ABSTRACT
BACKGROUND: Acute type A aortic dissection (ATAD) can cause visceral malperfusion. Central aortic repair may resolve malperfusion, but some require further intervention. This study aimed to review outcomes after ATAD presenting with visceral malperfusion and to evaluate the predictive value of true lumen (TL) morphologies in preoperative computed tomography scan for persistent superior mesenteric artery (SMA) ischemia after central repair. METHODS: Open surgical repair of ATAD performed between 2008 and 2023 at our institution was reviewed retrospectively. Patients with central repair first approach were included for analysis. Patients with inadequate computed tomography scan data to assess luminal morphology were excluded. TL morphology was reviewed at the diaphragm level and categorized as concave or convex. The malperfusion pattern, static vs dynamic, was assessed at SMA orifices. Data were analyzed using a contingency table and parametric and nonparametric methods. RESULTS: A total of 543 open ATAD repairs were performed. Of these, 263 patients were eligible under the inclusion criteria and, subsequently, analyzed. The mean age was 57±14, and 83 (31%) patients were female. SMA malperfusion developed in 42 (16%) of the 263 patients, including 26 patients with dynamic obstruction, 6 patients with static obstruction, and 10 patients with dynamic and static obstruction. Regarding dissection flap morphology, 78 patients (30%) exhibited concave morphology, while 185 patients (70%) had convex morphology. TL diameter was significantly larger in convex than concave (concave: 6 mm vs convex: 16 mm; P < .0001). The prevalence of clinically significant SMA malperfusion was higher in concave-shaped TL (concave 41% vs convex 5%; P < .0001). Dynamic SMA obstruction was more frequently observed in the concave group (concave 72% vs convex 30%; P < .001). However, significantly more patients with convex-shaped TL required bowel resection than concave (concave 13% vs convex 70%; P < .001). The operative mortality was higher in the convex group, although statistically insignificant (concave 19% vs convex 50%; P = .0059). CONCLUSIONS: Central repair first strategy could resolve more than 80% of SMA malperfusion in ATAD when the TL is concave-shaped at the level of the diaphragm. Convex-shaped TL morphology was associated with less incidence of SMA malperfusion but was more frequently associated with static obstruction and higher incidence of bowel resection. The morphology evaluation of the TL at the diaphragm level may be simple and beneficial for surgical planning for ATAD presenting with SMA malperfusion.
ABSTRACT
BACKGROUND: The objective of our present effort was to use an international blunt thoracic aortic injury (BTAI) registry to create a prediction model identifying important preoperative and intraoperative factors associated with postoperative mortality, and to develop and validate a simple risk prediction tool that could assist with patient selection and risk stratification in this patient population. METHODS: For the purpose of the present study, all patients undergoing thoracic endovascular aortic repair (TEVAR) for BTAI and registered in the Aortic Trauma Foundation (ATF) database from January 2016 as of June 2022 were identified. Patients undergoing medical management or open repair were excluded. The primary outcome was binary in-hospital all-cause mortality. Two predictive models were generated: a preoperative model (i.e. only including variables before TEVAR or intention-to-treat) and a full model (i.e. also including variables after TEVAR or per-protocol). RESULTS: Out of a total of 944 cases included in the ATF registry until June 2022, 448 underwent TEVAR and were included in the study population. TEVAR for BTAI was associated with an 8.5% in-hospital all-cause mortality in the ATF dataset. These study subjects were subsequently divided using 3:1 random sampling in a derivation cohort (336; 75.0%) and a validation cohort (112; 25.0%). The median age was 38 years, and the majority of patients were male (350; 78%). A total of 38 variables were included in the final analysis. Of these, 17 variables were considered in the preoperative model, 9 variables were integrated in the full model, and 12 variables were excluded owing to either extremely low variance or strong correlation with other variables. The calibration graphs showed how both models from the ATF dataset tended to underestimate risk, mainly in intermediate-risk cases. The discriminative capacity was moderate in all models; the best performing model was the full model from the ATF dataset, as evident from both the Receiver Operating Characteristic curve (Area Under the Curve 0.84; 95% CI 0.74-0.91) and from the density graph. CONCLUSIONS: In this study, we developed and validated a contemporary risk prediction model, which incorporates several preoperative and postoperative variables and is strongly predictive of early mortality. While this model can reasonably predict in-hospital all-cause mortality, thereby assisting physicians with risk-stratification as well as inform patients and their caregivers, its intrinsic limitations must be taken into account and it should only be considered an adjunctive tool that may complement clinical judgment and shared decision-making.
Subject(s)
Aortic Diseases , Endovascular Procedures , Thoracic Injuries , Vascular System Injuries , Wounds, Nonpenetrating , Humans , Male , Female , Adult , Endovascular Aneurysm Repair , Aorta, Thoracic/diagnostic imaging , Aorta, Thoracic/surgery , Aorta, Thoracic/injuries , Hospital Mortality , Risk Factors , Treatment Outcome , Time Factors , Aortic Diseases/surgery , Wounds, Nonpenetrating/diagnostic imaging , Wounds, Nonpenetrating/surgery , Thoracic Injuries/surgery , Vascular System Injuries/diagnostic imaging , Vascular System Injuries/surgery , Retrospective StudiesABSTRACT
OBJECTIVE: To determine if risk-adjusted survival of patients with CDH has improved over the last 25 years within centers that are long-term, consistent participants in the CDH Study Group (CDHSG). SUMMARY BACKGROUND DATA: The CDHSG is a multicenter collaboration focused on evaluation of infants with CDH. Despite advances in pediatric surgical and intensive care, CDH mortality has appeared to plateau. Herein, we studied CDH mortality rates amongst long-term contributors to the CDHSG. METHODS: We divided registry data into 5-year intervals, with Era 1 (E1) beginning in 1995, and analyzed multiple variables (operative strategy, defect size, and mortality) to assess evolution of disease characteristics and severity over time. For mortality analyses, patients were risk stratified using a validated prediction score based on 5-minute Apgar (Apgar5) and birth weight. A risk-adjusted, observed to expected (O:E) mortality model was created using E1 as a reference. RESULTS: 5203 patients from 23 centers with >22years of participation were included. Birth weight, Apgar5, diaphragmatic agenesis, and repair rate were unchanged over time (all P > 0.05). In E5 compared to E1, minimally invasive and patch repair were more prevalent, and timing of diaphragmatic repair was later (all P < 0.01). Overall mortality decreased over time: E1 (30.7%), E2 (30.3%), E3 (28.7%), E4 (26.0%), E5 (25.8%) ( P = 0.03). Risk-adjusted mortality showed a significant improvement in E5 compared to E1 (OR 0.78, 95% CI 0.62-0.98; P = 0.03). O:E mortality improved over time, with the greatest improvement in E5. CONCLUSIONS: Risk-adjusted and observed-to-expected CDH mortality have improved over time.
