Impact of age on the use of adjuvant treatments in patients undergoing surgery for colorectal cancer: patients with stage III colon or stage II/III rectal cancer.

BACKGROUND: Many older patients don't receive appropriate oncological treatment. Our aim was to analyse whether there are age differences in the use of adjuvant chemotherapy and preoperative radiotherapy in patients with colorectal cancer. METHODS: A prospective cohort study was conducted in 22 hospitals including 1157 patients with stage III colon or stage II/III rectal cancer who underwent surgery. Primary outcomes were the use of adjuvant chemotherapy for stage III colon cancer and preoperative radiotherapy for stage II/III rectal cancer. Generalised estimating equations were used to adjust for education, living arrangements, area deprivation, comorbidity and clinical tumour characteristics. RESULTS: In colon cancer 92% of patients aged under 65 years, 77% of those aged 65 to 80 years and 27% of those aged over 80 years received adjuvant chemotherapy (χ2trends < 0.001). In rectal cancer preoperative radiotherapy was used in 68% of patients aged under 65 years, 60% of those aged 65 to 80 years, and 42% of those aged over 80 years (χ2trends < 0.001). Adjusting by comorbidity level, tumour characteristics and socioeconomic level, the odds ratio of use of chemotherapy compared with those under age 65, was 0.3 (0.1-0.6) and 0.04 (0.02-0.09) for those aged 65 to 80 and those aged over 80, respectively; similarly, the odds ratio of use of preoperative radiotherapy was 0.9 (0.6-1.4) and 0.5 (0.3-0.8) compared with those under 65 years of age. CONCLUSIONS: The probability of older patients with colorectal cancer receiving adjuvant chemotherapy and preoperative radiotherapy is lower than that of younger patients; many of them are not receiving the treatments recommended by clinical practice guidelines. Differences in comorbidity, tumour characteristics, curative resection, and socioeconomic factors do not explain this lower probability of treatment. Research is needed to identify the role of physical and cognitive functional status, doctors' attitudes, and preferences of patients and their relatives, in the use of adjuvant therapies.

Predictors of 1- and 2-year mortality in patients with rectal cancer.

AIM: Tools are needed to aid in the assessment of the prognosis of patients with rectal cancer regarding the risk of medium-term mortality. The aim of this study was to develop and validate clinical prediction rules for 1- and 2-year mortality in patients undergoing surgery for rectal cancer. METHOD: A prospective cohort study of patients diagnosed with rectal cancer who underwent surgery was carried out. The main outcomes were mortality at 1 and 2 years after surgery. Background, clinical parameters and diagnostic test findings were evaluated as possible predictors. Multivariable survival models were used in the statistical analyses. RESULTS: Predictors of 1-year mortality were being a current smoker [hazard ratio (HR) 4.98], having a Charlson index adjusted by age > 5 (HR 2.61), the presence of vascular, perineural or lymphatic invasion (HR 3.30), the presence of residual tumour at the operation (R-stage) (HR 8.64) and TNM stage (HR for TNM IV 5.10) [concordance index (C-index) 0.799 (95% CI: 0.71-0.89)]. Age greater than 80 years (HR 2.19), being a current smoker (HR 2.20), the pre-intervention haemoglobin level (HR 2.02), need for blood transfusion (HR 2.12), vascular, perineural or lymphatic invasion (HR 2.59), R-stage of the operation (HR 6.13) and TNM stage (HR for TNM IV 4.43) were predictors of 2-year mortality [C-index 0.779 (0.718-0.840)]. Adjuvant chemotherapy was an additional predictor at both outcome durations. CONCLUSION: These clinical parameters show good predictive values and are easy and quick-to-use tools to help in clinical decision making.

Association between social support, functional status, and change in health-related quality of life and changes in anxiety and depression in colorectal cancer patients.

