Analysis of the Early Results of 693 Patients Undergoing Valvular Reoperation Between 1993 and 2011.

BACKGROUND: The study aim was to identify factors affecting early mortality in valvular reoperations. METHODS: Between January 1993 and December 2011, a total of 693 patients who had undergone valvular reoperations due to problems with previously implanted mechanical and biological valves, new valve degeneration or valve failure after a reconstructive procedure was included in the study. Factors affecting early mortality were identified by the examination of preoperative and perioperative data, using multivariate analysis. RESULTS: The average age of the patients was 44.9 years. For all patients, overall hospital mortality was 15.9%, while hospital mortality rates were 12.9% and 35.3% for elective operation and urgent/emergency treatment, respectively. Factors affecting early mortality in the multivariate analysis were longer total perfusion time (>120 min, p = 0.001), emergency or urgent treatment (p = 0.001), and the presence of preoperative renal failure (p = 0.001). CONCLUSIONS: Mortality for elective patients in valvular reoperations was within an acceptable range. Total mortality was dependent on a high mortality level of emergency/urgency of the cases. The use of a well-defined protocol in valvular reoperations may decrease hospital mortality.

Acute type-A aortic dissection with obstruction of the right coronary artery.

Occlusion of a coronary artery by an acute type A aortic dissection presents a life-threatening emergency that is rarely seen and easy to misdiagnose. We present the case of a 75-year-old male who experienced sudden onset of severe left-sided chest pain due to an acute type A aortic dissection that obstructed the right coronary artery. Following an initial misdiagnosis of acute coronary syndrome, imaging revealed the presence of an aortic dissection. An emergency modified Bentall procedure was performed, in which the damaged aorta and aortic valve were replaced.

Posterobasal left ventricular aneurysms: surgical treatment and long-term outcomes.

This retrospective study analyzes short- and long-term outcomes in 18 patients who underwent repair of posterobasal left ventricular aneurysm from January 1993 through December 2009. As concomitant procedures, mitral reconstruction was performed in 4 patients, ventricular septal defect repair in 2 patients, and coronary artery bypass grafting in 17 patients. In regard to surgical technique, 10 patients underwent patch repair and 8 underwent closure by linear suture. The in-hospital mortality rate was 11% (2 patients). An intra-aortic balloon pump was placed postoperatively in 1 patient. One patient underwent reoperation for mediastinitis and 2 for bleeding. The 1-, 5-, and 10-year survival rates were 82%, 76%, and 52%, respectively. Posterobasal left ventricular aneurysm repair can be performed with low short-term mortality rates and good long-term outcomes. It must be judged whether a linear repair or patch repair is better, in accordance with aneurysm size and the concomitant operative procedure, if any.

Simultaneous beating heart coronary artery bypass surgery and modified radical mastectomy.

Concomitant surgeries for unrelated diseases can be performed to minimize the risks associated with surgery and general anesthesia. In treating a male patient with breast cancer and severe coronary artery disease, we used the beating heart technique for a coronary artery bypass graft to avoid the negative effects of on-pump bypass on the possible acceleration of tumor growth. In this report, we present a unique case of concomitant off-pump coronary artery bypass graft surgery and modified radical mastectomy in a 56-year-old man.

Repair of an extensive iatrogenic tracheal rupture with a pleural patch and a vascular graft.

Here we describe a 48-year-old woman who suffered a 7-cm rupture in the lower trachea after intubation with a double-lumen tube. We repaired the rupture with a new technique using a pleural patch reinforced by a ringed vascular graft. This technique appears to be appropriate for use in patients who have large tracheal ruptures to avoid tracheal stenosis.

Surgical treatment of culture-negative aortic infective endocarditis.

