Preoperative Anemia and Postoperative Outcomes in Cardiac Surgery: A Mediation Analysis Evaluating Intraoperative Transfusion Exposures.

BACKGROUND: Preoperative anemia is associated with adverse outcomes in cardiac surgery, yet it remains unclear what proportion of this association is mediated through red blood cell (RBC) transfusions. METHODS: This is a historical observational cohort study of adults undergoing coronary artery bypass grafting or valve surgery on cardiopulmonary bypass at an academic medical center between May 1, 2008, and May 1, 2018. A mediation analysis framework was used to evaluate the associations between preoperative anemia and postoperative outcomes, including a primary outcome of acute kidney injury (AKI). Intraoperative RBC transfusions were evaluated as mediators of preoperative anemia and outcome relationships. The estimated total effect, average direct effect of preoperative anemia, and percent of the total effect mediated through transfusions are presented with 95% confidence intervals and P -values. RESULTS: A total of 4117 patients were included, including 1234 (30%) with preoperative anemia. Overall, 437 of 4117 (11%) patients went on to develop AKI, with a greater proportion of patients having preoperative anemia (219 of 1234 [18%] vs 218 of 2883 [8%]). In multivariable analyses, the presence of preoperative anemia was associated with increased postoperative AKI (6.4% [4.2%-8.7%] absolute difference in percent with AKI, P < .001), with incremental decreases in preoperative hemoglobin concentrations displaying greater AKI risk (eg, 11.9% [6.9%-17.5%] absolute increase in probability of AKI for preoperative hemoglobin of 9 g/dL compared to a reference of 14 g/dL, P < .001). The association between preoperative anemia and postoperative AKI was primarily due to direct effects of preoperative anemia (5.9% [3.6%-8.3%] absolute difference, P < .001) rather than mediated through intraoperative RBC transfusions (7.5% [-4.3% to 21.1%] of the total effect mediated by transfusions, P = .220). Preoperative anemia was also associated with longer hospital durations (1.07 [1.05-1.10] ratio of geometric mean length of stay, P < .001). Of this total effect, 38% (22%, 62%; P < .001) was estimated to be mediated through subsequent intraoperative RBC transfusion. Preoperative anemia was not associated with reoperation or vascular complications. CONCLUSIONS: Preoperative anemia was associated with higher odds of AKI and longer hospitalizations in cardiac surgery. The attributable effects of anemia and transfusion on postoperative complications are likely to differ across outcomes. Future studies are necessary to further evaluate mechanisms of anemia-associated postoperative organ injury and treatment strategies.

Peer review of clinical and translational research manuscripts: Perspectives from statistical collaborators.

Research articles in the clinical and translational science literature commonly use quantitative data to inform evaluation of interventions, learn about the etiology of disease, or develop methods for diagnostic testing or risk prediction of future events. The peer review process must evaluate the methodology used therein, including use of quantitative statistical methods. In this manuscript, we provide guidance for peer reviewers tasked with assessing quantitative methodology, intended to complement guidelines and recommendations that exist for manuscript authors. We describe components of clinical and translational science research manuscripts that require assessment including study design and hypothesis evaluation, sampling and data acquisition, interventions (for studies that include an intervention), measurement of data, statistical analysis methods, presentation of the study results, and interpretation of the study results. For each component, we describe what reviewers should look for and assess; how reviewers should provide helpful comments for fixable errors or omissions; and how reviewers should communicate uncorrectable and irreparable errors. We then discuss the critical concepts of transparency and acceptance/revision guidelines when communicating with responsible journal editors.

Lung Injury Prediction Model in Bone Marrow Transplantation: A Multicenter Cohort Study.

Rationale: Pulmonary complications contribute significantly to nonrelapse mortality following hematopoietic stem cell transplantation (HCT). Identifying patients at high risk can help enroll such patients into clinical studies to better understand, prevent, and treat posttransplantation respiratory failure syndromes. Objectives: To develop and validate a prediction model to identify those at increased risk of acute respiratory failure after HCT. Methods: Patients underwent HCT between January 1, 2019, and December 31, 2021, at one of three institutions. Those treated in Rochester, MN, formed the derivation cohort, and those treated in Scottsdale, AZ, or Jacksonville, FL, formed the validation cohort. The primary outcome was the development of acute respiratory distress syndrome (ARDS), with secondary outcomes including the need for invasive mechanical ventilation (IMV) and/or noninvasive ventilation (NIV). Predictors were based on prior case-control studies. Measurements and Main Results: Of 2,450 patients undergoing stem cell transplantation, there were 1,718 hospitalizations (888 patients) in the training cohort and 1,005 hospitalizations (470 patients) in the test cohort. A 22-point model was developed, with 11 points from prehospital predictors and 11 points from posttransplantation or early (<24-h) in-hospital predictors. The model performed well in predicting ARDS (C-statistic, 0.905; 95% confidence interval [CI], 0.870-0.941) and the need for IMV and/or NIV (C-statistic, 0.863; 95% CI, 0.828-0.898). The test cohort differed markedly in demographic, medical, and hematologic characteristics. The model also performed well in this setting in predicting ARDS (C-statistic, 0.841; 95% CI, 0.782-0.900) and the need for IMV and/or NIV (C-statistic, 0.872; 95% CI, 0.831-0.914). Conclusions: A novel prediction model incorporating data elements from the pretransplantation, posttransplantation, and early in-hospital domains can reliably predict the development of post-HCT acute respiratory failure.

