Insulin-based strategies to prevent hypoglycaemia during and after exercise in adult patients with type 1 diabetes on pump therapy: the DIABRASPORT randomized study.

AIMS: To validate strategies to prevent exercise-induced hypoglycaemia via insulin-dose adjustment in adult patients with type 1 diabetes (T1D) on pump therapy. METHODS: A total of 20 patients randomly performed four 30-min late post-lunch (3 h after lunch) exercise sessions and a rest session: two moderate sessions [50% maximum oxygen consumption (VO2 max)] with 50 or 80% basal rate (BR) reduction during exercise + 2 h and two intense sessions (75% VO2 max) with 80% BR reduction or with their pump stopped. Two additional early post-lunch sessions (90 min after lunch) were analysed to compare hypoglycaemia incidence for BR reduction versus bolus reduction. RESULTS: In all, 100 late post-lunch sessions were analysed. Regardless of exercise type and BR reduction, no more hypoglycaemic events occurred in the period until the next morning than occurred after the rest sessions. In the afternoon, no more hypoglycaemic events occurred with 80% BR reduction/moderate exercise or with pump discontinuation/intense exercise than for the rest session, whereas more hypoglycaemic events occurred with 50% BR reduction/moderate exercise and 80% BR reduction/intense exercise. After early post-lunch exercise (n = 37), a trend towards fewer hypoglycaemic episodes was observed with bolus reduction versus BR reduction (p = 0.07). Mean blood glucose fell by ∼3.3 mmol/l after 30 min of exercise, irrespective of dose reduction, remaining stable until the next morning with no rebound hyperglycaemia. CONCLUSION: In adults with T1D, to limit the hypoglycaemic risk associated with 30 min of exercise 3 h after lunch, without carbohydrate supplements, the best options seem to be to reduce BR by 80% or to stop the pump for moderate or intense exercise, or for moderate exercise 90 min after lunch, to reduce the prandial bolus rather than the BR.

Implementation of an ERAS program in patients undergoing thoracic surgery at a third-level university hospital: an ambispective cohort study.

OBJECTIVE: To analyze the effects of an ERAS program on complication rates, readmission, and length of stay in patients undergoing pulmonary resection in a tertiary university hospital. METHODS: Ambispective cohort study with a prospective arm of 50 patients undergoing thoracic surgery within an ERAS program (ERAS group) versus a retrospective arm of 50 patients undergoing surgery before the protocol was implemented (Standard group). The primary outcome was the number of patients with 30-day surgical complications. Secondary outcomes included ERAS adherence, non-surgical complications, mortality, readmission, reintervention rate, pain, and hospital length of stay. We performed a multivariate logistic analysis to study the correlation between outcomes and ERAS adherence. RESULTS: In the univariate analysis, we found no difference between the two groups in terms of surgical complications (Standard 18 [36%] vs. ERAS 12 [24%], p=0.19). In the ERAS group, only the readmission rate was significantly lower (Standard 15 [30%] vs. ERAS 6 [12%], p=0.03). In the multivariate analysis, ERAS adherence was the only factor associated with a reduction in surgical complications (OR [95% CI]=0.02 [0.00, 0.59], p=0.03) and length of stay (HR [95% CI]=18.5 [4.39, 78.4], p<0.001). CONCLUSIONS: The ERAS program significantly reduced the readmission rate at our hospital. Adherence to the ERAS protocol reduced surgical complications and length of stay.

Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

Modeling the variability of insulin sensitivity for people with Type 1 Diabetes based on clinical data from an artificial pancreas study.

Type 1 Diabetes is an autoimmune disease that eliminates endogenous insulin production. Without the crucial hormone insulin, which is necessary to equilibrate the blood glucose level, the patient must inject insulin subcutaneously. Treatment must be personalized (timing and size of insulin delivery) to achieve glycaemic equilibrium and avoid long-term comorbidities. Patients are educated on Functional Insulin Therapy (FIT) in order to independently adjust insulin delivery several times a day (at least prior to each meal and physical activity). Among personalized parameters, the Correction Factor is used to occasionally correct hyperglycemia via the injection of an insulin dose (bolus) and its value determines the bolus size. Although well-known in common diabetes practice for chronically poorly controlled patients, the phenomenon of "hyperglycemia induces insulin resistance" on a short term basis in patients with rather well controlled diabetes is presented here. Using a new database of evidence, we show that the insulin sensitivity factor, depends on the current level of glycaemia. This opens the door to refining dosing rules for patients and insulin delivery devices in artificial pancreas systems.

