Role of the Atypical MAPK ERK3 in Cancer Growth and Progression.

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose structural and regulatory features are distinct from those of conventional MAPKs, such as ERK1/2. Since its identification in 1991, the regulation, substrates and functions of ERK3 have remained largely unknown. However, recent years have witnessed a wealth of new findings about ERK3 signaling. Several important biological functions for ERK3 have been revealed, including its role in neuronal morphogenesis, inflammation, metabolism, endothelial cell tube formation and epithelial architecture. In addition, ERK3 has been recently shown to play important roles in cancer cell proliferation, migration, invasion and chemoresistance in multiple types of cancers. Furthermore, accumulating studies have uncovered various molecular mechanisms by which the expression level, protein stability and activity of ERK3 are regulated. In particular, several post-translational modifications (PTMs), including ubiquitination, hydroxylation and phosphorylation, have been shown to regulate the stability and activity of ERK3 protein. In this review, we discuss recent findings regarding biochemical and cellular functions of ERK3, with a main focus on its roles in cancers, as well as the molecular mechanisms of regulating its expression and activity.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

Patient reported treatment burden and attitudes towards in-home intravesical therapy among patients with bladder cancer.

PURPOSE: To quantify patient reported treatment burden while receiving intravesical therapy for bladder cancer and to survey patient perspectives on in-home intravesical therapy. MATERIALS AND METHODS: We conducted a cross-sectional survey of the Bladder Cancer Advocacy Network Patient Survey Network. Survey questions were developed by investigators, then iteratively revised by clinician and patient advocates. Eligible participants had to have received at least 1 dose of intravesical therapy delivered in an ambulatory setting. RESULTS: Two hundred thirty-three patients responded to the survey with median age of 70 years (range 33-88 years). Two-thirds of respondents (66%, 151/232) had received greater than 12 bladder instillations. A travel time of >30 minutes to an intravesical treatment facility was reported by 55% (126/231) of respondents. Fifty-six percent (128/232) brought caregivers to their appointments, and 36% (82/230) missed work to receive treatment. Sixty-one respondents (26%) felt the process of receiving bladder instillations adversely affected their ability to perform regular daily activities. Among those surveyed, 72% (168/232) reported openness to receiving in-home intravesical instillations and 54% (122/228) answered that in-home instillations would make the treatment process less disruptive to their lives. CONCLUSIONS: Bladder cancer patients reported considerable travel distances, time requirements, and need for caregiver support when receiving intravesical therapy. Nearly three-quarters of survey respondents reported openness to receiving intravesical instillations in their home, with many identifying potential benefits for home over clinic-based therapy.

Novel laser therapies and new technologies in the endoscopic management of upper tract urothelial carcinoma: a narrative review.

Background and Objective: Upper tract urothelial carcinoma (UTUC) is a rare disease. The gold standard treatment is radical nephroureterectomy (RNU). Endoscopic management of UTUC has emerged as an alternative therapy that aims to preserve kidney function while providing effective oncologic control. Over the years, this has become an increasingly important alternative to RNU for treating UTUC in patients with localized disease. Advancements in lasers and endoscopic technology have continued to expand the applications of endoscopic nephron-sparing treatment. This review aims to provide an overview of the available lasers and ureteroscopic technologies used in treating UTUC with a focus on their clinical applications and outcomes. Methods: A comprehensive literature review was completed using PubMed to create this narrative mini review. Publications from peer-reviewed journals written in English between 1987 to 2022 were evaluated by the authors for inclusion. Key Content and Findings: Improvements in ureteroscopic technology have led to improved visualization and tumor detection. Laser ablation using different laser energies including the holmium/yttrium-aluminum-garnet, neodymium/YAG, and thulium/YAG has demonstrated promising oncologic outcomes. However, accurate staging and risk-stratification remain limitations to the role of laser ablation for the treatment of UTUC. This review also highlights appropriate patient selection as a critical component of successful endoscopic management. Conclusions: The continued evolution of endoscopic management will rely on the development of new technologies to improve risk stratification and oncologic outcomes. Overall, this review provides insights into the available laser therapies and ureteroscopic technologies for the endoscopic management of UTUC.

Contemporary Role of Lymph Node Dissection in Genitourinary Cancers: Where Are We in 2023?