Subject(s)
Hernias, Diaphragmatic, Congenital , Infant , Child , Humans , Hernias, Diaphragmatic, Congenital/surgery , Birth Weight , RegistriesABSTRACT
PURPOSE: To analyze differences in baseline characteristics, overall mortality, device-related mortality, and re-intervention rates in patients who underwent thoracic endovascular aortic repair (TEVAR) for descending thoracic aortic aneurysm (DTAA) with atherosclerotic/degenerative cause or acute aortic syndrome (AAS), using the Global Registry For Endovascular Aortic Treatment (GREAT). MATERIALS AND METHODS: Patients submitted to TEVAR for AAS or DTAA, included in GREAT, were eligible for this analysis. Primary outcome was 30-day all-cause mortality rate. Secondary outcomes were 30-day aorta-related mortality and re-intervention rate, 1-year and 3-year all-cause mortality, aorta-related mortality and re-intervention rate. RESULTS: Five-hundred and seventy-five patients were analyzed (305 DTAA and 270 AAS). Thirty-day mortality rate was 1.3% and 1.8% for DTAA and AAS, respectively (p=0.741). One-year and 3-year mortality rates were 6.2% versus 9.3 and 17.3% versus 15.9% for DTAA and AAS, respectively (p=0.209 and p=0.655, respectively). Aorta-related mortality rates at 30 days, 1 year and 3 years were 1.3%, 1.3%, and 2.6% for DTAA, 1.8%, 4.2%, and 4.2% for AAS (p=ns). Re-intervention rates at 30 days, 1 year, and 3 years were 1.3%, 4.3%, and 7.5% for DTAA, 3.3%, 8.1%, and 10.7% for AAS (p=ns). Furthermore, a specific analysis with similar outcomes was performed dividing follow-up in 3 periods (1-30 days, 31-365 days, 366-1096 days) and describing mutual differences between 2 groups and temporal trends in each group. CONCLUSION: Patients who underwent TEVAR for DTAA or AAS experienced different mortality and re-intervention rates among years during mid-term follow-up. Although all-cause related deaths within 30 days were TEVAR-related, aorta-related deaths were more common for AAS patients within 1 year. A greater re-intervention rate was described for AAS patients, although only 1 year after TEVAR.
Subject(s)
Aneurysm , Aortic Aneurysm, Thoracic , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Aneurysm/etiology , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/etiology , Aortic Aneurysm, Thoracic/surgery , Blood Vessel Prosthesis Implantation/adverse effects , Endovascular Procedures/adverse effects , Humans , Registries , Retrospective Studies , Risk Factors , Syndrome , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVE: In the present study, we defined the outcomes and effects of pregnancy in a cohort of women of childbearing age with acute aortic dissection (AAD). METHODS: We reviewed our database of AAD to identify all eligible female patients. Women aged <45 years were included. Data on pregnancy timing with respect to the occurrence of dissection, the demographic data, dissection extent, dissection treatment, dissection-related outcomes, overall maternal and fetal mortality, and genetic testing results were analyzed. RESULTS: A total of 62 women aged <45 years had presented to us with AAD from 1999 to 2017. Of the 62 women, 37 (60%) had had a history of pregnancy at AAD. Of these 37 patients, 10 (27%) had had a peripartum aortic dissection, defined as dissection during pregnancy or within 12 months postpartum. Of the 10 AADs, 5 were type A and 5 were type B. Three patients had presented with AAD during pregnancy (one in the second and two in the third trimester). Five patients (50%) had developed AAD in the immediate postpartum period (within 3 months) and two (20%) in the late postpartum period. For the immediate postpartum AADs (<3 months), four of the five patients delivered via cesarean section. Of these 10 peripartum AADs, 3 (30%) had occurred in patients with known Marfan syndrome. In-hospital mortality for those with peripartum AAD was 10% (1 of 10). Fetal mortality was 20% (2 of 10). CONCLUSIONS: The frequency of aortic dissection in women of childbearing age at our institution was low. However, pregnancy might increase the risk of those young women genetically predisposed to dissection events. From these data, this risk appears to be greatest in the immediate postpartum period, even for those who undergo cesarean section. Close clinical and radiographic surveillance is required for all women with suspected aortopathy, especially in the third trimester and early postpartum period.