BACKGROUND: We retrospectively analyzed the results of operations done for culture-negative aortic infective endocarditis at a single center over a period of 26 years. METHODS: From June 1985 to January 2011, we operated on 82 patients with infective endocarditis of the aortic valve for which the results of culture were negative. Sixty-five of the patients (79.3%) were male and the patients' mean age was 38.0±14.4 years (range, 9 to 73 years). Nineteen of the patients (23.2%) had a history of previous cardiac surgery, and 16 of the patients (19.5%) had endocarditis of a prosthetic valve. Two patients (2.4%) had conduction blocks. The mean duration of follow-up was 7.1±4.3 years (range, 0.1 to 16.9 years), yielding a total of 477.0 patient-years for the study population. RESULTS: One hundred and thirty-eight procedures were done on the 82 patients in the study. The most common procedure was aortic valve replacement, which was done on 67 patients (81.7%). Thirty-nine patients (47.6%) had concomitant procedures done on the mitral valve. In-hospital death occurred in 14 patients (17.1%). Postoperatively, 17 patients (20.7%) had a low cardiac output and 9 patients (11.0%) had heart block, of whom 3 required implantation of a permanent pacemaker. The actuarial rate of survival of the patient population at 1, 5, 10, and 15 years was 92.5%±3.2%, 85.6%±4.5%, 82.5±5.3%, and 72.2±10.7% respectively. CONCLUSIONS: Culture-negative infective endocarditis is a major problem in the diagnosis and treatment of a significant proportion of cases of endocarditis. Most of the affected patients are in a healed state, which could be a cause of negative culture results. In-hospital mortality in patients with culture-negative infective aortic endocarditis is associated with a history of previous cardiac surgery, whereas long-term mortality in this patient population is associated with nonaortic procedures.

Surgical treatment of cardiac hydatid disease in 13 patients.

Cardiac hydatidosis is an uncommon but potentially fatal disease. It remains endemic in developed and developing countries. Its clinical presentation ranges from an absence of symptoms to congestive heart failure or other life-threatening sequelae. Herein, we report our clinical experience with the disease. From 1991 through 2009, 7 male and 6 female patients (mean age, 36 +/- 18.3 yr; age range, 10-68 yr) underwent surgical treatment at our hospital for cardiac hydatid disease. Cardiac hydatidosis was established as a component of multiorgan echinococcosis in 8 patients, and it was diagnosed upon echocardiographic examination in the other 5 during investigation of their nonspecific symptoms. Hydatid cysts were found in the left ventricle (in 5 patients); the right ventricle (in 3); the interventricular septum (in 2); and the interatrial septum, right atrium, and left atrium (in 1 each). All 13 patients underwent sternotomy and surgery under cardiopulmonary bypass. No intraoperative rupture or operative death occurred. The only sequela was complete atrioventricular block that necessitated pacemaker implantation in a patient whose hydatid cyst had involved the basal interventricular septum. All patients underwent subsequent treatment with albendazole (400 mg/d). One patient experienced a recurrence 1 year postoperatively. We discuss our surgical approaches, the outcomes in our patients, and diagnostic and therapeutic recommendations.

Increasing numbers of penetrating cardiac trauma in a new center.

BACKGROUND: Our aim was to express the importance of emergency diagnosis and surgical approach in penetrating cardiac trauma patients. METHODS: Kosuyolu Heart and Research Hospital moved to its new location in Cevizli Kartal in June 2005. Due to its close proximity to the main roads of the city, the number of trauma cases has increased tremendously. We have retrospectively examined our penetrating cardiac trauma cases treated between June 2005 and September 2008. RESULTS: Twenty-six trauma cases were admitted to our clinic with penetrating cardiac trauma. Twenty of them were operated on an emergency basis. One (5%) had a gunshot wound while the other 19 (95%) had stab wounds. Four were female (20%) and 16 were male (80%). Average age of the patients was 24.9+/-10.1 (12-49) years. Telecardiography and transthoracic echocardiography were used for diagnosis. Surgical approaches were median sternotomy in 14 and left anterolateral thoracotomy in 6 cases. The right ventricle was damaged in 12, left ventricle in 7 and pulmonary artery in 1. Additionally, 5 patients had lung injury, 1 had brachiocephalic vein injury and 1 had coronary artery injury. One patient was re-explored for bleeding. There were two mortalities (10%) postoperatively. CONCLUSION: Rapid transfer to the emergency department, accurate and quick diagnosis and aggressive surgical approach will increase survival in penetrating cardiac trauma.

Extended septal myectomy for hypertrophic obstructive cardiomyopathy with anomalous insertion of chordae tendineae.