CONTEXT: Lymphadenectomy during surgery for genitourinary malignancies has varying benefits. OBJECTIVE: To review contemporary evidence on lymph node dissection in genitourinary cancers. EVIDENCE ACQUISITION: We performed a collaborative review to summarize current evidence supporting lymph node dissection in urothelial, prostate, kidney, penile, and testis cancers. We present the evidence on patient selection and recommended dissection templates, and highlight knowledge gaps and ongoing areas of investigation. EVIDENCE SYNTHESIS: Lymph node dissection remains the reference standard for lymph node staging. Pathologic nodal stage informs prognosis and guides adjuvant treatment. Appropriate template and patient selection are paramount to optimize outcomes and capitalize on the selective therapeutic benefits. CONCLUSIONS: Accurate staging with lymphadenectomy is contingent on appropriate template selection. The cumulative benefit will depend on judicious patient selection. PATIENT SUMMARY: We performed a collaborative review by a diverse group of experts in urology. We reviewed current evidence on lymph node dissection.

Introduction to the Coproduction of Supervision Standards for Digital Peer Support: Qualitative Study.

BACKGROUND: Digital peer support enhances engagement in mental and physical health services despite barriers such as location, transportation, and other accessibility constraints. Digital peer support involves live or automated peer support services delivered through technology media such as peer-to-peer networks, smartphone apps, and asynchronous and synchronous technologies. Supervision standards for digital peer support can determine important administrative, educative, and supportive guidelines for supervisors to maintain the practice of competent digital peer support, develop knowledgeable and skilled digital peer support specialists, clarify the role and responsibility of digital peer support specialists, and support specialists in both an emotional and developmental capacity. OBJECTIVE: Although digital peer support has expanded recently, there are no formal digital supervision standards. The aim of this study is to inform the development of supervision standards for digital peer support and introduce guidelines that supervisors can use to support, guide, and develop competencies in digital peer support specialists. METHODS: Peer support specialists that currently offer digital peer support services were recruited via an international email listserv of 1500 peer support specialists. Four 1-hour focus groups, with a total of 59 participants, took place in October 2020. Researchers used Rapid and Rigorous Qualitative Data Analysis methods. Researchers presented data transcripts to focus group participants for feedback and to determine if the researcher's interpretation of the data match their intended meanings. RESULTS: We identified 51 codes and 11 themes related to the development of supervision standards for digital peer support. Themes included (1) education on technology competency (43/197, 21.8%), (2) education on privacy, security, and confidentiality in digital devices and platforms (33/197, 16.8%), (3) education on peer support competencies and how they relate to digital peer support (25/197, 12.7%), (4) administrative guidelines (21/197, 10.7%), (5) education on the digital delivery of peer support (18/197, 9.1%), (6) education on technology access (17/197, 8.6%), (7) supervisor support of work-life balance (17/197, 8.6%), (8) emotional support (9/197, 4.6%), (9) administrative documentation (6/197, 3%), (10) education on suicide and crisis intervention (5/197, 2.5%), and (11) feedback (3/197, 1.5%). CONCLUSIONS: Currently, supervision standards from the Substance Abuse and Mental Health Services Administration (SAMHSA) for in-person peer support include administrative, educative, and supportive functions. However, digital peer support has necessitated supervision standard subthemes such as education on technology and privacy, support of work-life balance, and emotional support. Lack of digital supervision standards may lead to a breach in ethics and confidentiality, workforce stress, loss of productivity, loss of boundaries, and ineffectively serving users who participate in digital peer support services. Digital peer support specialists require specific knowledge and skills to communicate with service users and deliver peer support effectively, while supervisors require new knowledge and skills to effectively develop, support, and manage the digital peer support role.

ERK3 and DGKζ interact to modulate cell motility in lung cancer cells.

Extracellular signal-regulated kinase 3 (ERK3) promotes cell migration and tumor metastasis in multiple cancer types, including lung cancer. The extracellular-regulated kinase 3 protein has a unique structure. In addition to the N-terminal kinase domain, ERK3 includes a central conserved in extracellular-regulated kinase 3 and ERK4 (C34) domain and an extended C-terminus. However, relatively little is known regarding the role(s) of the C34 domain. A yeast two-hybrid assay using extracellular-regulated kinase 3 as bait identified diacylglycerol kinase ζ (DGKζ) as a binding partner. DGKζ was shown to promote migration and invasion in some cancer cell types, but its role in lung cancer cells is yet to be described. The interaction of extracellular-regulated kinase 3 and DGKζ was confirmed by co-immunoprecipitation and in vitro binding assays, consistent with their co-localization at the periphery of lung cancer cells. The C34 domain of ERK3 was sufficient for binding to DGKζ, while extracellular-regulated kinase 3 bound to the N-terminal and C1 domains of DGKζ. Surprisingly, in contrast to extracellular-regulated kinase 3, DGKζ suppresses lung cancer cell migration, suggesting DGKζ might inhibit ERK3-mediated cell motility. Indeed, co-overexpression of exogenous DGKζ and extracellular-regulated kinase 3 completely blocked the ability of ERK3 to promote cell migration, but DGKζ did not affect the migration of cells with stable ERK3 knockdown. Furthermore, DGKζ had little effect on cell migration induced by overexpression of an ERK3 mutant missing the C34 domain, suggesting DGKζ requires this domain to prevent ERK3-mediated increase in cell migration. In summary, this study has identified DGKζ as a new binding partner and negative regulator of extracellular-regulated kinase 3 in controlling lung cancer cell migration.

