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Abstract: Chronic posttraumatic pain (CPTP) is common after traumatic stress exposure (TSE) and disproportionately burdens women. We previously showed across 3 independent longitudinal cohort studies that, in women, increased peritraumatic 17β-estradiol (E2) levels were associated with substantially lower CPTP over 1 year. Here, we assessed this relationship in a fourth longitudinal cohort and also assessed the relationship between E2 and CPTP at additional time points post-TSE. Furthermore, we used a well-validated animal model of TSE to determine whether exogenous E2 administration protects against mechanical hypersensitivity. Using nested samples and data from the Advancing Understanding of RecOvery afteR traumA study (n = 543 samples, 389 participants), an emergency department-based prospective study of TSE survivors, we assessed the relationship between circulating E2 levels and CPTP in women and men using multivariate repeated-measures mixed modeling. Male and ovariectomized female Sprague Dawley rats were exposed to TSE and administered E2 either immediately after or 3 days post-TSE. Consistent with previous results, we observed an inverse relationship between peritraumatic E2 and longitudinal CPTP in women only (β = -0.137, P = 0.033). In animals, E2 protected against mechanical hypersensitivity in female ovariectomized rats only if administered immediately post-TSE. In conclusion, peritraumatic E2 levels, but not those at post-TSE time points, predict CPTP in women TSE survivors. Administration of E2 immediately post TSE protects against mechanical hypersensitivity in female rats. Together with previous findings, these data indicate that increased peritraumatic E2 levels in women have protective effects against CPTP development and suggest that immediate post-TSE E2 administration in women could be a promising therapeutic strategy for reducing risk of CPTP., (Copyright © 2024 International Association for the Study of Pain.)

Background: Overdose remains a pressing public health concern in the United States, particularly with the emergence of fentanyl and other potent synthetic opioids in the drug supply. We evaluated trends in recurrent overdose and opioid use disorder (OUD) treatment initiation following emergency department (ED) visits for opioid overdose to inform response efforts., Methods: This retrospective cohort study used electronic health record and statewide administrative data from Rhode Island residents who visited EDs for opioid overdose between July 1, 2016, and June 30, 2021, a period with fentanyl predominance in the local drug supply. The primary outcome was recurrent overdose in the 365 days following the initial ED visit. OUD treatment initiation within 180 days following the initial ED visit was considered as a secondary outcome. Trends in study outcomes were summarized by year of the initial ED visit., Results: Among 1745 patients attending EDs for opioid overdose, 20 % (n=352) experienced a recurrent overdose within 365 days, and this percentage was similar by year (p=0.12). Among patients who experienced any recurrent overdose, the median time to first recurrent overdose was 88 days (interquartile range=23-208), with 85 % (n=299/352) being non-fatal. Among patients not engaged in OUD treatment at their initial ED visit, 33 % (n=448/1370) initiated treatment within 180 days; this was similar by year (p=0.98)., Conclusions: Following ED visits for opioid overdose in Rhode Island from 2016-2021, the one-year risk of recurrent overdose and six-month treatment initiation rate remained stable over time. Innovative prevention strategies and improved treatment access are needed., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Data evaluating cardiovascular disease (CVD) risk by cancer treatment among young women (≤ 40 years) with breast cancer are limited., Methods: Among 372 five-year breast cancer survivors aged 30-40 years from the Young Women's Breast Cancer Study, we assessed the association of cancer treatments (anthracyclines, trastuzumab, radiation/laterality, endocrine therapy) and excess heart age (difference between predicted 10-year CVD risk as assessed by adapted Framingham Risk Score and chronological age), prevalent elevated excess heart age (≥ 2 years), and worsening excess heart age (change of ≥ 2 excess heart age years) at breast cancer diagnosis and two- and five-year follow-up using multivariable linear and logistic regressions., Results: Most women had stage I or II (79%), ER + (71%), or PR + (65%) breast cancer. At diagnosis, women had little excess heart age by treatment receipt (range of means = -0.52,0.91 years). Left-sided radiation (β = 2.49,SE = 0.96,p = 0.01) was associated with higher excess heart age at five-year follow-up. For prevalent elevated excess heart age (two-year = 26%;five-year = 27%), women treated with right-sided radiation had increased risk at two-years (OR = 2.17,95%CI = 1.12-4.19), yet at five-years, associations were observed after any radiation (OR = 1.92,95%CI = 1.09-3.41), especially after left-sided (OR = 2.13,95%CI = 1.09-3.41) radiation. No associations were observed between systemic treatments and prevalent elevated excess heart age or any treatments with worsening excess heart age., Conclusions: Among young breast cancer survivors, radiation, but not other cancer treatments, was associated with elevated excess heart age., Implications for Cancer Survivors: CVD risk tools that incorporate cancer treatment, such as radiation, are needed to identify high