We present a case of hypertrophic cardiomyopathy with anomalous insertion of mitral valve chordae tendineae diagnosed with two-dimensional echocardiogram. A high gradient was found in left ventricular outflow tract (LVOT) obstruction, which was attributed to the fixed gradient caused by anomalous insertion of chordae tendineae in addition to the gradient of dynamic LVOT obstruction. The misinserted chordae tendineae were resected, and an extended septal myectomy was performed. Follow-up echocardiography showed reduction of the pressure gradient to less than 40 mm Hg in the LVOT, and the patient had no symptoms during the 1-year follow-up period.

A highly fatal intraoperative urgency--aortic dissection complicating heart surgery.

BACKGROUND: Aortic dissection is associated with high mortality. Despite its rarity, it is often fatal. AIM: We have retrospectively analysed acute aortic dissections occurring intraoperatively (IAAD). METHODS: Patients' preoperative risk factors, and operative and postoperative courses were analysed from the hospital records retrospectively. RESULTS: From 1985 to 2009, we performed 29 683 cardiac operations. Ten patients (0.43 per thousand) (mean age 66.5+/-7 years) were diagnosed with IAAD. There were type 2 dissections in 9 and one patient had it extending beyond the arcus. Four patients were operated on for coronary artery disease, 2 for mitral and 2 for aortic valve diseases. Two patients had concomitant valvular or valvular and coronary procedures. IAAD was identified after decannulation in 5, after creating the holes for proximal anastomoses in 3 and after declamping the aorta in 2 patients. Preoperatively, 6 (60%) patients had hypertension and 4 had hypercholesterolaemia (40%). No other significant risk factors could be identified. Hypothermic circulatory arrest was used in 6 operations. The dissected segment was replaced with a graft in 9 patients whereas the remaining patient had concomitant arcus aorta replacement and elephant trunk procedure. Aortoplasty with Dacron patch was used in one patient. All patients required inotropic and 4 patients IABP support postoperatively. Three (30%) patients died. CONCLUSIONS: The IAAD may occur in any patient at any phase of cardiac surgery. The surgeon should always be aware of the possibility of this complication. It is much better to prevent the IAAD than to treat it. When detected, abrupt change of the operation plan and reparative measures for the dissection should be undertaken.

Does acute aortic dissection display seasonal variation?

BACKGROUND: The relation between cardiovascular diseases and the seasons is well known; however, only a few reports have addressed the seasonal aspects of acute aortic dissections. We investigated whether presentation of acute aortic dissection has monthly/seasonal variations. METHODS: From February 1985 to January 2006, 165 consecutive patients with aortic dissection admitted to our institution were reviewed. During this period, regional monthly atmospheric pressure data were supplied by the state's meteorological service. The mean and SD of atmospheric pressure data were analyzed statistically. RESULTS: The frequency of acute aortic dissection was found to be significantly higher during winter versus other seasons (P = .041). A relatively high positive correlation was found between the incidence of acute aortic dissection and the mean atmospheric pressure (P = .037). The study confirmed monthly variation with a peak in January. In winter, the frequency of acute aortic dissection was higher in male than in female patients. CONCLUSIONS: This study demonstrates that the occurrence of acute aortic dissection has significant seasonal/monthly variations. Thus, these observations may be a guide for prevention of acute aortic dissections by structuring treatment approaches with consideration given to the times of the year that patients are most vulnerable.

Long-term results of aortic root replacement: 15 years' experience.

BACKGROUND: Long-term results of aortic root replacements and the factors affecting long-term mortality were analyzed. METHODS: We operated on 254 patients from June 1993 to November 2008 for aortic root replacement with Bentall de Bono procedure. Two hundred five patients were male (80.7%) and 49 patients (19.3%) were female. The mean age was 48.3 +/- 14.7 years (range, 14 to 78 years). We performed 72 concomitant procedures in 69 patients, and the most commonly performed procedure was coronary artery bypass grafting in 37 patients (14.6%). The most common indication for aortic root replacement was aneurysm in 235 patients (92.5%). Thirty-four patients (13.4%) had Marfan syndrome. Hypothermic circulatory arrest was used in 52 patients (20.5%). After removing the clamp, we had to reclamp the aorta in 26 patients (10.2%) undergoing operation. RESULTS: Postoperatively 30 patients (11.8%) had in-hospital mortality. The late mortality was 2.8% (7 patients). The most common reason for hospital mortality was low cardiac output (18 in 30 patients; 51.4%). Neurologic complications were seen in 16 patients (6.3%). The mean duration of hospital stay was 16.6 +/- 11.3 days (range, 5 to 77 days). Postoperative follow-up was 6.3 +/- 4.5 years (range, 0 to 15.5 years) on average. Late mortality was significantly affected by Marfan syndrome (p = 0.025) and reclamping the aorta (p = 0.036). Actuarial survival for the overall 254 patients is 88.4% +/- 2.1%, 87.4% +/- 2.2%, and 84.5% +/- 2.56% at 1, 3, and 10 years, respectively. CONCLUSIONS: The late-term results of aortic root replacement with the modified Bentall de Bono procedure are satisfactory. Survival is decreased in patients with Marfan syndrome and in the patients who had reclamping intraoperatively.