Complex Urethral Diverticulectomy: Is a Synchronous Prophylactic Autologous Fascial Sling Needed?

IMPORTANCE: Urethral diverticulectomy is performed with or without concomitant pubovaginal sling (PVS). Patients with complex UD are more frequently offered concomitant PVS. However, there is paucity of literature comparing postoperative incontinence rates for patients with simple versus complex UD. OBJECTIVE: The objective of this study is to examine postoperative stress urinary incontinence (SUI) rates after Urethral Diverticulectomy without concomitant PVS for both complex and simple cases. STUDY DESIGN: A retrospective cohort study was conducted among 55 patients who underwent Urethral Diverticulectomy from 2007 to 2021. Preoperative SUI was patient-reported and confirmed with cough stress test result. Complex cases were defined as circumferential or horseshoe configurations, prior diverticulectomy, and/or anti-incontinence procedure. Primary outcome was postoperative SUI. Secondary outcome was interval PVS. Complex and simple cases were compared using the Fisher exact test. RESULTS: Median age was 49 years (interquartile range, 36-58 years). Median follow-up was 5.4 months (IQR, 2-24 months). Thirty of 55 (55%) cases were simple, and 25 of 55 (45%) complex. Preoperative SUI was present in 19/57 (35%) (11 complex vs 8 simple, P = 0.25). Stress urinary incontinence persisted postoperatively in 10 of 19 (52%) (6 complex vs 4 simple, P = 0.48). De novo SUI occurred in 7 of 55, 12% (4 complex vs 3 simple, P = 0.68). Overall, 17 of 55 (31%) patients had postoperative SUI (10 complex vs 7 simple, P = 0.24). Of those, 8 of 17 underwent subsequent PVS placement (P = 0.71) and 9 of 17 had resolution of pad use after physical therapy (P = 0.27). CONCLUSIONS: We did not find evidence of an association between complexity and postoperative SUI. Age at surgery and preoperative frequency were the strongest predictors of postoperative SUI in this cohort. Our findings suggest successful complex urethral diverticulum repair does not require concomitant PVS.

What does heritability of Alzheimer's disease represent?

INTRODUCTION: Both late-onset Alzheimer's disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. METHODS: We compute heritability in five large independent cohorts (N = 7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. RESULTS: SNP-based heritability of late onset Alzheimer's disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD = 8%] on average when the APOE region is excluded and an additional 1% [SD = 3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. CONCLUSION: The heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes.

Urinary Outcomes After Magnetic Resonance Imaging-Guided Whole-Gland Transurethral Ultrasound Ablation for Prostate Cancer: Comparison of Suprapubic Tube to Indwelling Urethral Catheter.

Background: MRI-guided transurethral ultrasound ablation (TULSA) is under investigation for whole-gland ablation of low- and intermediate-risk prostate cancer. The ideal method for post-TULSA bladder drainage through postoperative suprapubic tube (SPT) vs indwelling urethral catheter (UC) has not been established. The objective of this study was to evaluate urinary outcomes after whole-gland TULSA, comparing postoperative SPT with UC. Materials and Methods: Two-institution retrospective analysis of whole-gland TULSA for men with grade group 1 and 2 prostate cancer. One institution placed SPT at the time of TULSA with clamp trials (day 10) and removal once voiding. The second placed UC until void trial (day 7). Outcomes included the International Prostate Symptom Score (IPSS), urinary bother score, catheter reinsertion, stricture, clean intermittent catheterization (CIC), and incontinence. Results: Forty-five patients (median age 67) were analyzed. The UC cohort (N = 26) was older (p = 0.007) than the SPT cohort (N = 19) but with similar baseline prostate volumes, IPSS, and urinary bother scores. Patients receiving UC had fewer days with catheter (p = 0.013). Although UC patients suffered more lower urinary tract symptoms at 1-month post-TULSA, there was no significant difference between IPSS scores at baseline and 6 months after surgery regardless of urinary management strategy, although the UC group noted significantly decreased urinary bother. Rates of infection were similar between groups. Six strictures were observed overall, with more in the SPT group, although the difference was not significant (4/19 [21.1%] SPT; 2/26 [7.7%] UC). At 6 months, incontinence rates were low and similar between groups (2/19 [10.5%] SPT; 4/26 [15.4%] UC) and only one patient (UC) required CIC. Conclusions: Our overall findings suggest that SPT and UC are both acceptable options for postoperative bladder drainage after whole-gland TULSA, with statistically similar rates of urinary complications but a slightly different side effect profile.