OBJECTIVE: The aim of this study was to explore the association between baseline social support, functional status, and change in health-related quality of life (HRQoL) in colorectal cancer patients and change in anxiety and depression measured by Hospital Anxiety and Depression Scale (HADS) at 1 year after surgery. METHODS: Consecutive patients who were due to undergo therapeutic surgery for the first time for colon or rectal cancer in 9 hospitals in Spain were eligible for the study. Patients completed the following questionnaires before surgery and 12 months afterward: 1 HRQoL instrument, the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire; a social support questionnaire, the Duke-UNC Functional Social Support Questionnaire; the Barthel Index, to assess functional status; the HADS, to assess anxiety and depression; and questions about sociodemographic information. General linear models were built to explore the association between social support, functional status, and change in HRQoL and changes in anxiety and depression 12 months after surgery. RESULTS: A total of 947 colorectal cancer patients took part in the study. Patients' functional status, social support, and change in HRQoL were associated with changes in anxiety and depression. Greater social support and improvements in physical, cognitive, and social functioning and in insomnia resulted in improvements in anxiety and depression. No functionally independent patients were associated with lesser improvements in anxiety and depression. CONCLUSIONS: Colorectal cancer patients who have more social support, are functionally independent and have higher improvements in HRQoL may have better results in anxiety and depression at 1 year after surgery, adjusting for age, gender, location, occupation, and baseline HADS scores.

Association of social support, functional status, and psychological variables with changes in health-related quality of life outcomes in patients with colorectal cancer.

BACKGROUND: The aim of this study was to explore the association of social support received, and functional and psychological status of colorectal cancer patients before surgery with changes in health-related quality of life (HRQoL) outcomes measured by EORTC QLQ-C30 at 1-year post-intervention. METHODS: Consecutive patients that were because of undergo therapeutic surgery for the first time for colon or rectum cancer in nine hospitals in Spain were eligible for the study. Patients completed questionnaires before surgery and 12 months afterwards: one HRQoL instrument, the EORTC QLQ-C30; a social network and social support questionnaire, the Duke-UNC Functional Social Support Questionnaire; the Hospital Anxiety and Depression Scale, to assess anxiety and depression; and the Barthel Index, to assess functional status; as well as questions about sociodemographic information. General linear models were built to explore the association of social support, functional status, and psychological variables with changes in HRQoL 12 months after intervention. RESULTS: A total of 972 patients with colorectal cancer took part in the study. Patients' functional status, social support, and anxiety and depression were associated with changes in at least one HRQoL domain. The higher functional status, and the higher social support, the more they improved in HRQoL domains. Regarding anxiety and depression, the more anxiety and depression patients have at baseline, less they improve in HRQoL domains. CONCLUSIONS: Patients with colorectal cancer who have more social support and no psychological distress may have better results in HRQoL domains at 1 year after surgery. Copyright © 2015 John Wiley & Sons, Ltd.

Late renal vein thrombosis associated with recurrence of membranous nephropathy in a renal allograft: a case report.

Allograft renal vein thrombosis (RVT) is an uncommon but potentially catastrophic complication. Although it usually occurs in the early posttransplant period and is associated with surgical complications or vascular rejection, it may develop later, when it is generally related with a hypercoagulable state. Typical clinical presentation is sudden oligoanuric acute renal failure, and hematuria, with a painful and swollen renal allograft. Confirmation of the diagnosis requires Doppler ultrasound and computed tomography. Herein we have reported a successfully treated case of late RVT that developed in an allograft with recurrent membranous nephropathy associated with the nephrotic syndrome. The patient fully recovered renal graft function a few days after presentation, which was related to anticoagulant therapy. We demonstrated complete recanalization of the venous thrombosis.

[Chemotherapy registry quality in Andalusian hospital pharmacy departments]. / Original breve Calidad del registro de quimioterapia en los servicios de farmacia hospitalaria de Andalucía.

OBJECTIVE: To analyze registry quality in centralized cytostatic therapy units in Andalusian hospitals, and the availability of data to analyze the use of these drugs. METHOD: An ad hoc questionnaire was designed using variables related to information coverage on patients and their treatments, data processing extent, and organization. Questionnaires were completed in September 2005 by surveying people responsible for chemotherapy in all 19 pharmacy departments in Andalusian hospitals that treat oncologic patients. RESULTS: Response rate was 100%, but one department had no centralized cytostatic therapy unit. Centralized preparation coverage was 89% for the day hospital, 84% for inpatients, 79% for hematologic patients, and 69% for pediatric patients. Registries are computerized in only 13 hospitals (68%) with a variety of software programs. Temozolamide and capecitabine dispensation has a separate registry in 68% and 42% of cases, respectively. Patient name, and cytostatic name and dosage are the only data recorded in all instances, while protocol name is only recorded in 47%, and diagnosis, staging, and TNM categorization in 58%, 31%, and 16% of cases, respectively. CONCLUSIONS: There is great variability regarding information systems for cytostatic use management, and a relevant shortage of patient data available for prescription use and adaptation studies.

