Post-discharge Mental Healthcare and Emergency General Surgery Readmission for Patients with Serious Mental Illness.

OBJECTIVE: To determine the association between post-discharge mental healthcare and odds of readmission after emergency general surgery (EGS) hospitalization for patients with serious mental illness (SMI). BACKGROUND DATA: A mental health visit (MHV) after medical hospitalization is associated with decreased readmissions for patients with SMI. The impact of a MHV after surgical hospitalization is unknown. METHODS: Using Medicare claims, we performed a retrospective cohort study of hospitalized EGS patients with SMI aged >65.5 (2016-2018). EGS included colorectal, general abdominal, hepatopancreatobiliary, hernia, intestinal obstruction, resuscitation, and upper gastrointestinal conditions. SMI was defined as schizophrenia spectrum, mood, or anxiety disorders. The exposure was MHV within 30 days of discharge. The primary outcome was 30-day readmission. Secondary outcomes included emergency department presentation and psychiatric admission. Inverse probability weighting was used to evaluated outcomes. RESULTS: Of 88,092 analyzed patients, 11,755 (13.3%) had a MHV within 30 days of discharge. 23,696 (26.9%) of patients were managed operatively, 64,395 (73.1%) non-operatively. After adjustment for potential confounders, patients with a post-discharge MHV had lower odds of acute care readmission than patients without a MHV in both operative (OR 0.60; 95% CI: [0.40-0.90]) and non-operative (OR 0.67; 95% CI [0.53-0.84]) cohorts. There was no association between post-discharge MHV and ED presentation or psychiatric admission in the operative or non-operative groups. CONCLUSIONS: Post-discharge MHV after EGS hospitalization was associated with decreased odds of readmission for patients with SMI managed operatively and nonoperatively. In older EGS patients with SMI, coordination of MHVs may be a mechanism to reduce readmission disparities.

Costs of Care for Operative and Nonoperative Management of Emergency General Surgery Conditions.

OBJECTIVE: Many emergency general surgery (EGS) conditions can be managed operatively or nonoperatively, with outcomes that vary by diagnosis. We hypothesized that operative management would lead to higher in-hospital costs but to cost savings over time. BACKGROUND: EGS conditions account for $28 billion in health care costs in the United States annually. Compared with scheduled surgery, patients who undergo emergency surgery are at increased risk of complications, readmissions, and death, with accompanying costs of care that are up to 50% higher than elective surgery. Our prior work demonstrated that operative management had variable impacts on clinical outcomes depending on the EGS condition. METHODS: This was a nationwide, retrospective study using fee-for-service Medicare claims data. We included patients 65.5 years of age or older with a principal diagnosis for an EGS condition 7/1/2015-6/30/2018. EGS conditions were categorized as: colorectal, general abdominal, hepatopancreaticobiliary (HPB), intestinal obstruction, and upper gastrointestinal. We used near-far matching with a preference-based instrumental variable to adjust for confounding and selection bias. Outcomes included Medicare payments for the index hospitalization and at 30, 90, and 180 days. RESULTS: Of 507,677 patients, 30.6% received an operation. For HPB conditions, costs for operative management were initially higher but became equivalent at 90 and 180 days. For all others, operative management was associated with higher inpatient costs, which persisted, though narrowed, over time. Out-of-pocket costs were nearly equivalent for operative and nonoperative management. CONCLUSIONS: Compared with nonoperative management, costs were higher or equivalent for operative management of EGS conditions through 180 days, which could impact decision-making for clinicians, patients, and health systems in situations where clinical outcomes are similar.

Belonging in Surgery: A Validated Instrument and Single Institutional Pilot.

OBJECTIVE: The aim of this study was to develop and validate an instrument to measure Belonging in Surgery among surgical residents. BACKGROUND: Belonging is the essential human need to maintain meaningful relationships and connections to one's community. Increased belongingness is associated with better well-being, job performance, and motivation to learn. However, no tools exist to measure belonging among surgical trainees. METHODS: A panel of experts adapted a belonging instrument for use among United States surgery residents. After administration of the 28-item instrument to residents at a single institution, a Cronbach alpha was calculated to measure internal consistency, and exploratory principal component analyses were performed. Multiple iterations of analyses with successively smaller item samples suggested the instrument could be shortened. The expert panel was reconvened to shorten the instrument. Descriptive statistics measured demographic factors associated with Belonging in Surgery. RESULTS: The overall response rate was 52% (114 responses). The Cronbach alpha among the 28 items was 0.94 (95% CI: 0.93-0.96). The exploratory principal component analyses and subsequent Promax rotation yielded 1 dominant component with an eigenvalue of 12.84 (70% of the variance). The expert panel narrowed the final instrument to 11 items with an overall Cronbach alpha of 0.90 (95% CI: 0.86, 0.92). Belonging in Surgery was significantly associated with race (Black and Asian residents scoring lower than White residents), graduating with one's original intern cohort (residents who graduated with their original class scoring higher than those that did not), and inversely correlated with resident stress level. CONCLUSIONS: An instrument to measure Belonging in Surgery was validated among surgical residents. With this instrument, Belonging in Surgery becomes a construct that may be used to investigate surgeon performance and well-being.

