Evaluation of Extracorporeal Membrane Oxygenation Therapy as a Bridging Method.

BACKGROUND: With the implementation of the new heart allocation system, heart transplantation teams are prompted to reevaluate management of patients requiring mechanical circulatory support. The purpose of our study is to compare the outcomes of patients supported with extracorporeal membrane oxygenation (ECMO) before transplantation. METHODS: The United Network for Organ Sharing database was queried for all adult patients (aged 18 years or more) who required support with ECMO before heart transplantation from 2001 to 2018. Patients were stratified into patients who did not require ECMO before transplantation, who were weaned off ECMO before transplantation, who were bridged immediately to transplantation from ECMO, and who were bridged to a left ventricular assist device (LVAD) before transplantation. Demographics and outcomes including 1-year survival, postoperative stroke, postoperative renal failure requiring dialysis, episodes of rejection, and graft failure were compared. RESULTS: Overall, 29,370 patients did not require ECMO before transplantation, 101 patients were weaned off ECMO before transplantation, 118 were bridged from ECMO directly to transplantation, and 55 patients were successfully bridged from ECMO to LVAD before transplantation. Kaplan-Meier survival estimates found a statistically significant decrease in 1-year survival for patients who were bridged from ECMO to transplantation compared with patients who were bridged to LVAD before subsequent transplantation (P < .001). CONCLUSIONS: Our study suggests bridging ECMO patients to an LVAD before transplantation will result in improved 1-year survival compared with patients bridged to immediate transplantation. With the new heart allocation system, continued evaluation of outcomes is required to inform management strategies.

Increased Use of Multiorgan Transplantation in Heart Transplantation: Only Time Will Tell.

BACKGROUND: The utilization of multiorgan transplantation in cardiac transplantation has steadily increased over the past several years. We sought to characterize the trends and outcomes in simultaneous heart and other organ transplantation compared with heart transplantation alone. METHODS: The United Network for Organ Sharing database was queried for all adult patients (age ≥ 18 y) who underwent isolated heart transplantation or simultaneous heart-lung or heart-kidney transplantation from 1987-2016. Patients were stratified into 3 equal time intervals. Demographics and postoperative outcomes were compared. RESULTS: A total of 58,060 patients were identified with a distribution based on era. Dual organ recipients had more factors associated with increased operative risk including higher rates of diabetes, pulmonary hypertension, intensive care unit admissions, and dialysis prior to transplantation. Heart-lung and heart-kidney recipients had decreased 1-year survival compared with isolated heart recipients from 2007-2016. However, heart-kidney recipients had significantly increased 5-year post-transplantation survival compared with isolated heart recipients with impaired renal function. For isolated heart transplants and heart-lung transplants, 5-year survival rates improved over time, whereas 5-year survival for heart-kidney recipients did not improve with time. CONCLUSIONS: We found a significantly increased 5-year survival rate for heart-kidney transplant recipients compared with isolated heart transplant recipients with renal impairment. Lack of improvement in 5-year postoperative outcomes for heart-kidney recipients in the setting of higher-risk pretransplant clinical characteristics suggests decreased selectivity regarding heart-kidney recipients. Continued scrutiny and evaluation of postoperative outcomes are required to ensure just and appropriate utilization of organs.

Impact of the New Pulmonary Hypertension Definition on Heart Transplant Outcomes: Expanding the Hemodynamic Risk Profile.

BACKGROUND: At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of heart transplant (HT) recipients is unknown. METHODS: The United Network for Organ Sharing database was queried to identify adult recipients who underwent primary HT from 1996 to 2015. Recipients were subdivided into those with mean pulmonary artery pressure (mPAP) < 25 mm Hg and ≥ 25 mm Hg. Exploratory univariable analysis was undertaken to identify candidate risk factors associated with 30-day and 1-year survival (conditional on 30-day survival) in recipients with mPAP < 25 mm Hg, and subsequently, parsimonious multivariable Cox proportional hazards models were constructed to assess the independent association with PVR. RESULTS: Over the study period, 32,465 patients underwent HT, including 12,257 (38%) with mPAP < 25 mm Hg. The median age was 55 years (interquartile range, 47-62) and the median PVR was 1.5 Wood units (WU) (interquartile range, 1-2.2) in recipients with mPAP < 25 mm Hg. After controlling for confounders, PVR was independently associated with increased risk for 30-day mortality (hazard ratio, 1.16; 95% CI, 1.05-1.27; P < .01), but not conditional 1-year mortality (hazard ratio, 1.03; 95% CI, 0.94-1.12; P = .55). PVR ≥ 3 WU was associated with an absolute 1.9% increase in 30-day mortality in those with mPAP < 25 mm Hg, a similar risk to recipients with PVR ≥ 3 WU and mPAP ≥ 25 mm Hg. CONCLUSIONS: Elevated PVR remains associated with a significant increase in the hazard for 30-day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. These data support the validity of the new definition of pulmonary hypertension.