Phosphorylation of the yeast ribosomal stalk. Functional effects and enzymes involved in the process.

The ribosomal stalk is directly involved in the interaction of the elongation factors with the ribosome during protein synthesis. The stalk is formed by a complex of five proteins, four small acidic polypeptides and a larger protein which directly interacts with the rRNA at the GTPase center. In eukaryotes the acidic components correspond to the 12-kDa P1 and P2 proteins, and the RNA binding component is the P0 protein. All these proteins are found phosphorylated in eukaryotic organisms, and previous in vitro data suggested this modification was involved in the activity of this structure. Results from mutational studies have shown that phosphorylation takes place at a serine residue close to the carboxy end of the P proteins. Modification of this serine residue does not affect the formation of the stalk and the activity of the ribosome in standard conditions but induces an osmoregulation-related phenotype at 37 degrees C. The phosphorylatable serine is part of a consensus casein kinase II phosphorylation site. However, although CKII seems to be responsible for part of the stalk phosphorylation in vivo, it is probably not the only enzyme in the cell able to perform this modification. Five protein kinases, RAPI, RAPII and RAPIII, in addition to the previously reported CKII and PK60 kinases, are able to phosphorylate the stalk proteins. A comparison of the five enzymes shows differences among them that suggest some specificity regarding the phosphorylation of the four yeast acidic proteins. It has been found that some typical effectors of the PKC kinase stimulate the in vitro phosphorylation of the stalk proteins. All the data suggest that although phosphorylation is not involved in the interaction of the acidic P proteins with the ribosome, it can affect the ribosome activity and might participate in a possible ribosome regulatory mechanism.

Effects of a small quantity of omega-3 fatty acids on cardiovascular risk factors in NIDDM. A randomized, prospective, double-blind, controlled study.

OBJECTIVE: To study the effects of a low dose of omega-3 fatty acids on platelet function and other cardiovascular risk factors in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: We performed a randomized, prospective, double-blind, controlled study of a low dose of omega-3 fatty acids (2.5 g/day) in 20 ambulatory subjects with NIDDM. Subjects ingested five 1-g fish oil capsules each containing 0.5 g omega-3 fatty acids or five 1-g safflower oil capsules per day for 6 weeks followed by a 6-week washout period. RESULTS: Nine subjects completed the study in each group. Both groups exhibited moderate control of glucose levels; modest elevations in baseline total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels; and normal blood pressure values. In the fish oil group, plasma omega-3 fatty acid levels increased significantly. Fish oil significantly reduced the slope of the dose-response curves for collagen-induced platelet aggregation to one-third the value observed with safflower oil. No difference was observed in collagen-induced production of thromboxane A2 (TXA2, measured as the stable derivative TXB2), or in adenosine-5'-diphosphate- (ADP) induced platelet aggregation or TXA2 generation. Patients with high initial collagen-induced platelet TXA2 production showed a significantly larger drop after fish oil than safflower oil. Fish oil significantly reduced TG levels by 44 mg/dl and decreased upright systolic blood pressure (sBP) by 8 mmHg compared with safflower oil. Fish oil caused a significant but small increase in HbA1c (0.56%) and total cholesterol (20 mg/dl) but had no effect on fasting glucose, high-density lipoprotein cholesterol, or LDL-cholesterol levels. CONCLUSIONS: Small doses of fish oil inhibit platelet aggregation and TXA2 production, reduce upright sBP and TG levels, and have only a small effect on glucose and cholesterol levels in patients with moderately controlled NIDDM. Small quantities of omega-3 fatty acids or dietary fish are safe and potentially beneficial in NIDDM patients.

Sucrose sensitivity of patients with coronary artery disease.