risk young breast cancer survivors given the long survivorship and long latency of cardiovascular disease., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: This study examined if emergency department (ED) operational metrics, such as wait time or length of stay, are associated with interest in substance use disorder (SUD) treatment referral among patients at high risk of opioid overdose., Methods: In this observational study, 648 ED patients at high risk of opioid overdose completed a baseline questionnaire. Operational metrics were summarized using electronic health record data. The association between operational metrics and treatment interest was estimated with multivariable logistic regression., Results: Longer time to room (adjusted odds ratio [AOR]=1.12, 95% confidence interval [CI]=1.01-1.25) and length of stay (AOR=1.02, 95% CI=1.00-1.05) were associated with treatment referral interest. Time to provider and number of treating providers showed no significant association., Conclusion: Longer rooming wait times and longer ED visits were associated with increased SUD treatment referral interest. This suggests patients who wait for longer periods may be motivated for treatment and warrant further resource investment.

In the United States, 8,000,000 people seek emergency care for traumatic injury annually. Motor vehicle collisions (MVCs) and sexual assault are two common sources of trauma, with evidence that reduced neighborhood-level socioeconomic characteristics increase posttraumatic pain and stress after an MVC. We evaluated whether neighborhood disadvantage was also associated with physical and mental posttrauma outcomes after sexual assault in a sample of adult women (N = 656) who presented for emergency care at facilities in the United States following sexual assault and were followed for 1 year. Neighborhood characteristics were assessed via the Area Deprivation Index, and self-reported pain, anxiety, depression, and posttraumatic stress disorder (PTSD) symptoms were collected at 6 weeks posttrauma. Adjusted log-binomial regression models examined the association between each clinical outcome and neighborhood disadvantage. Women in more disadvantaged neighborhoods were more likely to be non-White and have lower annual incomes. At 6 weeks posttrauma, the prevalence of clinically significant pain, anxiety, and depressive symptoms more than doubled from baseline (41.7% vs. 18.8%, 62.4% vs. 23.9%, and 55.2% vs. 22.7%, respectively); 40.7% of women also reported PTSD symptoms. Black, Hispanic, and lower-income participants were more likely to report pre- and postassault pain, anxiety, and depression. After adjusting for race, ethnicity, and income, no significant association existed between neighborhood disadvantage and any outcome, ps = .197 - .859. Although neighborhood disadvantage was not associated with posttrauma outcomes, these findings highlight the need for continued research in diverse populations at high risk of adverse physical and mental health symptoms following sexual assault., (© 2024 International Society for Traumatic Stress Studies.)

Importance: Many veterans who served in Afghanistan and Iraq during Operations Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) were deployed to military bases with open burn pits and exposed to their emissions, with limited understanding of the long-term health consequences., Objective: To determine the association between deployment to military bases where open burn pits were used for waste disposal and the subsequent risk of developing respiratory and cardiovascular diseases., Design, Setting, and Participants: This retrospective observational cohort study used Veterans Health Administration medical records and declassified deployment records from the Department of Defense to assess Army and Air Force veterans who were deployed between 2001 and 2011 and subsequently received health care from the Veterans Health Administration, with follow-up through December 2020. Data were analyzed from January 2023 through February 2024., Exposure: Duration of deployment to military bases with open burn pits., Main Outcomes and Measures: Diagnosis of asthma, chronic obstructive pulmonary disease, interstitial lung disease, hypertension, myocardial infarction, congestive heart failure, ischemic stroke, and hemorrhagic stroke., Results: The study population included 459 381 OEF and OIF veterans (mean [SD] age, 31.6 [8.7] years; 399 754 [87.0%] male). Median (IQR) follow-up from end of deployment was 10.9 (9.4-12.7) years. For every 100 days of deployment to bases with burn pits, veterans experienced increased adjusted odds for asthma (adjusted odds ratio [aOR], 1.01; 95% CI, 1.01-1.02), chronic obstructive pulmonary disease (aOR, 1.04; 95% CI, 1.02-1.07), hypertension (aOR, 1.02; 95% CI, 1.02-1.03), and ischemic stroke (aOR, 1.06; 95% CI, 0.97-1.14). Odds of interstitial lung disease, myocardial infarction, congestive heart failure, or hemorrhagic stroke were not increased. Results based on tertiles of duration of burn pit exposures were consistent with those from the continuous exposure measures., Conclusions and Relevance: In this cohort study, prolonged deployment to military bases with open burn pits was associated with increased risk of developing asthma, COPD, and hypertension. The results also point to a possible increased risk in ischemic stroke. The novel ability to use integrated data on deployment and health outcomes provides a model for additional studies of the health impact of environmental exposures during military service.