Effects of Systemic and Device-Related Complications in Patients Bridged to Transplantation With Left Ventricular Assist Devices.

BACKGROUND: The use of left ventricular assist devices (LVADs) as a bridge to heart transplantation has increased rapidly over the last 2 decades. We aim to explore the effect of pretransplant systemic and device-related complications on posttransplant survival for patients bridged with LVADs. MATERIALS AND METHODS: The United Network of Organ Sharing (Organ Procurement and Transplantation Network) database was queried for all adult heart transplant recipients (aged ≥ 18 y) transplanted from April 1, 2015, to June 31, 2018. Device-related complications included thrombosis, device infection, device malfunction, life-threatening arrhythmia, and other device complications. Systemic complications included a new dialysis need or ventilator dependence between the time of listing and transplantation, transfusion, or systemic infection requiring treatment with intravenous antibiotics within 2 wk of transplantation. RESULTS: A total of 2131 patients were identified as requiring LVAD support before transplantation. LVAD patients had high rates of preoperative systemic complications (53%) and high rates of device-related complications (42.7% experienced at least one device-related complication). Kaplan-Meier analysis revealed a significantly decreased 1-y survival for LVAD patients bridged to transplantation who experienced a pretransplant systemic complication (P = 0.041). Interestingly, preoperative device-related complications had no effect on 1-y posttransplantation survival (P = 0.93). Multivariate Cox modeling revealed that systemic complications were associated with a significantly increased risk of posttransplant mortality for LVAD patients (hazard ratio 1.45; P = 0.033). CONCLUSIONS: Recipients who suffered a systemic complication while awaiting heart transplantation experienced higher short-term mortality rates. Device-related complications do not appear to impact posttransplantation outcomes.

A Century of Heparin.

The year 2018 was the centennial of the naming of heparin by Emmett Holt and William Howell and the 102nd anniversary of Jay McLean's discovery of an anticoagulant heparphosphatide at Johns Hopkins Hospital in Baltimore. This article discusses recently discovered historical artifacts that shed new light on heparin's christening, including McLean's unpublished letter written in 1950 that represents one of the most complete accounts of heparin's discovery before his untimely death. In addition, the article describes the finding of a plaque dedicated to McLean and explores the circumstances of its removal from public display, as learned from interviews with present and former staff members.

Racial Disparities in Patients Bridged to Heart Transplantation With Left Ventricular Assist Devices.

BACKGROUND: Left ventricular assist devices (LVADs) are an effective therapy in bridging patients with end-stage heart failure to heart transplantation. The aim of this study was to identify the role of race in survival of patients bridged to heart transplantation with a LVAD. METHODS: The United Network of Organ Sharing database was queried for all adult heart transplant recipients (age 18 years or older) who were bridged to transplantation with a LVAD from 2005 to 2018. Patients were stratified based on their race, with whites as the reference group. Demographic characteristics, 5-year survival, and graft failure after transplantation were assessed with χ2 test, analysis of variance, Kaplan-Meier survival analyses, log-rank tests, and Cox proportional hazards modeling or logistic regression modeling as appropriate. RESULTS: Patients (N = 6476) successfully bridged with a LVAD to heart transplantation were identified. There were 4263 whites, 1536 African Americans, 508 Hispanics, and 169 Asians. Compared with whites, African Americans had higher body mass indexes, were more likely to be women, pay with private insurance, and be working for income at the time of transplantation. African Americans were found to have increased odds of graft failure (odds ratio 1.27, P = .048) compared with whites. In addition, African Americans were found to have increased risk of mortality at 5 years (hazard ratio 1.26, P = .003). CONCLUSIONS: The African American race is associated with increased rates of graft failure after transplantation and decreased 5-year survival compared with the white race. Given these findings, directed clinical attention may be warranted in African American patients bridged to heart transplantation with a LVAD.

