Biomedical subjects

Evert de Jonge

Publications and source records attributed to Evert de Jonge.

At least 19 recordsLinked to original sources

PubMed2006

Design and implementation of an ICU incident registry.

Due to its complexity intensive care is vulnerable to errors. On the ICU adults of the AMC (Amsterdam, The Netherlands) the available registries used for error reporting did not give insight in the occurrence of unwanted events, and did not lead to preventive measures. Therefore, a new registry has been developed on the basis of a literature study on the various terms and definitions that refer to unintended events, and on the methods to register and monitor them. As this registry intends to provide an overall insight into errors, a neutral term ('incident') -- which does not imply guilt or blame -- has been sought together with a broad definition. The attributes of an incident further describe the unwanted event, but they should not form an impediment for the ICU nurses and physicians to report. The properties of a registry that contribute to making it accessible and user friendly have been determined. This has resulted in an electronic registry where incidents can be reported rapidly, voluntarily, anonymously and free of legal consequences. Evaluation is required to see if the new registry indeed provides the ICU management with the intended information on the current situation on incidents. For further refinement of the design, additional development and adjustments are required. However, we expect that the awareness of errors of the ICU personnel has already improved, forming the first step to increased patient safety.

Documentation↗

PubMed2006

Emergence of multidrug-resistant Gram-negative bacteria during selective decontamination of the digestive tract on an intensive care unit.

OBJECTIVES: During treatment with selective decontamination of the digestive tract (SDD), four multidrug-resistant (MDR) strains, three different Escherichia coli and one Klebsiella pneumoniae, were isolated from four patients not known as carriers of such MDR strains before their admission to the intensive care unit (ICU) in the Academic Medical Center (AMC) in Amsterdam. These isolates were extended-spectrum beta-lactamase (ESBL)-positive. We investigated whether this was due to interspecies transfer of resistance genes. METHODS: The MDR strains were typed by amplified fragment length polymorphism (AFLP) analysis. The plasmids from these strains were characterized by restriction fragment length polymorphism and the resistance genes were characterized by PCR and sequence analysis. RESULTS: The strains were genetically unrelated and contained identical plasmids with ESBL genes. CONCLUSIONS: We identified an outbreak of plasmid-mediated ESBL genes during SDD treatment in the ICU. The use of third-generation cephalosporins in SDD is associated with the emergence of ESBLs. We conclude that identification of emerging MDR Gram-negative bacteria and recognition of resistance plasmid transfer during SDD treatment are crucial for optimal application of this regimen in ICUs.

Anti-Bacterial Agents↗

PubMed2006

The use of a registry database in clinical trial design: assessing the influence of entry criteria on statistical power and number of eligible patients.

Randomized clinical trials (RCTs) are prospective empirical studies used to investigate the effect of a particular medical intervention. The design of a clinical trial is a delicate decision process, as each of the decisions that are taken in this process influences the eventual result of the clinical trial. Despite the efforts that are put into trial design, many trials fail to show an effect of the intervention. In some of these situations the intervention may be truly ineffective, however, more often this is caused by problems with the inclusion of patients and a resulting lack of statistical power to show the effect. To avoid this problem, in the design of a trial, the statistical power that can be achieved with the current design choices is calculated and balanced with economic considerations. In the choice of the entry criteria however, an important step in the design process, the influence of the chosen criteria on statistical power and number of eligible patients is not quantified. As these criteria influence the characteristics of the study population and the number of patients that will be eligible for the trial, and thereby the chances of finding an effect of the intervention, we believe that also in the choice of entry criteria explicit estimates of the number of eligible patients should be made. This paper presents a method to arrive at precise, objective estimates of statistical power and the number of eligible patients, using a registry database. Furthermore, we describe how this method is incorporated in the process of choosing entry criteria for a clinical trial. We illustrate the method with an example in the area of severe sepsis.

Humans↗

PubMed2006

Influence of severity of illness, medication and selective decontamination on defecation.

