The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.

The sixth international RASopathies symposium: Precision medicine-From promise to practice.

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.

Proceedings of the fifth international RASopathies symposium: When development and cancer intersect.

This report summarizes and highlights the fifth International RASopathies Symposium: When Development and Cancer Intersect, held in Orlando, Florida in July 2017. The RASopathies comprise a recognizable pattern of malformation syndromes that are caused by germ line mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Because of their common underlying pathogenetic etiology, there is significant overlap in their phenotypic features, which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, gastrointestinal and ocular abnormalities, neurological and neurocognitive issues, and a predisposition to cancer. The RAS pathway is a well-known oncogenic pathway that is commonly found to be activated in somatic malignancies. As in somatic cancers, the RASopathies can be caused by various pathogenetic mechanisms that ultimately impact or alter the normal function and regulation of the MAPK pathway. As such, the RASopathies represent an excellent model of study to explore the intersection of the effects of dysregulation and its consequence in both development and oncogenesis.

Assessing approaches and barriers to reduce antipsychotic drug use in Florida nursing homes.

OBJECTIVES: Antipsychotic medications have been federally regulated since 1987, yet research suggests they continue to be used inappropriately to alleviate behavioral symptoms associated with dementia. In 2012, the Centers of Medicare and Medicaid launched a new initiative to reduce antipsychotic medication in nursing homes by 15% nationally. The aim of this study was to examine qualitative data to explore strategies that have been implemented, to assess which strategies are evidence-based, and to make recommendations to improve upon practices to reduce antipsychotic medication use. METHOD: A convenience sample of 276 nursing home professional staff members were surveyed about these topics using open-ended questions. RESULTS: Theme-based content analysis yielded three main themes. The themes related to changes in practice included the following: (1) increased review of resident behavior and antipsychotic medication regimens; (2) reduction in antipsychotic medications or dosage; and (3) increased use of nonpharmacological interventions. The main themes relevant to needed assistance included the following: (1) education; (2) clinical support; and (3) increased financial resources and reimbursement. DISCUSSION: Overall findings indicate that the majority of facilities are actively responding to the initiative, but challenges remain in education, finding mental health support, and in reimbursement.

Survey of master's gerontology students spanning over 40 years.

The University of South Florida's master's degree in gerontology is a long-established program that focuses on a multidisciplinary approach to population aging. This study identifies graduate students' needs in preparation for a professional career in gerontology. An online survey was distributed to graduates and those currently enrolled (N = 56) in order to better understand expectations for the program, identify outcomes of graduation, and obtain program recommendations for future students. The program's 40 year history was well represented with participants ranging from the first graduating class to current students. Results indicated high satisfaction in students' expectations of the program, educational experience, and assessment of faculty. Further, 68% of graduates reported success in gaining age-related employment shortly after graduation. However, students echoed well-known barriers in gerontology, reporting tough competition for jobs versus those with licensure, and challenges in promoting their nonclinical gerontology degree to employers. Respondents recommended more applied coursework and assistance with career planning to enhance employment opportunities upon graduation. Implications of these findings are discussed in further detail.

Missed opportunities in heart failure diagnosis and management: study of an urban UK population.

AIMS: This study aimed to examine the diagnostic pathways and outcomes of patients with heart failure (HF), stratified by left ventricular ejection fraction (EF), and to highlight deficiencies in real-world HF diagnosis and management. METHODS AND RESULTS: We conducted a retrospective cohort study in Salford, United Kingdom, utilizing linked primary and secondary care data for HF patients diagnosed between January 2010 and November 2019. We evaluated characteristics, diagnostic patterns, healthcare resource utilization, and outcomes. Patients were categorized according to baseline (the latest measure prior to or within 90 days post-diagnosis) as having HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF), or preserved EF (HFpEF). The data encompassed a 2 year period before diagnosis and up to 5 years post-diagnosis. A total of 3227 patients were diagnosed with HF between January 2010 and November 2019. The mean follow-up time was 2.6 [±1.9 standard deviation (SD)] years. The mean age at diagnosis was 74.8 (±12.7 SD) years, and 1469 (45.5%) were female. HFpEF was the largest cohort (46.6%, npEF = 1505), HFmrEF constituted 16.1% (nmrEF = 520), and HFrEF 18.5% (nrEF = 596) of the population, while 18.8% (nu = 606) of patients remained unassigned due to insufficient evidence to support categorization. At baseline, measurement of natriuretic peptide (NP; brain NP and N-terminal pro-B-type NP) and echocardiographic report data were available for 592 (18.3%) and 2621 (81.2%) patients, respectively. A total of 2099 (65.0%) of the HF cohort had access to a cardiology-led outpatient clinic prior to the HF diagnosis, and 602 (18.7%) attended cardiac rehabilitation post-diagnosis. The 5 year crude survival rate was 37.8% [95% confidence interval (CI) (35.2-40.7%)], 42.3% [95% CI (38.0-47.2%)], and 45.5% [95% CI (41.0-50.4%)] for HFpEF, HFrEF, and HFmrEF, respectively. CONCLUSIONS: Low survival rates were observed across all HF groups, along with suboptimal rates of NP testing and specialist assessments. These findings suggest missed opportunities for timely and accurate HF diagnosis, a pivotal first step in improving outcomes for HF patients. Addressing these gaps in diagnosis and management is urgently needed.