Early Outcomes After Heart Transplantation in Recipients Bridged With a HeartMate 3 Device.

BACKGROUND: Left ventricular assist devices are increasingly used as bridge-to-transplantation in eligible patients. The HeartMate 3 (HM3; Abbott Laboratories, Abbot Park, IL) is the latest device to obtain US Food and Drug Administration approval as bridge-to-transplantation. This study examines early outcomes of transplant recipients after HM3 in comparison with recipients bridged with the HeartMate 2 (HM2; Abbott Laboratories) and HeartWare Ventricular Assist System (HVAD; Medtronic, Minneapolis, MN) devices. METHODS: Using the Organ Procurement and Transplantation Network database, we identified all adult patients who were slated for bridge-to-transplantation with a continuous-flow left ventricular assist devices (HM2, HVAD, or HM3) between April 1, 2015 and January 31, 2018. The primary endpoint was all-cause mortality 6 months after transplantation. The independent influence of the bridging device on outcomes was determined using Cox proportional hazard models. RESULTS: Patients (N = 1,978) were successfully bridged to transplantation with the HM2 (n = 881), HVAD (n = 920), or HM3 (n = 177) device. Six-month mortality rates were similar across these devices (HM2, 5.9%; HVAD, 7.7%; HM3, 4.7%; log-rank p = 0.30). On average HM2 patients were on a left ventricular assist device for 2 months longer (p < 0.01). The HVAD had the lowest rate of device exchange before transplant (p = 0.01). The HM3 had no events of pump thrombosis (p < 0.01). HVAD patients had the lowest rate of device malfunction before to transplant (p < 0.01). Panel reactive antibodies at the time of transplantation were lower for HM3 patients (p < 0.01); however rates of graft rejection at 6 months were not different (p = 0.25). CONCLUSIONS: The HM3 device provides excellent early outcomes as a bridge to transplantation and may be associated with a reduction in comorbidities. Longer follow-up is needed to better define differences between durable left ventricular assist devices.

Spontaneous Aortoesophageal Fistula in an Acute Type B Aortic Dissection and a Right-Sided Arch.

Primary aortoesophageal fistula (AEF) in the absence of prosthetic graft replacement or aortic endovascular therapy can develop as a rare but life-threatening complication of acute aortic dissection. This case demonstrates that primary AEF should be maintained on the clinical differential of a patient presenting with massive gastrointestinal bleed in the context of an aortic dissection.

A Contemporary Analysis of Heart Transplantation and Bridge-to-Transplant Mechanical Circulatory Support Outcomes in Cardiac Sarcoidosis.

BACKGROUND: Patients with end-stage cardiomyopathy due to cardiac sarcoidosis (CS) may be referred for mechanical circulatory support (MCS) and heart transplantation (HT). We describe outcomes of patients with CS undergoing HT, focusing on the use of MCS as a bridge to transplant (BTT). METHODS: Using the United Network for Organ Sharing Scientific Registry of Transplant Recipients, we identified all adult waitlisted patients and isolated HT recipients from 2006 to 2015. These were divided into those with and without CS and further divided into those who did or did not receive MCS as BTT. Outcomes included 1- and 5-year post-transplantation freedom from mortality and 5-year freedom from primary graft failure. RESULTS: Over the study period, 31,528 patients were listed for HT, 148 (0.4%) of whom had CS. Among the CS patients, 34 (23%) received MCS as BTT. 18,348 patients (58%) eventually underwent HT, including 67 (0.4%) with CS, 20 (30%) of whom had received BTT MCS. Compared with non-CS diagnoses, CS patients had similar 1-year (91% vs 90%; log rank P = .88) and 5-year (83% vs 77%; log rank P = .46) freedom from mortality. Survival was also similar between CS BTT and non-CS BTT groups at 1 year (89% vs 89%; log-rank P = .92) and 5 years (72% vs 75%; log-rank P = .77). CONCLUSIONS: Survivals after HT were similar between CS and non-CS patients out to 5 years, and were also similar between CS and non-CS BTT cohorts. Both HT and BTT MCS should be considered in patients with CS.

