Temporal data mining for the assessment of the costs related to diabetes mellitus pharmacological treatment.

Diabetes care and chronic disease management represent data-intensive contexts which allow Local Healthcare Agencies (ASL) to collect a huge amount of information. Time is often an essential component of such information, given the strong importance of the temporal evolution of the considered disease and of its treatment. In this paper we show the application of a temporal data mining technique to extract temporal association rules over an integrated repository including both administrative and clinical data related to a sample of diabetic patients. We will show how the method can be used to highlight cases and conditions which lead to the highest pharmaceutical costs. Considering the perspective of a Regional Healthcare Agency, this method could be properly exploited to assess the overall standards and quality of care, while lowering costs.

Enzyme replacement therapy in severe adult-onset glycogen storage disease type II.

Glycogen storage disease type II (GSDII) is an autosomal recessive myopathy caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Enzyme replacement therapy (ERT) with recombinant GAA (rh-GAA) has become available for GSDII, although its effectiveness in adults remains unknown. We present a case of ERT with rhGAA in a 49-year-old male with GSDII in a severe stage of the disease. Quantitative magnetic resonance imaging showed an increase in muscle mass of the inferior limb, especially evident on the quadriceps femoris and the patient's body weight increased up to 30%, although his reported dietary habits were the same as before ERT. Beyond improvement in muscle strength and respiratory function, we observed a dramatic increase in body mass index from 12.7 to 16.6 kg/m(2). This may reflect a change from a catabolic state to a more balanced metabolic state during ERT.

Association of the metabolic syndrome and insulin resistance with silent myocardial ischemia in patients with type 2 diabetes mellitus.

Metabolic syndrome is associated with elevated morbidity and mortality for overt coronary artery disease (CAD). In diabetic patients, CAD is often silent. The relation between metabolic syndrome and silent CAD has never been studied. We investigated whether metabolic syndrome is associated with silent CAD in patients with type 2 diabetes mellitus. We evaluated the prevalence of metabolic syndrome in 169 patients with uncomplicated diabetes and angiographically verified silent CAD and in 158 diabetic patients without myocardial ischemia on exercise electrocardiography, 48-hours ambulatory electrocardiography, and stress echocardiography. The groups were comparable for gender, age, glycemic control, and diabetes duration. Metabolic syndrome was defined according to the National Cholesterol Education Program criteria. To estimate insulin resistance in patients treated with diet alone or oral agents (122 patients with CAD and 115 patients without CAD), the Homeostasis Model Insulin-Resistance Assessment (HOMA) was used. The prevalence of metabolic syndrome (59.8% vs 44.3%, p = 0.005) and HOMA (5.4 +/- 2.1 vs 4.9 +/- 2.8, p = 0.044) were significantly higher in those with CAD than in those without CAD. Multiple logistic regression analysis showed that the metabolic syndrome was associated with silent CAD (odds ratio 2.44, 95% confidence interval 1.19 to 5.02, p = 0.015). Among patients on diet alone or oral agents, the HOMA was the strongest predictor of silent CAD (odds ratio 10.16, 95% confidence interval 2.60 to 39.63, p < 0.001). In conclusion, our data have shown an independent association of metabolic syndrome and insulin resistance with silent CAD in patients with type 2 diabetes mellitus. Other studies are needed to establish whether metabolic syndrome and HOMA are reliable markers to identify diabetic patients for additional screening for silent CAD.

[A model for epidemiological study in general practice: mortality. Study of cohort in Pavia]. / Modello d'indagine epidemiologica in medicina generale: mortalità. Studio di coorte in Pavia.

For defining the health state of the population and demonstrating that computed general practice can be a preferential observation point for epidemiological study, we analyzed, as general practitioners, database of a dynamic cohort of 1501 subjects (m:724, f:777) living in Pavia and monitored from 1/1/1992 to 12/31/2001. In this paper we present mortality data compared to Italy in 1994. During the period, 209 deaths occurred (m:107, f:102). Differently from Italy, in Pavia cancer was the first cause of death in both sexes. When cardiovascular fatal events were analysed, age of death occurred 8.7 years in advance in males, while age of death for cancer was similar in both sexes. Sudden death represented one quarter of cardiovascular deaths. General practitioners' database can be an important and useful epidemiological source to detect areas with different risks of illness. Furthermore database offers the possibility to determine mortality rate for illness like sudden death not included in national statistical studies.

Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients.

BACKGROUND: Erectile dysfunction (ED) is associated with coronary artery disease (CAD). In diabetic patients, CAD is often silent. Among diabetic patients with silent CAD, the prevalence of ED has never been evaluated. We investigated whether ED is associated with asymptomatic CAD in type 2 diabetic patients. METHODS AND RESULTS: We evaluated the prevalence of ED in 133 uncomplicated diabetic men with angiographically verified silent CAD and in 127 diabetic men without myocardial ischemia at exercise ECG, 48-hour ambulatory ECG, and stress echocardiography. The groups were comparable for age and diabetes duration. Patients were screened for ED using the validated International Index of Erectile Function (IIEF-5) questionnaire. The prevalence of ED was significantly higher in patients with than in those without silent CAD (33.8% versus 4.7%; P=0.000). Multiple logistic regression analysis showed that ED, apolipoprotein(a) polymorphism, smoking, microalbuminuria, HDL, and LDL were significantly associated with silent CAD; among these risk factors, ED appeared to be the most efficient predictor of silent CAD (OR, 14.8; 95% CI, 3.8 to 56.9). CONCLUSIONS: Our study first shows a strong and independent association between ED and silent CAD in apparently uncomplicated type 2 diabetic patients. If our findings are confirmed, ED may become a potential marker to identify diabetic patients to screen for silent CAD. Moreover, the high prevalence of ED among diabetics with silent CAD suggests the need to perform an exercise ECG before starting a treatment for ED, especially in patients with additional cardiovascular risk factors.

Management of patients with diabetes through information technology: tools for monitoring and control of the patients' metabolic behavior.

BACKGROUND: The junction of telemedicine home monitoring with multifaceted disease management programs seems nowadays a promising direction to combine the need for an intensive approach to deal with diabetes and the pressure to contain the costs of the interventions. Several projects in the European Union and the United States are implementing information technology-based services for diabetes management using a comprehensive approach. Within these systems, the role of tools for data analysis and automatic reminder generation seems crucial to deal with the information overload that may result from large home monitoring programs. The objective of this study was to describe the automatic reminder generation system and the summary indicators used in a clinical center within the telemedicine project M2DM, funded by the European Commission, and to show their usage during a 7-month on-field testing period. METHODS: M2DM is a multi-access service for management of patients with diabetes. The basic functionality of the technical service includes a Web-based electronic medical record and messaging system, a computer telephony integration service, a smart-modem located at home, and a set of specialized software modules for automated data analysis. The information flow is regulated by a software scheduler, called the Organizer, that, on the basis of the knowledge on the health care organization, is able to automatically send e-mails and alerts notifications as well as to commit activities to software agents, such as data analysis. Thanks to this system, it was possible to define an automatic reminder system, which relies on a data analysis tool and on a number of technologies for communication. Within the M2DM system, we have also defined and implemented a number of indexes able to summarize the patients' day-by-day metabolic control. In particular, we have defined the global risk index (GRI) of developing microangiopathic complications. RESULTS: The system for generating automatic alarms and reminders coupled with the indexes for evaluating the patients' metabolic control has been used for 7 months at the Fondazione Salvatore Maugeri (FSM) in Pavia, Italy. Twenty-two patients (43 +/- 16 years old, 12 men and 10 women) have been involved; six dropped out from the study. The average number of monthly automatic messages was 29.44 +/- 9.83, i.e., about 1.8 messages per patient per month. The number of monthly alarm reminders generated by the system was 16.44 +/- 4.39, so that the number of alarms per patient was about 1. The number of messages sent by patients and physicians during the project was about 13 per month. The GRI analysis shows, during the last trimester, a slight improvement of the performance of the FSM clinic, with a decrease in the percentage of badly controlled values from 33% to 27%. Finally, we found the presence of a linear increasing correlation between the mean GRI values and the number of alarms generated by the system. CONCLUSIONS: A telemedicine system may incorporate features that make it a suitable technological backbone for implementing a disease management program. The availability of data analysis tools, automated messaging system, and summary indicators of the effectiveness of the health care program may help in defining efficient clinical interventions.