OBJECTIVE: To describe the pattern of defecation in critically ill ventilated patients and the influence of selective decontamination (SDD) and other medication. DESIGN: Descriptive cohort study. SETTING: Mixed surgical-medical ICU in a university Hospital. PATIENTS: Ventilated patients with a length of stay >or=7 days taking part in a study on SDD. MEASUREMENTS: Daily registration of defecation, SOFA (sepsis-related organ failure assessment score) score, administration of dopamine, noradrenaline, morphine and other medications. RESULTS: The first defecation occurred after a mean of 6.2 days. Patients with defecation within 6[Symbol: see text]days had lower mean SOFA scores, received more cisapride and lactulose and less dopamine, noradrenaline and morphine, and had a shorter duration of mechanical ventilation and ICU stay. On 57% of the days, no stools were produced; on 31% diarrhea, and on 12%, normal stools. Patients receiving SDD had more days with normal stools and less with diarrhea. Diarrhea was preceded by the administration of lactulose in the majority of patients. CONCLUSION: Time to first defecation correlated with severity of illness, vasoactive medication, administration of morphine, cisapride and lactulose, duration of mechanical ventilation and length of stay. Diarrhea seemed at least partially iatrogenic.

Adult↗

PubMed2006

Plasma and plasma components in the management of disseminated intravascular coagulation.

A variety of clinical conditions can cause systemic activation of coagulation that ranges from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). DIC consists of a widespread systemic activation of coagulation, resulting in diffuse fibrin deposition in small and midsize vessels. There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation can result in depletion of platelets and coagulation factors, which might cause bleeding. Recent insight into important pathogenetic mechanisms that might lead to DIC has resulted in novel preventive and therapeutic approaches to patients with sepsis and derangement of coagulation. Supportive strategies aimed at inhibition of coagulation activation might theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways.

Anticoagulants↗

PubMed2006

Predisposing factors for hypoglycemia in the intensive care unit.

OBJECTIVE: The introduction of strict glycemic control in the intensive care unit has increased the risk for hypoglycemia. In this study we examined the association between predefined circumstances and the occurrence of hypoglycemia in the intensive care unit. DESIGN: : Retrospective cohort study. SETTING: Academic medical center. PATIENTS: All episodes of hypoglycemia (glucose value <45 mg/dL) in our intensive care unit between September 2002 and September 2004 were identified. Presence of predefined circumstances previously associated with hypoglycemia was scored around the moment of hypoglycemia using a patient data management system and in-hospital charts. Patients with a first hypoglycemic event were contrasted to controls from the same cohort, who were matched for time since admission, to correct for the effect of length of stay. Data were analyzed using conditional logistic regression analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 2,272 patients, 156 (6.9%) experienced at least one episode of hypoglycemia. Continuous venovenous hemofiltration with bicarbonate-based substitution fluid (odds ratio [OR], 14; 95% confidence interval [CI], 1.8-106), a decrease of nutrition without adjustment for insulin infusion (OR, 6.6; 95% CI, 1.9-23), diabetes mellitus (OR, 2.6; 95% CI, 1.5-4.7), insulin use (OR, 5.3; 95% CI, 2.8-11), sepsis (OR, 2.2; 95% CI, 1.2-4.1), and inotropic support (OR, 1.8; 95% CI, 1.1-2.9) were associated with hypoglycemia. Simultaneous octreotide and insulin use (OR, 6.0; 95% CI, 0.72-50) may also be associated with hypoglycemia. Gastric residual during enteral nutrition without adjusting insulin infusion, liver failure, continuous venovenous hemofiltration with lactate-based substitution fluid, diminished glomerular filtration rate, dose diminishment of glucocorticoids or catecholamines, and use of beta-blocking agents were not associated with hypoglycemia. Adjusting for age, gender, and Acute Physiology and Chronic Health Evaluation II score at admission did not materially change ORs. CONCLUSION: Use of bicarbonate-based substitution fluid during continuous venovenous hemofiltration, a decrease of nutrition without adjustment for insulin infusion, a prior diagnosis of diabetes mellitus, sepsis, and need for inotropic support were found to be associated with hypoglycemia. Simultaneous use of insulin and octreotide may be associated with hypoglycemia.

Adult↗

PubMed2006

Evaluation of short-term consequences of hypoglycemia in an intensive care unit.