Subject(s)
Aortic Aneurysm/epidemiology , Aortic Dissection/epidemiology , Hospitalization , Maternal Age , Pregnancy Complications, Cardiovascular/epidemiology , Reproductive Health , Adult , Aortic Dissection/diagnostic imaging , Aortic Dissection/mortality , Aortic Dissection/therapy , Aortic Aneurysm/diagnostic imaging , Aortic Aneurysm/mortality , Aortic Aneurysm/therapy , Databases, Factual , Female , Hospital Mortality , Humans , Maternal Mortality , Middle Aged , Pregnancy , Pregnancy Complications, Cardiovascular/diagnostic imaging , Pregnancy Complications, Cardiovascular/mortality , Pregnancy Complications, Cardiovascular/therapy , Prognosis , Retrospective Studies , Risk Assessment , Risk Factors , Texas/epidemiology , Time FactorsABSTRACT
BACKGROUND: Thoracic outlet syndrome (TOS) results from compression of the neurovascular structures in the thoracic outlet. Decompression provides relief of TOS symptoms. However, little is known about long-term function and quality of life (QoL) from a patient's perspective. The purpose of this study was to evaluate surgical and QoL outcomes after surgical decompression of the thoracic outlet using a paraclavicular approach. METHODS: A prospectively maintained database was used to conduct a retrospective review of patients who underwent thoracic outlet decompression between August 2004 and August 2018. We excluded patients without complete follow-up data. Functional outcomes were assessed by the Derkash classification (poor, fair, good, excellent) using contingency table methods, and QoL was assessed by the 12-Item Short Form Health Survey (SF-12) using general linear models. SF-12 was scored by published criteria, and scale-specific and aggregate mental and physical health-related QoL scores were computed. Aggregate QoL scores range from 0 (terrible) to 100 (perfect). Secondary outcomes included mortality, complications, and duration of hospital stay. RESULTS: We performed 105 operations for TOS, and 100 patients with complete follow-up data were included in the study. Five patients were lost to follow-up. Median age was 35 (interquartile range, 24-47) years, and 58 (58%) were female. The median duration of hospital stay was 4 (interquartile range, 3-5.5) days. Of these patients, 46 had venous etiology, 8 arterial, 42 neurogenic, and 4 mixed vascular and neurogenic. Good or excellent Derkash results were reported in 77 (77%) patients, 46 of 54 (85%) of those with vascular TOS vs 31 of 46 (67%) of those with neurogenic etiology (P < .036). SF-12 score was obtained in 93 of 100 (93%) with a median duration from surgery of 6.1 (3.3-9.3) years. Patients with neurogenic TOS (NTOS) reported significantly lower aggregate mental health QoL than patients with vascular-only TOS (57 vs 59; P < .016). This effect persisted across the entire duration of follow-up and was unaffected by time from surgery (regression P for time = .509). In contrast, aggregate physical function QoL was unaffected by neurogenic etiology (P = .303), and all patients improved linearly with time (0.5 scale unit/y; P < .009). Three patients with incomplete relief of symptoms after paraclavicular decompression for NTOS underwent pectoralis minor decompression. There were no deaths or injuries to the long thoracic nerve. Complications included pleural effusion or hemothorax requiring evacuation (n = 6), neurapraxia (n = 6), and lymph leak (n = 2) treated with tube thoracostomy. CONCLUSIONS: NTOS is associated with significantly worse functional outcome assessed by the Derkash classification. NTOS also demonstrated worse composite mental health QoL, which did not improve over time. In contrast, composite physical health QoL improved linearly with time from surgery regardless of etiology of TOS.
Subject(s)
Decompression, Surgical/methods , Mental Health/statistics & numerical data , Postoperative Complications/epidemiology , Quality of Life , Thoracic Outlet Syndrome/surgery , Adult , Decompression, Surgical/adverse effects , Female , Follow-Up Studies , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Postoperative Complications/etiology , Prospective Studies , Retrospective Studies , Surveys and Questionnaires/statistics & numerical data , Thoracic Outlet Syndrome/etiology , Thoracic Outlet Syndrome/mortality , Thoracic Outlet Syndrome/psychology , Time Factors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Suitability for transcatheter aortic valve (AV) implantation (TAVI) is determined by using transthoracic echocardiography (TTE), although left-sided cardiac catheterization (LCC) provides directly measured pressure data. TAVI in awake patients permits simultaneous comparison of TTE and LCC under physiologically relevant left ventricular loading conditions. We hypothesized that clinically important discrepancies between TTE and LCC would be identified. METHODS AND RESULTS: TAVI was performed in 108 awake patients undergoing intra-procedural TTE and LCC between January 1, 2016 and December 31, 2016, based upon pre-procedure TTE data. Intra-procedural assessments simultaneously were performed before and after prosthesis implantation. Based upon mean trans-AV systolic ejection pressure gradient (MSEPG), AS was graded as: mild (<20 mm Hg; grade 1), moderate (20 - <40 mm Hg; grade 2), or severe (≥40 mm Hg; grade 3). In 79 of the 108 (73.1%) patients, intra-procedural TTE and LCC assessments were concordant. In 2 of the 108 (1.9%) patients, TTE overestimated AS severity by ≥1 grade. In 27 of the 108 (25.0%) patients, TTE underestimated AS severity by ≥1 grade. In total, AS severity reclassification occurred in 29 (26.9%) patients. Overall, TTE underestimated MSEPG by 8.9 ± 1.2 mm Hg (TTE MSEPG versus LCC MSEPG; P < .001). CONCLUSION: Current TTE criteria appear to frequently and importantly underestimate AS severity. Because decision-making regarding TAVI often exclusively is based upon TTE data, these findings suggest either a continued role for LCC in the diagnostic assessment of AS in patients who do not meet standard TTE criteria or lowering TTE cutoffs for TAVI.
Subject(s)
Aortic Valve Stenosis/surgery , Aortic Valve/surgery , Cardiac Catheterization/methods , Echocardiography, Transesophageal/methods , Surgery, Computer-Assisted/methods , Transcatheter Aortic Valve Replacement/methods , Wakefulness , Aortic Valve/diagnostic imaging , Aortic Valve/physiopathology , Aortic Valve Stenosis/classification , Aortic Valve Stenosis/diagnosis , Echocardiography, Three-Dimensional/methods , Follow-Up Studies , Humans , Intraoperative Period , Reproducibility of Results , Retrospective Studies , Severity of Illness Index , Ventricular Function, Left/physiologyABSTRACT
The use of cardiopulmonary bypass (CPB) contributes significantly to intraoperative anemia. The use of a prescriptive circuit that is tailored to the patient size could significantly reduce priming volumes, resulting in less hemodilution. The purpose of this study was to determine whether a prescriptive circuit resulted in decreased hemodilution, reduced blood product usage, and improved outcomes. In total, 204 patients prospectively received the prescriptive protocol between March 2019 and November 2019. This protocol was composed of three circuit sizes: small [body surface area (BSA) ≤ 1.85 m2], medium (BSA 1.86-2.30 m2), and large (BSA ≥ 2.31 m2). Data for CPB and post-bypass transfusions were collected, along with postoperative outcomes. These patients were then 1:2 propensity score matched to 401 patients who were retrospectively reviewed who had undergone cardiac surgery using a one-sized CPB circuit. The prescriptive protocol cohort had more patients with renal disease, whereas the conventional cohort had more history of hypertension. Intraoperative results show the prescriptive circuit had lower mean prime volume and total prime volume after reverse autologous prime (1,084 mL vs. 1,798 mL, p < .0001; 725 mL vs. 1,181 mL, p < .0001). Ultrafiltration was higher in the prescriptive group (872 vs. 645 mL, p < .0001), which likely balanced the increased use of del Nido cardioplegia in the prescriptive group (1,295 vs. 377 mL, p < .0001). The drop in hematocrit (HCT) from baseline was less in the prescriptive group (15.1 ± 4.91 vs. 16.2 ± 4.88, p = .0149), whereas the postoperative HCT was higher (32.79 ± 4.88 vs. 31.68 ± 4.99, p = .0069). Transfusion of packed red cells did not change between the two groups. Implementation of a prescriptive circuit did not reduce on-bypass or intraoperative blood product usage. However, there was a significant reduction in on-bypass hemodilution and increased postoperative HCT.