Hypercholesterolemia association with aortic stenosis of various etiologies.

BACKGROUND: Hypercholesterolemia has been found to be associated with aortic valve stenosis and to resemble the inflammatory process of atherosclerosis in many studies. The aim of this study was to investigate the role of hypercholesterolemia in development of aortic valve calcification in different etiologies. METHODS: The study included 988 patients with rheumatic, congenital, or degenerative aortic stenosis, who underwent aortic valve replacement at Kosuyolu Heart and Research Hospital between 1985 and 2005. Effects of hypercholesterolemia and high low-density lipoprotein level on calcific aortic stenosis or massive aortic valve calcification were analyzed for each etiologic group. RESULTS: Both univariate and multivariate analyses revealed that the high serum cholesterol level (>200 mg/dL) was related to massive aortic valve calcification in all patients (p = 0.003). Hypercholesterolemia was linked to calcific aortic stenosis and massive calcification in patients with degenerative etiology (p = 0.02 and p = 0.01, respectively) and it was related to massive calcification in patients with congenital bicuspid aorta (p = 0.02). Other independent risk factors for calcific aortic stenosis and massive calcification in the degenerative group were high low-density lipoprotein level (>130 mg/dL; p = 0.03 and p = 0.05, respectively) and high serum C-reactive protein level (p = 0.04 and p = 0.05, respectively). CONCLUSIONS: Hypercholesterolemia is related to increased risk of aortic valve calcification in patients with degenerative and congenital etiology. Preventive treatment of hypercholesterolemia could play an important role to decrease or inhibit development of aortic valve calcification.

Effects of patient-prosthesis mismatch on postoperative early mortality in isolated aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Small valve size and patient-prosthesis mismatch (PPM) generate high postoperative transvalvular gradients and may decrease both early and long-term survival. The study aim was to evaluate whether mismatch affected early mortality after aortic valve replacement (AVR) for isolated aortic stenosis (AS). METHODS: A total of 701 patients (437 males, 264 females; mean age 53.3 +/- 15.1 years; range: 14-84 years) with pure AS underwent AVR at the authors' institution between 1985 and 2005. The majority of patients (92%) received a mechanical valve. PPM was considered severe if the indexed effective orifice area was < or =0.65 cm2/m2, and moderate if > 0.65 but < or = 0.85 cm2/m2. RESULTS: Moderate-severe PPM was present in 47% of patients, and severe PPM in 13%. The early mortality was 5.4% (n=38). Multivariate analysis revealed age > or = 70 years (p < 0.001), female gender (p = 0.04) and severe PPM (p = 0.003) as independent predictors of early mortality. Moderate mismatch was not a predictor of early mortality on both univariate and multivariate analysis. Left ventricular dysfunction (ejection fraction < or = 40%) was a risk factor for early mortality only in patients with severe PPM. CONCLUSION: Patient-prosthesis mismatch should be prevented in patients undergoing AVR for isolated AS, especially in those with left ventricular dysfunction.

Aortic valve replacement in isolated severe aortic stenosis with left ventricular dysfunction: long-term survival and ventricular recovery.