Long-Term Outcomes and Risk of Pancreatic Cancer in Intraductal Papillary Mucinous Neoplasms.

Importance: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can give rise to pancreatic cancer (PC). Limited population data exist on their prevalence, natural history, or risk of malignant transformation (IPMN-PC). Objective: To fill knowledge gaps in epidemiology of IPMNs and associated PC risk by estimating population prevalence of IPMNs, associated PC risk, and proportion of IPMN-PC. Design, Setting, and Participants: : This retrospective cohort study was conducted in Olmsted County, Minnesota. Using the Rochester Epidemiology Project (REP), patients aged 50 years and older with abdominal computed tomography (CT) scans between 2000 and 2015 were randomly selected (CT cohort). All patients from the REP with PC between 2000 and 2019 were also selected (PC cohort). Data were analyzed from November 2021 through August 2023. Main outcomes and Measures: CIs for PC incidence estimates were calculated using exact methods with the Poisson distribution. Cox models were used to estimate age, sex, and stage-adjusted hazard ratios for time-to-event end points. Results: The CT cohort included 2114 patients (1140 females [53.9%]; mean [SD] age, 68.6 [12.1] years). IPMNs were identified in 231 patients (10.9%; 95% CI, 9.7%-12.3%), most of which were branch duct (210 branch-duct [90.9%], 16 main-duct [6.9%], and 5 mixed [2.2%] IPMNs). There were 5 Fukuoka high-risk (F-HR) IPMNs (2.2%), 39 worrisome (F-W) IPMNs (16.9%), and 187 negative (F-N) IPMNs (81.0%). After a median (IQR) follow-up of 12.0 (8.1-15.3) years, 4 patients developed PC (2 patients in F-HR and 2 patients in F-N groups). The PC incidence rate per 100 person years for F-HR IPMNs was 34.06 incidents (95% CI, 4.12-123.02 incidents) and not significantly different for patients with F-N IPMNs compared with patients without IPMNs (0.16 patients; 95% CI, 0.02-0.57 patients vs 0.11 patients; 95% CI, 0.06-0.17 patients; P = .62). The PC cohort included 320 patients (155 females [48.4%]; mean [SD] age, 72.0 [12.3] years), and 9.8% (95% CI, 7.0%-13.7%) had IPMN-PC. Compared with 284 patients with non-IPMN PC, 31 patients with IPMN-PC were older (mean [SD] age, 76.9 [9.2] vs 71.3 [12.5] years; P = .02) and more likely to undergo surgical resection (14 patients [45.2%] vs 60 patients [21.1%]; P = .003) and more-frequently had nonmetastatic PC at diagnosis (20 patients [64.5%] vs 130 patients [46.8%]; P = .047). Patients with IPMN-PC had better survival (adjusted hazard ratio, 0.62; 95% CI, 0.40-0.94; P = .03) than patients with non-IPMN PC. Conclusions and Relevance: In this study, CTs identified IPMNs in approximately 10% of patients aged 50 years or older. PC risk in patients with F-N IPMNs was low and not different compared with patients without IPMNs; approximately 10% of patients with PC had IPMN-PC, and they had better survival compared with patients with non-IPMN PC.

Advanced Heart Failure Characteristics and Outcomes in Commercially Insured U.S. Adults.

BACKGROUND: The characteristics and outcomes of patients with advanced heart failure (HF) have been poorly defined due to challenges in applying the complex advanced HF definition broadly to populations. OBJECTIVES: In this study, the authors sought to apply a validated advanced HF algorithm to a large U.S. administrative claims database and describe the population and use of advanced HF therapies. METHODS: This study included adults with advanced HF identified in the OptumLabs Data Warehouse from 2009 to 2019. The algorithm for advanced HF required 2 hospitalizations for HF plus 1 additional sign of advanced HF in a 12-month period. The association of baseline characteristics with mortality was examined with the use of Cox proportional hazards models. Associations of patient characteristics with advanced therapies were estimated with the use of cause-specific Cox proportional hazard models. RESULTS: In 60,197 patients identified with advanced HF, the mean age was 73 years, 51.5% were men, and 64.3% were non-Hispanic White, 1.9% Asian, 21.2% Black, and 8.2% Hispanic. The median survival with advanced HF was 2.0 years (IQR: 0.4-5.5 years). Differences in mortality and use of advanced therapies by age, sex, and race/ethnicity were observed. Adjusted mortality was higher in patients who were older, male, non-Hispanic White, and from rural areas (P < 0.05 for all). Advanced therapies were used less in older patients and women (P < 0.05 for both). Black patients were more likely to be treated with a left ventricular assist device (P = 0.010) but less likely to receive a heart transplant compared with White patients (P = 0.034). CONCLUSIONS: In U.S. adults with advanced HF, variation in outcomes and use of advanced therapies exist by age, sex, and race/ethnicity.