The Conditional Effects of Multimorbidity on Operative Versus Nonoperative Management of Emergency General Surgery Conditions: A Retrospective Observational Study Using an Instrumental Variable Analysis.

OBJECTIVE: To understand how multimorbidity impacts operative versus nonoperative management of emergency general surgery (EGS) conditions. BACKGROUND: EGS is a heterogenous field, encompassing operative and nonoperative treatment options. Decision-making is particularly complex for older patients with multimorbidity. METHODS: Using an instrumental variable approach with near-far matching, this national, retrospective observational cohort study of Medicare beneficiaries examines the conditional effects of multimorbidity, defined using qualifying comorbidity sets, on operative versus nonoperative management of EGS conditions. RESULTS: Of 507,667 patients with EGS conditions, 155,493 (30.6%) received an operation. Overall, 278,836 (54.9%) were multimorbid. After adjustment, multimorbidity significantly increased the risk of in-hospital mortality associated with operative management for general abdominal patients (+9.8%; P = 0.002) and upper gastrointestinal patients (+19.9%, P < 0.001) and the risk of 30-day mortality (+27.7%, P < 0.001) and nonroutine discharge (+21.8%, P = 0.007) associated with operative management for upper gastrointestinal patients. Regardless of multimorbidity status, operative management was associated with a higher risk of in-hospital mortality among colorectal patients (multimorbid: + 12%, P < 0.001; nonmultimorbid: +4%, P = 0.003), higher risk of nonroutine discharge among colorectal (multimorbid: +42.3%, P < 0.001; nonmultimorbid: +55.1%, P < 0.001) and intestinal obstruction patients (multimorbid: +14.6%, P = 0.001; nonmultimorbid: +14.8%, P = 0.001), and lower risk of nonroutine discharge (multimorbid: -11.5%, P < 0.001; nonmultimorbid: -11.9%, P < 0.001) and 30-day readmissions (multimorbid: -8.2%, P = 0.002; nonmultimorbid: -9.7%, P < 0.001) among hepatobiliary patients. CONCLUSIONS: The effects of multimorbidity on operative versus nonoperative management varied by EGS condition category. Physicians and patients should have honest conversations about the expected risks and benefits of treatment options, and future investigations should aim to understand the optimal management of multimorbid EGS patients.

Operative and Nonoperative Outcomes of Emergency General Surgery Conditions: An Observational Study Using a Novel Instrumental Variable.

OBJECTIVE: To determine the effect of operative versus nonoperative management of emergency general surgery conditions on short-term and long-term outcomes. BACKGROUND: Many emergency general surgery conditions can be managed either operatively or nonoperatively, but high-quality evidence to guide management decisions is scarce. METHODS: We included 507,677 Medicare patients treated for an emergency general surgery condition between July 1, 2015, and June 30, 2018. Operative management was compared with nonoperative management using a preference-based instrumental variable analysis and near-far matching to minimize selection bias and unmeasured confounding. Outcomes were mortality, complications, and readmissions. RESULTS: For hepatopancreaticobiliary conditions, operative management was associated with lower risk of mortality at 30 days [-2.6% (95% confidence interval: -4.0, -1.3)], 90 days [-4.7% (-6.50, -2.8)], and 180 days [-6.4% (-8.5, -4.2)]. Among 56,582 intestinal obstruction patients, operative management was associated with a higher risk of inpatient mortality [2.8% (0.7, 4.9)] but no significant difference thereafter. For upper gastrointestinal conditions, operative management was associated with a 9.7% higher risk of in-hospital mortality (6.4, 13.1), which increased over time. There was a 6.9% higher risk of inpatient mortality (3.6, 10.2) with operative management for colorectal conditions, which increased over time. For general abdominal conditions, operative management was associated with 12.2% increased risk of inpatient mortality (8.7, 15.8). This effect was attenuated at 30 days [8.5% (3.8, 13.2)] and nonsignificant thereafter. CONCLUSIONS: The effect of operative emergency general surgery management varied across conditions and over time. For colorectal and upper gastrointestinal conditions, outcomes are superior with nonoperative management, whereas surgery is favored for patients with hepatopancreaticobiliary conditions. For obstructions and general abdominal conditions, results were equivalent overall. These findings may support patients, clinicians, and families making these challenging decisions.