Various loads of simple carbohydrates were fed to 148 patients with known coronary-artery disease (CAD) for 4 days in the Clinical Research Center. The 148 patients were grouped according to the diet regimen tested-sucrose (low and high), glucose, and fructose. A high-sucrose diet was fed to 29 control subjects. Diets containing 2 g of simple carbohydrate (predominantly either sucrose or glucose) per kilogram of body weight per day had no significant effect on fasting plasma glucose, serum triglycerides, or serum free fatty acids. However, diets containing 4 g of simple carbohydrate (predominantly sucrose) or 2 g fructose per kilogram of body weight per day produced a significant rise in serum triglycerides with decreases in fasting plasma glucose and free fatty acids. Serum cholesterol diminished in all the diet groups, probably because of the decrease fat and cholesterol intakes. The increase of serum triglycerides in CAD patients receiving simple carbohydrate at the 4-g/kg rate was significantly greater than in the normal control subjects fed the same diet, suggesting a sensitivity of CAD patients to this stimulus. No significant correlation could be demonstrated between changes in serum triglycerides and the extent of CAD (one, two, or three vessels) as determined from coronary angiograms.

Plasma lipids and apolipoprotein A-I and A-II levels in alcoholic patients.

This prospective study compared total plasma lipids, high-density lipoprotein cholesterol (HDL-C), and apolipoproteins A-I (apo A-I) and A-II (apo A-II) in 72 alcoholic patients and in 285 nonalcoholic controls. The HDL-C in the alcoholic group was not significantly different from that in the nonalcoholic controls. Alcoholic men had significantly higher levels of cholesterol and triglycerides and lower levels of apo A-I when compared with nonalcoholic controls. Alcoholic women had significantly higher levels of cholesterol and apo A-II when compared with nonalcoholic controls. Serial measurements in 25 alcoholic patients showed a significant decline in HDL-C, apo A-I, and apo A-II levels during the 4-wk hospital stay. HDL-C demonstrated its expected inverse relationship with plasma triglyceride level and its direct relationship with apo A-I, apo A-II, and the hepatic enzyme aspartate aminotransferase.

Sterol excretion and cholesterol absorption in diabetics and nondiabetics with and without hyperlipidemia.

Fecal neutral and acidic sterols and cholesterol absorption were measured in 12 normal control subjects, 40 diabetic subjects with and without hyperlipidemia, and 27 subjects with hyperlipidemia but without diabetes mellitus. All subjects were on a low-cholesterol diet (less than 300 mg cholesterol/day). Fecal excretion of neutral and acidic sterols was increased in patients with hypertriglyceridemia and was more marked in diabetic patients with hypertriglyceridemia. Cholesterol absorption was decreased in diabetic patients with hypertriglyceridemia. Otherwise, there were no significant differences in sterol excretion or cholesterol absorption in diabetic and nondiabetic subjects compared with control groups with similar lipid levels. The best predictors of fecal neutral- and acidic-sterol excretion and of estimated cholesterol synthesis were very low [corrected]-density lipoprotein triglycerides and high-density lipoprotein cholesterol. Correction of hyperlipidemia may be beneficial in decreasing cholesterol synthesis and, thereby, in decreasing the risk of atherogenesis.

Primary hypercholesterolemia: effect of treatment on serum lipids, lipoprotein fractions, cholesterol absorption, sterol balance, and platelet aggregation.

The nonabsorbable bile acid sequestrant resin, colestipol, was administered to 16 patients with primary hypercholesterolemia, and its effect on serum lipids, lipoprotein fractions, and circulating platelet aggregate ratio and platelet aggregation in response to adenosine diphosphate (ADP) was compared with that of sitosterol. Cholesterol absorption and sterol balance studies were done in four of the subjects during the following treatment periods: diet alone, colestipol, and sitosterol. Total serum cholesterol was significantly reduced by colestipol but only slightly decreased by sitosterol. Combination treatment with colestipol and sitosterol was associated with a smaller decrease in serum cholesterol than was demonstrated with colestipol alone. Serum triglycerides tended to increase during colestipol therapy (this increase was not clinically significant) but showed a minimal nonsignificant decrease with sitosterol treatment. Colestipol decreased cholesterol absorption, whereas sitosterol slightly increased it. Fecal sterol excretion was increased with colestipol treatment but was minimally affected by administration of sitosterol. Low-density lipoprotein and high-density lipoprotein cholesterol significantly decreased with colestipol treatment. The circulating platelet aggregate ratio was significantly lower in the group of patients with hypercholesterolemia who received colestipol initially than in control subjects, but platelet aggregation in response to ADP was not significantly different between these two groups. No significant change in platelet aggregation was noted during colestipol or sitosterol treatment despite a significant decrease in total serum cholesterol with colestipol therapy, a suggestion that the platelet and lipid abnormalities are not interrelated.