Fetal Type Morphologies Suggest the Presence of DICER1 Hotspot Mutations in Non-small Cell Lung Cancer.

Germline and somatic pathogenic variants (PVs) in DICER1 , encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic entities. The lung tumors pleuropulmonary blastoma, pulmonary blastoma (PB), and well-differentiated fetal lung adenocarcinoma (WDFLAC) are all known to harbor DICER1 biallelic variants (loss of function and/or somatic hotspot missense mutations), and all share pathologic features reminiscent of the immature lung. However, the role of DICER1 PVs in non-small cell lung cancer (NSCLC) is relatively unknown. Here, we aimed to establish the spectrum of lung pathologies associated with DICER1 hotspot PVs and to compare the mutational landscape of DICER1 -mutated NSCLC with and without hotspots. We queried DNA sequencing data from 12,146 NSCLCs featuring somatic DICER1 variants. 235 (1.9%) cases harboring ≥ 1 DICER1 PV were found and 9/235 (3.8%) were DICER1 hotspot-positive cases. Histologic review of DICER1 hotspot-positive cases showed that all but one tumor were classified as within the histologic spectrum of PB/WDFLAC, whereas all the DICER1 non-hotspot double variants were classified as lung adenocarcinomas, not otherwise specified. Comparison between the mutational landscape of DICER1 hotspot-positive and hotspot-negative cases revealed a higher frequency of CTNNB1 mutations in the hotspot-positive cases (5/9 vs. 2/225; P <0.00001). We conclude that DICER1 somatic hotspots are not implicated in the most common forms of NSCLC but rather select for morphologic features of lung tumor types such as PB and WDFLAC. As a corollary, cases showing this tumor morphology should undergo testing for DICER1 variants, and if positive, genetic counseling should be considered.

Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.

PURPOSE: KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments. EXPERIMENTAL DESIGN: Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination. RESULTS: Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden-high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin. CONCLUSIONS: KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.

Comprehensive Analysis of R-Spondin Fusions and RNF43 Mutations Implicate Novel Therapeutic Options in Colorectal Cancer.

PURPOSE: Gene fusions involving R-spondin (RSPOfp) and RNF43 mutations have been shown to drive Wnt-dependent tumor initiation in colorectal cancer. Herein, we aimed to characterize the molecular features of RSPOfp/RNF43 mutated (mut) compared with wild-type (WT) colorectal cancers to gain insights into potential rationales for therapeutic strategies. EXPERIMENTAL DESIGN: A discovery cohort was classified for RSPOfp/RNF43 status using DNA/RNA sequencing and IHC. An independent cohort was used to validate our findings. RESULTS: The discovery cohort consisted of 7,245 colorectal cancer samples. RSPOfp and RNF43 mutations were detected in 1.3% (n = 94) and 6.1% (n = 443) of cases. We found 5 RSPO fusion events that had not previously been reported (e.g., IFNGR1-RSPO3). RNF43-mut tumors were associated with right-sided primary tumors. No RSPOfp tumors had RNF43 mutations. In comparison with WT colorectal cancers, RSPOfp tumors were characterized by a higher frequency of BRAF, BMPR1A, and SMAD4 mutations. APC mutations were observed in only a minority of RSPOfp-positive compared with WT cases (4.4% vs. 81.4%). Regarding RNF43 mutations, a higher rate of KMT2D and BRAF mutations were detectable compared with WT samples. Although RNF43 mutations were associated with a microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) phenotype (64.3%), and a tumor mutation burden ≥10 mt/Mb (65.8%), RSPOfp was not associated with MSI-H/dMMR. The validation cohort replicated our genetic findings. CONCLUSIONS: This is the largest series of RSPOfp/RNF43-mut colorectal cancers reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO/RNF43 and suggested potential alternative strategies to overcome the low clinical impact of Wnt-targeted agents and immunotherapy.

