Protocol of a randomized controlled trial on the effectiveness and cost-effectiveness of the PLACES intervention: a supported employment intervention aimed at enhancing work participation of unemployed and/or work-disabled cancer survivors.

BACKGROUND: Approximately onethird of cancer survivors encounter challenges reintegrating into the workforce, often experiencing involuntary unemployment and/or partial or full work disability following diagnosis and treatment. Returning to paid employment presents evident challenges due to uncertainties regarding work ability, perceived employer discrimination, and a lack of support, thereby risking social exclusion. However, interventions addressing return to paid employment among unemployed and/or work-disabled cancer survivors are scarce. Here, we describe the protocol of a randomized controlled trial (RCT), including a process and economic evaluation, evaluating the effectiveness and cost-effectiveness of the PLACES (unemPLoyed cAnCEr survivors Support) intervention aimed at supporting unemployed and/or work-disabled cancer survivors returning to paid employment. METHODS: A two-armed RCT with a 12-month follow-up period will be conducted. Eligible participants: (1) are of working age (18-65 years), (2) are diagnosed with cancer between 6 months and 10 years ago, (3) are unemployed and/or partially or fully work-disabled, (4) have completed cancer treatment, and (5) are seeking paid employment and are motivated to initiate work immediately. Participants will primarily be identified through the Dutch Social Security Agency and the Netherlands Cancer Registry and recruited via healthcare professionals. Participants randomly allocated to the intervention group (n = 82) will receive the PLACES intervention: a tailored supported employment intervention based on the principles of Individual Placement and Support (IPS). This includes support in seeking, returning to, and maintaining paid employment. Participants allocated to the control group (n = 82) will receive care as usual. All participants will be asked to complete questionnaires, at baseline (T0), and after 3 (T1), 6 (T2), and 12 (T3) months of follow-up. The primary outcome is paid employment [yes/no]. Secondary outcomes are time until paid employment, change in working hours, work ability, quality of (working) life, and self-efficacy regarding return to work. Additionally, process and economic evaluations will be conducted. DISCUSSION: We hypothesize that the PLACES intervention will be effective in obtaining paid employment, enhancing work ability, and improving quality of life. In addition, we expect the intervention to be cost-effective. If proven effective and cost-effective, actions should be taken to implement the intervention in usual care. TRIAL REGISTRATION: NCT06028048.

Avoiding Treatment in Hospital With Subcutaneous Furosemide for Worsening Heart Failure: A Pilot Study (AT HOME-HF).

BACKGROUND: Therapies are needed to address worsening congestion, without hospitalization, in patients with chronic heart failure (HF). OBJECTIVES: This pilot study assessed outcomes of a novel subcutaneous (SC) furosemide formulation compared to usual care in outpatients with worsening congestion. METHODS: Participants with chronic HF and worsening congestion were randomized open-label 2:1 to SC furosemide compared to usual care (UC). Decongestion was estimated by tracking body weight. The primary endpoint was a win ratio of a 30-day hierarchical composite of cardiovascular death, HF events, and change in N-terminal pro-B-type natriuretic peptide. Secondary endpoints included dyspnea severity, functional capacity, and quality of life. RESULTS: Thirty-four participants were randomized to SC furosemide and 17 to UC. SC furosemide caused greater reduction in body weight: between-group difference in least square mean change was -2.02 kg at day 3 (95% CI: -3.9 to -0.14; P = 0.035). SC furosemide-to-UC win ratio was 1.11 (95% CI: 0.48-2.50; P = 0.806). Significant between-group least square mean differences favoring SC furosemide occurred in 7-point dyspnea score (P = 0.017) and 6-minute walk test (P = 0.032), with trend in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Score of 9.15 (95% CI: 1.95-20.3; P = 0.106). The most common related adverse event with SC furosemide was mild infusion site pain (11.8%). CONCLUSIONS: SC furosemide augmented weight loss in patients with HF and worsening congestion. The composite primary endpoint was not statistically significant in this pilot investigation. However, findings of improved dyspnea scores and functional capacity, with favorable trend in KCCQ-12 score, warrant additional investigation to further document the clinical value of SC furosemide as an alternative to hospitalization (AT HOME-HF [Avoiding Treatment in the Hospital With Furoscix for the Management of Congestion in Heart Failure-A Pilot Study]; NCT04593823).