Acute effects of a glucose load on plasma apolipoproteins A-I, A-II, C-II, and C-III in normal and non-insulin-dependent diabetic men.

Changes in plasma levels of apolipoproteins A-I, A-II, C-II, and C-III, cholesterol, triglycerides, glucose, and insulin were studied after administration of a glucose load in six normal subjects and five patients with non-insulin-dependent diabetes mellitus. The main finding of our study was the significantly increased responses of total triglycerides and apolipoproteins C-II and C-III from the baseline values in the normal subjects but not in the diabetic group. High-density lipoprotein cholesterol levels at baseline and after glucose loading were significantly lower in diabetic than in normal subjects. As expected, abnormal glucose tolerance and hyperinsulinemia were observed in the diabetic subjects after the glucose loading. The peak glucose and insulin levels and their decline after the glucose loading were delayed in the diabetic patients. The glucose load did not significantly alter total plasma cholesterol, high-density lipoprotein cholesterol, and apolipoprotein A-I and A-II concentrations in normal and diabetic subjects. The apparent blunted response of total triglycerides and apolipoproteins C-II and C-III in the diabetic subjects may be related to maximal stimulation of synthesis of triglycerides and apolipoproteins C-II and C-III by the hyperglycemia and hyperinsulinemia (or both) present in these patients.

Molecular aspects of MAP-1 and MAP-2: microheterogeneity, in vitro localization and distribution in neuronal and nonneuronal cells.

We have studied various aspects of MAP-1 and MAP-2 from neuronal as well as nonneuronal sources. MAP-1 and MAP-2 polymerized from brain were resolved into a number of subcomponents upon electrophoresis on low percentage gels. Based on peptide mappings performed under a variety of different conditions, we conclude that the three major subcomponents of MAP-1 have very similar, though not identical structures. The two major MAP-2 subcomponents might have identical structure, because their peptide maps were hardly distinguishable. The apparent microheterogeneity of high Mr MAPs is not yet understood on a molecular basis. Proteolysis during isolation or a different degree of phosphorylation, however, seems to be an unlikely cause for microheterogeneity. When localized on microtubules polymerized in vitro by electron microscopy, both MAP-1 and MAP-2 polypeptides apparently form helical arrays on the polymer's surface with periodicities of 100 nm. In the presence of taxol, MAPs form irregular and bulky extensions. Both MAPs are found to be widespread in neuronal as well as nonneuronal cells. MAP-1- and MAP-2-related polypeptides, together with other high Mr proteins, such as plectin, were associated with microtubules polymerized by taxol from extracts of a nonneuronal cultured cell line. MAP-2 from cultured cells was found to be extremely sensitive to proteolysis, in particular in the presence of free Ca-ions. MAP-1 and MAP-2 generally were found associated with typical microtubule structures such as interphase and spindle microtubules and primary cilia. A differential distribution of MAP-1 and MAP-2 was clearly evident in neural tissues, where MAP-2 was restricted to cell bodies and dendrites, whereas MAP-1 was present also in axons. Moreover, a differential distribution of MAPs and tubulin was observed in de-and regenerating peripheral nerve, and in a few occasions, also with nonneuronal cells. A quite unexpected result was the identification of a protein in the extracellular matrix of cultured fibroblast cells, which has antigenic determinants in common with MAP-1 and MAP-2 from brain. As a whole, the data presented support a concept in which a family of structurally homologous, though not identical, high Mr polypeptides constitute the crosslinking elements between microtubules and various other cellular components. The structural diversity of these polypeptides might play a role in the development and dynamic changes in the cytoskeletal architecture.

Analysis of plasma lipids and apolipoproteins in insulin-dependent and noninsulin-dependent diabetics.