Trends in the surgical treatment of ulcerative colitis over time: increased mortality and centralization of care.

BACKGROUND: New medical therapies available to ulcerative colitis (UC) patients have influenced operative mortality for patients requiring colectomy. We sought to examine trends in treatment and outcome for UC patients treated surgically. METHODS: A review of 36,447 UC patients from the Nationwide Inpatient Sample was performed, comparing the pre-monoclonal antibody era (1990-1996) to the present-day era (2000-2006). Patients treated with total colectomy with ileostomy or proctocolectomy with ileal pouch were reviewed for outcome measures and practice setting (rural, urban non-teaching, urban teaching). Our main outcome measures were in-hospital mortality, length of stay, and total charges. RESULTS: Total colectomy (n = 30,362) was performed five times more often than proctocolectomy (n = 6,085). When comparing the two study periods, mortality after total colectomy increased 3.8% to 4.6% (p = 0.0003). This difference was primarily due to increasing mortality in later years; when 1995-1996 was compared to 2005-2006, mortality increased from 3.6% to 5.6% (p < 0.0001). There were no deaths in the proctocolectomy group (p < 0.0001). The distribution by practice setting shifted over the two study periods, decreasing in rural (7.0% to 4.8%) and urban non-teaching (43.7% to 28.4%) centers, and increasing in urban teaching centers (49.3% to 66.8%). The total inflation-adjusted charges per patient increased significantly ($34,638 vs. $43,621; p < 0.0001). CONCLUSIONS: The mortality rate after total colectomy is increasing, and the difference is accentuated in the years since widespread use of monoclonal antibody therapy. The care of these patients is being shifted to urban teaching centers and is becoming more expensive.

Surgical treatment of intrahepatic cholangiocarcinoma: outcomes and predictive factors.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) remains a rare tumour, although its incidence is increasing. Surgical resection is the mainstay of treatment. Published data regarding prognostic factors and optimal patient selection for resection are scant. We sought to determine the clinicopathologic characteristics of resectable ICC and outcomes following surgical treatment. METHODS: We reviewed prospectively collected clinical data including patient, pathologic and operative details. Survival and recurrence outcomes were analysed using Cox hazard models and the Kaplan-Meier method. RESULTS: We identified 31 surgically treated patients. Their 3-year overall survival rate (OS) was 40.1%; median follow-up was 16.2 months (range: 0.2-86.9 months). R0 resection was associated with significantly improved OS compared with R1/R2 resection (3-year OS was 68.6% in R0 vs. 24.0% in R1/R2; P= 0.042). The postoperative complication rate was 58.1%. Two patients died of postoperative liver failure within 30 days. Preoperative hypoalbuminaemia was significantly associated with worse survival. CONCLUSIONS: Surgical therapy for ICC is associated with longterm survival in the subset of nutritionally replete patients in whom an R0 resection can be achieved. Surgical mortality is significant in patients undergoing extended resection. The margin involvement rate is high and surgeons should consider the infiltrative nature of the disease in operative planning.

The impact of rarity in NICE's health technology appraisals.

BACKGROUND: In the absence of a framework designed to evaluate medicines for rare diseases in the UK, most orphan medicines are appraised by the National Institute for Health and Care Excellence (NICE) through the Single Technology Appraisal (STA) process. RESULTS: An analysis of STA appraisals of orphan and non-orphan medicines revealed that orphan medicines were subject to a significantly longer mean time in the NICE process than non-orphan medicines [370 days (n = 44) vs. 277 days (n = 118), p = < 0.0001]. A higher proportion of orphan STAs required more than one Appraisal Committee Meeting (ACM) versus non-orphan STAs, and orphan STAs were disadvantaged by worse outcomes with respect to positive recommendations than those orphan medicines assessed by Highly Specialised Technology evaluation (HST). CONCLUSIONS: The uncertainties inherent to developing orphan medicines may contribute to these disadvantages. Improved understanding of the challenges in drug development for orphan medicines and clearer guidance for decision makers on navigating uncertainty in the HTA process may promote greater equity in access to medicines across rare and common conditions.