Design, methods, and evaluation directions of a multi-access service for the management of diabetes mellitus patients.

Recent advances in information and communication technology allow the design and testing of new models of diabetes management, which are able to provide assistance to patients regardless of their distance from the health care providers. The M2DM project, funded by the European Commission, has the specific aim to investigate the potential of novel telemedicine services in diabetes management. A multi-access system based on the integration of Web access, telephone access through interactive voice response systems, and the use of palmtops and smart modems for data downloading has been implemented. The system is based on a technological platform that allows a tight integration between the access modalities through a middle layer called the multi-access organizer. Particular attention has been devoted to the design of the evaluation scheme for the system: A randomized controlled study has been defined, with clinical, organizational, economic, usability, and users' satisfaction outcomes. The evaluation of the system started in January 2002. The system is currently used by 67 patients and seven health care providers in five medical centers across Europe. After 6 months of usage of the system no major technical problems have been encountered, and the majority of patients are using the Web and data downloading modalities with a satisfactory frequency. From a clinical viewpoint, the hemoglobin A1c (HbA1c) of both active patients and controls decreased, and the variance of HbA1c in active patients is significantly lower than the control ones. The M2DM system allows for the implementation of an easy-to-use, user-tailored telemedicine system for diabetes management. The first clinical results are encouraging and seem to substantiate the hypothesis of its clinical effectiveness.

HYAFF 11-based autologous dermal and epidermal grafts in the treatment of noninfected diabetic plantar and dorsal foot ulcers: a prospective, multicenter, controlled, randomized clinical trial.

OBJECTIVE: To evaluate the clinical efficacy and safety of HYAFF 11-based autologous dermal and epidermal grafts in the management of diabetic foot ulcers. RESEARCH DESIGN AND METHODS: A total of 79 patients with diabetic dorsal (n = 37) or plantar (n = 42) ulcers were randomized to either the control group with nonadherent paraffin gauze (n = 36) or the treatment group with autologous tissue-engineered grafts (n = 43). Weekly assessment, aggressive debridement, wound infection control, and adequate pressure relief (fiberglass off-loading cast for plantar ulcers) were provided in both groups. Complete wound healing was assessed within 11 weeks. Safety was monitored by adverse events. RESULTS: Complete ulcer healing was achieved in 65.3% of the treatment group and 49.6% of the control group (P = 0.191). The Kaplan-Meier mean time to closure was 57 and 77 days, respectively, for the treatment versus control groups. Plantar foot ulcer healing was 55% and 50% in the treatment and control groups, respectively. Dorsal foot ulcer healing was significantly different, with 67% in the treatment group and 31% in the control group (P = 0.049). The mean healing time in the dorsal treatment group was 63 days, and the odds ratio for dorsal ulcer healing compared with the control group was 4.44 (P = 0.037). Adverse events were equally distributed between the two groups, and none were related to the treatments. CONCLUSIONS: The autologous tissue-engineered treatment exhibited improved healing in dorsal ulcers when compared with the current standard dressing. For plantar ulcers, the off-loading cast was presumably paramount and masked or nullified the effects of the autologous wound treatment. This treatment, however, may be useful in patients for whom the total off-loading cast is not recommended and only a less effective off-loading device can be applied.

Hypertension among HIV patients: prevalence and relationships to insulin resistance and metabolic syndrome.