Insulin-pump use in everyday practice: data from an exhaustive regional registry in France.

AIM: The aim of this study is to evaluate the effectiveness and safety of continuous subcutaneous insulin infusion (CSII) under real-life conditions among all patients treated with CSII in the south of Paris. METHODS: The 42 diabetologists practising in the region enrolled all patients treated with CSII or admitted for CSII initiation. During the study visit, the data for pump use and clinical results were recorded. RESULTS: Data were obtained for 424 patients, mean age 44.2+/-15.6 years, disease duration 18.7+/-10.6 years, including 339 treated with CSII for longer than three months (mean duration: 3.5+/-3.5 years; range: 3-258 months). Most of the patients (N=285, 84.8%) had type 1 diabetes; 44 (13.1%) had type 2 diabetes. In patients treated for more than three months, HbA1c decreased significantly between CSII initiation (9.1+/-1.9%) and the study visit (7.8+/-1.4%; P<0.0001). Patients with HbA1c >9%, using the pump, experienced a significant 0.9% improvement in their HbA1c levels with CSII versus multiple daily injections (P=0.001). The number of episodes of moderate hypoglycaemia was 2.7+/-2.5 per patient per week; of severe hypoglycaemia, 0.34 per patient per year and of ketoacidosis, 0.11 per patient per year. Factors significantly associated with HbA1c levels included amount of physical activity, pregnancy, HbA1c at CSII initiation and number of glucose self-determinations. Those associated with the number of moderate hypoglycaemia episodes were basal rate number, female gender and HbA1c level. HbA1c was negatively correlated with moderate hypoglycaemia (P<0.001), but not with severe hypoglycaemia. CONCLUSION: This 'pump' registry establishes the effectiveness of CSII in everyday practice, yet underscores the risks of severe hypoglycaemia and ketosis episodes. It could help diabetologists to improve patient training programmes and follow-up.

Prior automatic posture and activity identification improves physical activity energy expenditure prediction from hip-worn triaxial accelerometry.

Accelerometry is increasingly used to quantify physical activity (PA) and related energy expenditure (EE). Linear regression models designed to derive PAEE from accelerometry-counts have shown their limits, mostly due to the lack of consideration of the nature of activities performed. Here we tested whether a model coupling an automatic activity/posture recognition (AAR) algorithm with an activity-specific count-based model, developed in 61 subjects in laboratory conditions, improved PAEE and total EE (TEE) predictions from a hip-worn triaxial-accelerometer (ActigraphGT3X+) in free-living conditions. Data from two independent subject groups of varying body mass index and age were considered: 20 subjects engaged in a 3-h urban-circuit, with activity-by-activity reference PAEE from combined heart-rate and accelerometry monitoring (Actiheart); and 56 subjects involved in a 14-day trial, with PAEE and TEE measured using the doubly-labeled water method. PAEE was estimated from accelerometry using the activity-specific model coupled to the AAR algorithm (AAR model), a simple linear model (SLM), and equations provided by the companion-software of used activity-devices (Freedson and Actiheart models). AAR-model predictions were in closer agreement with selected references than those from other count-based models, both for PAEE during the urban-circuit (RMSE = 6.19 vs 7.90 for SLM and 9.62 kJ/min for Freedson) and for EE over the 14-day trial, reaching Actiheart performances in the latter (PAEE: RMSE = 0.93 vs. 1.53 for SLM, 1.43 for Freedson, 0.91 MJ/day for Actiheart; TEE: RMSE = 1.05 vs. 1.57 for SLM, 1.70 for Freedson, 0.95 MJ/day for Actiheart). Overall, the AAR model resulted in a 43% increase of daily PAEE variance explained by accelerometry predictions. NEW & NOTEWORTHY Although triaxial accelerometry is widely used in free-living conditions to assess the impact of physical activity energy expenditure (PAEE) on health, its precision and accuracy are often debated. Here we developed and validated an activity-specific model which, coupled with an automatic activity-recognition algorithm, improved the variance explained by the predictions from accelerometry counts by 43% of daily PAEE compared with models relying on a simple relationship between accelerometry counts and EE.