Introduction: Chronic pain and serious mental illness increase risk of opioid use, and opioid use can exacerbate both conditions. Substance use disorder (SUD) treatment can be lifesaving, but chronic pain and serious mental illness may make recovery challenging. We evaluated the association between current chronic pain and prior hospitalization for mental illness and 90-day SUD treatment engagement, among emergency department (ED) patients at high risk of opioid overdose., Methods: We conducted a cohort analysis of 648 ED patients enrolled in a randomized controlled trial in Rhode Island. We linked baseline study data on chronic pain and prior hospitalization for mental illness to statewide administrative data on state-licensed treatment programs (including methadone) and buprenorphine treatment via prescription. We defined treatment engagement as initiation of a state-licensed treatment program, transfer between state-licensed programs/providers, or a buprenorphine prescription (re-)fill. We used modified Poisson models to estimate the association between each baseline comorbidity and treatment engagement within 90 days following the ED visit, adjusted for a priori potential confounders. In an exploratory analysis, models were stratified by baseline treatment status., Results: The mean age of participants was 37 years; 439 (68 %) were male, and 446 (69 %) had been recently unhoused. Overall, 278 participants (43 %) engaged in treatment within 90 days of the ED visit. Participants with prior hospitalization for mental illness were more likely to engage in treatment than those without (adjusted risk ratio [ARR] = 1.24, 95 % confidence interval [CI] = 1.01-1.53), although this association was only among those already accessing treatment at baseline (ARR = 1.58, 95 % CI = 1.10-2.27). Chronic pain was not associated with 90-day treatment engagement overall (ARR = 1.12, 95 % CI = 0.91-1.38) or within baseline treatment subgroups., Conclusions: Among ED patients at high risk of opioid overdose and accessing treatment at baseline, those with prior hospitalization for mental illness (but not chronic pain) were more likely to engage in treatment following the ED visit, which may reflect disproportionate initiation of additional treatment programs, transfer between programs/providers, or ongoing buprenorphine treatment. Touchpoints within the medical system should be leveraged to ensure that everyone, including those with serious mental illness, can access high-quality SUD treatment at the desired intensity level., Competing Interests: Declaration of competing interest Dr. Beaudoin received grants from the National Institutes of Health, Centers for Disease Control and Prevention, and Institute for Clinical and Economic Review outside the submitted work. Dr. Marshall received grants from the National Institutes of Health outside of the submitted work. All other authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Buprenorphine treatment for opioid use disorder (OUD) has more than doubled since 2009. However, current US Food and Drug Administration buprenorphine dosing guidelines are based on studies among people using heroin, prior to the emergence of fentanyl in the illicit drug supply., Objective: To estimate the association between buprenorphine dose and time to treatment discontinuation during a period of widespread fentanyl availability., Design, Setting, and Participants: This retrospective cohort study used statewide Rhode Island Prescription Drug Monitoring Program data. Participants were Rhode Island residents initiating buprenorphine treatment for OUD between October 1, 2016, and September 30, 2020. Data analysis was performed from December 9, 2022, to August 10, 2023., Exposure: Daily dose of buprenorphine (16 mg and 24 mg) defined starting on the day of initiation based on total quantity and days' supply dispensed. Patients were censored on any dose change., Main Outcomes and Measures: Buprenorphine treatment discontinuation in the 180 days following initiation, defined as a gap in treatment of more than 27 days based on prescription fill dates and days' supply. Kaplan-Meier and Cox regression survival analyses were conducted to estimate the association between buprenorphine dose and time to treatment discontinuation, controlling for potential informative censoring and measured potential confounders., Results: Among 6499 patients initiating buprenorphine treatment for OUD, most