Sex-specific associations between daytime sleepiness, chronic diseases and mortality in obstructive sleep apnea.

Objective: Excessive daytime sleepiness (EDS) is common in obstructive sleep apnea (OSA) and has been linked to adverse outcomes, albeit inconsistently. Furthermore, whether the prognostic impact of EDS differs as a function of sex is unclear. We aimed to assess the associations between EDS and chronic diseases and mortality in men and women with OSA. Methods: Newly-diagnosed adult OSA patients who underwent sleep evaluation at Mayo Clinic between November 2009 and April 2017 and completed the Epworth Sleepiness Scale (ESS) for assessment of perceived sleepiness (N = 14,823) were included. Multivariable-adjusted regression models were used to investigate the relationships between sleepiness, with ESS modeled as a binary (ESS > 10) and as a continuous variable, and chronic diseases and all-cause mortality. Results: In cross-sectional analysis, ESS > 10 was independently associated with lower risk of hypertension in male OSA patients (odds ratio [OR], 95% confidence interval [CI]: 0.76, 0.69-0.83) and with higher risk of diabetes mellitus in both OSA men (OR, 1.17, 95% CI 1.05-1.31) and women (OR 1.26, 95% CI 1.10-1.45). Sex-specific curvilinear relations between ESS score and depression and cancer were noted. After a median 6.2 (4.5-8.1) years of follow-up, the hazard ratio for all-cause death in OSA women with ESS > 10 compared to those with ESS ≤ 10 was 1.24 (95% CI 1.05-1.47), after adjusting for demographics, sleep characteristics and comorbidities at baseline. In men, sleepiness was not associated with mortality. Conclusion: The implications of EDS for morbidity and mortality risk in OSA are sex-dependent, with hypersomnolence being independently associated with greater vulnerability to premature death only in female patients. Efforts to mitigate mortality risk and restore daytime vigilance in women with OSA should be prioritized.

Changes in Kidney Function After Diagnosis of Advanced Heart Failure.

BACKGROUND: Kidney function and its association with outcomes in patients with advanced heart failure (HF) has not been well-defined. METHODS AND RESULTS: We conducted a retrospective cohort study comprising all adult residents of Olmsted County, Minnesota, with HF who developed advanced HF from 2007 to 2017. Patients were grouped by estimated glomerular filtration rate (eGFR) at advanced HF diagnosis using the 2021 Chronic Kidney Disease Epidemiology Collaboration equation. A linear mixed effects model was fitted to assess the relationship between development of advanced HF and longitudinal eGFR trajectory. A total of 936 patients with advanced HF (mean age 77 years, 55% male, 93.7% White) were included. Twenty-two percent of these patients had an eGFR of <30 at advanced HF diagnosis, 22% had an eGFR of 30-44, 23% had an eGFR of 45-59, and 32% had an eGFR of ≥60 mL/min/1.73 m2. The eGFR decreased faster after advanced HF (7.6% vs 10.9% annual decline before vs after advanced HF), with greater decreases after advanced HF in those with diabetes and preserved ejection fraction. An eGFR of <30 mL/min/1.73 m2 was associated with worse survival after advanced HF compared with an eGFR of ≥60 mL/min/1.73 m2 (adjusted hazard ratio 1.30, 95% confidence interval 1.07-1.57). CONCLUSIONS: eGFR deteriorated faster after patients developed advanced HF. An eGFR of <30 mL/min/1.73 m2 at advanced HF diagnosis was associated with higher mortality.

Coping Mechanisms for Financial Toxicity Among Patients With Metastatic Prostate Cancer: A Survey-based Assessment.