Practical implementation, education and interpretation guidelines for continuous glucose monitoring: A French position statement.

The use by diabetes patients of real-time continuous interstitial glucose monitoring (CGM) or the FreeStyle Libre® (FSL) flash glucose monitoring (FGM) system is becoming widespread and has changed diabetic practice. The working group bringing together a number of French experts has proposed the present practical consensus. Training of professionals and patient education are crucial for the success of CGM. Also, institutional recommendations must pay particular attention to the indications for and reimbursement of CGM devices in populations at risk of hypoglycaemia. The rules of good practice for CGM are the precursors of those that need to be enacted, given the oncoming emergence of artificial pancreas devices. It is necessary to have software combining user-friendliness, multiplatform usage and average glucose profile (AGP) presentation, while integrating glucose and insulin data as well as events. Expression of CGM data must strive for standardization that facilitates patient phenotyping and their follow-up, while integrating indicators of variability. The introduction of CGM involves a transformation of treatment support, rendering it longer and more complex as it also includes specific educational and technical dimensions. This complexity must be taken into account in discussions of organization of diabetes care.

An original piecewise model for computing energy expenditure from accelerometer and heart rate signals.

OBJECTIVE: Activity energy expenditure (EE) plays an important role in healthcare, therefore, accurate EE measures are required. Currently available reference EE acquisition methods, such as doubly labeled water and indirect calorimetry, are complex, expensive, uncomfortable, and/or difficult to apply on real time. To overcome these drawbacks, the goal of this paper is to propose a model for computing EE in real time (minute-by-minute) from heart rate and accelerometer signals. APPROACH: The proposed model, which consists of an original branched model, uses heart rate signals for computing EE on moderate to vigorous physical activities and a linear combination of heart rate and counts per minute for computing EE on light to moderate physical activities. Model parameters were estimated from a given data set composed of 53 subjects performing 25 different physical activities (light-, moderate- and vigorous-intensity), and validated using leave-one-subject-out. A different database (semi-controlled in-city circuit), was used in order to validate the versatility of the proposed model. Comparisons are done versus linear and nonlinear models, which are also used for computing EE from accelerometer and/or HR signals. MAIN RESULTS: The proposed piecewise model leads to more accurate EE estimations ([Formula: see text], [Formula: see text] and [Formula: see text] J kg-1 min-1 and [Formula: see text], [Formula: see text], and [Formula: see text] J kg-1 min-1 on each validation database). SIGNIFICANCE: This original approach, which is more conformable and less expensive than the reference methods, allows accurate EE estimations, in real time (minute-by-minute), during a large variety of physical activities. Therefore, this model may be used on applications such as computing the time that a given subject spent on light-intensity physical activities and on moderate to vigorous physical activities (binary classification accuracy of 0.8155).

Indication, organization, practical implementation and interpretation guidelines for retrospective CGM recording: A French position statement.

AIM: The benefits of retrospective continuous glucose monitoring (retroCGM) recording have been widely explored in clinical studies, and many diabetes physicians routinely use this examination. However, the method of interpretation of CGM recordings has never been precisely described. METHOD: An expert French panel of physicians met for two days to discuss several aspects of retroCGM use and to produce a position statement. RESULTS: The guidelines cover the indications for retroCGM, the general organization and practical implementation of CGM recordings, a description of the different devices available and guidelines for the interpretation of retroCGM recordings. CONCLUSION: This consensus document should help clinicians in the proper use of retroCGM.

Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients.

