors due to a mediating role, since healthcare professionals in both sectors experienced lack of organisational structures supporting collaborative network, perceived temporal barriers, limited knowledge exchange and differences in approaches to patients.

Correction: Longitudinal models for the progression of disease portfolios in a nationwide chronic heart disease population.

[This corrects the article DOI: 10.1371/journal.pone.0284496.].

A characterization of patients with low soluble urokinase plasminogen activator receptor who died within 90 days of hospital discharge.

Soluble urokinase plasminogen activator receptor (suPAR) is a marker of systemic chronic inflammation. Elevated suPAR levels are associated with adverse clinical outcomes, but a small subset of patients with low suPAR also experience poor outcomes. Therefore, we aimed to characterize patients presenting to the emergency department with low suPAR (<3 ng/mL) who died within 90 days after discharge in a registry-based study. Compared to patients with low suPAR who survived (n = 15 122), those who died within 90 days (n = 87) had higher age (75.4 years), higher medication use (7.0; 71.3% with polypharmacy) and more blood tests outside reference intervals (5.0) (including C-reactive protein, neutrophils and albumin), and the most common diagnoses were chronic pulmonary disease (27.6%), cerebrovascular disease (18.4%) and dementia (11.5%). Patients with low suPAR were more morbid than what was reflected by suPAR alone. Future studies must determine which factors that contribute the most to potential algorithms when stratifying patients based on their risk of adverse clinical outcomes. These data indicate that inclusion of medication data could be relevant.

A registry-based study on universal screening for defective mismatch repair in colorectal cancer in Denmark highlights disparities in screening uptake and counselling referrals.

Universal screening for defective mismatch repair (dMMR) in colorectal cancer utilizes immunohistochemical staining for MLH1, MSH2, MSH6 and PSM2. Additionally, BRAF V600E mutations status and MLH1 hypermethylation should be performed to distinguish germline and somatic dMMR alterations. A decade of Danish population-based registries has been analysed regarding screening uptake, detection rate and referral to genetic counselling. MMR testing was performed in 71·8% (N = 34,664) of newly diagnosed colorectal cancers with an increasing trend to 88·8% coverage in the study's final year. The likelihood of undergoing MMR testing was reduced in males with 2% (95% CI 0·4-2·7, p = 0·008), with 4·1% in patients above age 70 years (95% CI 1·5-6·6, p = 0·003) compared in patients below age 51 years, with 16·3% in rectal cancers (95% CI 15·1-17·6, p < 0·001) and 1·4% left-sided colon cancers (95% CI 0·1-1·7, p = 0·03) compared to right-sided colon cancers. Tumour stage II and III increased the likelihood of being tested, with 3·7% for stage II (95% CI 2·2-5·6, p < 0·001) and 3·3% for stage III tumours (95% CI 1·8-4·8, p < 0·001) compared to stage I tumours, whereas the likelihood for stage IV tumours is reduced by 35·7% (95% CI 34·2-37·2, p < 0·001). Test rates significantly differed between the Danish health care regions. dMMR was identified in 15·1% (95% CI 14·8-15·6, p < 0·001) cases with somatic MMR inactivation in 6·7% of the cases. 8·3% tumours showed hereditary dMMR expression patterns, and 20·0% of those were referred to genetic counselling. Despite the high uptake rates, we found disparities between patient groups and missed opportunities for genetic diagnostics.

Growth differentiation factor 15 (GDF15) levels are associated with malnutrition in acutely admitted older adults.