Impact of Medicaid expansion on outcomes after abdominal aortic aneurysm repair.

OBJECTIVE: Lack of insurance has been independently associated with an increased risk of in-hospital mortality after abdominal aortic aneurysm repair, possibly due to worse control of comorbidities and delays in diagnosis and treatment. Medicaid expansion has improved insurance rates and access to care, potentially benefiting these patients. We sought to assess the association between Medicaid expansion and outcomes after abdominal aortic aneurysm repair. METHODS: A retrospective analysis of Healthcare Cost and Utilization Project State Inpatient Databases data from 14 states between 2012 and 2018 was conducted. The sample was restricted to first-record abdominal aortic aneurysm repairs in adults under age 65 in states that expanded Medicaid on January 1, 2014 (Medicaid expansion group) or had not expanded before December 31, 2018 (non-expansion group). The Medicaid expansion and non-expansion groups were compared between pre-expansion (2012-2013) and post-expansion (2014-2018) time periods to assess baseline demographic and operative differences. We used difference-in-differences multivariable logistic regression adjusted for patient factors, open vs endovascular repair, and standard errors clustered by state. Our primary outcome was in-hospital mortality. Outcomes were stratified by insurance type. RESULTS: We examined 8995 patients undergoing abdominal aortic aneurysm repair, including 3789 (42.1%) in non-expansion states and 5206 (57.9%) in Medicaid expansion states. Rates of Medicaid insurance were unchanged in non-expansion states but increased in Medicaid expansion states post-expansion (non-expansion: 10.9% to 9.8%; P = .346; expansion: 9.7% to 19.7%; P < .001). One in 10 patients from both non-expansion and Medicaid expansion states presented with ruptured aneurysms, which did not change over time. Rates of open repair decreased in both non-expansion and Medicaid expansion states over time (non-expansion: 25.1% to 19.2%; P < .001; expansion: 25.2% to 18.4%; P < .001). On adjusted difference-in-differences analysis between expansion and non-expansion states pre-to post-expansion, Medicaid expansion was associated with a 1.02% absolute reduction in in-hospital mortality among all patients (95% confidence interval, -1.87% to -0.17%; P = .019). Additionally, among patients who were either on Medicaid or were uninsured (ie, the patients most likely to be impacted by Medicaid expansion), a larger 4.17% decrease in in-hospital mortality was observed (95% confidence interval, -6.47% to -1.87%; P < .001). In contrast, no significant difference-in-difference in mortality was observed for privately insured patients. CONCLUSIONS: Medicaid expansion was associated with decreased in-hospital mortality after abdominal aortic aneurysm repair among all patients and particularly among patients who were either on Medicaid or were uninsured. Our results provide support for improved access to care for patients undergoing abdominal aortic aneurysm repair through Medicaid expansion.

Conditional Effects of Race on Operative and Nonoperative Outcomes of Emergency General Surgery Conditions.

INTRODUCTION: Many emergency general surgery (EGS) conditions can be managed both operatively or nonoperatively; however, it is unknown whether the decision to operate affects Black and White patients differentially. METHODS: We identified a nationwide cohort of Black and White Medicare beneficiaries, hospitalized for common EGS conditions from July 2015 to June 2018. Using near-far matching to adjust for measurable confounding and an instrumental variable analysis to control for selection bias associated with treatment assignment, we compare outcomes of operative and nonoperative management in a stratified population of Black and White patients. Outcomes included in-hospital mortality, 30-day mortality, nonroutine discharge, and 30-day readmissions. An interaction test based on a t test was used to determine the conditional effects of operative versus nonoperative management between Black and White patients. RESULTS: A total of 556,087 patients met inclusion criteria, of which 59,519 (10.7%) were Black and 496,568 (89.3%) were White. Overall, 165,932 (29.8%) patients had an operation and 390,155 (70.2%) were managed nonoperatively. Significant outcome differences were seen between operative and nonoperative management for some conditions; however, no significant differences were seen for the conditional effect of race on outcomes. CONCLUSIONS: The decision to manage an EGS patient operatively versus nonoperatively has varying effects on surgical outcomes. These effects vary by EGS condition. There were no significant conditional effects of race on the outcomes of operative versus nonoperative management among universally insured older adults hospitalized with EGS conditions.