Familial medullary thyroid carcinoma only is related to germline mutations in the protooncogene RET, mainly in exons 10, whereas noncysteine mutations (exons 13-15) are considered infrequent. We analyzed 148 patients from 47 familial medullary thyroid carcinoma only families, and we found noncysteine RET mutations in 59.5% of these families. Of the index cases with noncysteine mutations, 43.4% presented with a multinodular goiter and high basal calcitonin; they were older at diagnosis than those with mutation in exon 10 and had more multifocal medullary thyroid carcinoma, but no difference in size, bilaterality, presence of C cell hyperplasia, or nodal metastases was found. Gene carriers with noncysteine RET mutations had a lower incidence of medullary thyroid carcinoma (78.2% vs. 94.1%) than those with mutation in exon 10; 20.2% had C cell hyperplasia only, although thyroidectomized at an older age. In conclusion, familial medullary thyroid carcinoma with noncysteine RET mutations are not infrequent and are overrepresented in presumed sporadic medullary thyroid carcinoma, suggesting that RET analysis should routinely be extended to exons 13, 14, and 15. The phenotype is characterized by a late onset of the disease, suggesting a delayed appearance of C cell disease rather than a less aggressive form. In familial medullary thyroid carcinoma gene carriers, the optimal timing for thyroidectomy remains controversial. Based on these data, we propose that surgery should be performed before elevation of the basal calcitonin level, potentially as soon as the pentagastrin test becomes abnormal.

Synthesis and structural organization of zonular fibers during development and aging.

Zonular fibers are a specific form of extracellular matrix composed mainly of fibrillins. The purpose of this study was to determine which cells secrete fibrillin-1 during development and aging. A specific guinea pig fibrillin-1 mRNA probe was designed and cloned in order to identify fibrillin-secreting cells in guinea pig eye, using in situ hybridization. Immunofluorescence, with a specific guinea pig monoclonal antibody, was used to compare protein levels at different stages from birth to 35 months of age. Electron microscopy and immunolabeling were used to investigate the organization of zonular microfibril bundles. We identified the cells of non-pigmented epithelium of the ciliary body as the main source of fibrillin secreted into the zonule. Moreover, while mRNA expression decreased during aging, there was no decrease in fibrillin immunoreactivity, as previously described in human aorta. These data indicate a very slow turnover of the zonular microfibrils which can be correlated with the appearance during aging of a new periodic fibrillar structure. This new structure may reflect an increased cross-linking in the long-lived zonular microfibrillar bundles.

A routine method for contrasting elastin at the ultrastructural level.

A reliable, simple, and inexpensive method for ultrastructural investigation of elastin is described. This method uses uranyl acetate dissolved in absolute methanol, followed by an optional lead citrate counterstain. The procedure was tested on a number of animal and human tissues that had been fixed and processed differently.

Microfibrillar composition of umbilical cord matrix: characterization of fibrillin, collagen VI and intact collagen V.

Ultrastructural studies made on human umbilical cord revealed that the striated collagen fibrils of the Wharton's jelly matrix are mixed with many microfibrillar structures. Microfibrils were found with a tubular cross-section of 10-12 nm diameter and were organized as beaded filaments characteristic of fibrillin-rich microfibrils. Beads had an average diameter of 25 nm and were spaced at about 50-80 nm. This ultrastructural observation was confirmed by indirect immunofluorescent staining of the jelly matrix using monoclonal antibody to fibrillin. Another constituent of the microfibrillar network was present as typical 100-nm periodic filaments of type VI collagen. Indirect immunofluorescent staining using antibodies to collagen VI showed for the first time that this collagen appeared to be distributed largely in the jelly matrix. In addition, other microfibrils with no specific banding pattern were observed. These microfibrils may constitute an organization of type V collagen different from the one which is generally assembled in heterotypic fibrils with collagen I. Among the latter heterotypic fibrils, type V collagen was studied using an anti-peptide antibody to the most N-terminal non-collagenous region of its alpha 2(V) chain. This antibody recognized a filamentous mesh decorating the bundles of collagen fibrils by immunofluorescent staining. This indicates that at least this part of alpha 2(V) chain may be accessible to the antibody at the surface of the fibrils.

Of/Lb collagen promotes chemoinvasion of breast-cancer cells and directs epithelial-cell migration into granulation-tissue of experimental dermal wounds.