PURPOSE: Assessments of financial toxicity among patients with metastatic prostate cancer are lacking. Using patient surveys, we sought to identify coping mechanisms and assess characteristics associated with lower financial toxicity. MATERIALS AND METHODS: Surveys were administered to all patients seen at a single center's Advanced Prostate Cancer Clinic over a 3-month period. Surveys included the COST-FACIT (COmprehensive Score for Financial Toxicity) and coping mechanism questionnaires. Patients with metastatic disease (lymph nodes, bone, visceral) were included for analysis. Coping mechanisms were compared between patients experiencing low (COST-FACIT >24) vs high (COST-FACIT ≤24) financial toxicity using Fisher's exact test. Multivariable linear regression was used to evaluate characteristics associated with lower financial toxicity. RESULTS: Overall, 281 patients met inclusion criteria of which 79 reported high financial toxicity. In multivariable analysis, characteristics associated with lower financial toxicity included older age (estimate: 0.36, 95%CI: 0.21-0.52), applying for patient assistance programs (estimate: 4.42, 95%CI: 1.72-7.11), and an annual income of at least $100,000 (estimate: 7.81, 95%CI: 0.97, 14.66). Patients with high financial toxicity were more likely to decrease spending on basic goods (35% vs 2.5%, P < .001) and leisure activities (59% vs 15%, P > .001), as well as use savings (62% vs 17%, P < .001) to pay for their treatment. CONCLUSIONS: In this cross-sectional study, patients with metastatic prostate cancer and high financial toxicity were more likely to decrease spending on basic goods and leisure activities and use savings to pay for care. Understanding the impact of financial toxicity on patients' lives is crucial to inform shared decision-making and interventions designed to mitigate financial toxicity in this population.

Effect of an oxytocin protocol on secondary uterotonic use in patients undergoing Cesarean delivery.

PURPOSE: Protocol-driven oxytocin regimens can reduce oxytocin administration compared with a nonprotocol free-flow continuous infusion. Our aim was to compare secondary uterotonic use between a modified "rule of threes" oxytocin protocol and a free-flow continuous oxytocin infusion after Cesarean delivery. METHODS: We conducted a retrospective before-and-after study to compare patients who underwent Cesarean delivery between 1 January 2010 and 31 December 2013 (preprotocol) with patients who underwent Cesarean delivery between 1 January 2015 and 31 August 2017 (postprotocol). The preprotocol group received free-flow oxytocin administration and the postprotocol group received oxytocin according to a modified rule of threes algorithm. The primary outcome was secondary uterotonic use and the secondary outcomes included blood transfusion, hemoglobin value < 8 g·dL-1, and estimated blood loss. RESULTS: In total, 4,010 Cesarean deliveries were performed in 3,637 patients (2,262 preprotocol and 1,748 postprotocol). The odds of receiving secondary uterotonic drugs were increased in the postprotocol group (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.04 to 1.70; P = 0.02). Patients in the postprotocol group were less likely to receive a blood transfusion. Nevertheless, the two groups were similar for the composite end point of transfusion or hemoglobin < 8 g·dL-1 (OR, 0.86; 95% CI, 0.66 to 1.11; P = 0.25). The odds of an estimated blood loss greater than 1,000 mL were reduced in the postprotocol group (OR, 0.64; 95% CI, 0.50 to 0.84; P = 0.001). CONCLUSIONS: Patients in the modified rule of threes oxytocin protocol group were more likely to receive a secondary uterotonic than those in the preprotocol group. Estimated blood loss and transfusion outcomes were similar.

RéSUMé: OBJECTIF: Les schémas thérapeutiques d'ocytocine basés sur un protocole peuvent réduire l'administration d'ocytocine par rapport à une perfusion continue en débit libre hors protocole. Notre objectif était de comparer l'utilisation secondaires d'agents utérotoniques entre un protocole modifié d'ocytocine en « règle de trois ¼ et une perfusion continue d'ocytocine à débit libre après un accouchement par césarienne. MéTHODE: Nous avons mené une étude rétrospective avant-après pour comparer les personnes ayant bénéficié d'une césarienne entre le 1er janvier 2010 et le 31 décembre 2013 (pré-protocole) avec les personnes ayant subi une césarienne entre le 1er janvier 2015 et le 31 août 2017 (post-protocole). Le groupe pré-protocole a reçu une administration d'ocytocine en débit libre et le groupe post-protocole a reçu de l'ocytocine selon un algorithme de règle de trois modifié. Le critère d'évaluation principal était l'utilisation secondaire d'agents utérotoniques et les critères d'évaluation secondaires incluaient la transfusion sanguine, un indice d'hémoglobine < 8 g·dL­1 et les pertes de sang estimées. RéSULTATS: Au total, 4010 accouchements par césarienne ont été réalisés chez 3637 patient·es (2262 pré-protocole et 1748 post-protocole). Les chances de recevoir des médicaments utérotoniques secondaires étaient plus élevées dans le groupe post-protocole (rapport de cotes [RC], 1,33; intervalle de confiance [IC] à 95 %, 1,04 à 1,70; P = 0,02). Les patient·es du groupe post-protocole étaient moins susceptibles de recevoir une transfusion sanguine. Néanmoins, les deux groupes étaient similaires en ce qui touchait au critère d'évaluation composite de transfusion ou d'hémoglobine < 8 g·dL­1 (RC, 0,86; IC 95, 0,66 à 1,11; P = 0,25). Les risques d'une perte de sang estimée supérieure à 1000 mL ont été réduits dans le groupe post-protocole (RC, 0,64; IC 95 %, 0,50 à 0,84; P = 0,001). CONCLUSION: Les patient·es du groupe du protocole d'ocytocine en règle de trois modifiée étaient plus susceptibles de recevoir un utérotonique secondaire que les personnes du groupe pré-protocole. Les pertes sanguines estimées et les résultats transfusionnels étaient similaires.