BACKGROUND: Introduction of strict glycemic control has increased the risk for hypoglycemia in the intensive care unit. Little is known about the consequences of hypoglycemia in this setting. We examined short-term consequences (seizures, coma, and death) of hypoglycemia in the intensive care unit. PATIENTS AND METHODS: All occurrences of hypoglycemia (glucose of <45 mg/dL) in our intensive care unit between September 1, 2002, and September 1, 2004, were identified. Patients with hypoglycemia (n = 156) were matched for time to hypoglycemia with control patients drawn from the at-risk population (nested case control method). Seizures observed within 8 hrs after hypoglycemia were scored. Discharge summaries for cases and controls were reviewed for occurrence of possible hypoglycemia-associated coma and death. A hazard ratio for in-hospital death was calculated with Cox regression analysis. RESULTS: The hazard ratio for in-hospital death was 1.03 (95% confidence interval, 0.68-1.56; p = .88) in patients with a first occurrence of hypoglycemia relative to the controls without hypoglycemia, corrected for duration of intensive care unit admittance before hypoglycemia, age, sex, and Acute Physiology and Chronic Health Evaluation II score at admission. No cases of hypoglycemia-associated death were reported. Hypoglycemic coma was reported in two patients. Seizures after hypoglycemia were observed in one patient. CONCLUSIONS: In this study, no association between incidental hypoglycemia and mortality was found. However, this data set is too small to definitely exclude the possibility that hypoglycemia is associated with intensive care unit mortality. In three patients with possible hypoglycemia-associated coma or seizures, a causal role for hypoglycemia seemed likely but could not fully be established.

Adult↗

PubMed2006

Endotoxaemia induces resistance to activated protein C in healthy humans.

Systemic inflammation activates the tissue factor/factor VIIa complex (TF/FVIIa), leading to a procoagulant state, which may be enhanced by impairment of physiological anticoagulant pathways, such as the protein C system. Besides impaired protein C activation, resistance to activated protein C (APC) may occur. We studied the effect of endotoxemia on APC resistance, analysed its determinants and evaluated the effect of TF/FVIIa inhibition on endotoxin-induced APC resistance. Sixteen healthy male volunteers participated in the study, eight receiving endotoxin alone and eight receiving the combination of endotoxin and recombinant Nematode Anticoagulant Protein c2 (rNAPc2), a potent inhibitor of TF/FVIIa. Parameters of coagulation were subsequently studied. The sensitivity to APC was determined by two tests: a test based on the endogenous thrombin potential and a test based on the activated partial thromboplastin time. In response to endotoxemia, both tests detected a transient APC resistance that was predominantly mediated by an increase in factor VIII and was not influenced by TF/FVIIa inhibition. In vitro tests confirmed that an increase in factor VIII induced APC resistance, as measured by both tests. This finding suggests that APC resistance might play a role in the procoagulant state occurring during human endotoxemia.

Activated Protein C Resistance↗

PubMed2006

The effects of continuous venovenous hemofiltration on coagulation activation.

INTRODUCTION: The mechanism of coagulation activation during continuous venovenous hemofiltration (CVVH) has not yet been elucidated. Insight into the mechanism(s) of hemostatic activation within the extracorporeal circuit could result in a more rational approach to anticoagulation. The aim of the present study was to investigate whether CVVH using cellulose triacetate filters causes activation of the contact factor pathway or of the tissue factor pathway of coagulation. In contrast to previous studies, CVVH was performed without anticoagulation. METHODS: Ten critically ill patients were studied prior to the start of CVVH and at 5, 15 and 30 minutes and 1, 2, 3 and 6 hours thereafter, for measurement of prothrombin fragment F1+2, soluble tissue factor, activated factor VII, tissue factor pathway inhibitor, kallikrein-C1-inhibitor and activated factor XII-C1-inhibitor complexes, tissue-type plasminogen activator, plasminogen activator inhibitor type I, plasmin-antiplasmin complexes, protein C and antithrombin. RESULTS: During the study period the prothrombin fragment F1+2 levels increased significantly in four patients (defined as group A) and did not change in six patients (defined as group B). Group A also showed a rapid increase in transmembrane pressure, indicating clotting within the filter. At baseline, the activated partial thromboplastin time, the prothrombin time and the kallikrein-C1-inhibitor complex and activated factor XII-C1-inhibitor complex levels were significantly higher in group B, whereas the platelet count was significantly lower in group B. For the other studied markers the differences between group A and group B at baseline were not statistically significant. During CVVH the difference in the time course between group A and group B was not statistically significant for the markers of the tissue factor system (soluble tissue factor, activated factor VII and tissue factor pathway inhibitor), for the markers of the contact system (kallikrein-C1-inhibitor and activated factor XII-C1-inhibitor complexes) and for the markers of the fibrinolytic system (plasmin-antiplasmin complexes, tissue-type plasminogen activator and plasminogen activator inhibitor type I). CONCLUSION: Early thrombin generation was detected in a minority of intensive care patients receiving CVVH without anticoagulation. Systemic concentrations of markers of the tissue factor system and of the contact system did not change during CVVH. To elucidate the mechanism of clot formation during CVVH we suggest that future studies are needed that investigate the activation of coagulation directly at the site of the filter. Early coagulation during CVVH may be related to lower baseline levels of markers of contact activation.