were aged 25 to 44 years (57%; n = 3682), were male (61%; n = 3950), and had private (47%; n = 3025) or Medicaid (33%; n = 2153) insurance. More than half of patients were prescribed a daily dose of interest at initiation (16 mg: 50%; n = 3264; 24 mg: 10%; n = 668). In Kaplan-Meier analyses, 58% of patients discontinued buprenorphine treatment within 180 days (16 mg: 59% vs 24 mg: 53%; log-rank test P = .005). In Cox regression analyses, patients prescribed a dose of 16 mg had a greater risk of treatment discontinuation than those prescribed 24 mg (adjusted hazard ratio, 1.20; 95% CI, 1.06-1.37)., Conclusions and Relevance: In this cohort study of patients initiating buprenorphine treatment from 2016 to 2020, patients prescribed a 24 mg dose of buprenorphine remained in treatment longer than those prescribed 16 mg. The value of higher buprenorphine doses than currently recommended needs to be considered for improving retention in treatment.

Background: Substance use patterns are diverse, and multiple substances are often involved in fatal and nonfatal overdoses. Additionally, polysubstance use is associated with greater difficulty accessing and remaining in substance use disorder (SUD) treatment. The aim of this study was to identify substance use patterns and determine their association with SUD treatment engagement among emergency department (ED) patients at risk of opioid overdose., Methods: This was a sub-analysis of a randomized controlled trial comparing two behavioral interventions for individuals at two EDs in Rhode Island from 2018 to 2021. Past six-month substance use frequency for eight substances plus injection drug use was self-reported at trial enrollment, and SUD treatment engagement within 90 days after enrollment was obtained using administrative data linkages. Latent class analysis identified substance use patterns and multivariable log-binomial models estimated the association with SUD treatment engagement., Results: Among 607 participants, there were four substance use patterns: 1) low reported use (n = 295), 2) frequent injection and heroin use (n = 131), 3) high frequency broad polysubstance use (n = 62), and 4) low frequency broad polysubstance use (n = 119). Compared to participants with the low reported use pattern, those with the frequent injection and heroin pattern had a greater likelihood of SUD treatment engagement (adjusted risk ratio = 1.28; 95% confidence interval = 1.02-1.61)., Conclusions: Distinct and meaningful polysubstance use patterns showed differential SUD treatment engagement after ED discharge. Nuanced relationships between substance use patterns and treatment highlight the necessity for tailored harm reduction, treatment, and recovery services., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Abstract: This study investigated the tolerability and preliminary efficacy of duloxetine as an alternative nonopioid therapeutic option for the prevention of persistent musculoskeletal pain (MSP) among adults presenting to the emergency department with acute MSP after trauma or injury. In this randomized, double-blind, placebo-controlled study, eligible participants (n = 78) were randomized to 2 weeks of a daily dose of one of the following: placebo (n = 27), 30 mg duloxetine (n = 24), or 60 mg duloxetine (n = 27). Tolerability, the primary outcome, was measured by dropout rate and adverse effects. Secondary outcomes assessed drug efficacy as measured by (1) the proportion of participants with moderate to severe pain (numerical rating scale ≥ 4) at 6 weeks (pain persistence); and (2) average pain by group over the six-week study period. We also explored treatment effects by type of trauma (motor vehicle collision [MVC] vs non-MVC). In both intervention groups, duloxetine was well tolerated and there were no serious adverse events. There was a statistically significant difference in pain over time for the 60 mg vs placebo group ( P = 0.03) but not for the 30 mg vs placebo group ( P = 0.51). In both types of analyses, the size of the effect of duloxetine was larger in MVC vs non-MVC injury. Consistent with the role of stress systems in the development of chronic pain after traumatic stress, our data indicate duloxetine may be a treatment option for reducing the transition from acute to persistent MSP. Larger randomized controlled trials are needed to confirm these promising results., (Copyright © 2022 International Association for the Study of Pain.)