Outpatient Antibiotic Use is Not Associated with an Increased Risk of First-Time Symptomatic Kidney Stones.

SIGNIFICANCE STATEMENT: Antibiotics modify human microbiomes and may contribute to kidney stone risk. In a population-based case-control study using 1247 chart-validated first-time symptomatic kidney stone formers and 4024 age- and sex-matched controls, the risk of kidney stones was transiently higher during the first year after antibiotic use. However, this risk was no longer evident after adjustment for comorbidities and excluding participants with prior urinary symptoms. Findings were consistent across antibiotic classes and the number of antibiotic courses received. This suggests that antibiotics are not important risk factors of kidney stones. Rather, kidney stones when they initially cause urinary symptoms are under-recognized, resulting in antibiotic use before a formal diagnosis of kidney stones ( i.e. , reverse causality). BACKGROUND: Antibiotics modify gastrointestinal and urinary microbiomes, which may contribute to kidney stone formation. This study examined whether an increased risk of a first-time symptomatic kidney stone episode follows antibiotic use. METHODS: A population-based case-control study surveyed 1247 chart-validated first-time symptomatic kidney stone formers with a documented obstructing or passed stone (cases) in Olmsted County, Minnesota, from 2008 to 2013 and 4024 age- and sex-matched controls. All prescriptions for outpatient oral antibiotic use within 5 years before the onset of symptomatic stone for the cases and their matched controls were identified. Conditional logistic regression estimated the odds ratio (OR) of a first-time symptomatic kidney stone across time after antibiotic use. Analyses were also performed after excluding cases and controls with prior urinary tract infection or hematuria because urinary symptoms resulting in antibiotic prescription could have been warranted because of undiagnosed kidney stones. RESULTS: The risk of a symptomatic kidney stone was only increased during the 1-year period after antibiotic use (unadjusted OR, 1.31; P = 0.001), and this risk was attenuated after adjustment for comorbidities (OR, 1.16; P = 0.08). After excluding cases and controls with prior urinary symptoms, there was no increased risk of a symptomatic kidney stone during the 1-year period after antibiotic use (unadjusted OR, 1.04; P = 0.70). Findings were consistent across antibiotic classes and the number of antibiotic courses received. CONCLUSIONS: The increased risk of a first-time symptomatic kidney stone with antibiotic use seems largely due to both comorbidities and prescription of antibiotics for urinary symptoms. Under-recognition of kidney stones that initially cause urinary symptoms resulting in antibiotic use may explain much of the perceived stone risk with antibiotics ( i.e. , reverse causality).

Characterization of Stone Events in Patients With Type 3 Primary Hyperoxaluria.

PURPOSE: Hallmarks of primary hyperoxaluria type 3 are nephrolithiasis and hyperoxaluria. However, little is known about factors influencing stone formation in this disease. We characterized stone events and examined associations with urine parameters and kidney function in a primary hyperoxaluria type 3 population. MATERIALS AND METHODS: We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry. RESULTS: Kidney stones occurred in 65/70 primary hyperoxaluria type 3 patients (93%). Among the 49 patients with imaging available, the median (IQR) number of stones was 4 (2, 5), with largest stone 7 mm (4, 10) at first imaging. Clinical stone events occurred in 62/70 (89%) with median number of events per patient 3 (2, 6; range 1-49). Age at first stone event was 3 years (0.99, 8.7). Lifetime stone event rate was 0.19 events/year (0.12, 0.38) during follow-up of 10.7 (4.2, 26.3) years. Among 326 total clinical stone events, 139 (42.6%) required surgical intervention. High stone event rates persisted for most patients through the sixth decade of life. Analysis was available for 55 stones: pure calcium oxalate accounted for 69%, with mixed calcium oxalate and phosphate in 22%. Higher calcium oxalate supersaturation was associated with increased lifetime stone event rate after adjusting for age at first event (IRR [95%CI] 1.23 [1.16, 1.32]; P < .001). By the fourth decade, estimated glomerular filtration rate was lower in primary hyperoxaluria type 3 patients than the general population. CONCLUSIONS: Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.