Four-Chamber Intracardiac Thrombi Complicating Wild-Type TTR Amyloidosis.

Cardiac amyloidosis is a rare disease, and its prevalence varies depending on the type of amyloid protein involved. Several case reports make reference to the increased risk of thrombosis and thromboembolic events in cardiac amyloidosis. We report a case of rapidly evolving, multichamber thrombi in a patient who was ultimately diagnosed with wild-type TTR cardiac amyloidosis.

A Comprehensive Risk Score to Predict Prolonged Hospital Length of Stay After Heart Transplantation.

BACKGROUND: Prolonged hospital length of stay (PLOS) after heart transplantation increases cost and morbidity. To better inform care, we developed a risk score to identify patients at risk for PLOS after heart transplantation. METHODS: We queried the United Network for Organ Sharing Scientific Registry of Transplant Recipients database for adult patients who underwent isolated heart transplantation from 2003 to 2012. The population was randomly divided into a derivation cohort (80%) and a validation cohort (20%). The outcome of interest was PLOS, defined as a posttransplant hospital length of stay of more than 30 days. Associated univariables (p < 0.20) in the derivation cohort were included in a multivariable model, and a risk index was derived from the adjusted odds ratios of significant covariates. RESULTS: During the study period, 16,723 patients underwent heart transplantation with an average PLOS of 19 ± 21 days, and 2,020 orthotopic heart transplant recipients (12%) had PLOS. Baseline characteristics were similar between the derivation and validation cohorts. Twenty-four recipient and nine donor variables, cold ischemic time, and center volume were tested as univariables. Seventeen covariates significantly affected PLOS and comprised the prolonged hospitalization after heart transplant risk score, which was stratified into three risk groups. The risk model was subsequently validated, and predicted rates of PLOS correlated well with observed rates (R = 0.79). Rates of PLOS in the validation cohort were 8.3%, 11%, and 22% for low, moderate, and high risk groups, respectively. CONCLUSIONS: The risk of PLOS after heart transplantation can be determined at the time of transplant. The prolonged hospitalization after heart transplant score may lead to individualized postoperative management strategies to reduce duration of hospitalization for patients at high risk.

Robotic-assisted microvascular surgery: skill acquisition in a rat model.

Microsurgery is a technically demanding field with long learning curves. Robotic-assisted microsurgery has the ability to decrease these learning curves. We, therefore, sought to assess the feasibility of robotic-assisted microvascular surgery in a rat model, and whether this could be translated into a worthwhile skills acquisition exercise for residents. Twenty-eight rats underwent microvascular anastomosis. Procedures were performed by a trained microvascular surgeon with no robotic experience (n = 14), or a trained robotic surgeon with no microvascular experience (n = 14). Anesthetized rats were subjected to complete transection and end-to-end anastomosis of the abdominal aorta using 10-0 prolene. Manually (n = 6) and robotic-assisted (n = 8) procedures were performed by both surgeons. A successful procedure required a patent anastomosis and no bleeding. After approximately 35 days, angiography and histopathological studies of the anastomoses were performed. Median times for robotic-assisted anastomoses were 37.5 (34.2-42.7) min for the microsurgeon and 38.5 (32.7-52) min for robotic surgeon. In the manual group, it took 17 (13.5-23) min for microsurgeon and 44 (34.5-60) min for robotic surgeon. Within the robotic-assisted group, there was a trend toward improvement in both surgeons, but greater in the microsurgeon. Robotic-assisted microvascular anastomosis in a rat model is a feasible skill acquisition exercise. By eliminating the need for a skilled microsurgical assistant, as well as, improved microsurgical technology, the robotic system may prove to be a crucial player in future microsurgical skill training.

The Paradoxical Relationship Between Donor Distance and Survival After Heart Transplantation.