Objective: Mood disorders complicated by suicidal ideation (SI) frequently present to the emergency department (ED) for care. Currently, patients with SI in the ED do not typically receive targeted interventions. Ketamine may have a role in treating SI within the ED because subanesthetic doses have rapid-acting antidepressant and antisuicidal properties., Methods: This single-arm, open-label feasibility study enrolled 14 participants from the ED with acute SI who were awaiting voluntary admission to inpatient psychiatry to receive ketamine at 0.5 mg/kg, administered intravenously. Participants were assessed post administration to evaluate feasibility of administration in the ED and short-term effectiveness. Feasibility was determined by acceptability by patients and physicians as well as tolerability and ability to recruit participants into the study. Efficacy was assessed based on changes in (1) self-reported mood and (2) suicidal ideation pre- and postinfusion of ketamine., Results: All patients reported severe depression and active SI at baseline. No serious adverse events were reported, and acceptability was rated highly by both participants and physicians (>70%). Two hours after receiving ketamine 0.5 mg/kg, the mean SI and somatic symptom burden were decreased compared to baseline ( P  < 0.001 and P  = 0.005, respectively), and the mean self-reported mood was increased ( P  = 0.006). Improvements in mood and decreases in suicidality persisted at 6 hours., Conclusions: Overall, ketamine was well tolerated, considered feasible by both participants and physicians, and demonstrated short-term efficacy. There is a growing body of evidence demonstrating the feasibility of ketamine administration in the ED, and larger randomized trials should be conducted to establish treatment recommendations for patients with SI in the ED., Competing Interests: None of the study authors have any conflicts of interest., (© 2022 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Objective: We aimed to investigate eligibility for breast conserving surgery (BCS) pre- and post-neoadjuvant systemic therapy (NST), and trends in the surgical treatment of young breast cancer patients., Background: Young women with breast cancer are more likely to present with larger tumors and aggressive phenotypes, and may benefit from NST. Little is known about how response to NST influences surgical decisions in young women., Methods: The Young Women's Breast Cancer Study, a multicenter prospective cohort of women diagnosed with breast cancer at age ≤40, enrolled 1302 patients from 2006 to 2016. Disease characteristics, surgical recommendations, and reasons for choosing mastectomy among BCS-eligible patients were obtained through the medical record. Trends in use of NST, rate of clinical and pathologic complete response, and surgery were also assessed., Results: Of 1117 women with unilateral stage I-III breast cancer, 315 (28%) received NST. Pre-NST, 26% were BCS eligible, 17% were borderline eligible, and 55% were ineligible. After NST, BCS eligibility increased from 26% to 42% (P < 0.0001). Among BCS-eligible patients after NST (n = 133), 41% chose mastectomy with reasons being patient preference (53%), BRCA or TP53 mutation (35%), and family history (5%). From 2006 to 2016, the rates of NST (P = 0.0012), clinical complete response (P < 0.0001), and bilateral mastectomy (P < 0.0001) increased, but the rate of BCS did not increase (P = 0.34)., Conclusion: While the proportion of young women eligible for BCS increased after NST, many patients chose mastectomy, suggesting that surgical decisions are often driven by factors beyond extent of disease and treatment response., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Early reports suggested increased mortality from COVID-19 in patients with cancer but lacked rigorous comparisons to patients without cancer. We investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death in hospitalized patients with COVID-19., Patients and Methods: We identified patients with a history of cancer admitted to two large hospitals between March 13, 2020, and May 10, 2020, with laboratory-confirmed COVID-19 and matched them 1:2 to patients without a history of cancer., Results: Men made up 56.2% of the population, with a median age of 69 years (range, 30-96). The median time since cancer diagnosis was 35.6 months (range, 0.39-435); 80% had a solid tumor, and 20% had a hematologic malignancy. Among patients with cancer, 27.8% died or entered hospice versus 25.6% among patients without cancer. In multivariable analyses, the odds of death/hospice were similar (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.65-1.82). The odds of intubation (OR, 0.46; 95% CI, 0.28-0.78), shock (OR, 0.54; 95% CI, 0.32-0.91), and intensive care unit admission (OR, 0.51; 95% CI, 0.32-0.81) were lower for patients with a history of cancer versus controls. Patients with active cancer or who had received cancer-directed therapy in the past 6 months had similar odds of death/hospice compared with cancer survivors (univariable OR, 1.31; 95% CI, 0.66-2.60; multivariable OR, 1.47; 95% CI, 0.69-3.16)., Conclusion: Patients with a history of cancer hospitalized for COVID-19 had similar mortality to matched hospitalized patients with COVID-19 without cancer, and a lower risk of complications. In this population, patients with active cancer or recent cancer treatment had a similar risk for adverse outcomes compared with survivors of cancer., Implications for Practice: This study investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death or hospice admission in hospitalized patients with COVID-19. Active cancer, systemic cancer therapy, and a cancer history are not independent risk factors for death from COVID-19 among hospitalized patients, and hospitalized patients without cancer are more likely to have severe COVID-19. These findings provide reassurance to survivors of cancer and patients with cancer as to their relative risk of severe COVID-19, may encourage oncologists to provide standard anticancer therapy in patients at risk of COVID-19, and guide triage in future waves of infection., (© 2021 AlphaMed Press.)