BACKGROUND AND AIMS: The aging process is often accompanied by high risk of malnutrition and elevated levels of growth differentiation factor 15 (GDF15). GDF15 is an increasingly recognized biomarker for regulation of metabolism, but few studies have investigated the connection between GDF15 and malnutrition in older age and how it relates to other features of aging such as decreased appetite and physical function. Therefore, we investigated the associations between GDF15 levels and nutritional status, appetite, and physical function in acutely admitted older adults. METHODS: Plasma GDF15 levels were measured using immunoassays in 302 older adults (≥65 years) admitted to the emergency department (ED). Nutritional status was evaluated with the Mini Nutritional Assessment Short-Form (MNA®-SF), appetite was evaluated with the Simplified Nutritional Appetite Questionnaire (SNAQ), and physical function was evaluated with handgrip strength (HGS), 30-s chair stand test (30s-RSS), and gait speed (GS). Associations between GDF15 and each outcome was determined by logistic regression adjusted for age, sex, and C-reactive protein (CRP). RESULTS: Each doubling in plasma GDF15 level was associated with an adjusted odds ratio (OR) (95% confidence interval) of 1.59 (1.10-2.29, P = 0.01) for risk of malnutrition compared to normal nutrition and 1.19 (0.85-1.69, P = 0.3)) for malnutrition compared to risk of malnutrition. Each doubling in GDF15 was associated with an adjusted OR of 1.63 (1.21-2.23)) for having poor appetite, 1.46 (1.07-1.99) for having low HGS, 1.74 (1.23-2.51) for having low 30s-RSS, and 1.99 (1.39-2.94) for having low GS. CONCLUSION: Among older adults admitted to the ED, higher GDF15 levels were significantly associated with malnutrition, poor appetite, and low physical function independent of age, sex, and CRP.

How do oilcloth sessions work? A realist evaluation approach to exploring ripple effects in an implementation strategy.

PURPOSE: To explore the mechanisms of the implementation strategy, "oilcloth sessions" and understand and explain the ripple effects of oilcloth sessions as a strategy to implement a new emergency department. DESIGN/METHODOLOGY/APPROACH: A qualitative design was used whereby data were collected using field notes from an ethnographic study of the oilcloth sessions and follow-up semi-structured interviews with staff, managers and key employees who participated in the oilcloth sessions. The data analysis was inspired by the realist evaluation approach of generative causality proposed by Pawson and Tilley. FINDINGS: The primary ripple effect was that the oilcloth sessions were used for different purposes than the proposed program theory, including being used as: (1) a stage, (2) a battlefield, (3) a space for imagination and (4) a strategic management tool influencing the implementation outcomes. The results bring essential knowledge that may help to explain why and how a well-defined implementation strategy has unplanned outcomes. ORIGINALITY/VALUE: Unintended outcomes of implementation strategies are an underexplored issue. This study may help implementation researchers rethink the activities required to reduce unintended negative outcomes or explore potential unplanned outcomes and, in this way, hinder or enhance outcomes, effectiveness and sustainability. Future studies within implementation research should incorporate attention to unintended outcomes to fully understand the impact of implementation strategies.

Effectiveness of a multidisciplinary and transitional nutritional intervention compared with standard care on health-related quality of life among acutely admitted medical patients aged ≥65 years with malnutrition or risk of malnutrition: A randomized controlled trial.