Subject(s)
Cardiac Surgical Procedures , Hemodilution , Blood Transfusion , Cardiopulmonary Bypass , Hematocrit , Humans , Retrospective StudiesABSTRACT
OBJECTIVE: Recent studies demonstrate that uncomplicated acute type B aortic dissection (uATBAD) patients with enlarged descending thoracic aortic diameters are at high risk for development of complications. This study aimed to determine the association of maximum ascending aortic diameter and area and outcomes in patients with uATBAD. METHODS: All patients admitted with uATBAD from June 2000 to January 2015 were reviewed, and those with available imaging were included. All measurements were obtained by a specialized cardiovascular radiologist, including the maximum ascending aortic diameter and area. Outcomes, including the need for intervention and mortality, were tracked over time. Data were analyzed by stratified Kaplan-Meier and multiple Cox regression analyses using SAS 9.4 software (SAS Institute, Cary, NC). RESULTS: During the study period, 298 patients with uATBAD were admitted, with 238 having available computed tomography and 131 having computed tomography angiography imaging and adequate follow-up available for analysis. The cohort had an average age of 60.96 ± 13.4 years (60% male, 53% white). Ascending aortic area >12.1 cm2 and ascending aortic diameter >40.8 mm were associated with subsequent arch and proximal progression necessitating open ascending aortic repair (P < .027 and P < .033, respectively). Ascending diameter >40.8 mm predicted lower intervention-free survival (P = .01). However, it failed to predict overall survival (P = .12). Ascending aortic area >12.1 cm2 predicted lower intervention-free survival (P = .005). However, this was not predictive of mortality (P = .08). Maximum aortic diameter along the length of the aorta >44 mm persisted as a risk factor for mortality (P < .001). Neither maximum ascending aortic diameter >40.8 mm (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.42-2.83; P = .85) nor area >12.1 cm2 (HR, 0.992; 95% CI, 0.38-2.61; P = .99) significantly predicted mortality when controlling for maximum aortic diameter along the length of the aorta >44 mm (HR, 7.34; 95% CI, 2.3-23.41; P < .001), diabetes mellitus (HR, 6.4; 95% CI, 2.17-18.93; P < .001), age (HR, 1.06/y; 95% CI, 1.03-1.10; P < .001), history of stroke (HR, 5.03; 95% CI, 1.52-16.63; P = .008), and syncope on admission (HR, 21.11; 95% CI, 2.3-193.84; P = .007). Ascending aortic diameter >40.8 mm (HR, 2.01; 95% CI, 1.03-3.95; P = .04) and maximum ascending aortic area >12.1 cm2 (HR, 1.988; 95% CI, 1.02-3.87; P = .04) on admission persisted as predictors of decreased intervention-free survival after controlling for maximum aortic diameter along the length of the aorta >44 mm (HR, 3.142; 95% CI, 1.47-6.83; P < .004), syncope on admission (HR, 26.3; 95% CI, 2.81-246; P < .004), and pleural effusion on admission (HR, 3.02; 95% CI, 1.58-5.77; P < .001). CONCLUSIONS: uATBAD patients with ascending aortic area >12.1 cm2 or maximum ascending aortic diameter >40.8 mm are at high risk for development of subsequent arch and proximal progression and may require closer follow-up or earlier intervention. Ascending aortic size (diameter and area) is predictive of decreased intervention-free survival in patients with uATBAD.
Subject(s)
Aortic Aneurysm/surgery , Aortic Dissection/surgery , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Aged , Aortic Dissection/diagnostic imaging , Aortic Aneurysm/diagnostic imaging , Aortography/methods , Blood Vessel Prosthesis Implantation/adverse effects , Blood Vessel Prosthesis Implantation/instrumentation , Computed Tomography Angiography , Endovascular Procedures/adverse effects , Endovascular Procedures/instrumentation , Female , Humans , Male , Middle Aged , Postoperative Complications/etiology , Progression-Free Survival , Retrospective Studies , Risk Factors , Time FactorsABSTRACT
BACKGROUND: Trauma remains a leading cause of morbidity and mortality worldwide. Vascular injuries are present in approximately 1% to 2% of trauma patients, with the majority of injuries occurring to the extremities. Trauma patients with vascular injuries have been shown to have increased morbidity and mortality as well as the need for increased resources compared with those without vascular injuries. This study aimed to determine predictors of poor outcomes in infrainguinal bypasses performed for traumatic arterial injury. METHODS: All patients admitted between September 1999 and July 2015 who underwent infrainguinal arterial bypass for trauma at a single level I trauma center were included for analysis. The primary outcome was a composite of thrombosis leading to graft abandonment, revision, amputation, or death. Data were analyzed by univariate descriptive and multiple logistic regression analyses. Long-term data were analyzed by Kaplan-Meier method. RESULTS: During the study period, 108 patients presented with and underwent infrainguinal arterial bypass for traumatic arterial injury. The cohort had a mean age of 35.8 years (16/108 female [15%]). The average Injury Severity Score was 15.2; admission glomerular filtration rate, 79.3 mL/min/1.73 m2; Mangled Extremity Severity Score (MESS), 6; and injury to operating room time, 5.1 hours. Of 108 patients, 37 (34%) had penetrating injury, 71 (66%) had blunt injury, 10 (9.3%) had diabetes mellitus, and 76 (70.4%) had a below-knee target for bypass. Univariate risk factors for poor outcome included age >40 years (odds ratio [OR], 3.27 [1.40-7.65]; P < .01), MESS ≥7 (OR, 5.19 [2.08-19.97]; P < .01), blunt mechanism (OR, 3.35 [1.24-9.07]; P = .02), popliteal artery injury (OR, 3.04 [1.22-7.6]; P = .02), and below-knee target vessel (OR, 4.32 [1.37-13.58]; P = .01). Concomitant orthopedic injuries (P = .08) were not associated with poor outcome. Baseline renal function, type of repair performed (end-to-side vs interposition bypass), injury to surgery time, surgeon's specialty, and associated venous injuries were not significantly predictive of poor outcome. MESS was strongly predictive of poor outcome, with probability rising as high as 95% when MESS reached 12. A score ≥7 (high MESS) was 73% sensitive and 70% specific to predict poor outcomes. Age (OR, 1.03/y; P < .05) and MESS ≥7 (OR, 3.6; P < .03) were persistent predictors of poor outcome in multivariable analysis. CONCLUSIONS: Poor outcomes in infrainguinal bypass for trauma are significantly predicted by the MESS, with poor outcomes occurring >50% of the time when MESS is ≥9 and >75% of the time when MESS is ≥11. Whereas amputation vs revascularization is a decision that also depends on nerve and soft tissue damage and other comorbidities, the MESS helps frame the data for the clinician and can aid in decision-making. Patients and family should understand that poor outcomes are more likely when MESS is ≥9. For patients with MESS ≥11, primary amputation can be considered.