Purpose: Synchronous bilateral breast cancer is uncommon, and its pattern and incidence among younger women is unknown. Here we report the incidence, phenotypes, and long-term oncologic outcomes of bilateral breast cancer in women enrolled in the Young Women's Breast Cancer Study (YWS)., Methods: The YWS is a multi-center, prospective cohort study of women with breast cancer diagnosed at age ≤ 40 years. Those with synchronous bilateral breast cancer formed our study cohort. Tumor phenotypes were categorized as luminal A (hormone receptor (HR)+/HER2-/grade 1/2), luminal B (HR+ /HER2+ or HER2- and grade 3), HER2-enriched (HR-/HER2+), or basal-like (HR-/HER2-). Descriptive statistics were used to evaluate tumor phenotypes of bilateral cancers for concordance., Results: Among 1302 patients enrolled in the YWS, 21 (1.6%) patients had synchronous bilateral disease. The median age of diagnosis was 38 years (range 18-40 years). Seventeen (81.0%) underwent genetic testing with 6 found to have pathogenic germline mutations in BRCA1, BRCA2, or TP53. The majority of patients (76.2%) underwent bilateral mastectomy. On pathology, 2 patients had bilateral in-situ disease, 6 had unilateral invasive and contralateral in-situ disease, and 13 had bilateral invasive disease. Of those with bilateral invasive disease, 10 (76.9%) had bilateral luminal tumors and, when fully characterized, 6 were of the same luminal subtype. Only 1 patient had bilateral basal-like breast cancer. At median follow-up of 8.2 years, 14 patients are alive with no recurrent disease., Conclusions: Bilateral breast cancer is uncommon among young women diagnosed with breast cancer at age ≤ 40. In our cohort, the majority of invasive tumors were of the luminal phenotype, though some differed by grade or HER2 status. These findings support the need for thorough pathologic workup of bilateral disease when it is found in young women with breast cancer to determine risk and tailor treatment.

Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR), robustly extends the lifespan of model organisms including mice. We recently found that chronic treatment with rapamycin not only inhibits mTOR complex 1 (mTORC1), the canonical target of rapamycin, but also inhibits mTOR complex 2 (mTORC2) in vivo. While genetic evidence strongly suggests that inhibition of mTORC1 is sufficient to promote longevity, the impact of mTORC2 inhibition on mammalian longevity has not been assessed. RICTOR is a protein component of mTORC2 that is essential for its activity. We examined three different mouse models of Rictor loss: mice heterozygous for Rictor, mice lacking hepatic Rictor, and mice in which Rictor was inducibly deleted throughout the body in adult animals. Surprisingly, we find that depletion of RICTOR significantly decreases male, but not female, lifespan. While the mechanism by which RICTOR loss impairs male survival remains obscure, we find that the effect of RICTOR depletion on lifespan is independent of the role of hepatic mTORC2 in promoting glucose tolerance. Our results suggest that inhibition of mTORC2 signaling is detrimental to males, which may explain in part why interventions that decrease mTOR signaling show greater efficacy in females., (© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)