BACKGROUND & AIM: Malnutrition, risk of malnutrition, and risk factors for malnutrition are prevalent among acutely admitted medical patients aged ≥65 years and have significant health-related consequences. Consequently, we aimed to investigate the effectiveness of a multidisciplinary and transitional nutritional intervention on health-related quality of life compared with standard care. METHODS: The study was a block randomized, observer-blinded clinical trial with two parallel arms. The Intervention Group was offered a multidisciplinary transitional nutritional intervention consisting of dietary counselling and six sub-interventions targeting individually assessed risk factors for malnutrition, while the Control Group received standard care. The inclusion criteria were a Mini Nutritional Assessment Short-Form score ≤11, age ≥65 years, and an acute admittance to the Emergency Department. Outcomes were assessed on admission and 8 and 16 weeks after hospital discharge. The primary outcome was the difference between groups in change in health-related quality of life (assessed by the EuroQol-5D-5L) from baseline to 16 weeks after discharge. The secondary outcomes were difference in intake of energy and protein, well-being, muscle strength, and body weight at all timepoints. RESULTS: From October 2018 to April 2021, 130 participants were included. Sixteen weeks after discharge, 29% in the Intervention Group and 19% in the Control Group were lost to follow-up. Compliance varied between the sub-interventions targeting nutritional risk factors and was generally low after discharge, ranging from 0 to 61%. No difference was found between groups on change in health-related quality of life or on well-being, muscle strength, and body weight at any timepoint, neither using the intention-to-treat analysis nor the per-protocol analysis. The protein intake was higher in the Intervention Group during hospitalization (1.1 (Standard Deviation (SD) 0.4) vs 0.8 (SD 0.5) g/kg/day, p = 0.0092) and 8 weeks after discharge (1.2 (SD 0.5) vs 0.9 (0.4) g/kg/day, p = 0.0025). The percentual intake of calculated protein requirements (82% (SD 24) vs 61% (SD 32), p = 0.0021), but not of calculated energy requirements (89% (SD 23) vs 80% (SD 37), p = 0.2), was higher in the Intervention Group than in the Control Group during hospitalization. Additionally, the Intervention Group had a significantly higher percentual intake of calculated protein requirements (94% (SD 41) vs 74% (SD 30), p = 0.015) and calculated energy requirements (115% (SD 37) vs 94% (SD 31), p = 0.0070) 8 weeks after discharge. The intake of energy and protein was comparable between the groups 16 weeks after discharge. CONCLUSION: We found no effect of a multidisciplinary and transitional nutritional intervention for acutely admitted medical patients aged ≥65 years with malnutrition or risk of malnutrition on our primary outcome, health-related quality of life 16 weeks after discharge. Nor did the intervention affect the secondary outcomes, well-being, muscle strength, and body weight from admission to 8 or 16 weeks after discharge. However, the intervention improved energy and protein intake during hospitalization and 8 weeks after discharge. Low compliance with the intervention after discharge may have compromised the effect of the intervention. The study is registered at ClinicalTrials.gov (identifier: NCT03741283).

Correction: Longitudinal models for the progression of disease portfolios in a nationwide chronic heart disease population.

[This corrects the article DOI: 10.1371/journal.pone.0284496.].

Opportunistic screening for COPD among socially marginalized patients.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common disease associated with premature death. Tobacco exposure is the main risk factor, but lower socioeconomic status, early life insults, and occupational exposures are also important risk factors. Socially marginalized people, facing homelessness, substance use disorder, and mental illness, are likely to have a higher risk of developing COPD, and, furthermore, experience barriers to healthcare access and consequently poorer outcomes. OBJECTIVE: This study aims to assess COPD prevalence and the impact of opportunistic screening among hospitalized patients who are in contact with hospital social nurses. These patients constitute a group of patients with a high prevalence of psychiatric and somatic diseases, substance use, low life expectancy, and are socially marginalized. METHODS: The present prospective longitudinal study includes a clinical examination at baseline. Participants will have spirometry done and be interviewed regarding risk factors, socioeconomic conditions, and respiratory symptoms. The 5-year follow-up assessment incorporates data from baseline and register data over the 5 years, including information on morbidity, use of COPD medication, hospital contacts, mortality, and socioeconomic factors. ANTICIPATED RESULTS: Referral for further diagnostic work-up and management after the screening, including COPD treatment and smoking cessation support, is expected to improve survival rates. The study is still enrolling patients. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov , NCT04754308 with study status: "enrolling".

Development and validation of prognostic machine learning models for short- and long-term mortality among acutely admitted patients based on blood tests.