Comparative Effectiveness of Intravenous Ketamine and Intranasal Esketamine in Clinical Practice Among Patients With Treatment-Refractory Depression: An Observational Study.

Objective: Ketamine has been redeveloped as a rapid-acting antidepressant for treatment-resistant depression (TRD). There is a paucity of literature comparing subanesthetic intravenous (IV) ketamine and US Food and Drug Administration (FDA)-approved intranasal (IN) esketamine for TRD in real-world clinical settings. We compared the efficacy and time to achieve remission/response with repeated ketamine and esketamine.Methods: An observational study of adults with TRD received up to 6 IV ketamine (0.5 mg/kg over 40 minutes) or up to 8 IN esketamine (56- or 84-mg) treatments from August 17, 2017, to June 24, 2021. Depressive symptoms were measured utilizing the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) before and 24 hours after treatment. Cox proportional hazard models were used to evaluate associations between time to response ( ≥ 50% change in QIDS-SR score) and remission (QIDS-SR score ≤ 5).Results: Sixty-two adults (median age = 50 years, 65% female) received IV ketamine (76%, n = 47) or IN esketamine (24%, n = 15). Neither baseline-to-endpoint change in QIDS-SR score nor response/remission rates were significantly different between groups. Time to remission, defined as number of treatments (adjusting for age, body mass index [BMI], sex, and baseline QIDS-SR score), was faster for IV versus IN treatment (HR = 5.0, P = .02).Conclusions: Intravenous ketamine and intranasal esketamine showed similar rates of response and remission in TRD patients, but the number of treatments required to achieve remission was significantly lower with IV ketamine compared to IN esketamine. These findings need to be investigated in a randomized control trial comparing these two treatment interventions.

Application of multivariate joint modeling of longitudinal biomarkers and time-to-event data to a rare kidney stone cohort.

Background: Time-dependent Cox proportional hazards regression is a popular statistical method used in kidney disease research to evaluate associations between biomarkers collected serially over time with progression to kidney failure. Typically, biomarkers of interest are considered time-dependent covariates being updated at each new measurement using last observation carried forward (LOCF). Recently, joint modeling has emerged as a flexible alternative for multivariate longitudinal and time-to-event data. This study describes and demonstrates multivariate joint modeling using as an example the association of serial biomarkers (plasma oxalate [POX] and urinary oxalate [UOX]) and kidney function among patients with primary hyperoxaluria in the Rare Kidney Stone Consortium Registry. Methods: Time-to-kidney failure was regressed on serially measured biomarkers in two ways: time-dependent LOCF Cox proportional hazards regression and multivariate joint models. Results: In time-dependent LOCF Cox regression, higher POX was associated with increased risk of kidney failure (HR = 2.20 per doubling, 95% CI = [1.38-3.51], p < 0.001) whereas UOX was not (HR = 1.08 per doubling, [0.66-1.77], p = 0.77). In multivariate joint models, estimates suggest higher UOX may be associated with lower risk of kidney failure (HR = 0.42 per doubling [0.15-1.04], p = 0.066), though not statistically significant, since impaired urinary excretion of oxalate may reflect worsening kidney function. Conclusions: Multivariate joint modeling is more flexible than LOCF and may better reflect biological plausibility since biomarkers are not steady-state values between measurements. While LOCF is preferred to naïve methods not accounting for changes in biomarkers over time, results may not accurately reflect flexible relationships that can be captured with multivariate joint modeling.

The 5 Phenotypes of Tricuspid Regurgitation: Insight From Cluster Analysis of Clinical and Echocardiographic Variables.

BACKGROUND: The recent morphologic classification of tricuspid regurgitation (TR) (ie, atrial functional, ventricular functional, lead related, and primary) does not capture underlying comorbidities and clinical characteristics. OBJECTIVES: This study aimed to identify the different phenotypes of TR using unsupervised cluster analysis and to determine whether differences in clinical outcomes were associated with these phenotypes. METHODS: We included 13,611 patients with ≥moderate TR from January 2004 to April 2019 in the final analyses. Baseline demographic, clinical, and echocardiographic data were obtained from electronic medical records and echocardiography reports. Ward's minimum variance method was used to cluster patients based on 38 variables. The analysis of all-cause mortality was performed using the Kaplan-Meier method, and groups were compared using log-rank test. RESULTS: The mean age of patients was 72 ± 13 years, and 56% were women. Cluster analysis identified 5 distinct phenotypes: cluster 1 represented "low-risk TR" with less severe TR, a lower prevalence of right ventricular enlargement, atrial fibrillation, and comorbidities; cluster 2 represented "high-risk TR"; and clusters 3, 4, and 5 represented TR associated with lung disease, coronary artery disease, and chronic kidney disease, respectively. Cluster 1 had the lowest mortality followed by clusters 2 (HR: 2.22 [95% CI: 2.1-2.35]; P < 0.0001) and 4 (HR: 2.19 [95% CI: 2.04-2.35]; P < 0.0001); cluster 3 (HR: 2.45 [95% CI: 2.27-2.65]; P < 0.0001); and, lastly, cluster 5 (HR: 3.48 [95% CI: 3.07-3.95]; P < 0.0001). CONCLUSIONS: Cluster analysis identified 5 distinct novel subgroups of TR with differences in all-cause mortality. This phenotype-based classification improves our understanding of the interaction of comorbidities with this complex valve lesion and can inform clinical decision making.