Septo-dentate gyrus cholinergic circuits modulate function and morphogenesis of adult neural stem cells through granule cell intermediaries.

Cholinergic neurons in the basal forebrain play a crucial role in regulating adult hippocampal neurogenesis (AHN). However, the circuit and molecular mechanisms underlying cholinergic modulation of AHN, especially the initial stages of this process related to the generation of newborn progeny from quiescent radial neural stem cells (rNSCs), remain unclear. Here, we report that stimulation of the cholinergic circuits projected from the diagonal band of Broca (DB) to the dentate gyrus (DG) neurogenic niche promotes proliferation and morphological development of rNSCs, resulting in increased neural stem/progenitor pool and rNSCs with longer radial processes and larger busy heads. Interestingly, DG granule cells (GCs) are required for DB-DG cholinergic circuit-dependent modulation of proliferation and morphogenesis of rNSCs. Furthermore, single-nucleus RNA sequencing of DG reveals cell type-specific transcriptional changes in response to cholinergic circuit stimulation, with GCs (among all the DG niche cells) exhibiting the most extensive transcriptional changes. Our findings shed light on how the DB-DG cholinergic circuits orchestrate the key niche components to support neurogenic function and morphogenesis of rNSCs at the circuit and molecular levels.

Entropy as a Window Into Behavioral Phase Transitions: Unveiling Contextual Dynamics in Affordance-Based Reaching.

Prior work has demonstrated the presence of hysteresis effects in the control of affordance-guided behavior, in that behavioral transitions around a critical action boundary vary with directions of change in said action boundary. To date, research on this topic has overlooked the influence of the global context on these phenomena. We employ an affordance-based reaching task, whereby participants were asked to move a target to a goal by passing through one of two apertures (size variable or size constant). It was found that the direction of change in the size of the variable aperture influenced the point of behavioral transitions, and this effect interacted with the location of a given goal. In addition, we considered fluctuations in the entropy of participants' reach trajectories as a window into the nature of the behavioral phase transitions. Differences in the structure of entropy were found depending on the direction of change in the size variable aperture. These results are discussed in light of a dynamical systems approach, and recommendations for future work are made.

QSAR Reveals Decreased Lipophilicity of Polar Residues Determines the Selectivity of Antimicrobial Peptide Activity.

Antimicrobial resistance has increased rapidly, causing daunting morbidity and mortality rates worldwide. Antimicrobial peptides (AMPs) have emerged as promising alternatives to traditional antibiotics due to their broad range of targets and low tendency to elicit resistance. However, potent antimicrobial activity is often accompanied by excessive cytotoxicity toward host cells, leading to a halt in AMP therapeutic development. Here, we present multivariate analyses that correlate 28 peptide properties to the activity and toxicity of 46 diverse African-derived AMPs and identify the negative lipophilicity of polar residues as an essential physiochemical property for selective antimicrobial activity. Twenty-seven active AMPs are identified, of which the majority are of scorpion or frog origin. Of these, thirteen are novel with no previously reported activities. Principal component analysis and quantitative structure-activity relationships (QSAR) reveal that overall hydrophobicity, lipophilicity, and residue side chain surface area affect the antimicrobial and cytotoxic activity of an AMP. This has been well documented previously, but the present QSAR analysis additionally reveals that a decrease in the lipophilicity, contributed by those amino acids classified as polar, confers selectivity for a peptide to pathogen over mammalian cells. Furthermore, an increase in overall peptide charge aids selectivity toward Gram-negative bacteria and fungi, while selectivity toward Gram-positive bacteria is obtained through an increased number of small lipophilic residues. Finally, a conservative increase in peptide size in terms of sequence length and molecular weight also contributes to improved activity without affecting toxicity. Our findings suggest a novel approach for the rational design or modification of existing AMPs to increase pathogen selectivity and enhance therapeutic potential.