OBJECTIVE: The aim of this study was to assess the effects of aortic valve replacement (AVR) on the recovery of left ventricular function and the predictors for long-term survival in patients suffering from isolated severe aortic stenosis (AS) with a significant left ventricular dysfunction (LVD). METHODS: This retrospective study was conducted on 46 patients with isolated severe AS and LVD [left ventricular ejection fraction (LVEF) = or < 40%] who underwent AVR in our clinic between January 1993 and March 2006. Patients with coronary artery disease, with more than moderate aortic regurgitation (>2), with previous valve replacement or repair, and with other valve pathologies were excluded. The mean aortic valve area was 0.7+/- 0.09 cm2. The following fourteen variables were analyzed: etiology, age (= or >70 years), sex, preoperative New York Heart Association (NYHA) functional class, chronic obstructive pulmonary disease, hypertension, diabetes, peripheral arterial disease, chronic renal insufficiency, need for concomitant procedures for the ascending aorta, cardiopulmonary bypass time = or >120 min, aortic cross-clamp time = or >90 min, intraaortic balloon pump support and inotropic support. Statistical analysis for comparison of pre- and postoperative changes in clinical and functional variables was performed using Wilcoxon rank test. The predictors of early mortality after AVR were analyzed using logistic regression analysis and late survival was studied using Cox proportional regression and Kaplan Meier survival analyses. RESULTS: Operative mortality was 8.6% with four patients. As the result of univariate logistic regression analysis, preoperative NYHA functional class = or >3 was found to be predictive of early mortality. Patients with NYHA class = or >3 had 12.6 times (OR: 12.6; 95%CI: 1.2-131.3; p=0.035) higher probability of early mortality than those with a lower NYHA class. However, multivariate logistic regression analysis demonstrated no predictor for early mortality. A positive change was observed in the LVEF in 79.3% of survivors and the mean LVEF increased from 34.5+/- 3.9% to 44.7+/- 10.4% (p<0.001). There were eight (19%) late deaths. Actuarial survival was 83. +/- 5.9% at 5 years and 59.6% +/- 10.9% at 10 years. Cox proportional hazards regression analysis demonstrated diabetes mellitus (HR: 6.6; 95% CI: 1.19-36.9, p=0.031) and intraaortic balloon pump use (HR: 10.7; 95% CI: 2.9-39.7, p<0.001) as significant predictors for late mortality. CONCLUSION: Left ventricular ejection fraction and symptoms improve after AVR in patients with isolated severe AS and LVD with an acceptable operative mortality and satisfactory long-term survival.

Second and third cardiac valve reoperations: factors influencing death and long-term survival.

We retrospectively investigated preoperative and postoperative characteristics in order to determine factors that affected hospital death in patients who underwent 3 or 4 separate cardiac valvular surgeries. The hospital records of 53 such patients who were operated upon from 1985 through 2006 were obtained. The patients were divided into 2 groups according to whether their initial operation was a closed mitral commissurotomy (group C, n = 33) or open-heart surgery with cardiopulmonary bypass (group O, n = 20). In group C, all patients who had initially undergone 1 or 2 closed mitral commissurotomy procedures underwent subsequent reoperations that entailed median sternotomy and cardiopulmonary bypass. Sternotomy and cardiopulmonary bypass had been used in valvular operations of all group O patients. The total early mortality rate was 11.3% (6 of 53 patients). Multivariate analysis revealed that longer aortic cross-clamp times and double valve replacement at last operation significantly increased the risk of death. Herein, we discuss our conclusion that 3rd or 4th cardiac valvular operations incurred acceptable early postoperative mortality rates.

Factors associated with long-term survival following cardiac transplantation.