Subject(s)
Lower Extremity/blood supply , Lower Extremity/injuries , Vascular System Injuries/surgery , Adult , Arteries/injuries , Arteries/surgery , Cohort Studies , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Treatment Outcome , Vascular Surgical Procedures/methods , Wounds, Nonpenetrating/surgery , Wounds, Penetrating/surgeryABSTRACT
OBJECTIVE: The objective of this retrospective study was to characterize the neutrophil to lymphocyte ratio (NLR) on the waitlist and determine its prognostic utility in liver transplantation (LT) for hepatocellular carcinoma (HCC) with special focus on longitudinal data. Biomarkers such as pre-operative NLR have been suggested to predict poor oncological outcomes for patients with HCC seeking LT. NLR's utility is thought to be related to tumor biology. However, recent studies have demonstrated that a high NLR conveys worse outcomes in non-HCC cirrhotics. This study investigated the relationship between NLR, liver function, tumor factors and patient prognosis. METHODS: Patients with HCC undergoing LT were identified between 2002 and 2014 (n = 422). Variables of interest were collected longitudinally from time of listing until LT. The prognostic utility of NLR was assessed using Kaplan-Meier and Cox Proportional Hazard regression. Associations between NLR and MELD-Na, AFP, and tumor morphology were also assessed. RESULTS: NLR demonstrated a positive correlation with MELD-Na at LT (R2 = 0.125, P < 0.001) and had parallel trends over time. The lowest NLR quartile had a median MELD-Na of 9 while the highest had a median MELD-Na of 19. There were minimal differences in AFP, tumor morphology, and rates of vascular invasion between quartiles. NLR was a statistically significant predictor of OS (HR = 1.64, P = 0.017) and recurrence (HR = 1.59, P = 0.016) even after controlling for important tumor factors. However, NLR lost its statistical significance when MELD-Na was added to the Cox regression model (OS: HR = 1.46, P = 0.098) (recurrence: HR = 1.40, P = 0.115). CONCLUSIONS: NLR is a highly volatile marker on the waitlist that demonstrates a significant correlation and collinearity with MELD-Na temporally and at the time of LT. These characteristics of NLR bring into question its utility as a predictive marker in HCC patients.
Subject(s)
Carcinoma, Hepatocellular/mortality , Liver Neoplasms/mortality , Liver Transplantation/mortality , Lymphocytes/pathology , Neutrophils/pathology , Waiting Lists/mortality , Aged , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/surgery , Female , Follow-Up Studies , Humans , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Survival RateABSTRACT
Use of tobacco products before or after a cardiac event increases risk of morbidity and mortality. Unlike cigarette smoking, which is generally screened in the healthcare system, identifying the use of other tobacco products remains virtually unexplored. This study aimed at characterizing the use of other non-combusted tobacco products in addition to combusted products among cardiac patients and identifying a profile of patients who are more likely to use non-combusted products. Patients (Nâ¯=â¯168) hospitalized for a coronary event who reported being current cigarette smokers completed a survey querying sociodemographics, cardiac diagnoses, use of other tobacco products, and perceptions towards these products. Classification and regression tree (CART) analysis was used to identify which interrelationships of participants characteristics led to profiles of smoking cardiac patients more likely to also be using non-combusted tobacco products. Results showed that non-combusted tobacco product use ranged from 0% to 47% depending on patient characteristic combinations. Younger age and lower perception that cigarette smoking is responsible for their cardiac condition were the strongest predictive factors for use of non-combusted products. Tobacco product use among cardiac patients extends beyond combusted products (13.7% non-combusted product use), and consequently, screening in health care settings should be expanded to encompass other tobacco product use. This study also characterizes patients likely to be using non-combusted products in addition to combusted, a group at high-risk due to their multiple product use, but also a group that may be amenable to harm reduction approaches and evidence-based tobacco treatment strategies.