Effect of Preoperative Multiparametric Magnetic Resonance Imaging on Oncologic and Functional Outcomes Following Radical Prostatectomy.

Background: Advancements in imaging technology have been associated with changes to operative planning in treatment of localized prostate cancer. The impact of these changes on postoperative outcomes is understudied. Objective: To compare oncologic and functional outcomes between men who had computed tomography (CT) and those who had multiparametric magnetic resonance imaging (mpMRI) prior to undergoing radical prostatectomy. Design setting and participants: In this retrospective cohort study, we identified all men who underwent radical prostatectomy (n = 1259) for localized prostate cancer at our institution between 2009 and 2016. Of these, 917 underwent preoperative CT and 342 mpMRI. Outcome measurements and statistical analysis: Biochemical recurrence-free survival, positive margin status, postoperative complications, and 1-yr postprostatectomy functional scores (using the 26-item Expanded Prostate Cancer Index Composite [EPIC-26] questionnaire) were compared between those who underwent preoperative CT and those who underwent mpMRI using propensity score weighted Cox proportional hazard regression, logistic regression, and linear regression models. Results and limitations: Baseline and 1-yr follow-up EPIC-26 data were available for 449 (36%) and 685 (54%) patients, respectively. After propensity score weighting, no differences in EPIC-26 functional domains were observed between the imaging groups at 1-yr follow-up. Positive surgical margin rates (odds ratio 1.03, 95% confidence interval [CI] 0.77-1.38, p = 0.8) and biochemical recurrence-free survival (hazard ratio 1.21, 95% CI 0.84-1.74, p = 0.3) were not significantly different between groups. Early and late postoperative complications occurred in 219 and 113 cases, respectively, and were not different between imaging groups. Our study is limited by a potential selection bias from the lack of functional scores for some patients. Conclusions: In this single-center study of men with localized prostate cancer undergoing radical prostatectomy, preoperative mpMRI had minimal impact on functional outcomes and oncologic control compared with conventional imaging. These findings challenge the assumptions that preoperative mpMRI improves operative planning and perioperative outcomes. Patient summary: In this study, we assessed whether the type of prostate imaging performed prior to surgery for localized prostate cancer impacted outcomes. We found that urinary and sexual function, cancer control, and postoperative complications were similar regardless of whether magnetic resonance imaging or computed tomography was utilized prior to surgery.

Aloud real- time reading of intensive care unit diaries: A feasibility study.

OBJECTIVES: Memories of frightening/delusional intensive care unit experiences are a major risk factor for subsequent psychiatric morbidity of critical illness survivors; factual memories are protective. Systematically providing factual information during initial memory consolidation could mitigate the emotional character of the formed memories. We explored feasibility and obtained stakeholder feedback of a novel approach to intensive care unit diaries whereby entries were read aloud to the patients right after they were written to facilitate systematic real time orientation and formation of factual memories. RESEARCH METHODOLOGY: Prospective interventional pilot study involving reading diary entries aloud. We have also interviewed involved stakeholders for feedback and collected exploratory data on psychiatric symptoms from patients right after the intensive care stay. SETTING: Various intensive care units in a single academic center. MAIN OUTCOME MEASURES: Feasibility was defined as intervention delivery on ≥80% of days following patient recruitment. Content analysis was performed on stakeholder interview responses. Questionnaire data were compared for patients who received real-time reading to the historical cohort who did not. RESULTS: Overall, 57% (17 of 30) of patients achieved the set feasibility threshold. Following protocol adjustment, we achieved 86% feasibility in the last subset of patients. Patients reported the intervention as comforting and appreciated the reorientation aspect. Nurses overwhelmingly liked the idea; most common concern was not knowing what to write. Some therapists were unsure whether reading entries aloud might overwhelm the patients. There were no significant differences in psychiatric symptoms when compared to the historic cohort. CONCLUSION: We encountered several implementation obstacles; once these were addressed, we achieved set feasibility target for the last group of patients. Reading diary entries aloud was welcomed by stakeholders. Designing a trial to assess efficacy of the intervention on psychiatric outcomes appears warranted. IMPLICATIONS FOR CLINICAL PRACTICE: There is no recommendation to change current practice as benefits of the intervention are unproven.