Prevalence and characteristics of campus-based employee wellness programs among United States accredited colleges and universities.

BACKGROUND: Employee wellness programs (EWPs) aim to support positive changes in employees' modifiable behavioral health risk factors for disease prevention and management. OBJECTIVE: This study described the prevalence and characteristics of EWPs in US accredited college and university campuses. METHODS: Identification of the prevalence of EWPs and programming activities offered in 3039 accredited higher education institutions/campuses, and characteristics of these institutions/campuses were conducted, mainly through searching the institution's web page. RESULTS: Overall, 36%of the institutions/campuses offered EWPs, with a significantly larger percentage of 4-year public colleges/universities providing EWPs and wellness programming activities than the 4-year private colleges/universities and community colleges. When limiting the institutions/campuses to 4-year colleges and universities with at least 500 employees, the percentage of these institutions/campuses offering EWPs increased to 57.7%, which was comparable to the findings in the literature. The percentage of the institutions/campuses offering wellness programming activities ranged from 18.1%for injury prevention and ergonomics to 30.2%for stress management. The percentage of institutions/campuses offering injury prevention and ergonomics was significantly lower than the percentage of institutions/campuses offering other typical wellness activities. CONCLUSIONS: The prevalence of EWPs offered in accredited college and university campuses do not meet the national goal of 75%, which was set by Healthy People 2010.

TERT Gene Fusions Characterize a Subset of Metastatic Leydig Cell Tumors.

OBJECTIVE: Metastatic Leydig cell tumors (LCT) are rare, difficult-to-treat malignancies without known underlying molecular-genetic events. An index case of metastatic LCT showed an LDLR-TERT gene fusion upon routine genetic profiling for detection of therapeutic targets, which was then followed by an investigation into a cohort of additional LCTs. PATIENTS AND METHODS: Twenty-nine LCT (27 male and 2 female patients) were profiled using next-generation sequencing and immunohistochemistry. RESULTS: TERT gene fusions were detected only in testicular metastatic LCTs, in 3 of 7 successfully analyzed cases (RMST:TERT, LDLR:TERT, and B4GALT5:TERT). TOP1 and CCND3 amplifications were identified in the case with a B4GALT5:TERT fusion. A TP53 mutation was detected in 1 metastatic tumor without a TERT fusion. Five primary (4 testicular and 1 ovarian) LCTs showed multiple gene amplifications, without a consistent pattern. A single metastatic ovarian LCT showed BAP1 mutation and copy number amplifications affecting the NPM1, PCM1, and SS18 genes. At the protein level, 4 of 7 metastatic and 6 of 10 primary testicular LCTs overexpressed Topo1. Androgen receptor was overexpressed in 10 of 13 primary testicular tumors and 2 of 5 metastatic testicular LCTs (without detectable ARv7 messenger RNA or ARv7 protein). Only 1 metastatic testicular LCT exhibited a high tumor mutational burden; all tested cases were microsatellite instability stable and did not express programmed cell death ligand 1. CONCLUSIONS: Our study for the first time identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in metastatic LCTs. Topo1 and androgen receptor may guide decisions on chemotherapy and/or hormone therapy for selected individual patients.

Gastrostomy tube placement by radiological versus endoscopic methods in an acute care setting: a retrospective review of frequency, indications, complications and outcomes.

OBJECTIVES: To describe the current practice of placing gastrostomy tubes (endoscopic and radiological), patient characteristics, indications for enteral support, complications and outcomes over a 13-month period, and explore factors that influenced complications and outcomes. Second, to provide Canadian data regarding feeding tube placement because no current literature reflecting these practices for Canadian hospitals is available. METHODS: Retrospective chart reviews were conducted. Patients who had initial percutaneous endoscopic gastrostomy (PEG) or percutaneous radiological gastrostomy (PRG) tubes inserted for nutritional purposes were included in the study. RESULTS: A total of 136 charts which included 30 PEG and 44 PRG procedures were reviewed. The PRG group was older than the PEG group (mean [+/-SD+/-5D; age 68+/-19 years versus 55+/-21 years, respectively; P=0.008). Patients in PEG group had longer lengths of hospital stay and more intensive care unit admissions than the PRG group (P=0.029). The main reason for tube insertion was dysphagia/aspiration (PEG [60%] and PRG [77%]). Minor complications were comparable between the two groups (P=0.678). There were three cases of major complications overall. More subjects in the PRG group died (18%) while in hospital than in the PEG group (3%) (P=0.055). No procedure-related deaths occurred in either group. CONCLUSIONS: Both methods of tube insertion provided a safe route for nutrition delivery despite a significant cost differential with PEGs costing 44% more than PRGs. Characteristics such as age, presence of ascites and severity of disease influenced the method of insertion despite the lack of current guidelines. Overall, the present study provides new descriptive data in a Canadian context.