OF/LB collagen is a recently described once-fetal form of collagen, with laminin-binding properties, composed of three alpha(1)(I)-sized chains, one of which displaying an unusually acidic pI. This collagen appears able to direct the migration of breast cancer cells through Matrigel, and of injury-activated epithelial cells into the underlying granulation stromal tissue. The effect exerted by OF/LB collagen in vitro appears preferentially linked to its acidic chain. The data reported strongly support the hypothesis that the presence and accumulation of OF/LB collagen in cancer may play a fundamental role in the invasive growth.

The evolution of fibrillar collagens: a sea-pen collagen shares common features with vertebrate type V collagen.

The extracellular matrix of marine primitive invertebrates (sponges, polyps and jellyfishes) contains collagen fibrils with narrow diameters. From various data, it has been hypothesized that these primitive collagens could represent ancestral forms of the vertebrate minor collagens, i.e., types V or XI. Recently we have isolated a primitive collagen from the soft tissues of the sea-pen Veretillum cynomorium. This report examines whether the sea-pen collagen shares some features with vertebrate type V collagen. Rotary shadowed images of acid-soluble collagen molecules extracted from beta-APN treated animals, positive staining of segment-long-spacing crystallites precipitated from pepsinized collagen, Western blots of the pepsinized alpha1 and alpha2 chains with antibodies to vertebrate types I, III and V collagens, and in situ gold immunolabeling of ECM collagen fibrils were examined. Our results showed that the tissue form of the sea-pen collagen is a 340-nm threadlike molecule, which is close to the vertebrate type V collagen with its voluminous terminal globular domain, the distribution of most of its polar amino-acid residues, and its antigenic properties.

Ultrastructural evidences of a distinct axial domain within native rat tail tendon collagen fibrils.

The structure of collagen fibrils of tail tendon in young and mature rats was investigated by transmission (TEM) electron microscopy after cytochemical methods associated with special procedures of dehydration and fixation. All the collagen fibrils show a central condensed material of 4 nm in diameter which remains preserved even when fibrils have been swollen and partly disorganized by the ethyl glycol dehydration. A cytochemical characterization using PTA and TCH treatments strongly suggests the glycoprotein nature of this central compact material and reveals the heterogeneous structure of each fibril. The first morphological evidence that the construction of the collagen fibrils must take place around a condensed material which serves as a scaffolding is obtained. These observations are in agreement with the now well established existence of heterotypic collagen fibrils in many extracellular matrices.

Fibrillin-rich microfibrils: structural modifications during ageing in normal human zonule.

Ageing is marked by ultrastructural and functional changes in most tissues. In part, these changes are caused by a loss of elasticity in the elastic fibers of the extracellular matrix. These fibers are composed of the protein elastin associated with microfibrils of 8 to 12 nm in diameter. Microfibrils contain fibrillins as major constituents. Mutations in fibrillin genes are considered as primary causes of Marfan syndrome, a genetic disorder with pathological manifestations in the cardiovascular and skeletal systems, in addition to dysfunctions in the eye. Fibrillin is also the major protein of the ciliary zonule fibers. During ageing, these fibers become more fragile, and concomitantly, an increased risk for ocular pathologies is observed. We have investigated structural modifications in fibrillin-rich microfibrils during ageing of human ciliary zonule. Observations using light microscopy and transmission electron microscopy after rotary shadowing allowed us to describe the organization of the zonule fibers and their insertion into the ciliary body. Our results emphasize qualitative differences between young and old zonules, which are likely due to modifications in the structure of microfibrils.

[Assessment of the management of arterial hypertension in a population of (type 2) diabetic patients undergoing hospitalization. Diabetes and prognostic factors in the control of arterial hypertension]. / Evaluation de la prise en charge de l'HTA dans une population de patients diabétiques (de type 2) suivis en hospitalisation. Diabète et facteurs pronostiques du contrôle de l'HTA.