Several scores predicting mortality at the emergency department have been developed. However, all with shortcomings either simple and applicable in a clinical setting, with poor performance, or advanced, with high performance, but clinically difficult to implement. This study aimed to explore if machine learning algorithms could predict all-cause short- and long-term mortality based on the routine blood test collected at admission. METHODS: We analyzed data from a retrospective cohort study, including patients > 18 years admitted to the Emergency Department (ED) of Copenhagen University Hospital Hvidovre, Denmark between November 2013 and March 2017. The primary outcomes were 3-, 10-, 30-, and 365-day mortality after admission. PyCaret, an automated machine learning library, was used to evaluate the predictive performance of fifteen machine learning algorithms using the area under the receiver operating characteristic curve (AUC). RESULTS: Data from 48,841 admissions were analyzed, of these 34,190 (70%) were randomly divided into training data, and 14,651 (30%) were in test data. Eight machine learning algorithms achieved very good to excellent results of AUC on test data in a of range 0.85-0.93. In prediction of short-term mortality, lactate dehydrogenase (LDH), leukocyte counts and differentials, Blood urea nitrogen (BUN) and mean corpuscular hemoglobin concentration (MCHC) were the best predictors, whereas prediction of long-term mortality was favored by age, LDH, soluble urokinase plasminogen activator receptor (suPAR), albumin, and blood urea nitrogen (BUN). CONCLUSION: The findings suggest that measures of biomarkers taken from one blood sample during admission to the ED can identify patients at high risk of short-and long-term mortality following emergency admissions.

Influences of specialty identity when implementing a new emergency department in Denmark: a qualitative study.

BACKGROUND: The Danish Health Authority recommended the implementation of new types of emergency departments. Organizational changes in the hospital sector challenged the role, identity, and autonomy of medical specialists. They tend to identify with their specialty, which can challenge successful implementation of change. However, investigations on specialty identity are rare in implementation science, and how the co-existence of different specialty identities influences the implementation of new emergency departments needs to be explored for the development of tailored implementation strategies. The aim of this study was to examine how medical specialty identity influences collaboration between physicians when implementing a new emergency department in Denmark. METHODS: Qualitative methods in the form of participants' observations at 13 oilcloth sessions (a micro-simulation method) were conducted followed up by 53 individual semi-structured interviews with participants from the oilcloth sessions. Out of the 53 interviews, 26 were conducted with specialists. Data from their interviews are included in this study. Data were analysed deductively inspired by Social Identity Theory. RESULTS: The analysis yielded three overarching themes: [1] ongoing creation and re-creation of specialty identity through boundary drawing; [2] social categorization and power relations; and [3] the patient as a boundary object. CONCLUSIONS: Specialty identity is an important determinant of collaboration among physicians when implementing a new emergency department. Specialty identity involves social categorization, which entails ongoing creation and re-creation of boundary drawing and exercising of power among the physicians. In some situations, the patient became a positive boundary object, increasing the possibility for a successful collaboration and supporting successful implementation, but direct expressions of boundaries and mistrust were evident. Both were manifested through a dominating power expressed through social categorization in the form of in- and out-groups and in an "us and them" discourse, which created distance and separation among physicians from different specialties. This distancing and separation became a barrier to the implementation of the new emergency department.

Associations between alcohol intake and hospital contacts due to alcohol and unintentional injuries in 71,025 Danish adolescents - a prospective cohort study.