Association of Indication for Hospitalization With Subsequent Amyloid Positron Emission Tomography and Magnetic Resonance Imaging Biomarkers.

BACKGROUND: Hospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and brain neurodegeneration. METHODS: Included were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression. RESULTS: Of 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change -0.003 mm [95% confidence interval (CI) -0.005 to -0.001], p = .002), but not amyloid accumulation (0.003 [95% CI -0.001 to 0.006], p = .107), or WMH increase (0.011 cm3 [95% CI -0.001 to 0.023], p = .062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (-0.004 mm [95% CI -0.008 to -0.001, p = .014); amyloid accumulation (0.010, [95% CI 0.002 to 0.017, p = .011), and WMH increase (0.035 cm3 [95% CI 0.012 to 0.058, p = .006). Hospitalization was not associated with developing abnormal cortical thinning (p = .407), amyloid accumulation (p = .596), or WMH/infarctions score (p = .565). CONCLUSIONS: Medical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold.

Hemodynamic course during ablation and selective hepatic artery embolization for metastatic liver carcinoid: a retrospective observational study.

BACKGROUND: Manipulation of carcinoid tumors during ablation or selective hepatic artery embolization (transarterial embolization, TAE) can release vasoactive mediators inducing hemodynamic instability. The main aim of our study was to review hemodynamics and complications related to minimally invasive treatments of liver carcinoids with TAE or ablation. METHODS: Electronic medical records of all patients with metastatic liver carcinoid undergoing ablation or TAE from 2003 to 2019 were abstracted. Noted were severe hypotension (mean arterial pressure [MAP] ..± 55.ßmmHg), severe hypertension (systolic blood pressure ... 180.ßmmHg), and perioperative complications. Associations of procedure type and pre-procedure octreotide use with intraprocedural hemodynamics were assessed using linear regression. A robust covariance approach using generalized estimating equation method was used to account for multiple observations. RESULTS: A total of 161 patients underwent 98 ablations and 207 TAEs. Severe hypertension was observed in 24 (24.5%) vs. 15 (7.3%), severe hypotension in 56 (57.1%) vs. 6 (2.9%), and cutaneous flushing observed in 2 (2.0%) vs. 48 (23.2%) ablations and TAEs, respectively. After adjusting for preprocedural MAP, ablation was associated with lower intraprocedural MAP compared to TAE (estimate -27.ßmmHg, 95%CI -30 to -24.ßmmHg, p.ß<.ß0.001). Intraprocedural declines in MAP were not affected by preprocedural use of octreotide (p.ß=.ß0.7 for TAE and p.ß=.ß0.4 for ablation). CONCLUSIONS: Ablation of liver carcinoids was associated with substantial hemodynamic instability, especially hypotension. In contrast, a higher number of TAE patients had cutaneous flushing. Preprocedural use of octreotide was not associated with attenuation of intraprocedural hypotension.

Hemodynamic course during ablation and selective hepatic artery embolization for metastatic liver carcinoid: a retrospective observational study

Abstract Background: Manipulation of carcinoid tumors during ablation or selective hepatic artery embolization (transarterial embolization, TAE) can release vasoactive mediators inducing hemodynamic instability. The main aim of our study was to review hemodynamics and complications related to minimally invasive treatments of liver carcinoids with TAE or ablation. Methods: Electronic medical records of all patients with metastatic liver carcinoid undergoing ablation or TAE from 2003 to 2019 were abstracted. Noted were severe hypotension (mean arterial pressure [MAP] ≤ 55 mmHg), severe hypertension (systolic blood pressure ≥ 180 mmHg), and perioperative complications. Associations of procedure type and pre-procedure octreotide use with intraprocedural hemodynamics were assessed using linear regression. A robust covariance approach using generalized estimating equation method was used to account for multiple observations. Results: A total of 161 patients underwent 98 ablations and 207 TAEs. Severe hypertension was observed in 24 (24.5%) vs. 15 (7.3%), severe hypotension in 56 (57.1%) vs. 6 (2.9%), and cutaneous flushing observed in 2 (2.0%) vs. 48 (23.2%) ablations and TAEs, respectively. After adjusting for preprocedural MAP, ablation was associated with lower intraprocedural MAP compared to TAE (estimate −27 mmHg, 95%CI −30 to −24 mmHg, p < 0.001). Intraprocedural declines in MAP were not affected by preprocedural use of octreotide (p = 0.7 for TAE and p = 0.4 for ablation). Conclusions: Ablation of liver carcinoids was associated with substantial hemodynamic instability, especially hypotension. In contrast, a higher number of TAE patients had cutaneous flushing. Preprocedural use of octreotide was not associated with attenuation of intraprocedural hypotension.