Sex-specific expression of distinct serotonin receptors mediates stress vulnerability of adult hippocampal neural stem cells in mice.

Women are more vulnerable to stress and have a higher likelihood of developing mood disorders. The serotonin (5HT) system has been highly implicated in stress response and mood regulation. However, sex-dependent mechanisms underlying serotonergic regulation of stress vulnerability remain poorly understood. Here, we report that adult hippocampal neural stem cells (NSCs) of the Ascl1 lineage (Ascl1-NSCs) in female mice express functional 5HT1A receptors (5HT1ARs), and selective deletion of 5HT1ARs in Ascl1-NSCs decreases the Ascl1-NSC pool only in females. Mechanistically, 5HT1AR deletion in Ascl1-NSCs of females leads to 5HT-induced depolarization mediated by upregulation of 5HT7Rs. Furthermore, repeated restraint stress (RRS) impairs Ascl1-NSC maintenance through a 5HT1AR-mediated mechanism. By contrast, Ascl1-NSCs in males express 5HT7R receptors (5HT7Rs) that are downregulated by RRS, thus maintaining the Ascl1-NSC pool. These findings suggest that sex-specific expression of distinct 5HTRs and their differential interactions with stress may underlie sex differences in stress vulnerability.

Exploring Alternatives for Marine Toxicity Testing: Initial Evaluation of Fish Embryo and Mysid Tests.

Current regulations require that toxicity assessments be performed using standardized toxicity testing methods, often using fish. Recent legislation in both the European Union and United States has mandated that toxicity testing alternatives implement the 3Rs of animal research (replacement, reduction, and refinement) whenever possible. There have been advances in the development of alternatives for freshwater assessments, but there is a lack of analogous developments for marine assessments. One potential alternative testing method is the fish embryo toxicity (FET) test, which uses fish embryos rather than older fish. In the present study, FET methods were applied to two marine model organisms, the sheepshead minnow and the inland silverside. Another potential alternative is the mysid shrimp survival and growth test, which uses an invertebrate model. The primary objective of the present study was to compare the sensitivity of these three potential alternative testing methods to two standardized fish-based tests using 3,4-dichloroaniline (DCA), a common reference toxicant. A secondary objective was to characterize the ontogeny of sheepshead minnows and inland silversides. This provided a temporal and visual guide that can be used to identify appropriately staged embryos for inclusion in FET tests and delineate key developmental events (e.g., somite development, eyespot formation, etc.). Comparison of the testing strategies for assessing DCA indicated that: (1) the standardized fish tests possessed comparable sensitivity to each other; (2) the mysid shrimp tests possessed comparable sensitivity to the standardized fish tests; (3) the sheepshead minnow and inland silverside FET tests were the least sensitive testing strategies employed; and (4) inclusion of sublethal endpoints (i.e., hatchability and pericardial edema) in the marine FETs increased their sensitivity. Environ Toxicol Chem 2024;43:1285-1299. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Tryptophan End-Tagging Confers Antifungal Activity on a Tick-Derived Peptide by Triggering Reactive Oxygen Species Production.

WHO has identified several Candida species including Candida albicans as critical priority fungal pathogens due to greater infection prevalence and formation of recalcitrant biofilms. Novel antifungal agents are urgently needed, and antimicrobial peptides (AMPs) are being considered as potential alternatives, but inactivity in physiological salt environments, serum, and plasma often limits further therapeutic development. Tryptophan end-tagging is a strategy to overcome these limitations and is thought to selectively enhance membrane permeabilization in both fungal and bacterial plasma membranes. Here, we show that C-terminal tryptophan end-tagging of the tick-derived peptide Os-C transforms an inactive peptide into Os-C(W5), an antifungal peptide capable of preventing the formation of C. albicans biofilms. Mechanistic insight is provided by circular dichroism spectroscopy and molecular dynamics simulations, which demonstrate that tryptophan end-tagging alters the secondary structure of Os-C, while the latter reveals that end-tagging reduces interactions with, and insertion into, a model C. albicans membrane but promotes peptide aggregation on its surface. Interestingly, this leads to the induction of reactive oxygen species production rather than membrane permeabilization, and consequently, oxidative stress leads to cell wall damage. Os-C(W5) does not induce the hemolysis of human erythrocytes. Reduced cell adhesion and viability contribute to decreased biofilm extracellular matrix formation which, although reduced, is retained in the serum-containing medium. In this study, tryptophan end-tagging was identified as a promising strategy for enhancing the antifungal activity, including the biofilm inhibitory activity of Os-C against C. albicans in physiological salt environments.