Adult↗

PubMed2006

Errors associated with applying decision support by suggesting default doses for aminoglycosides.

BACKGROUND: Medication errors, and the resultant adverse drug events (ADEs), are one of the main preventable causes of morbidity and mortality. Computerised physician order entry (CPOE) is reported to reduce the frequency of these errors. However, CPOE systems themselves may be associated with errors. The aim of this study was to investigate the effects of a CPOE system that displays an initial default dose for gentamycin and tobramycin administration on the frequency of medication errors and potential ADEs in patients with renal insufficiency. METHODS: Gentamycin and tobramycin prescriptions from the CPOE records of a Dutch tertiary adult intensive care unit were retrospectively compared with doses recommended by a locally developed guideline. The default dose for gentamycin and tobramycin in the CPOE system is 240 mg/day. A dose prescribing error was defined as an administered dose that exceeded the recommended dose by >10%. RESULTS: Three hundred and ninty two prescriptions, relating to 253 patients (of whom 184 had renal insufficiency), were analysed. There was a high frequency (58%, 227 of 392) of prescriptions that used the CPOE system's default dose of 240 mg/day. The dose was wrong in 73% (165) of these orders. Default orders for patients with renal insufficiency amounted to 52% (132 of 259). A total of 86% (113 of 132) of these resulted in potential ADEs compared with 53% (66 of 124) for the rest of orders (p < 0.0001). DISCUSSION: A markedly high frequency of prescriptions followed the default dose value and, in patients with renal insufficiency, there was a high frequency of doses exceeding the guideline recommendation (+10%), amounting to potential ADEs. CONCLUSION: Initial CPOE dose values for prescribing gentamycin and tobramycin, which are based on a fixed default value, form a source of potential ADEs for patients with renal insufficiency.

Adult↗

PubMed2006

A Markov model to describe daily changes in organ failure for patients at the ICU.

As the support and stabilization of organ function is a major goal of treatment in the Intensive Care Unit (ICU), changes in the function of organ systems are an important indicator of the progression of the disease and recovery. This paper presents how to construct a model that describes changes in organ failure of ICU patients on a day-to-day basis. The model is based on the daily Sequential Organ Failure Assessment (SOFA) scores for six organ systems and predicts, for each of these organ systems, whether failure or recovery is due on the next day, using six logistic regression equations. The joint set of equations, extended with equations for predicting ICU discharge and death, constitutes a firstorder multivariate Markov model. We applied the procedure on a dataset and found that most types of organ failure are highly persistent.

Humans↗

PubMed2005

Recombinant human activated protein C resets thrombin generation in patients with severe sepsis - a case control study.