Intraoperative Blood Transfusion Is Associated With Increased Risk of Venous Thromboembolism After Radical Cystectomy.

PURPOSE: Our objective was to examine whether perioperative blood transfusion is associated with venous thromboembolism following radical cystectomy adjusting for both patient- and disease-related factors. MATERIALS AND METHODS: Patients who underwent radical cystectomy for bladder cancer from 1980-2020 were identified in the Mayo Clinic cystectomy registry. Blood transfusion during the initial postoperative hospitalization was analyzed as a 3-tiered variable: no transfusion, postoperative transfusion alone, or intraoperative with or without postoperative transfusion. The primary outcome was venous thromboembolism within 90 days of radical cystectomy. Associations between clinicopathological variables and 90-day venous thromboembolism were assessed using multivariable logistic regression, with transfusion analyzed as both a categorical and a continuous variable. RESULTS: A total of 3,755 radical cystectomy patients were identified, of whom 162 (4.3%) experienced a venous thromboembolism within 90 days of radical cystectomy. Overall, 2,112 patients (56%) received a median of 1 (IQR: 0-3) unit of blood transfusion, including 811 (38%) with intraoperative transfusion only, 572 (27%) with postoperative transfusion only, and 729 (35%) with intraoperative and postoperative transfusion. On multivariable analysis, intraoperative with or without postoperative blood transfusion was associated with a significantly increased risk of venous thromboembolism (adjusted OR 1.73, 95% CI 1.17-2.56, P = .002). Moreover, when analyzed as a continuous variable, each unit of blood transfused intraoperatively was associated with 7% higher odds of venous thromboembolism (adjusted OR 1.07, 95% CI 1.01-1.13, P = .03). CONCLUSIONS: Intraoperative blood transfusion was significantly associated with venous thromboembolism within 90 days of radical cystectomy. To ensure optimal perioperative outcomes, continued effort to limit blood transfusion in radical cystectomy patients is warranted.

Assessing the Feasibility, Acceptability, and Preliminary Effectiveness of a School-Aged Program that Supports Physical Activity and Wellness.

The prevalence of anxiety symptoms in children and adolescents aged 4 to 18 years has nearly doubled after the first year of the pandemic. However, only one in five adolescents diagnosed with anxiety is treated. We R H.O.P. E. is a school-based mental health program that includes evidence-based principles designed to engage children and adolescents in anxiety treatment, including wellness and emotional regulation, and the emotional CPR method. We R H.O.P. E. augments traditional services provided by school administrators, school social workers, school teachers, and school nurses. The purpose of this study was to examine the feasibility, acceptability, and preliminary effectiveness of We R H.O.P. E.

Guidelines to Establish an Equitable Mobile Health Ecosystem.

Mobile health (mHealth)-that is, use of mobile devices, such as mobile phones, monitoring devices, personal digital assistants, and other wireless devices, in medical care-is a promising approach to the provision of support services. mHealth may aid in facilitating monitoring of mental health conditions, offering peer support, providing psychoeducation (i.e., information about mental health conditions), and delivering evidence-based practices. However, some groups may fail to benefit from mHealth despite a high need for mental health services, including people from racially and ethnically disadvantaged groups, rural residents, individuals who are socioeconomically disadvantaged, and people with disabilities. A well-designed mHealth ecosystem that considers multiple elements of design, development, and implementation can afford disadvantaged populations the opportunity to address inequities and facilitate access to and uptake of mHealth. This article proposes inclusion of the following principles and standards in the development of an mHealth ecosystem of equity: use a human-centered design, reduce bias in machine-learning analytical techniques, promote inclusivity via mHealth design features, facilitate informed decision making in technology selection, embrace adaptive technology, promote digital literacy through mHealth by teaching patients how to use the technology, and facilitate access to mHealth to improve health outcomes.