Subject(s)
Heart Diseases/psychology , Hospitalization/statistics & numerical data , Smokers/psychology , Smokers/statistics & numerical data , Smoking Cessation/psychology , Smoking Cessation/statistics & numerical data , Tobacco Use/trends , Adult , Aged , Female , Forecasting , Humans , Male , Middle Aged , Socioeconomic Factors , Surveys and Questionnaires , Tobacco Use/epidemiology , United States/epidemiologyABSTRACT
OBJECTIVES: The effect of superficial femoral artery (SFA) occlusion on long-term patency of aortofemoral bypasses (AFBs) for aortoiliac occlusive disease (AIOD) was examined. METHODS: The AIOD database was reviewed to identify risk factors for AFB failure. The status of the SFA at AFB procedure was categorised as patent; diseased treated (DT), if the SFA occlusion was intervened on concomitant to AFB; or diseased untreated (DU), if the SFA was occluded but not revascularised. Censoring hierarchies for primary patency and patent graft survival time were constructed. Data were analysed by contingency table, Kaplan-Meier, and Cox regression analysis. RESULTS: Between 2004 and 2015, 122 AFB (9 unifemoral, 113 bifemoral) for AIOD were performed. Seventy-five (61%) were female and the mean age was 60 ± 10 years. At the time of AFB, 50 (41%) had occluded SFAs (DT/DU). Of these, 15 had concomitant SFA revascularisation (i.e., DT) at the time of AFB. Patients with occluded SFAs had greater history of prior aortoiliac/infrainguinal procedures (aortoiliac 54% vs. 22%, infrainguinal 58% vs. 25%, both p < 0.001), Trans-Atlantic Inter-Society Consensus II classification of femoropopliteal type D lesions (78 vs. 10%, p < 0.001), Rutherford 4-6 categories (80% vs. 57%, p = 0.011), and longer hospital stay (median 11 vs. 7 days, p < 0.004). SFA status did not affect 30 day mortality (overall 9%); however, sub-analysis showed DT had significantly higher mortality than DU (p < 0.03). Over a median follow up of 7.7 (IQR 4.3-11.4) years, primary patency at one and five years was 98.3% and 91.2% in patients with patent SFAs, 87.9% and 82.7% in DU, and 72.7% and 43.6% in DT (p < 0.001), respectively. On multivariable analysis, low baseline glomerular filtration rate (HR 1.01, p = 0.022), DT (HR 3.7, p = 0.020), Rutherford 4-6 (HR 9.1, p = 0.048), and occluded SFA (HR 3.9, p = 0.009) adversely affected primary patency of AFBs. Long-term mortality was not different between the SFA status groups (p = 0.279). CONCLUSION: Baseline SFA occlusion predicted a fourfold increased hazard of primary AFB failure. Concomitant SFA revascularisation did not improve AFB durability and was associated with increased in hospital mortality.
Subject(s)
Aorta, Abdominal/surgery , Arterial Occlusive Diseases/surgery , Femoral Artery/surgery , Graft Occlusion, Vascular/etiology , Iliac Artery/surgery , Vascular Grafting , Vascular Patency , Aged , Female , Follow-Up Studies , Glomerular Filtration Rate , Hospital Mortality , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Postoperative Complications , Reoperation , Retrospective Studies , Risk Factors , Thrombosis/etiology , Vascular Grafting/adverse effectsABSTRACT
INTRODUCTION: Investigation into right and left-sided primary colon liver metastasis (CLM) has revealed differences in the tumor biology and prognosis. This indicates that preoperative and operative factors may affect outcomes of right-sided primary CLM differently than left. This retrospective analysis investigated the effects of resection margin stratified by left and right-sided primary CLM on overall survival (OS) for patients undergoing hepatectomy. METHODS: A total of 732 patients undergoing hepatic resection for CLM at the Cleveland Clinic and Johns Hopkins were identified between 2002 and 2016. Clinically significant variables were analyzed using Cox proportional hazard regression. The cohort was then divided into patients with right and left-sided CLM and analyzed separately using Kaplan Meier analysis and Cox proportional hazard regression. RESULTS: Cox proportional hazard regression showed that left-sided CLM with an R0 margin was a statistically significant predictor of OS even after controlling for other important factors (HR = 0.629, P = 0.024) but right-sided CLM with R0 margin was not (HR = 0.788, P = 0.245). Kaplan-Meier analysis demonstrated that patients with a left-sided CLM and R0 margin had the best prognosis (P = 0.037). CONCLUSION: Surgical margin is an important prognostic factor for left-sided primary CLM but tumor biology may override surgical technique for right-sided CLM.
Subject(s)
Colonic Neoplasms/pathology , Hepatectomy/methods , Liver Neoplasms/surgery , Margins of Excision , Neoplasm Staging , Aged , Colonic Neoplasms/mortality , Colonic Neoplasms/surgery , Female , Follow-Up Studies , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/secondary , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Rate/trends , United States/epidemiologyABSTRACT
OBJECTIVE: The objectives of this study were (i) to evaluate infants with congenital diaphragmatic hernia (CDH) that do not undergo repair, (ii) to identify nonrepair rate by institution, and (iii) to compare institutional outcomes based on nonrepair rate. BACKGROUND: Approximately 20% of infants with CDH go unrepaired and the threshold to offer surgical repair is variable. METHODS: Data were abstracted from a multicenter, prospectively collected database. Standard clinical variables, including repair (or nonrepair), and outcome were analyzed. Institutions were grouped based on volume and rate of nonrepair. Preoperative mortality predictors were identified using logistic regression, expected mortality for each center was calculated, and observed /expected (O/E) ratios were computed for center groups and compared by Kruskal-Wallis ANOVA. RESULTS: A total of 3965 infants with CDH were identified and 691 infants (17.5%) were not repaired. Nonrepaired patients had lower Apgar scores (P < 0.05) and increased incidence of anomalies (P < 0.0001). Low-volume centers ("Lo", n=44 total, < 10 CDH pts/yr) and high-volume centers ("Hi", n = 21) had median nonrepair rates of 19.8% (range 0%-66.7%) and 16.7% (5.1%-38.5%), respectively. High-volume centers were further dichotomized by rate of nonrepair (HiLo = 5.1-16.7% and HiHi = 17.6-38.5%), leaving 3 groups: HiLo, HiHi, and Lo. Predictors of mortality were lower birth weight, lower Apgar scores, prenatal diagnosis, and presence of congenital anomalies. O/E ratios for mortality in the HiLo, HiHi, and Lo groups were 0.81, 0.94, and 1.21, respectively (P < 0.0001). For every 100 CDH patients, HiLo centers have 2.73 (2.4-3.1, 95% confidence interval) survivors beyond expectation. CONCLUSIONS: There are significant differences between repaired and nonrepaired CDH infants and significant center variation in rate of nonrepair exists. Aggressive surgical management, leading to a low rate of nonrepair, is associated with improved risk-adjusted mortality.