OBJECTIVE: By improving short and long-term survivals, cardiac transplantation would be a more realistic curative treatment modality. The aim of this study was to evaluate factors associated with the long-term survival following cardiac transplantations in our center. METHODS: Forty-four patients were operated on cardiac transplantation between 1989 and November 2006. The study was designed in a retrospective manner and all data were collected from hospital records. Our study population consisted of 16 patients (Group A) who survived >1 month, but died <2 years after cardiac transplantation and 17 patients (Group B) who survived more than 2 years. All patients had triple immunosuppressive therapy (cyclosporine, azathioprine, corticosteroid). Statistical analyses were performed using Fischer's exact and Mann Whitney U tests, and multivariate regression analysis. Survival was analyzed using Cox proportional hazard regression analysis. RESULTS: Group B patients had lower pre-transplant creatinine levels (0.93+/-0.28 mg/dl vs. 1.16+/-0.21 mg/dl, p=0.033) younger donor age (24.5+/-6.3 years vs. 30.1+/-8.1 years, p=0.017) and more male donors (82.3% vs. 50%, p=0.05) as compared with Group A patients. The perioperative and follow-up analysis showed that patients with long-term survival had shorter ischemic time (141.5+/-33.2 min vs. 182.5+/-49.2 min, p=0.007), aortic cross clamp time (65.9+/-10.2 min vs. 83.6+/-7.9 min, p<0.001), less amount of blood transfusion (3.4+/-1.6 units vs. 5.0+/-1.5 units, p=0.01), better NYHA status after operation (1+/-0 vs. 1.63+/-0.72, p=0.014) and less frequent acute rejection episodes (11.8% vs. 68.8%, p<0.001) than those with short-term survival after operation. Cox proportional hazard regression analysis showed higher preoperative creatinine level (HR=42.6, 95% CI 4.67-388.21, p=0.001), acute rejection (HR=4.45, 95% 1.44-13.77, p=0.01), early postoperative functional status (HR=4.84, 95% CI 1.9-12.27, p=0.001) and unsatisfactory rejection surveillance protocol in the first 6 months after transplantation (HR=0.2, 95% CI 0.07-0.67, p=0.008) were prominent factors associated with the long-term survival. CONCLUSION: The availability of the donor hearts from younger male donors with the shortest ischemic times is identified as the most significant factor improving long-term survival. The main strategy in cardiac transplantation should be shortening ischemic times and applying strict postoperative follow-up.

Association of prolidase activity, oxidative parameters, and presence of atrial fibrillation in patients with mitral stenosis.

BACKGROUND: Mitral stenosis (MS) is a common cause of atrial fibrillation (AF). Oxidative stress and inflammation factors were shown to be involved in atrial remodeling. The study aim was to compare the oxidative parameters and prolidase activity in severe MS patients with and without AF. METHODS: The study population was comprised of 33 patients with MS and sinus rhythm (group I), 27 patients with MS and AF (group II), and 25 healthy controls (group III). Plasma prolidase activity, total antioxidant capacity (TAC), total oxidative status (TOS), and oxidative stress index (OSI) were determined. Additionally, we measured tissue TOS and TAC in patients with mitral valve replacement. RESULTS: TAC and OSI were higher, but TOS and prolidase were lower in patients with MS than control (all p <0.001). These parameters were similar in group I and group II (ANOVA p >0.05). Tissue TAC was significantly lower in group II than group I (0.015 +/- 0.01 vs. 0.026 +/- 0.01 mmol Trolox equiv/L, p = 0.014), tissue TOS was similar between groups I and II (0.24 +/- 0.06 vs. 0.22 +/- 0.05 mmol Trolox equiv/L, p = 0.161). Presence of AF was correlated with systolic blood pressure, left atrial diameter, plasma TAC, tissue TAC, plasma TOS, plasma OSI, and plasma prolidase activity. Tissue TAC level (beta = -0.435, p = 0.006) and left atrial diameter (beta = 0.460, p = 0.003) were independently related with presence of AF in patients with MS. CONCLUSIONS: This study suggested that the presence of AF in patients with severe MS may be associated with the plasma prolidase activity, tissue and plasma oxidative parameters.

Five-year follow-up of drug utilization for secondary prevention in coronary artery disease.

OBJECTIVE: Despite the availability of various prevention guidelines on coronary artery disease, secondary prevention practice utilizing aspirin, beta-blockers, angiotensin converting enzyme inhibitors and statins still can be sub-optimal. In this study, we aimed to assess the guideline adherence of secondary prevention prescribing and the continuity of adherence for a 5-year period in a small cohort of patients angiographically diagnosed to have coronary artery disease. METHOD: In this prospective study, 73 patients who were angiographically diagnosed to have CAD were followed up for 5 years. The baseline demographic and clinical data were collected just before angiography. The baseline drug data were collected at the day of discharge. The fifth year data were taken from the patients via face-to-face consultations or phone interviews. RESULTS: The 'initial prescribing rate' at discharge was found to be 82% for aspirin, 49% for statins, 44% for ACE inhibitors and 55% for beta-blockers. 'Continuity of prescribing' for 5 years was 45% for aspirin, 26% for statins, 17% for ACE inhibitors and 20% for beta-blockers. CONCLUSIONS: Besides the sub-optimal prescribing of secondary prevention drugs, absence of continuity of prescribing seems to be a challenging issue in pharmaceutical care of coronary artery disease patients.