BACKGROUND: Concerns over prolonged allograft ischemia have limited the widespread adoption of long-distance organ procurement in heart transplantation (HT). We sought to assess whether donor distance from the center of transplantation independently affects mortality. METHODS: We queried the United Network for Organ Sharing (UNOS) database for adults undergoing isolated HT from 2005 to 2012. Risk-adjusted Cox proportional hazards models were constructed for the primary outcomes of 30-day and 1-year mortality, and the independent impact of donor distance from transplantation center at the time of procurement was assessed. RESULTS: We included 14,588 heart transplant recipients. The mean distance from location of the donor heart to transplantation center was 184.4 ± 214.6 miles; 1,214 HTs (8.3%) occurred at the same location as the donor heart. Ischemic times were inversely related to the distance from the site of donor procurement to recipient transplantation. After risk adjustment, longer donor distances (in miles) were associated with a significantly lower risk of mortality at both 30 days (hazard ratio [HR] 0.9993, 95% confidence interval [CI]: 0.9988 to 0.9998, p < 0.01) and 1 year (HR 0.9994, 95% CI: 0.9989 to 0.9999, p = 0.015). Risk-adjusted hazards for mortality were significantly reduced in recipients receiving hearts from more than 25 miles away. The hazard reduction was greatest in recipients receiving donor hearts from more than 500 miles away (1-year HR 0.64, p < 0.01; 30-day HR 0.47, p < 0.01). CONCLUSIONS: Longer distances between donor location and center of heart transplantation are associated with a reduced hazard for survival at 30 days and 1 year, despite greater ischemic times. Future studies are necessary to elucidate the protective factors surrounding long-distance heart donation.

Complications After Cardiac Operations: All Are Not Created Equal.

BACKGROUND: Postoperative complications are associated with increased morbidity and mortality after cardiac operations. We sought to quantify the effect of multiple complications on noninstitutionalized recovery after cardiac operations. METHODS: We identified 2,477 adult patients from our institutional cardiac surgery database who underwent one of seven index cardiac surgical operations from 2011 to 2014. We calculated failure-to-rescue rates for all individual complications and combinations of complications. We used multivariable logistic regression to determine the effect of the interaction of postoperative complications on our primary outcome of operative death and secondary outcomes of prolonged hospital length of stay and discharge to a location other than home. RESULTS: From 2011 to 2014, at least one complication occurred in 366 patients (14.8%), and multiple complications occurred in 102 (4.1%), including three complications in 20 (0.8%). Operative mortality occurred in 41% of patients with multiple complications vs in 4.9% of those with an isolated complication and in 0.7% of those without complications. Significant interactions that negatively affected survival were noted between nearly every combination of complications. The occurrence of renal failure and unplanned reoperation together were associated with increased deaths (odds ratio, 108.4; 95% confidence interval, 13.5 to 869.9; p < 0.001). Median hospital length of stay and discharge rates to a location other than home correlated positively with the number of postoperative complications. CONCLUSIONS: Major complications after cardiac operations are associated with an increased risk for operative death, longer hospital length of stay, and higher rates of discharge to a location other than home. These adverse outcomes are magnified when multiple complications are encountered.

Planned Versus Unplanned Reexplorations for Bleeding: A Comparison of Morbidity and Mortality.

BACKGROUND: Mediastinal reexplorations for bleeding are associated with significant morbidity and mortality. This study hypothesized that bleeding patients who undergo delayed chest closure after an initial operation experience similar outcomes in comparison with patients who have initial chest closure and later require an unplanned reexploration. METHODS: This study included all patients in the Johns Hopkins University School of Medicine (Baltimore, MD) institutional Society of Thoracic Surgeons (STS) database who underwent cardiac surgical procedures or thoracic transplantation from 2011 to June 2014, had an intraoperative red blood cell transfusion requirement of 2 units or more, and required mediastinal reexploration for bleeding. Reexplorations were classified as planned (temporary chest closure for a planned "second look") or unplanned (initial sternal closure and subsequent reexploration). The two groups were then propensity matched. The primary outcome was 30-day mortality. Secondary outcomes were major complication rates, hospital length of stay, duration of mechanical ventilation, and incidence of postoperative pneumonia and cardiac arrest. RESULTS: Among 3,293 patients, 110 (3.3%) met inclusion criteria and required mediastinal reexploration for bleeding. This group included 62 planned (56%) and 48 unplanned (44%) reexplorations. After propensity matching 30 pairs of patients across 16 variables, operative mortality rates were comparable (37% vs 37%; p = 1.00) between unplanned and planned reexploration cohorts. There were no differences in rates of deep sternal wound infection, renal failure, postoperative hospital length of stay, pneumonia, or cardiac arrest, with the exception of a higher rate of prolonged intubation (93% vs 53%; p < 0.01) in the planned reexploration group. CONCLUSIONS: Delayed sternal closure is a safe alternative to initial definitive chest closure when concern exists for postoperative bleeding.