The control of hypertension in diabetic hypertensive patients prevents micro and macroangiopathy complications. Our prospective study was designed to evaluate the level of treatment of hypertension in type II diabetic patients at the time of referral to our endocrinology unit and after a mean follow-up of 9.2 months. Five hundred and sixty four patients (sex ratio: 1.15, mean age of 56 +/- 13, mean BMI of 28 +/- 15, mean duration of diabetes of 11.3 +/- 9.9) were referred to our unit. Among these, 42% had an antihypertensive drug (58% under monotherapy, 42% under combinations) and 92% had a documented history of CHD. Glycemic and blood pressure controls were stable during follow-up. HbA1c remained unchanged (8.95% at admission, 8.8% at 9 months) BP decreased from 143/84 +/- 26/13 mmHg to 142/82 +/- 23/13 mmHg. Fifty six percent reached a BP goal of 140/90 mmHg whereas 42% achieved a BP goal of 130/85 mmHg at 9 months compared to respectively 56% and 39% at admission. A multivariate logistic regression analysis showed that initial value of SBP (p < 0.0001), age (p < 0.0001), BMI (p = 0.006), HbA1c (p = 0.018) were independent factors of non control of hypertension. In conclusion, follow-up of hypertension diabetic patients would be focussed on identified and modifiable factors.

[Rhabdomyolysis in patients with preexisting myopathy, treated with antilipemic agents]. / Rhabdomyolyse chez des patients traités par hypolipémiants et ayant une myopathie préexistante. 4 Observations.

BACKGROUND: Lipid lowering drugs (fibrates and statins) are generally well tolerated and side effects, mainly hepatic and muscular disorders are rare. However, when they occur, muscular disorders may be severe, leading to rhabdomyolysis. We report here four cases of rhabdomyolysis in patients given lipid lowering drugs and who had pre-existing myopathy. CASE REPORTS: The four patients complained of muscle pain after treatment with niacin, HMGCoA inhibitors, as well as fibrates. The myopathy was not recognized at the time of prescription in three cases. Myopathy resolved rapidly upon discontinuation of the drugs and none of the patients developed renal failure. DISCUSSION: This is the first report of rhabdyomyosis induced by lipid lowering drugs in patients with pre-existing myopathy. Drug induced myopathy is a known complication of lipid lowering drugs either alone or in patients with other conditions such as renal failure, immunosuppressive therapy for cardiac transplantation, or in case of combination regimens. Such a side effect without concomitant disease has not been reported previously in patients with congenital myopathy. Cholestyramine is the drug of choice for these patients. Our observations suggest that the rhabdomyolysis provoked by lipid lowering drugs may be favored by pre-existing myopathy.

Telemedicine and type 1 diabetes: is technology per se sufficient to improve glycaemic control?

AIM: In the TELEDIAB-1 study, the Diabeo system (a smartphone coupled to a website) improved HbA1c by 0.9% vs controls in patients with chronic, poorly controlled type 1 diabetes. The system provided two main functions: automated advice on the insulin doses required; and remote monitoring by teleconsultation. The question is: how much did each function contribute to the improvement in HbA1c? METHODS: Each patient received a smartphone with an insulin dose advisor (IDA) and with (G3 group) or without (G2 group) the telemonitoring/teleconsultation function. Patients were classified as "high users" if the proportion of "informed" meals using the IDA exceeded 67% (median) and as "low users" if not. Also analyzed was the respective impact of the IDA function and teleconsultations on the final HbA1c levels. RESULTS: Among the high users, the proportion of informed meals remained stable from baseline to the end of the study 6months later (from 78.1±21.5% to 73.8±25.1%; P=0.107), but decreased in the low users (from 36.6±29.4% to 26.7±28.4%; P=0.005). As expected, HbA1c improved in high users from 8.7% [range: 8.3-9.2%] to 8.2% [range: 7.8-8.7%] in patients with (n=26) vs without (n=30) the benefit of telemonitoring/teleconsultation (-0.49±0.60% vs -0.52±0.73%, respectively; P=0.879). However, although HbA1c also improved in low users from 9.0% [8.5-10.1] to 8.5% [7.9-9.6], those receiving support via teleconsultation tended to show greater improvement than the others (-0.93±0.97 vs -0.46±1.05, respectively; P=0.084). CONCLUSION: The Diabeo system improved glycaemic control in both high and low users who avidly used the IDA function, while the greatest improvement was seen in the low users who had the motivational support of teleconsultations.