Emergency Surgery, Multimorbidity and Hospital-Free Days: A Retrospective Observational Study.

INTRODUCTION: Analyzing hospital-free days (HFDs) offers a patient-centered approach to health services research. We hypothesized that, within emergency general surgery (EGS), multimorbidity would be associated with fewer HFDs, whether patients were managed operatively or nonoperatively. METHODS: EGS patients were identified using national Medicare claims data (2015-2018). Patients were classified as multimorbid based on the presence of a Qualifying Comorbidity Set and stratified by treatment: operative (received surgery within 48 h of index admission) and nonoperative. HFDs were calculated through 180 d, beginning on the day of index admission, as days alive and spent outside of a hospital, an Emergency Department, or a long-term acute care facility. Univariate comparisons were performed using Kruskal-Wallis tests and risk-adjusted HFDs were compared between multimorbid and nonmultimorbid patients using multivariable zero-inflated negative binomial regression models. RESULTS: Among 174,891 operative patients, 45.5% were multimorbid. Among 398,756 nonoperative patients, 59.2% were multimorbid. Multimorbid patients had fewer median HFDs than nonmultimorbid patients among operative and nonoperative cohorts (P < 0.001). At 6 mo, among operative patients, multimorbid patients had 6.5 fewer HFDs (P < 0.001), and among nonoperative patients, multimorbid patients had 7.9 fewer HFDs (P < 0.001). When length of stay was included as a covariate, nonoperative multimorbid patients still had 7.9 fewer HFDs than nonoperative, nonmultimorbid patients (P < 0.001). CONCLUSIONS: HFDs offer a patient-centered, composite outcome for claims-based analyses. For EGS patients, multimorbidity was associated with less time alive and out of the hospital, especially when patients were managed nonoperatively.

A study analyzing outcomes after bariatric surgery by primary language.

BACKGROUND: Communication is key to success in bariatric surgery. This study aims to understand how outcomes after bariatric surgery differ between patients with a non-English primary language and those with English as their primary language. METHODS: This retrospective, observational cohort study of bariatric surgery patients age ≥ 18 years utilized the Michigan, Maryland, and New Jersey State Inpatient Databases and State Ambulatory Surgery and Services Databases, 2016 to 2018. Patients were classified by primary spoken language: English and non-English. Primary outcome was complications. Secondary outcomes included length of stay (LOS) and cost, with cost calculated using cost-to-charge ratios provided by Healthcare Cost and Utilization Project and reported in 2019 United States dollars. Multivariable regression models (logistic, Poisson, and quantile) were used to examine associations between primary language and outcomes. Given the uneven distribution of race by primary language, interaction terms were used to examine conditional effects of race. RESULTS: Among 69,749 bariatric surgery patients, 2811 (4.2%) spoke a non-English primary language. Covariates, notably race distribution, and unadjusted outcomes differed significantly by primary language. However, after adjustment, non-English primary language was not associated with significantly increased odds of complications (odds ratio 1.24, p = 0.389), significantly different LOS (- 0.02 days, p = 0.677), nor significantly different mean healthcare costs (- $265, p = 0.309). There were no significant conditional effects of race seen among outcomes. CONCLUSIONS: Though non-English primary language was associated with a significantly different distribution of observable characteristics (including race, income quartile, and insurance type), after adjustment, non-English primary language was not associated with significant differential risk of adverse outcomes after bariatric surgery, and there were no significant conditional effects of race. As such, this study suggests that disparities in bariatric surgery by primary spoken language more likely related to access to care, or the pre- and post-hospital care continuum, rather than index hospitalization after surgery.

Multimorbidity Confers Greater Risk for Older Patients in Emergency General Surgery Than the Presence of Multiple Comorbidities: A Retrospective Observational Study.