OBJECTIVES: Metabolic syndrome is a cluster of risk factors, such as central obesity, dyslipidemia, glucose intolerance, hypertension, related to insulin resistance. In HIV patients insulin resistance and several metabolic abnormalities of the metabolic syndrome have been described, but few and conflicting studies have investigated the behaviour of blood pressure. The aims of the present study were to evaluate the prevalence of hypertension in a large group of HIV-patients on highly active antiretroviral therapy (HAART) and to investigate the relationship between hypertension, metabolic syndrome and insulin resistance. DESIGN: Case control study. METHODS: We enrolled 287 HIV-positive patients on HAART (mean age 41.1 +/- 7.5 years) and 287 age- and sex-matched controls. Insulin resistance was estimated by the homeostasis model insulin resistance assessment (HOMA) index. Metabolic syndrome was defined according to the European Group for the Study of Insulin Resistance. RESULTS: HIV patients showed a prevalence of subjects with hypertension (34.2 versus 11.9%; P < 0.0001) and metabolic syndrome (33.1 versus 2.4%; P < 0.0001) higher than controls. HOMA was higher in HIV-patients than controls (3.3 +/- 1.2 versus 2.0 +/- 0.9; P < 0.0001). HOMA (3.7 +/- 1.0 versus 3.1 +/- 1.2; P < 0.001) and the prevalence of subjects with the metabolic syndrome (64.3 versus 16.9%; P < 0.0001) were greater in HIV-patients with than in those without hypertension. Multiple logistic regression analysis showed that family history of hypertension (odds ratio [(OR): 8.73; 95% confidence interval (CI): 4.31-17.70; P < 0.0001], metabolic syndrome (OR: 6.79; 95% CI: 3.27-14.10; P < 0.0001), lipodystrophy (OR: 4.80; 95% CI: 2.43-9.85; P < 0.0001) and HOMA (OR: 4.13; 95% CI: 1.14-14.91; P < 0.05) were predictors of hypertension in HIV-patients. CONCLUSIONS: The present study shows that hypertension is frequent in HIV patients on HAART and that hypertension appears to be linked to insulin resistance; in particular, hypertension seems to be a part of the metabolic syndrome.

Lipoprotein(a), apolipoprotein(a) polymorphism and restenosis after intracoronary stent placement in Type 2 diabetic patients.

The relationship between lipoprotein(a) [Lp(a)] and restenosis after intracoronary stent implantation has never been analysed in diabetic patients. The aim of the present prospective study was to evaluate whether Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes are predictors of restenosis after elective stent implantation in Type 2 diabetic patients with de novo lesions of coronary arteries. We recruited 102 Type 2 diabetic patients with a new lesion successfully treated with elective placement of one or two Palmaz-Schatz stents. Follow-up angiography was scheduled at 6 months or earlier if clinically indicated. Seven patients were lost to the follow up. Among 95 patients enrolled, restenosis was present in 37 (38.9%) and absent in 58 (61.1%). The restenosis group showed Lp(a) levels higher than the nonrestenosis group (25.1+/-14.4 vs. 21.3+/-14.6 mg/dl), but the difference was not significant. The restenosis group had a percentage of subjects with at least one apo(a) isoform of low molecular weight (MW) significantly greater than the nonrestenosis group (75.7% vs. 55.1%; P<.05). A multiple logistic regression analysis showed that presence of multivessel disease (risk relative [RR]: 5.83; 95% confidence interval [CI]: 1.21-28.15; P<.05) was the only predictor of restenosis after stent placement in diabetic patients. Lp(a) and apo(a) polymorphisms did not enter the model as predictive variables. Our study shows that the presence of multivessel disease is a predictor of restenosis after intracoronary stent implantation in diabetic patients. On the contrary, Lp(a) and apo(a) polymorphisms do not appear to be reliable markers of restenosis in patients with Type 2 diabetes mellitus.

Percutaneous ultrasound-guided radiofrequency thermal ablation of malignant osteolyses.

Metastases are the most common neoplastic pathology involving the skeletal system. The hallmark of skeletal metastases is pain that often compromises the patient's quality of life. Radiotherapy, surgery and chemotherapy are the cornerstones of the treatment, but these techniques are not completely effective. Radiofrequency thermal ablation (RFA) may offer an alternative to conventional therapies for pain control. At present, the main field of application of RFA is the treatment of primary or secondary tumors of the liver but, recently, the technique has been effectively used to treat various other tumors in organs such as the prostate, kidney, lung, brain, pancreas and breast and to control pain caused by osteoid osteomas. Five patients with six painful bone metastases underwent RFA. The patients were three women and two men, aged 40-77 years (mean: 63.4). The radiofrequency system consists of an insulated 18-gauge needle electrode attached to a 500-kHz RF generator (Radionics, Burlington, Mass, USA). Four of our five patients rapidly obtained pain relief. One patient was completely pain free within 48 hours of the procedure and the control of pain persisted for 88 weeks. Another three patients obtained at least fifty percent pain reduction that lasted, on average, 12 weeks. Our preliminary results confirm that ultrasound-guided RFA is a simple and safe technique for treating painful superficial bone metastases.

Restenosis after intracoronary stent placement: can apolipoprotein(a) polymorphism play a role?