Subject(s)
Forecasting , Hernias, Diaphragmatic, Congenital/surgery , Herniorrhaphy/methods , Registries , Female , Follow-Up Studies , Hernias, Diaphragmatic, Congenital/mortality , Humans , Infant , Infant, Newborn , Male , Prospective Studies , Survival Rate/trends , Treatment Outcome , United States/epidemiologyABSTRACT
OBJECTIVE: The natural history and parameters for successful nonoperative management of blunt traumatic aortic injuries (BTAIs) involving the descending aorta are poorly understood. We examined our experience with nonoperative BTAI treatment (anti-impulse, blood pressure) and evaluated for determinants of successful outcomes. METHODS: We performed a review of our institutional prospective trauma registry database for all BTAI patients from 1999 to 2015. Computed tomography angiography was used to classify aortic injuries on the basis of severity: grade I, intimal tear; grade II, intramural hematoma; grade III, aortic pseudoaneurysm; and grade IV, free rupture. Grade IV injuries were excluded from nonoperative management. Baseline characteristics, clinical outcomes, and follow-up lesion resolution were compared within the medically managed cohort and between surgical and nonoperative groups using univariate and multivariable analysis. RESULTS: Among 338 BTAI patients admitted between 1999 and 2015, 67 BTAI patients were managed nonoperatively; 26 (54%) had grade I BTAI, 22 (46%) had grade II, and 2 (4%) had grade III. Both grade III injuries required a late thoracic endovascular aortic repair after initial medical management and were excluded from analysis. In all, 48 were managed with initial medical therapy, and the remaining 19 died on admission or before definitive treatment. Among the 48 medically managed, the median age was 34 years, and 14 (29%) were female. Six of the 48 (12%) were transferred from other facilities. There was no significant difference in baseline characteristics or early outcomes between BTAI grades. Median injury resolution time was 39 days for grade I and 62 days for grade II (P = .03). Compared with a surgical cohort, BTAI grade and Abbreviated Injury Scale score for the chest were the only significant determinants of propensity to operate. CONCLUSIONS: Based on these limited data, it appears that patients with minimal aortic injuries (grades I and II) may be managed medically, with the majority resolving within 8 weeks. Minimal aortic injury is associated with low mortality and excellent intermediate-term outcomes. Further prospective studies are required to validate these findings.
Subject(s)
Aneurysm, False/therapy , Aorta, Thoracic/injuries , Aortic Aneurysm, Thoracic/therapy , Aortic Dissection/therapy , Aortic Rupture/therapy , Vascular System Injuries/therapy , Wounds, Nonpenetrating/therapy , Adolescent , Adult , Aortic Dissection/diagnostic imaging , Aortic Dissection/mortality , Aneurysm, False/diagnostic imaging , Aneurysm, False/mortality , Aorta, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/mortality , Aortic Rupture/diagnostic imaging , Aortic Rupture/mortality , Aortography/methods , Clinical Decision-Making , Computed Tomography Angiography , Female , Hospital Mortality , Humans , Injury Severity Score , Kaplan-Meier Estimate , Logistic Models , Male , Middle Aged , Multivariate Analysis , Propensity Score , Proportional Hazards Models , Registries , Retrospective Studies , Risk Factors , Texas , Time Factors , Treatment Outcome , Vascular System Injuries/diagnostic imaging , Vascular System Injuries/mortality , Wounds, Nonpenetrating/diagnostic imaging , Wounds, Nonpenetrating/mortality , Young AdultABSTRACT
OBJECTIVE: Aortic dissection is a dynamic process that can progress both proximal and distal to the initial entry tear. We sought to determine associations for development of proximal progression or new type A aortic dissection (NTAD) after acute type B dissection (ATBD) and its effect on survival of the patient. METHODS: We reviewed all cases of acute aortic dissection that we managed from 1999 to 2014. Univariate and bivariate analyses were performed to identify correlates of NTAD. Multivariable regression and proportional hazards regression analysis was done to determine the effect of dissection progression on long-term survival. RESULTS: Among 477 cases of ATBD managed, 19 (4.0%) patients developed NTAD during a median follow-up of 4.1 (interquartile range, 1.4-7.7) years. Median time from diagnosis of ATBD to NTAD was 124 (interquartile range, 23-1201) days. Baseline predictors for development of NTAD at initial ATBD admission included bicuspid aortic valve (P = .006) and age <60 years (P = .012). Although not statistically significant, point estimates indicate that thoracic endovascular aortic repair was twice as frequent in NTAD cases as in non-NTAD cases. Overall 5-year survival was 70.2%. Patients who had repair of NTAD appear to have longer survival, although this effect is on the margin of statistical significance (P = .051). After risk factor and correlates of NTAD adjustment, this effect was no longer apparent (P = .089). CONCLUSIONS: The natural history of ATBD is such that there is a persistent risk of NTAD, with the highest risk in the first 6 months. Factors associated with NTAD include bicuspid aortic valve and young age. Thoracic endovascular aortic repair did not have a large effect on risk. Timely diagnosis and repair of NTAD are associated with good survival rates. Lifelong surveillance is warranted in all cases of descending thoracic aortic dissection regardless of initial treatment modality.