The gold standard program (GSP) for smoking cessation: a cohort study of its effectiveness among smokers with and without cancer.

BACKGROUND: Smoking cessation treatment is an important prognostic factor for survival after a cancer diagnosis, especially for tobacco-related cancers. After being diagnosed with lung cancer, approximately 50% of patients continue smoking or frequently relapse after a quit attempt. Given the importance of smoking cessation treatment for cancer survivors, the objective was to compare the effectiveness of a 6-week intensive smoking cessation intervention, the Gold Standard Program (GSP), among cancer survivors compared with smokers without cancer. Second, we compared successful quitting among socioeconomically disadvantaged cancer survivors with that among nondisadvantaged cancer survivors. MATERIALS AND METHODS: This was a cohort study based on 38,345 smokers from the Danish Smoking Cessation Database (2006-2016). Linkage to the National Patient Register was used to identify cancer survivors undergoing the GSP after being diagnosed with cancer (except nonmelanoma skin cancer). Linkage to the Danish Civil Registration System was used to identify participants who died, went missing, or emigrated before the follow-up. Logistic regression models were applied to evaluate effectiveness. RESULTS AND CONCLUSION: Six percent (2438) of the included smokers were cancer survivors at the time they undertook the GSP. Their 6-month successful quitting showed no difference compared to that of smokers without cancer, neither before nor after adjustment; 35% versus 37% in crude rates and an aOR of 1.13 (95% CI: 0.97-1.32). Likewise, the results for disadvantaged compared to nondisadvantaged cancer survivors were not significantly different (32% versus 33% and an adjusted aOR of 0.87 (95% CI 0.69-1.11)). Overall, an intensive smoking cessation program seems effective in helping both people without cancer and cancer survivors become successful quitters.

Ability of high fat diet to induce liver pathology correlates with the level of linoleic acid and Vitamin E in the diet.

Increased uptake of fat, such as through the ingestion of high fat diet (HFD), can lead to fatty liver diseases and metabolic syndrome. It is not clear whether certain fatty acids may be more pathogenic than others to the liver. Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in the Western diet and its excessive consumption can lead to increased lipid peroxidation. We hypothesized that a high level of LA in HFD will contribute significantly to the hepatic steatosis and injury, whereas vitamin E (VIT-E) may reverse the effects from LA by inhibiting lipid peroxidation. To test this hypothesis, we fed mice with the following diets for 20 weeks: a standard low-fat diet (CHOW), HFD with a low level of LA (LOW-LA, 1% of energy from LA), HFD with a high level of LA (HI-LA, 8% of energy from LA), or HI-LA diet with VIT-E supplement (HI-LA + VIT-E). We found that the HI-LA diet resulted in more body weight gain, larger adipocyte area, and higher serum levels of triglycerides (TG) and free fatty acids (FFA) relative to the CHOW and LOW-LA diets. In mice fed with the HI-LA diet, severer hepatic steatosis was seen with higher levels of hepatic TG and FFA. Expression of genes related to lipid metabolism was altered in the liver by HI-LA diet, including fibroblast growth factor 21 (Fgf21), cluster of differentiation 36 (Cd36), stearoyl-CoA desaturase 1 (Scd1), and acyl-CoA oxidase 1 (Acox1). Liver injury, inflammation and fibrotic response were all enhanced in mice fed with the HI-LA diet when compared with the LOW-LA diet. Notably, addition of VIT-E supplement, which restores the proper VIT-E/PUFA ratio, significantly reduced the detrimental effects of the high level of LA. Taken together, our results suggest that a high level of LA and a low ratio of VIT-E/PUFA in HFD can contribute significantly to metabolic abnormalities and hepatic injury.