Case log review produces translational change in surgical oncology education.

BACKGROUND: The recently mandated reduction in surgical resident work hours led to concerns that surgical cancer education would suffer, as measured by cancer case exposure. METHODS: Final operative logs submitted to the American Board of Surgery by chief residents graduating from our program were compared for 2 time periods: prior to the mandate (2002-2003) and after (2006-2007). RESULTS: Case logs from graduating residents (n = 36) showed a nonsignificant decrease in cancer as the percentage of total major cases, due to an actual increase in total major cases. Conversely, endoscopy and minor cancer case experience both decreased. CONCLUSIONS: Exposure to minor cancer cases and endoscopies has decreased; this has led to a requirment for a minimum number of endoscopies/graduating resident, and to strategies for increasing exposure to minor cancer cases.

Spindle Epithelial Tumor with Thymus-Like Differentiation (SETTLE): A Next-Generation Sequencing Study.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a malignant biphasic neoplasm of the thyroid or neck with propensity for late metastasis. Unlike synovial sarcoma, its main morphologic mimic, SETTLE lacks synovial sarcoma-associated translocations. A single case of SETTLE has shown a KRAS mutation but to date no comprehensive next generation sequencing studies of this rare neoplasm have been undertaken. Herein, we subjected 5 well defined cases of SETTLE to direct sequence analysis of 592 genes and fusion gene analysis of 52 genes frequently rearranged in human cancers. We identified one case with two pathogenic variants in the KMT2D gene, one being in an intron splice site (c.674-1A>G) and the other being a frameshift variant (p.M2829fs). This same case also had a pathogenic nonsense variant in the KMT2C gene (p.R1237*). A second case of SETTLE carried a pathogenic NRAS missense variant, Q61R. No other molecular alterations, microsatellite instability, gene fusions or amplifications were identified.

Sickle cell anaemia and the experiences of young people living with the condition.

Sickle cell anaemia (SCA) is a life-threatening haemoglobin disorder acknowledged for its unpredictability and painful episodes. The aim of this qualitative literature review was to explore the experiences of young people living with SCA and its effect on their lives. The objective was to critically review selected primary research and make recommendations for practice, education and research. After reviewing potential articles using EBSCOhost, inclusion and exclusion criteria were devised and six appropriate studies were found with most participants in the 10-25 years age range. These studies were conducted in the UK and the United States. The Critical Appraisal Skills Programme qualitative research checklist was used to evaluate the articles. Thematic analysis identified three themes: acceptance, support and unpredictability, with sub-themes of spirituality and discrimination. It was clear that SCA affected multiple areas of young people's lives. Recommendations are made for practice, education and research.

Depressive Symptoms, Cognition, and Everyday Function Among Community-Residing Older Adults.

OBJECTIVE: The aim of this study was to understand the relationships among depressive symptoms, cognition, and functional performance in a community-based sample of older adults. METHOD: Older adults ( N = 885) from the Staying Keen in Later Life study completed tests of executive function, speed of processing, and memory. The Center for Epidemiologic Depression Scale assessed depressive symptoms. The Timed Instrumental Activities of Daily Living Test assessed participants' everyday functional performance. RESULTS: Depressive symptoms had significant associations with measures of executive function, speed of processing, memory, and everyday functional performance. Cognitive performance completely mediated the association between depressive symptoms and everyday function. DISCUSSION: Among community-dwelling older adults, depressive symptoms were associated with impaired cognition across multiple domains, which detrimentally affected everyday function. Health care providers should be aware of these associations to monitor and manage changes in depressive symptoms and cognitive performance and thereby potentially mitigate functional decline.