INTRODUCTION: Recombinant human activated protein C (rhAPC) is the first drug for which a reduction of mortality in severe sepsis has been demonstrated. However, the mechanism by which this reduction in mortality is achieved is still not clearly defined. The aim of the present study was to evaluate the dynamics of the anticoagulant, anti-inflammatory and pro-fibrinolytic action of rhAPC in patients with severe sepsis, by comparing rhAPC-treated patients with case controls. METHODS: In this prospectively designed multicenter case control study, 12 patients who were participating in the ENHANCE study, an open-label study of rhAPC in severe sepsis, were treated intravenously with rhAPC at a constant rate of 24 microg/kg/h for a total of 96 h. Twelve controls with severe sepsis matching the inclusion criteria received standard therapy. The treatment was started within 48 h after the onset of organ failure. Blood samples were taken before the start of the infusion and at 4, 8, 24, 48, 96 and 168 h, for determination of parameters of coagulation and inflammation. RESULTS: Sepsis-induced thrombin generation as measured by thrombin-antithrombin complexes and prothrombin fragment F1+2, was reset by rhAPC within the first 8 h of infusion. The administration of rhAPC did not influence parameters of fibrinolysis and inflammation. There was no difference in outcome or occurrence of serious adverse events between the treatment group and the control group. CONCLUSION: Sepsis-induced thrombin generation in severely septic patients is reset by rhAPC within the first 8 h of infusion without influencing parameters of fibrinolysis and inflammation.

Analysis of Variance↗

PubMed2005

Performance of prognostic models in critically ill cancer patients - a review.

INTRODUCTION: Prognostic models, such as the Acute Physiology and Chronic Health Evaluation (APACHE) II or III, the Simplified Acute Physiology Score (SAPS) II, and the Mortality Probability Models (MPM) II were developed to quantify the severity of illness and the likelihood of hospital survival for a general intensive care unit (ICU) population. Little is known about the performance of these models in specific populations, such as patients with cancer. Recently, specific prognostic models have been developed to predict mortality for cancer patients who are admitted to the ICU. The present analysis reviews the performance of general prognostic models and specific models for cancer patients to predict in-hospital mortality after ICU admission. METHODS: Studies were identified by searching the Medline databases from 1994 to 2004. We included studies evaluating the performance of mortality prediction models in critically ill cancer patients. RESULTS: Ten studies were identified that evaluated prognostic models in cancer patients. Discrimination between survivors and non-survivors was fair to good, but calibration was insufficient in most studies. General prognostic models uniformly underestimate the likelihood of hospital mortality in oncological patients. Two versions of a specific oncological scoring systems (Intensive Care Mortality Model (ICMM)) were evaluated in five studies and showed better discrimination and calibration than the general prognostic models. CONCLUSION: General prognostic models generally underestimate the risk of mortality in critically ill cancer patients. Both general prognostic models and specific oncology models may reliably identify subgroups of patients with a very high risk of mortality.

APACHE↗

PubMed2005

Factors that predict outcome of intensive care treatment in very elderly patients: a review.

INTRODUCTION: Advanced age is thought to be associated with increased mortality in critically ill patients. This report reviews available data on factors that determine outcome, on the value of prognostic models, and on preferences regarding life-sustaining treatments in (very) elderly intensive care unit (ICU) patients. METHODS: We searched the Medline database (January 1966 to January 2005) for English language articles. Selected articles were cross-checked for other relevant publications. RESULTS: Mortality rates are higher in elderly ICU patients than in younger patients. However, it is not age per se but associated factors, such as severity of illness and premorbid functional status, that appear to be responsible for the poorer prognosis. Patients' preferences regarding life-sustaining treatments are importantly influenced by the likelihood of a beneficial outcome. Commonly used prognostic models have not been calibrated for use in the very elderly. Furthermore, they do not address long-term survival and functional outcome. CONCLUSION: We advocate the development of new prognostic models, validated in elderly ICU patients, that predict not only survival but also functional and cognitive status after discharge. Such a model may support informed decision making with respect to patients' preferences.

Activities of Daily Living↗

PubMed2005

Influence of entry criteria on mortality risk and number of eligible patients in recent studies on severe sepsis.