Subject(s)
Aorta, Thoracic/pathology , Aortic Aneurysm, Thoracic/surgery , Aortic Dissection/surgery , Endovascular Procedures/statistics & numerical data , Vascular Grafting/statistics & numerical data , Acute Disease , Adult , Age Factors , Aged , Aortic Dissection/diagnostic imaging , Aortic Dissection/epidemiology , Aortic Dissection/etiology , Aorta, Thoracic/diagnostic imaging , Aorta, Thoracic/surgery , Aortic Aneurysm, Thoracic/complications , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/epidemiology , Aortic Valve/abnormalities , Aortography/methods , Bicuspid Aortic Valve Disease , Disease Progression , Endovascular Procedures/methods , Female , Follow-Up Studies , Heart Valve Diseases/epidemiology , Humans , Incidence , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Tomography, X-Ray Computed/methods , Treatment Outcome , Vascular Grafting/methodsABSTRACT
BACKGROUND: Staging retroperitoneal lymph node dissection (RPLND) for paratesticular rhabdomyosarcoma (RMS) is recommended for all patients aged ≥10 y. The purpose of this study was to evaluate adherence with surgical resection guidelines for RPLND in patients with paratesticular RMS as a measure for surgical quality. MATERIALS AND METHODS: All patients with paratesticular RMS were identified in the Surveillance, Epidemiology, and End Results database from 1973 to 2012. Patients were divided into two eras to reflect before (1973-2002) and after (2003-2012) the release and dissemination of the 2001 surgical guidelines for staging ipsilateral RPLND in all patients aged ≥10 y with paratesticular RMS. Survival outcomes associated with lymph node dissection were calculated using the Kaplan-Meier method and Cox proportional hazards analysis. RESULTS: Two hundred thirty-five patients with paratesticular RMS were identified and included in the study, among whom 111 were adolescents aged 10-20. RPLND did not significantly increase after 2003 among adolescents (45%-61%, P = 0.09). The benefit of RPLND on improved 5-y overall survival was evident among adolescents (92% versus 64%, P = 0.003). Adjusting for histology, age, stage at diagnosis, and race/ethnicity, RPLND was associated with improved overall survival among patients aged ≥10 y (hazard ratio 0.37, 95% confidence interval 0.17-0.83). CONCLUSIONS: Despite surgical guidelines recommending RPLND in pediatric patients aged ≥10 y, nearly one-third of adolescent patients did not undergo RPLND. These findings are disturbing considering the survival benefit associated with RPLND among adolescent patients and indicate an opportunity for improvement in surgical quality.
Subject(s)
Lymph Node Excision , Rhabdomyosarcoma/surgery , Testicular Neoplasms/surgery , Adolescent , Adult , Child , Humans , Lymph Nodes/pathology , Male , Neoplasm Staging , Retroperitoneal Space , Rhabdomyosarcoma/mortality , Rhabdomyosarcoma/pathology , SEER Program , Testicular Neoplasms/mortality , Testicular Neoplasms/pathology , Young AdultABSTRACT
BACKGROUND: Intracerebral hemorrhage is a devastating disease with no specific treatment modalities. A significant proportion of patients with intracerebral hemorrhage are transferred to large stroke treatment centers, such as Comprehensive Stroke Centers, because of perceived need for higher level of care. However, evidence of improvement in patient-centered outcomes for these patients treated at larger stroke treatment centers as compared to community hospitals is lacking. METHODS / DESIGN: "Efficient Resource Utilization for Patients with Intracerebral Hemorrhage (EnRICH)" is a prospective, multisite, state-wide, cohort study designed to assess the impact of level of care on long-term patient-centered outcomes for patients with primary / non-traumatic intracerebral hemorrhage. The study is funded by the Texas state legislature via the Lone Star Stroke Research Consortium. It is being implemented via major hub hospitals in large metropolitan cities across the state of Texas. Each hub has an extensive network of "spoke" hospitals, which are connected to the hub via traditional clinical and administrative arrangements, or by telemedicine technologies. This infrastructure provides a unique opportunity to track outcomes for intracerebral hemorrhage patients managed across a health system at various levels of care. Eligible patients are enrolled during hospitalization and are followed for functional, quality of life, cognitive, resource utilization, and dependency outcomes at 30 and 90 days post discharge. As a secondary aim, an economic analysis of the incremental cost-effectiveness of treating intracerebral hemorrhage patients at higher levels of care will be conducted. DISCUSSION: Findings from EnRICH will provide much needed evidence of the effectiveness and efficiency of regionalized care for intracerebral hemorrhage patients. Such evidence is required to inform policy and streamline clinical decision-making.
Subject(s)
Cerebral Hemorrhage/economics , Cerebral Hemorrhage/therapy , Hospitals/statistics & numerical data , Patient Outcome Assessment , Aged , Cost-Benefit Analysis , Female , Humans , Male , Middle Aged , Prospective Studies , Quality of Life , TexasABSTRACT
BACKGROUND: Although the incident risk of peripheral artery disease increases in patients with metabolic syndrome, several authors report favorable outcomes in obese patients after arterial bypass surgery. We examine the effect of the so-called "obesity paradox" and metabolic syndrome on outcomes after open aortoiliac bypass surgery. METHODS: We identified patients between 2004 and 2015 who had open surgical bypass for aortoiliac occlusive disease. We excluded patients with endovascular repair and those treated primarily for aneurysmal disease. Variables that were analyzed included preoperative medical history, Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease II classification, Rutherford classification, intra-operative, and postoperative outcomes. Metabolic syndrome was defined by World Health Organization criteria: diabetes and 2 or more of dyslipidemia, hypertension, and obesity (body mass index > 30 kg/m2). Data were analyzed by stratified Kaplan-Meier and multiple Cox regression for outcomes including long-term mortality and reintervention rate. RESULTS: There were 154 open bypass surgery patients during the study period with a median age of 60 years (interquartile range [IQR] 53-68), median glomerular filtration rate 76.1 mL/min (IQR 54-102), and 58% female prevalence. In all, 53 patients had metabolic syndrome (4%), and 14 patients (9%) were obese but did not have metabolic syndrome. Primary bypass graft patency was 89.0 ± 2.7% at 1 year and 77.4 ± 4.1% at 5 years and was not significantly different between metabolic syndrome, obese, and nonmetabolic syndrome patients. Reintervention rate for the entire cohort was 25.3 ± 3.7% at 1 year and 40.6 ± 4.7% at 5 years. In those with and without metabolic syndrome, reintervention rate at 1 and 5 years was 33.0 ± 6.8% vs. 21.1 ± 4.2% and 56.1 ± 7.9% vs. 30.7 ± 5.4%, respectively (log-rank P = 0.003). In multivariable analyses, metabolic syndrome (hazard ratio [HR] 1.8, P = 0.036) and critical limb ischemia (CLI) (HR: 3.2, P = 0.001) were the only independent predictors of reintervention. Neither obesity nor the individual components comprising metabolic syndrome was a risk for reintervention. Multivariate analysis demonstrated age, female gender, CLI, and nonobesity as the independent risk factors for long-term mortality. CONCLUSIONS: Our study supports the "obesity paradox" that obesity by itself is not a risk factor for reintervention and was a protective factor for mortality after open aortoiliac bypass surgery. Bypass graft patency and major amputation rates were not affected. Although the individual components do not predispose to worse outcome, metabolic syndrome is a constellation of factors that, together, are associated with adverse events.