BACKGROUND: Little is known about the impact of multimorbidity on outcomes for older emergency general surgery patients. OBJECTIVE: The aim was to understand whether having multiple comorbidities confers the same amount of risk as specific combinations of comorbidities (multimorbidity) for a patient undergoing emergency general surgery. RESEARCH DESIGN: Retrospective observational study using state discharge data. SUBJECTS: Medicare beneficiaries who underwent an operation for an emergency general surgery condition in New York, Florida, or Pennsylvania (2012-2013). MEASURES: Patients were classified as multimorbid using Qualifying Comorbidity Sets (QCSs). Outcomes included in-hospital mortality, hospital length of stay and discharge status. RESULTS: Of 312,160 patients, a large minority (37.4%) were multimorbid. Non-QCS patients did not have a specific combination of comorbidities to satisfy a QCS, but 64.1% of these patients had 3+ comorbid conditions. Multimorbidity was associated with increased in-hospital mortality (10.5% vs. 3.9%, P <0.001), decreased rates of discharge to home (16.2% vs. 37.1%, P <0.001), and longer length of stay (10.4 d±13.5 vs. 6.7 d±9.3, P <0.001) when compared with non-QCS patients. Risks varied between individual QCSs. CONCLUSIONS: Multimorbidity, defined by satisfying a specific QCS, is strongly associated with poor outcomes for older patients requiring emergency general surgery in the United States. Variation in risk of in-hospital mortality, discharge status, and length of stay between individual QCSs suggests that multimorbidity does not carry the same prognostic weight as having multiple comorbidities-the specifics of which are important in setting expectations for individual, complex patients.

Is There Color or Sex Behind the Mask and Sterile Blue? Examining Sex and Racial Demographics Within Academic Surgery.

BACKGROUND: The lack of underrepresented minorities has been a persistent issue within the surgical workforce. Equal sex representation has also been a problem in surgery. Underrepresented minorities females face the unique challenge of being a minority in both race and sex. OBJECTIVE: The objective of this retrospective cross-sectional study is to determine the racial and sex demographics of medical trainees and faculty and determine the degree to which minority women are underrepresented at higher ranks and leadership. METHODS: Race and sex demographic data for all medical students, surgical residents and faculty was extracted from the AAMC data files. This data was compared to the US population using chi squared tests. Race and sex breakdowns of the different surgical subspecialties was also analyzed using chi squared tests. Demographics of surgical faculty at various ranks are also reported. RESULTS: White men made up 37% of all surgical residents. Black men made up only 1.9% of all surgical residents whereas Black women made up 2.6%. The subspecialty with the smallest percentage of Black women was Orthopedic Surgery with 0.6%. The specialty with the highest representation of Black women was Ob/Gyn with 6.2%. There was a decrease in representation of Black women with each increase in professional rank, with 2.8%, 1.6%, and 0.7% for assistant, associate, and full professor, respectively, as compared to Black men, who as a percentage, remained stable at the various ranks with 2.1%, 2.4%, and 2.1% for assistant, associate, and full professor, respectively. CONCLUSIONS: There is a striking lack of minority women in surgery. This trend is amplified as surgeons progress from student, to resident, to attending, and then to leadership positions.

The Cost of Quarantine: Projecting the Financial Impact of Canceled Elective Surgery on the Nation's Hospitals.

OBJECTIVE: We sought to quantify the financial impact of elective surgery cancellations in the US during COVID-19 and simulate hospitals' recovery times from a single period of surgery cessation. BACKGROUND: COVID-19 in the US resulted in cessation of elective surgery-a substantial driver of hospital revenue-and placed patients at risk and hospitals under financial stress. We sought to quantify the financial impact of elective surgery cancellations during the pandemic and simulate hospitals' recovery times. METHODS: Elective surgical cases were abstracted from the Nationwide Inpatient Sample (2016-2017). Time series were utilized to forecast March-May 2020 revenues and demand. Sensitivity analyses were conducted to calculate the time to clear backlog cases and match expected ongoing demand in the post-COVID period. Subset analyses were performed by hospital region and teaching status. RESULTS: National revenue loss due to major elective surgery cessation was estimated to be $22.3 billion (B). Recovery to market equilibrium was conserved across strata and influenced by pre- and post-COVID capacity utilization. Median recovery time was 12-22 months across all strata. Lower pre-COVID utilization was associated with fewer months to recovery. CONCLUSIONS: Strategies to mitigate the predicted revenue loss of $22.3B due to major elective surgery cessation will vary with hospital-specific supply-demand equilibrium. If patient demand is slow to return, hospitals should focus on marketing of services; if hospital capacity is constrained, efficient capacity expansion may be beneficial. Finally, rural and urban nonteaching hospitals may face increased financial risk which may exacerbate care disparities.

Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes.