Uncovering the Ediacaran phosphorus cycle.

Phosphorus is a limiting nutrient that is thought to control oceanic oxygen levels to a large extent1-3. A possible increase in marine phosphorus concentrations during the Ediacaran Period (about 635-539 million years ago) has been proposed as a driver for increasing oxygen levels4-6. However, little is known about the nature and evolution of phosphorus cycling during this time4. Here we use carbonate-associated phosphate (CAP) from six globally distributed sections to reconstruct oceanic phosphorus concentrations during a large negative carbon-isotope excursion-the Shuram excursion (SE)-which co-occurred with global oceanic oxygenation7-9. Our data suggest pulsed increases in oceanic phosphorus concentrations during the falling and rising limbs of the SE. Using a quantitative biogeochemical model, we propose that this observation could be explained by carbon dioxide and phosphorus release from marine organic-matter oxidation primarily by sulfate, with further phosphorus release from carbon-dioxide-driven weathering on land. Collectively, this may have resulted in elevated organic-pyrite burial and ocean oxygenation. Our CAP data also seem to suggest equivalent oceanic phosphorus concentrations under maximum and minimum extents of ocean anoxia across the SE. This observation may reflect decoupled phosphorus and ocean anoxia cycles, as opposed to their coupled nature in the modern ocean. Our findings point to external stimuli such as sulfate weathering rather than internal oceanic phosphorus-oxygen cycling alone as a possible control on oceanic oxygenation in the Ediacaran. In turn, this may help explain the prolonged rise of atmospheric oxygen levels.

Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer's mouse model.

BACKGROUND: Alzheimer's disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined. METHODS: Circuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression. RESULTS: We identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons. CONCLUSION: We report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission.

Activation of hypothalamic-enhanced adult-born neurons restores cognitive and affective function in Alzheimer's disease.

Patients with Alzheimer's disease (AD) exhibit progressive memory loss, depression, and anxiety, accompanied by impaired adult hippocampal neurogenesis (AHN). Whether AHN can be enhanced in impaired AD brain to restore cognitive and affective function remains elusive. Here, we report that patterned optogenetic stimulation of the hypothalamic supramammillary nucleus (SuM) enhances AHN in two distinct AD mouse models, 5×FAD and 3×Tg-AD. Strikingly, the chemogenetic activation of SuM-enhanced adult-born neurons (ABNs) rescues memory and emotion deficits in these AD mice. By contrast, SuM stimulation alone or activation of ABNs without SuM modification fails to restore behavioral deficits. Furthermore, quantitative phosphoproteomics analyses reveal activation of the canonical pathways related to synaptic plasticity and microglia phagocytosis of plaques following acute chemogenetic activation of SuM-enhanced (vs. control) ABNs. Our study establishes the activity-dependent contribution of SuM-enhanced ABNs in modulating AD-related deficits and informs signaling mechanisms mediated by the activation of SuM-enhanced ABNs.

Lung cancer registries in Denmark, Finland, Norway and Sweden: a comparison and proposal for harmonization.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in all Nordic countries which, though similar in demographics and healthcare systems, have noticeable differences in lung cancer survival. Historically, Denmark and Finland have had higher lung cancer incidences and lower survival than Norway and Sweden. All four countries have national cancer registries. Data in these registries are often compared, but their full potential as a source of learning across the Nordic countries is impeded by differences between the registries. In this paper, we describe and compare the Nordic registries on lung cancer-specific data and discuss how a more harmonized registration practice could increase their usefulness as a source for mutual learning and quality improvements. METHODS: We describe and compare the characteristics of data on lung cancer cases from registries in Denmark, Finland, Norway and Sweden. Moreover, we compare the results from the latest annual reports and specify how data may be acquired from the registries for research. RESULTS: Denmark has a separate clinical lung cancer registry with more detailed data than the other Nordic countries. Finland and Norway report lung cancer survival as relative survival, whereas Denmark and Sweden report overall survival. The Danish Lung Cancer Registry and the Swedish Cancer Registry do not receive data from the Cause of Death registries in contrast to the Finnish Cancer Registry and the Cancer Registry of Norway. CONCLUSION: The lung cancer registries in Denmark, Finland, Norway and Sweden have high level of completeness. However, several important differences between the registries may bias comparative analyses.