BACKGROUND: The relationship between lipoprotein(a) and restenosis after intracoronary stent implantation has been analysed by two specific studies, but the role of apoliprotein(a) polymorphism was not considered. The aim of the present prospective study was to evaluate whether lipoprotein(a) levels and apolipoprotein(a) phenotypes are predictors of restenosis after elective stent implantation in patients with de novo lesions of coronary arteries. METHODS: We recruited 182 patients with a new lesion successfully treated with elective placement of one or two Palmaz-Schatz stents. Follow-up angiography was scheduled at 6 months or earlier if clinically indicated. Nine patients were lost to the follow up. Among 173 patients enrolled, restenosis was present in 52 (30.0%) and absent in 121 (70.0%). RESULTS: Lipoprotein(a) levels were higher in the restenosis than in the nonrestenosis group (29.5+/-17.2 versus 27.4+/-20.2 mg/dl), even if the difference did not attain statistical significance (P=0.067). The restenosis group had a percentage of subjects with at least one apolipoprotein(a) isoform of low molecular weight significantly greater than the nonrestenosis group (82.7 versus 66.9%; P=0.035). A multiple logistic regression analysis showed that multiple stenting (RR: 4.01; CI 95%: 1.65-13.91; P=0.004), presence of diabetes (RR: 3.96; CI 95%: 1.67-9.37; P=0.002) and presence of multivessel disease (RR: 2.71; CI 95%: 1.19-6.16; P=0.017) were predictors of restenosis after stent placement. Lipoprotein(a) and apolipoprotein(a) polymorphism did not enter the model as predictive variables. CONCLUSIONS: Our study confirms that multiple stenting, diabetes and multivessel disease are powerful predictors of restenosis after intracoronary stent implantation. On the contrary, lipoprotein(a) and apolipoprotein(a) polymorphism do not appear to be reliable markers of restenosis in patients with stent implantation.

Silent coronary artery disease in type 2 diabetes mellitus: the role of Lipoprotein(a), homocysteine and apo(a) polymorphism.

BACKGROUND: There is little data on the relationship between novel cardiovascular risk factors and silent coronary artery disease (CAD) in diabetic patients. We investigated whether Lipoprotein(a), homocysteine and apolipoprotein(a) polymorphism are associated with angiographically assessed asymptomatic coronary artery disease (CAD) in diabetic patients. METHODS: 1,971 type 2 diabetic patients without clinical signs of cardiovascular diseases and with a negative history of CAD were consecutively evaluated. Among them, 179 patients showed electrocardiographic abnormalities suggestive of ischemia or previous asymptomatic myocardial infarction. These 179 patients were subjected to a non-invasive test for CAD (ECG stress testing and/or scintigraphy). Among patients with a highly positive stress testing (n = 19) or a positive scintigraphy (n = 74), 75 showed an angiographically documented CAD (CAD group). Seventy-five patients without CAD (NO CAD group) were matched by age, sex and duration of diabetes to CAD patients. In NO CAD patients an exercise ECG test, a 48-hour ambulatory ECG and a stress echocardiogram were negative for CAD. RESULTS: Lipoprotein(a) levels (22.0 +/- 18.9 versus 16.0 +/- 19.4 mg/dl; p < 0.05), homocysteine levels (13.6 +/- 6.6 versus 11.4 +/- 4.9 mmol/l; p < 0.05) and the percentage of subjects with at least one small apolipoprotein(a) isoform (70.7% versus 29.3%; p < 0.0001) were higher in CAD than NO CAD group. Logistic regression analysis showed that apolipoprotein(a) polymorphism (OR:8.65; 95%CI:3.05-24.55), microalbuminuria (OR:6.16; 95%CI:2.21-17.18), smoking (OR:2.53; 95%CI:1.05-6.08), HDL (OR:3.16; 95%CI:1.28-7.81), homocysteine (OR:2.25; 95%CI:1.14-4.43) and Lipoprotein(a) (OR:2.62; 95%CI:1.01-6.79) were independent predictors of asymptomatic CAD. CONCLUSIONS: The present investigation shows an independent association of Lipoprotein(a), homocysteine and apo(a) polymorphism with silent CAD. Other studies are needed to establish whether these parameters are suitable for CAD screening in diabetic patients.