OBJECTIVE: To understand the impact of patient selection criteria used in recent sepsis trials on baseline mortality risk and number of eligible patients. DESIGN: Observational cohort study, with retrospective analysis of prospectively collected data. METHODS AND MAIN RESULTS: Using a MEDLINE search, we selected recent randomized controlled trials in patients with severe sepsis and studied the mortality rate in the control groups of these trials. Nine articles fulfilled the search criteria and were used in our analyses. The 28-day mortality rate in the control groups of these trials varied between 28.0% and 89.0%. Differences in this mortality rate might be due to the use of different entry criteria but also to other factors that vary between the trials. To eliminate the influence of these confounding factors when studying the effect of the use of entry criteria on baseline mortality risk and number of eligible patients, we projected the entry criteria of these nine trials on a large independent database of >70,000 Dutch intensive care patients admitted between 1996 and 2003. This yielded nine groups of patients who would have been eligible for the respective trials. The percentage of patients who would have been eligible for these trials varied between 1.5% and 6.0%. Six of these groups had a similar intensive care mortality rate (between 25.0% and 28.9%). The projection of the entry criteria of the three other trials onto the database resulted in groups of patients with considerably higher intensive care mortality. For in-hospital mortality rate in these groups, similar results were found. CONCLUSIONS: The majority of the trials we studied used entry criteria that select patients with a similar mortality risk. This suggests that differences in baseline mortality risk reported in recent sepsis trials are to be attributed to other factors that vary between trials rather than to differences in entry criteria. However, entry criteria do have an important influence on the number of eligible patients for sepsis trials without influencing baseline mortality rate.

Adolescent↗

PubMed2005

Effects of selective decontamination of digestive tract on mortality and antibiotic resistance in the intensive-care unit.

PURPOSE OF REVIEW: Since its introduction in 1984 several small trials have studied the infection prevention regimen of selective decontamination of the digestive tract (SDD) in intensive care patients. Although meta-analyses of these studies suggested that SDD could reduce mortality, it continued to be a highly controversial strategy. There were not only serious doubts about the methodological quality of the meta-analyses, fear also existed that SDD would lead to increased antibiotic resistance. Recently, two new large randomized trials have been published that studied the effects of SDD on mortality and resistance. In this article, we will review the concept on which SDD is based and the present knowledge of the effects of SDD on mortality and antibiotic resistance. RECENT FINDINGS: In accordance with earlier meta-analyses of small studies, two recent randomized trials have confirmed that selective decontamination of the digestive tract significantly lowers mortality and decreases the emergence of antibiotic resistance. Limitation of these studies is the fact that they were conducted in intensive-care units (ICUs) with a low prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). SUMMARY: There is convincing evidence that selective decontamination of the digestive tract (SDD) lowers mortality as well as resistance in circumstances with low prevalence of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE). SDD should still be considered experimental in area's where MRSA and VRE are endemic. However, given the important potential benefits of SDD, more studies are urgently needed to adapt SDD in a way that proves effective in those settings.

Antibiotic Prophylaxis↗

PubMed2005

Widespread transfer of resistance genes between bacterial species in an intensive care unit: implications for hospital epidemiology.

A transferable plasmid encoding SHV-12 extended-spectrum beta-lactamase, TEM-116, and aminoglycoside resistance was responsible for two sequential clonal outbreaks of Enterobacter cloacae and Acinetobacter baumannii bacteria. A similar plasmid was present among isolates of four different bacterial species. Recognition of plasmid transfer is crucial for control of outbreaks of multidrug-resistant nosocomial pathogens.

Acinetobacter Infections↗

PubMed2005

Design and implementation of an ICU incident registry.

Due to its complexity intensive care is vulnerable to errors. On the ICU Adults of the AMC (Amsterdam, the Netherlands) the available registries used for error reporting did not give insight in the occurrence of unwanted events, and did not lead to preventive measures. Therefore, a new registry has been developed on the basis of a literature study on the various terms and definitions that refer to unintended events, and on the methods to register and monitor them. As this registry intends to provide an overall insight into errors, a neutral term ('incident') -which does not imply guilt or blame- has been sought together with a broad definition. The attributes of an incident further describe the unwanted event, but they should not form an impediment for the ICU nurses and physicians to report. The properties of a registry that contribute to making it accessible and user friendly have been determined. This has resulted in an electronic registry where incidents can be reported rapidly, voluntarily, anonymously and free of legal consequences. Evaluation is required to see if the new registry indeed provides the ICU management with the intended information on the current situation on incidents. For further refinement of the design, additional development and adjustments are required. However, we expect that the awareness of errors of the ICU personnel has already improved, forming the first step to increased patient safety.

Critical Care↗