Analysis of fixed and variable operating room (or) time point efficiency in partial nephrectomies: open versus robotic-assisted.

To analyze operating room (OR) efficiency by evaluating fixed and variable OR times for open (OPN) and robotic-assisted partial nephrectomies (RAPN). We analyzed consecutive OPN and RAPN performed by one surgeon over a 24-month period. All patients were placed in the lateral decubitus position and secured with a beanbag regardless of approach. Fixed (non-procedural) OR times were prospectively collected and defined as: in-room to anesthesia-release time (IRAT), anesthesia release to cut time (ARCT), and close to wheels-out time (CTWO). Variable OR time was procedural cut to close time (CTCT). Comparisons of fixed and variable OR time points between OPN and RAPN were performed using the Wilcoxon rank-sum test. 146 RAPN and 31 OPN were evaluated from 2019-2020. Median IRAT was similar for RAPN versus OPN [20 min (IQR: 16-25) vs. 20 min (IQR: 16-26), P = 0.57]. Median ARCT was longer for RAPN than it was for OPN [40 min (IQR: 36-46) vs. 34 min (IQR: 30-39), P < 0.001]. Median CTWO was similar for OPN (12 min, IQR: 9-14) and RAPN (11 min, IQR: 7-15) (P = 0.89). Median CTCT was longer for RAPN (202 min, IQR: 170-236) compared to OPN (164 min, IQR: 154-184) (P < 0.001). In a single surgeon, partial nephrectomy series with the same patient positioning, utilization of robotic technology was associated with longer surgeon operating time as well as less efficient fixed OR times, specifically ARCT.

The Human Brainome: changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer's disease.

While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer's disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59-58.75). We sought to address whether the APOE E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing APOE E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that VGF had the greatest explanatory weight. High expression of VGF is a protective signal, even on the background of APOE E4 alleles. LOAD risk signals, considering an APOE background, include high levels of SPECC1L, HLA-DRA and RANBP3L. Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.

Effectiveness of a Digital Peer Support Training Program Designed for Rapid Uptake Among Peer Support Specialists Pilot Study.

Peer telemental health recently became Medicaid reimbursable during the COVID-19 crisis, increasing the need for standardized training on digital peer support (DPS) services. DPS has the potential to reduce barriers to services and expand the reach of peer support specialists. The 4-h Digital Peer Support Training program was developed to train peer support specialists for rapid uptake in providing digital peer support during the COVID-19 crisis. The purpose of this study was to examine the impact of the 4-h DPS course for peer support specialists. Surveys were administered to examine pre-post changes in DPS course for participants (N = 75) related to attitudes/ beliefs towards DPS, ability to use/ engage in DPS, and organizational readiness to implement DPS. Data were analyzed by conducting paired samples t-tests. Linear mixed models were used to explore significant results further. Statistically significant (< .05) changes were observed related to readiness to use DPS, attitudes/ beliefs towards DPS, and ability to use/ engage in DPS. The 4-h DPS course may be beneficial in providing diverse groups of peer support specialists with a standardized training framework. Widespread dissemination of the DPS short course may be beneficial in rapidly equipping peer support specialists with the skills and resources needed to expand the reach of peer support services during the COVID-19 crisis and beyond.

Risk and protective factors in relation to early mortality among people with serious mental illness: Perspectives of peer support specialists and service users.

OBJECTIVE: Individuals with serious mental illness (SMI) experience a 10-25-year reduced life expectancy when compared to the general population that is due, in part, to poor health behaviors. Yet, in spite of the development of health promotion and self-management interventions designed for people with SMI to promote health behavior change, the mortality gap has increased, suggesting that relevant factors are not being addressed. The objective of the present study was to explore potential contributors to early mortality among individuals with SMI by drawing from the lived experience of certified peer support specialists and service users (SUs). METHOD: Face-to-face semistructured interviews were conducted with a convenience sample of SU participants (n = 17) and certified peer specialists (n = 15). Qualitative data were analyzed using a grounded-theory approach. RESULTS: We identified a final set of 27 codes relating to five overarching themes that relate to both risk factors and protective factors for early death: social connectedness (24.1% of coded items), treatment (21.3%), coping (21.3%), physical health and wellness (18.5%), and resilience and mental health (14.8%). CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Findings add to the literature supporting the powerful role of social processes in shaping health in people with SMI beyond social determinants of health (SDOH; e.g., income, employment) and health behavior change. Interventions that reduce loneliness and isolation in combination with addressing more conventional SDOH may have the most potential to reduce early mortality in people with SMI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).