Fit for Surgery-feasibility of short-course multimodal individualized prehabilitation in high-risk frail colon cancer patients prior to surgery.

BACKGROUND: Prehabilitation is a promising modality for improving patient-related outcomes after major surgery; however, very little research has been done for those who may need it the most: the elderly and the frail. This study aimed to investigate the feasibility of a short course multimodal prehabilitation prior to primary surgery in high-risk, frail patients with colorectal cancer and WHO performance status I and II. METHODS: The study was conducted as a single-center, prospective one-arm feasibility study of eight patients with colon cancer between October 4, 2018, and January 14, 2019. The intervention consisted of a physical training program tailored to the patients with both high-intensity interval training and resistance training three times a week in sessions of approximately 1 h in length, for a duration of at least 4 weeks, nutritional support with protein and vitamins, a consultation with a dietician, and medical optimization prior to surgery. Feasibility was evaluated regarding recruitment, retention, compliance and adherence, acceptability, and safety. Retention was evaluated as the number of patients that completed the intervention, with a feasibility goal of 75% completing the intervention. Compliance with the high-intensity training was evaluated as the number of sessions in which the patient achieved a minimum of 4 min > 90% of their maximum heart rate and adherence as the attended out of the offered training sessions. RESULTS: During the study period, 64 patients were screened for eligibility, and out of nine eligible patients, eight patients were included and seven completed the intervention (mean age 80, range 66-88). Compliance to the high-intensity interval training using 90% of maximum heart rate as the monitor of intensity was difficult to measure in several patients; however, adherence to the training sessions was 87%. Compliance with nutritional support was 57%. Half the patients felt somewhat overwhelmed by the multiple appointments and six out of seven reported difficulties with the dosage of protein. CONCLUSIONS: This one-arm feasibility study indicates that multimodal prehabilitation including high-intensity interval training can be performed by patients with colorectal cancer and WHO performance status I and II. TRIAL REGISTRATION: Clinicaltrials.gov : the study current feasibility study was conducted prior to the initiation of a full ongoing randomized trial registered by NCT04167436; date of registration: November 18, 2019. Retrospectively registered. No separate prospectively registration of the feasibility trial was conducted but outlined by the approved study protocol (Danish Scientific Ethical Committee SJ-607).

Impact of comorbidity on renal cell carcinoma prognosis: a nationwide cohort study.

BACKGROUND: Presence of comorbid diseases at time of cancer diagnosis may affect prognosis. We evaluated the impact of comorbidity on survival of patients diagnosed with renal cell carcinoma (RCC), overall and among younger (<70 years) and older (≥70 years) patients. METHODS: We established a nationwide register-based cohort of 7894 patients aged ≥18 years diagnosed with RCC in Denmark between 2006 and 2017. We computed 1- and 5-year overall survival and hazard ratios (HRs) for death according to the Charlson Comorbidity Index (CCI) score. RESULTS: Survival decreased with increasing CCI score despite an overall increase in survival over time. The 5-year survival rate of patients with no comorbidity increased from 57% among those diagnosed in 2006-2008 to 69% among those diagnosed in 2012-2014. During the same periods, the survival rate increased from 46% to 62% among patients with a CCI score of 1-2 and from 39% to 44% for those with a CCI score of ≥3. Patients with CCI scores of 1-2 and ≥3 had higher mortality rates than patients with no registered comorbidity (HR 1.15, 95% CI 1.06-1.24 and HR 1.56, 95% CI 1.40-1.73). Patterns were similar for older and younger patients. Particularly, diagnoses of liver disease (HR 2.09, 95% CI 1.53-2.84 and HR 4.01, 95% CI 2.44-6.56) and dementia (HR 2.16, 95% CI 1.34-3.48) increased mortality. CONCLUSION: Comorbidity decreased the survival of patients with RCC, irrespective of age, despite an overall increasing survival over time. These results highlight the importance of focusing on comorbidity in this group of patients.