Assessment of asymptomatic coronary artery disease in apparently uncomplicated type 2 diabetic patients: a role for lipoprotein(a) and apolipoprotein(a) polymorphism.

OBJECTIVE: In patients with uncomplicated diabetes, there is low probability of finding significant coronary artery disease (CAD) by noninvasive tests. Therefore, screening for its presence is not justified, and it is important to find reliable predictors of silent CAD to identify patients with uncomplicated diabetes for further screening. The relationship between lipoprotein(a) [Lp(a)], apolipoprotein(a) [apo(a)] polymorphism, and silent CAD has never been studied. We investigated the association of Lp(a) and apo(a) polymorphism with angiographically documented asymptomatic CAD in type 2 diabetic patients without evident complications. RESEARCH DESIGN AND METHODS: A total of 1,323 diabetic patients without any clinical and electrocardiographic evidence of CAD were evaluated. Of 121 patients with highly positive results of exercise electrocardiography (ECG) (n = 30) or positive results on exercise thallium scintigraphy (n = 91), 103 subjects showed angiographically documented CAD (CAD group). Of 1,106 patients with negative results on exercise ECG, 103 subjects without CAD (NO CAD group) were selected and matched by age, gender, and duration of diabetes to patients in the CAD group. In patients in the NO CAD group, results of exercise ECG, 48-h ambulatory ECG, and stress echocardiography were negative for CAD. RESULTS: The CAD group had higher Lp(a) levels (21.7 +/- 17.7 vs. 15.2 +/- 19.0 mg/dl; P = 0.0093) than the NO CAD group, and a percentage of subjects had at least one small apo(a) isoform (68.9 vs. 29.1%; P = 0.0000) higher than the NO CAD group. Logistic regression analysis showed that apo(a) phenotypes (odds ratio [OR] 8.13, 95% CI 3.65-21.23), microalbuminuria (5.38, 2.44-11.88), smoking (2.72, 1.31-5.64), and Lp(a) levels (2.41, 1.15-5.03) were predictors of asymptomatic CAD. CONCLUSIONS: Our investigation reports the first evidence of an independent association of Lp(a) and apo(a) polymorphism with asymptomatic CAD. This suggests that Lp(a) levels and apo(a) phenotypes could be used together with other risk factors as markers of asymptomatic CAD in patients with diabetes.

Weight loss after Swedish Adjustable Gastric Banding: relationships to insulin resistance and metabolic syndrome.

BACKGROUND: The metabolic syndrome is a cluster of cardiovascular risk factors (central obesity, hypertension, dyslipidemia, disturbance in glucose metabolism) associated with insulin-resistance. The cluster of risk factors defining the metabolic syndrome increases cardiovascular risk more than each single component. The aim of the present longitudinal study was to evaluate the relationship between weight loss and changes in insulin-resistance and in the prevalence of the metabolic syndrome 1-year after SAGB implantation. METHODS: 51 premenopausal severely obese women (mean age 35.2 +/- 8.8 years, BMI 43.3 +/- 6.9) were enrolled. As a control group, 51 premenopausal non-obese women (BMI < 30) were enrolled. All obese subjects underwent successful implantation of the SAGB via videolaparoscopy. In all subjects insulin-resistance was estimated by HOMA index and metabolic syndrome was defined according to the criteria of the European Group for the Study of Insulin Resistance. RESULTS: HOMA (4.2 +/- 2.0 vs 1.9 +/- 0.8, P < 0.001) and the prevalence of the metabolic syndrome (58.8% vs 7.8%, P < 0.001) were significantly higher in obese than non-obese women. 1 year after SAGB, BMI significantly decreased from 43.3 +/- 6.9 to 34.5 +/- 7.4 (P < 0.001). HOMA index showed a significant dramatic breakdown (4.2 +/- 2.0 vs 2.4 +/- 1.0, P < 0.001). The prevalence of the metabolic syndrome declined significantly (58.8% vs 21.6%, P < 0.001). CONCLUSION: Our study shows that in severely obese women, insulin-resistance and the prevalence of the metabolic syndrome significantly decrease 1 year after SAGB. Our findings indicate that SAGB could be a useful tool to reduce the global cardiovascular risk in severely obese people and to improve their long-term prognosis.