Plasma triglycerides, cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoproteins (apo) A-I, A-II, C-II, and C-III were determined and analyzed in 170 diabetic patients and 46 age-matched healthy normal subjects. The diabetics were separated into two groups: insulin-dependent diabetes mellitus (IDDM, n = 78) and noninsulin-dependent diabetes mellitus (NIDDM, n = 92). Significantly increased triglycerides, low HDL cholesterol, and normal cholesterol levels were found in the diabetics. The lipid profiles were similar in the IDDM and NIDDM groups. Plasma apo A-I, but not apo A-II, was low in both groups of diabetics. However, only in the IDDM subjects was there a statistically significant decrease in apo A-I when compared to normal subjects. The decreased apo A-I level negatively correlated with plasma triglycerides. Apo C-II and apo C-III were slightly increased in the diabetics compared to normal subjects. Apo C-II and apo C-III levels significantly correlated with plasma triglycerides (apo C-II, r = 0.70, P less than 0.0001; apo C-III, r = 0.71, P less than 0.0001). Only apo C-II correlated with total cholesterol. Thirty-eight to forty-two percent of the IDDM and NIDDM subjects had a clinical diagnosis of coronary artery disease (CAD) and/or peripheral arteriovascular disease (PAD). In the IDDM subjects, but not in the NIDDM subjects the incidence of CAD and/or PAD was associated with the decreased apo A-I levels as evaluated by a univariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Discapseudes holthuisi (Crustacea: Tanaidacea) as an intermediate host of Caballerorhynchus lamothei (Acanthocephala: Cavisomidae).

The intermediate host of the acanthocephalan Caballerorhynchus lamothei Salgado-Maldonado, 1977, is reported for the first time. Cystacanths of C. lamothei were found in the hemocoel of the tanaid shrimp Discapseudes holthuisi Bacescu and Gutu, 1975, in Alvarado and Sontecomapan lagoons, Veracruz, Mexico. This is the first report of a palaeacanthocephalan using a tanaid shrimp as an intermediate host. Prevalence by locality, shrimp length, sex and developmental stage, and an analysis of the distribution of number of cystacanths per host are presented. A higher prevalence, and percentage of multiple infections and larger host size were found in Alvarado Lagoon.

Structure and function of the stalk, a putative regulatory element of the yeast ribosome. Role of stalk protein phosphorylation.

The ribosomal stalk is involved directly in the interaction of the elongation factors with the ribosome during protein synthesis. The stalk is formed by a complex of five proteins, four small acidic polypeptides and a larger protein which directly interacts with the rRNA at the GTPase center. In eukaryotes, the acidic components correspond to the 12 kDa P1 and P2 proteins, and the RNA binding component is protein P0. All these proteins are found to be phosphorylated in eukaryotic organisms. Previous in vitro data suggested this modification was involved in the activity of this structure. To confirm this possibility a mutational study has shown that phosphorylation takes place at a serine residue close to the carboxyl end of proteins P1, P2 and P0. This serine is part of a consensus casein kinase II phosphorylation site. However, by using a yeast strain carrying a temperature sensitive mutant, it has been shown that CKII is probably not the only enzyme responsible for this modification. Three new protein kinases, RAPI, RAPII and RAPIII, have been purified and compared with CKII and PK60, a previously reported enzyme that phosphorylates the stalk proteins. Differences among the five enzymes have been studied. It has also been found that some typical effectors of the PKC kinase stimulate the in vitro phosphorylation of the stalk proteins. All the data available suggest that phosphorylation, although it is not involved in the interaction of the acidic proteins with the ribosome, affects ribosome activity and might participate in some ribosome regulatory mechanism.

Cultural considerations: developing a nursing care delivery system for a Hispanic community.

Transcultural nursing should be the main focus of the nurse in any setting. Increased mobility of society demonstrates the need to understand anthropologic and cultural differences. The Valley provides a laboratory in which transcultural nursing can be examined more closely. Cadena recommends that MA nurses remain open to personal feelings generated by relationships with MA patients. The astute nurse assesses each patient's level of assimilation and provides care based on the findings. Comprehensive communication and patient and family participation are the keys to successful transcultural nursing. Sensitivity to modesty and pride translates into professional understanding of holistic needs rather than humiliation and alienation of the patient. At VBMC, these concepts are translated into working systems through the UACs and the bedside-managed care delivery system.