BACKGROUND: Squamous cell cancers of the anal canal (ASCC) are increasing in frequency and lack effective therapies for advanced disease. Although an association with human papillomavirus (HPV) has been established, little is known about the molecular characterization of ASCC. A comprehensive genomic analysis of ASCC was undertaken to identify novel genomic alterations (GAs) that will inform therapeutic choices for patients with advanced disease. PATIENTS AND METHODS: Hybrid-capture-based next-generation sequencing of exons from 236 cancer-related genes and intronic regions from 19 genes commonly rearranged in cancer was performed on 70 patients with ASCC. HPV status was assessed by aligning tumor sequencing reads to HPV viral genomes. GAs were identified using an established algorithm and correlated with HPV status. RESULTS: Sixty-one samples (87%) were HPV-positive. A mean of 3.5 GAs per sample was identified. Recurrent alterations in phosphoinositol-3-kinase pathway (PI3K/AKT/mTOR) genes including amplifications and homozygous deletions were present in 63% of cases. Clinically relevant GAs in genes involved in DNA repair, chromatin remodeling, or receptor tyrosine kinase signaling were observed in 30% of cases. Loss-of-function mutations in TP53 and CDKN2A were significantly enhanced in HPV-negative cases (P < 0.0001). CONCLUSIONS: This is the first comprehensive genomic analysis of ASCC, and the results suggest new therapeutic approaches. Differing genomic profiles between HPV-associated and HPV-negative ASCC warrants further investigation and may require novel therapeutic and preventive strategies.

A Randomized Controlled Trial of POWER: An Internet-Based HIV Prevention Intervention for Black Bisexual Men.

POWER is a theory-based, on-line HIV prevention intervention developed specifically for Black men who have sex with men and women (BMSMW), an understudied group significantly impacted by HIV. To test its efficacy, we recruited 224 BMSMW using chain referral methods and randomly assigned 108 to POWER and 103 to a health information comparison condition. Three months after the intervention, participants assigned to POWER had lower odds of reporting any condomless vaginal or condomless anal intercourse (CVAI) compared to those in the comparison group (aOR = 0.49; 95 % CI 0.25-0.98; p = 0.044). The intervention was associated with significantly lower odds of condomless anal intercourse with male partners (aOR = 0.55; 95 % CI 0.34-0.91; p = 0.020) but not with female partners and serodiscordant sex with male partners but not with female partners. Future studies are needed to replicate these findings in larger and more diverse samples of BMSMW and to understand the underlying mechanisms through which intervention efficacy was achieved.

Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization.

OBJECTIVE: To investigate the in vivo role of the IRE1/XBP1 unfolded protein response (UPR) signaling pathway in cartilage. DESIGN: Xbp1(flox/flox).Col2a1-Cre mice (Xbp1(CartΔEx2)), in which XBP1 activity is ablated specifically from cartilage, were analyzed histomorphometrically by Alizarin red/Alcian blue skeletal preparations and X-rays to examine overall bone growth, histological stains to measure growth plate zone length, chondrocyte organization, and mineralization, and immunofluorescence for collagen II, collagen X, and IHH. Bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were used to measure chondrocyte proliferation and cell death, respectively. Chondrocyte cultures and microdissected growth plate zones were analyzed for expression profiling of chondrocyte proliferation or endoplasmic reticulum (ER) stress markers by Quantitative PCR (qPCR), and of Xbp1 mRNA splicing by RT-PCR to monitor IRE1 activation. RESULTS: Xbp1(CartΔEx2) displayed a chondrodysplasia involving dysregulated chondrocyte proliferation, growth plate hypertrophic zone shortening, and IRE1 hyperactivation in chondrocytes. Deposition of collagens II and X in the Xbp1(CartΔEx2) growth plate cartilage indicated that XBP1 is not required for matrix protein deposition or chondrocyte hypertrophy. Analyses of mid-gestation long bones revealed delayed ossification in Xbp1(CartΔEx2) embryos. The rate of chondrocyte cell death was not significantly altered, and only minimal alterations in the expression of key markers of chondrocyte proliferation were observed in the Xbp1(CartΔEx2) growth plate. IRE1 hyperactivation occurred in Xbp1(CartΔEx2) chondrocytes but was not sufficient to induce regulated IRE1-dependent decay (RIDD) or a classical UPR. CONCLUSION: Our work suggests roles for XBP1 in regulating chondrocyte proliferation and the timing of mineralization during endochondral ossification, findings which have implications for both skeletal development and disease.