Differential outcomes of type A dissection with malperfusion according to affected organ system.

BACKGROUND: The management of malperfusion in patients with acute Stanford type A aortic dissection is controversial. We sought to determine the rate of resolution of malperfusion following primary repair of the dissection and to identify anatomic sites of malperfusion that may require additional management. METHODS: We reviewed the hospital records of patients who presented to our institution with acute type A aortic dissection. Patient demographics, operative details and post-operative course were retrospectively extracted from our institutional electronic database. Depending upon the anatomic site, malperfusion was identified by a combination of radiographic and clinical definitions. Data were analyzed using standard univariable and multivariable methods. RESULTS: Between 1997-2013, 101 patients underwent repair of an acute type A dissection. Thirty-day mortality was 14.9% (15/101); there were five intraoperative deaths. There was no difference in 30-day mortality between patients with or without malperfusion (15.4% vs. 14.7%, P=0.93). Twenty-five patients (24.7%), who survived surgery, presented with 31 sites of malperfusion. Anatomic sites included extremities [14], renal [10], cerebral [5] and intestinal [2]. Of these 31 sites, malperfusion resolved in 18 (58.1%) with primary aortic repair. Renal malperfusion resolved radiographically in 80.0%, with no difference in the incidence of insufficiency (44.0% vs. 35.2%; P=0.44) or dialysis (20.0% vs. 15.5%; P=0.61) between malperfusion and non-malperfusion patients. Extremity malperfusion resolved postoperatively in six out of 14 patients. Of the remaining eight, concomitant revascularization was performed in four, one had an amputation and three required postoperative interventions. Advanced patient age (OR: 1.06, 95% CI: 1.01-1.12, P=0.02) was an independent predictor of 30-day mortality, while preoperative malperfusion was not (OR: 0.77, 95% CI: 0.18-3.31, P=0.73). CONCLUSIONS: Malperfusion complicating acute type A dissection can be managed in many patients by aortic replacement alone with low overall mortality. Most cases of renal and cerebral malperfusion resolved following aortic surgery. Revascularization was frequently necessary in patients with extremity malperfusion. Patients presenting with intestinal ischemia had very poor outcomes. A patient-specific approach is recommended in such complex patients.

Bilateral internal thoracic artery grafting: Does graft configuration affect outcome?

BACKGROUND: Despite evidence that bilateral internal thoracic arteries (ITAs) improve long-term survival after coronary artery bypass grafting (CABG), uptake of this technique remains low. We directly compared bilateral ITA graft configurations and examined long-term outcomes. METHODS: We reviewed 762 patients who underwent CABG using bilateral ITA grafts at our institution between 1997 and 2014. The outcomes were mortality and a composite revascularization end point defined as need for percutaneous coronary intervention or repeat CABG. Adjusted subgroup analyses were performed using propensity score-adjusted Cox proportional hazards modeling. RESULTS: The cohort was divided into 4 groups: in situ (left ITA [LITA] anastomosed to the left anterior descending artery [LAD] with in situ right ITA [RITA] anastomosed to the left coronary circulation [239 patients]); in situ LITA-LAD and in situ RITA-right coronary circulation (239 patients); in situ RITA-LAD with in situ LITA-left coronary circulation (185 patients); and in situ LITA-LAD with a free RITA as a composite graft with inflow from the LITA or a saphenous vein graft (99 patients). Over a median follow-up of 1128 days, there were 47 deaths, 58 late percutaneous coronary interventions, and 7 repeat CABG procedures. Unadjusted Kaplan-Meier analysis revealed a difference in need for repeat revascularization among the 4 groups (log rank P = .049). However, after statistical adjustment, graft configuration was not an independent predictor of repeat revascularization or death. CONCLUSIONS: Bilateral ITA graft configuration has no independent effect on need for repeat revascularization or long-term survival. Therefore, the simplest technique, determined by individual patient characteristics, should be selected.