Background: Alcohol is a leading risk factor to adolescent health. However, it is unclear how associations between alcohol intake and injuries are shaped. We investigated the dose-response relationship between alcohol intake and risk of hospital contacts due to alcohol and unintentional injuries in adolescents. Methods: We conducted a prospective cohort study including 71,025 Danish students aged 15-24 years, followed up for five years from 2014 to 2019. The main outcome measures were hospital contacts due to alcohol and unintentional injuries (all injuries and head injuries), obtained from hospital registers. Findings: Approximately 90% of males and females reported drinking alcohol, and the median intake among those was 11 drinks/week in males and 8 drinks/week in females. During five years of follow-up, 1.3% had an alcohol-attributable hospital contact, the majority of which were due to acute intoxication (70%). Alcohol-attributable hospital contacts were equally frequent in males and females and between age groups (15-17-year-olds vs 18-24-year-olds). Compared with never drinking, the adjusted incidence rate ratios for weekly intake of <7, 7-13, 14-20, 21-27, and >27 drinks/week were 1.70 (95% confidence interval 1.23-2.34), 1.77 (1.27-2.46), 1.91 (1.35-2.70), 2.34 (1.59-3.46), and 3.25 (2.27-4.64) for having an alcohol-attributable hospital contact within five years of follow-up. Restricting follow-up to one year more than doubled risk estimates. During the five years of follow-up, 27% incurred an unintentional injury. The most frequent types of injury were to the wrist or hand (27.6%), ankle or foot (25.2%), or head (12.4%). Injuries were more frequent among males (first-time incidence rate 110 per 1000 person-years) compared to females (82 per 1000 person-years), with no differences between age groups. Compared with never drinking, the adjusted incidence rate ratios for weekly intake of <7, 7-13, 14-20, 21-27, and >27 drinks were 1.09 (1.03-1.15), 1.14 (1.07-1.20), 1.25 (1.17-1.33), 1.38 (1.28-1.49), and 1.58 (1.47-1.69) for having a hospital contact for any type of unintentional injury within five years of follow-up. Results for the one-year follow-up period were comparable. Separate analysis for head injuries showed similar results as the analysis on all injuries. Results were generally similar in males and females. Interpretation: Adolescents' drinking is associated with a higher risk of acute harm in terms of hospital contacts due to alcohol and unintentional injuries in a dose-response relationship. Thus, increased risk was apparent in those with low alcohol intake, suggesting a need for awareness of and initiatives to prevent youth drinking. Furthermore, initiatives should include a strengthened focus on people younger than 18 years. Funding: This study was funded by the Tryg Foundation (ID: 153539) and The Helse Foundation (21-B-0359).

Soluble Urokinase-Type Plasminogen Activator Receptor in Comatose Survivors After Out-of-Hospital Cardiac Arrest Treated with Targeted Temperature Management.

Exposure to whole-body ischemia/reperfusion after out-of-hospital cardiac arrest (OHCA) triggers a systemic inflammatory response where soluble urokinase plasminogen activator receptor (suPAR) is released. This study investigated serial levels of suPAR in differentiated target temperature management and the associations with mortality and 6-month neurological outcome. This is a single-center substudy of the randomized Targeted Temperature Management (TTM) for 24-hour versus 48-hour trial. In this analysis, we included 82 patients and measured serial levels of suPAR at 24, 48, and 72 hours after achievement of target temperature (32-34°C). We assessed all-cause mortality and neurological function evaluated by the Cerebral Performance Categories (CPC) at 6 months after OHCA. Levels of suPAR between TTH groups were evaluated in repeated measures mixed models. Mortality was assessed by the Kaplan-Meier method and serial measurements of suPAR (log2 transformed) were investigated by Cox proportional-hazards models. Good neurological outcome at 6 months was assessed by logistic regression analyses. Levels of suPAR were significantly different between TTH groups (pinteraction = 0.04) with the highest difference at 48 hours, 4.7 ng/mL (95% CI: 4.1-5.4 ng/mL) in the TTH24 group compared to 2.8 ng/mL (95% CI: 2.2-3.5 ng/mL) in the TTH48 group, p < 0.0001. Levels of suPAR above the median value were significantly associated with increased all-cause mortality at any time point (plog-rank<0.05). The interaction of suPAR levels and TTH group was not significant (pinteraction = NS). A twofold increase in levels of suPAR was significantly associated with a decreased odds ratio of a good neurological outcome in both unadjusted and adjusted analyses without interaction of TTH group (pinteraction = NS). Prolonged TTM of 48 hours versus 24 hours was associated with lower levels of suPAR. High levels of suPAR were associated with increased mortality and lower odds for good neurological outcome at 6 months with no significant interaction of TTH group.