Synthesis of M-UiO-66 (M = Zr, Ce or Hf) employing 2,5-pyridinedicarboxylic acid as a linker: defect chemistry, framework hydrophilisation and sorption properties.

Metal-organic frameworks of general composition [M6(OH)4(O)4(PDC)6-x(Cl)2x(H2O)2x] with M = Zr, Ce, Hf; PDC2- = 2,5-pyridinedicarboxylate and 0 ≤ x ≤ 2 were obtained under reflux using formic, nitric or acetic acid as an additive. Rietveld refinements carried out using a fixed occupancy of the linker molecules according to the results of thermogravimetric measurements confirmed that the MOFs crystallize in the UiO-66 type structure and demonstrate that the structural models describe the data well. Further characterization was carried out by NMR spectroscopy, thermogravimetric analysis, Zr K-edge EXAFS- and Ce L3-edge XANES measurements. To highlight the influence of the additional nitrogen atom of the pyridine ring, luminescence and vapour sorption measurements were carried out. The hydrophilisation of the MOFs was shown by the adsorption of water at lower p/p0 (<0.2) values compared to the corresponding BDC-MOFs (0.3). For water and methanol stability cycling adsorption experiments were carried out to evaluate the MOFs as potential adsorbents in heat transformation applications.

Perioperative factors and outcome associated with massive blood loss during major liver resections.

BACKGROUND: Mortality and morbidity rates from major liver resections have decreased sharply over the past 25 years. This improvement is due to a better understanding of liver anatomy and the introduction of new operative techniques, but also to improved anesthetic perioperative support. Certain cases are still associated with voluminous blood loss. These patients may be at higher risk for postoperative problems and increased length of stay (LOS) in hospital. METHODS: We have retrospectively reviewed 115 patients undergoing major hepatic resections (three or more anatomic segments) with respect to operative blood loss (EBL). Those with an EBL >or=5000 ml (group 1; n = 39) were compared to those with an EBL or=70 years), tumor size, mortality, morbidity, and hospital LOS were examined. Operative reports were examined for any explanation for excessive blood loss. Anesthetic support often entailed the use of a rapid infusion system. RESULTS: The EBL was 7692+/-3848 ml for group 1 and 1359+/-514 ml for group 2. Primary liver tumors were resected in 20 patients in group 1 and in 18 patients in group 2. The remaining resections were for metastatic tumors, primarily colorectal in origin. In group 1, 13/39 patients had a left hepatectomy compared to 10/42 patients in group 2 (p=0.34). The overall mortality was 5/1 15. Four deaths occurred in group 1 and one in group 2 (p=0.16). Two deaths in group 1 were intra-operative (hemorrhage, air embolism). There was no difference in the number of patients with complications, 12/ 39 in group 1 and 8/42 in group 2 (p=0.22). Two patients in group 1 required re-operation for bleeding; there were none in group 2. Largest tumor size did not differ between the two groups (p=0.08), nor did the proportion of patients aged 70 years or older (p=0.06). There was no difference in hospital LOS (10.54+/-6.1 vs 8.90+/-4.7 days, p=0.2l). Review of operative notes in group 1 indicated no unusual problems in 13/39, large tumors or proximity to the inferior vena cava in 10/39, and bleeding from the middle hepatic vein in 7/39. Three patients in group 1 required total vascular exclusion for tumor removal; there were none in group 2. DISCUSSION: Massive EBL during major liver resection seems to be provoked by tumors near the inferior vena cava or major hepatic veins, or injury to the middle hepatic vein during operation, and not by patient age, tumor size alone, or type of hepatectomy. However, by avoiding prolonged hypotension and hypothermia with the use of rapid infusion devices, the perioperative course of these patients does not differ from those with much less EBL.

Military, civilian, and rural application of the damage control philosophy.

Damage control surgery is a useful salvage strategy for the most critically injured patients. Conceptually, this approach to individual patients can be extrapolated to situations such as military field surgery, civilian mass casualty events, and long-range transfers from rural areas. The logistic realities of Army forward surgery teams are addressed with regard to typical damage control maneuvers and evacuation. Specific areas requiring improvement through directed research are identified. Initial civilian mass casualty strategies are discussed, and a plan to prevent transfer delays of rural trauma patients is presented. By transferring the lessons learned from individual damage control patients to military, civilian mass casualty, and rural casualty events, resource utilization is optimized. The concept of minimal acceptable care rather than optimal trauma care can be applied to these three seemingly different situations.

Cold ischemia time: an independent predictor of increased HLA class I antibody production after rejection of a primary cadaveric renal allograft.

BACKGROUND: Cadaveric kidneys experiencing longer cold ischemia time (CIT) are associated with higher levels of delayed graft function, acute rejection, and early graft loss. One mechanism to explain these results is that ischemia/reperfusion (I/R) injury makes the allograft more immunogenic by upregulating molecules involved in the immune response (e.g., HLA Class I/II). METHODS: We evaluated the influence of CIT on the production of HLA Class I antibody level, measured by an antihuman globulin panel reactive antibody (AHG PRA) level, in 90 unsensitized recipients of primary cadaveric renal transplants (from a total of 1442 between 1985 and 1997) who rejected their kidneys. RESULTS: By multivariate analysis, a CIT of 15 hr or more (vs. < 15 hr) independently increased the risk of the AHG Class I PRA level being > or = 20% after unsensitized patients rejected their first kidneys (relative risk=3.57; 95% confidence interval=1.26 to 10.14; P=0.01), despite the same degree of Class I/II mismatch between the two CIT groups. The overall mean peak PRA level after primary kidney rejection was significantly lower for the CIT < 15 hr group (25.9%+/-33.9; n=24) compared with the CIT > or = 15 hr group (46.3%+/-36.5; n=66) (P<0.001). CONCLUSION: Longer CIT induces a humorally more immunogenic kidney.

[Intensified conventional insulin therapy in patients with type 2 diabetes mellitus. Positive long-term effects of insulin lispro on metabolic control and microalbuminuria]. / Intensivierte konventionelle Insulintherapie (ICT) bei Patienten mit Typ 2 Diabetes mellitus. Günstige Langzeiteffekte von Insulin Lispro auf Stoffwechselkontrolle und Mikroalbuminurie.

AIMS: It was decided to demonstrate by the present observations to which extent beneficial long-term effects on metabolic control, body weight and microalbuminuria can be attained by applying intensive insulin therapy (IIT) to type 2 diabetic patients, particularly when using insulin lispro. METHODS: In our observational study, clinical data were evaluated during 6, 12 and 36 months after participation in our structured inpatient insulin treatment and teaching programme in 25 patients with conventional insulin therapy (CT), in 10 patients with IIT using human normal insulin and in 15 patients with IIT using insulin lispro who all could be followed for 3 years in our outpatient diabetic clinic. RESULTS: In the CT-treated patients, HbA1c decreased from 10.2 +/- 0.4% to 7.6 +/- 0.2% (average +/- SEM) after 3 years. Body weight increased from 27.8 +/- 0.9 kg/m2 to 28.6 +/- 0.9 kg/m2, insulin dose increased from 29 +/- 3 U/day to 48 +/- 5 U/day (all p < 0.05), urinary albumin concentration was only transiently reduced. In the IIT-treated patients using human normal insulin, HbA1c fell from 10.6 +/- 0.8% to 7.9 +/- 0.5%, body weight increased from 27.8 +/- 1.4 kg/m2 to 29.8 +/- 1.3 kg/m2, urinary albumin concentration was reduced from 26 +/- 10 mg/l to 13 +/- 3 mg/l (all p < 0.05). Insulin dose increased only slightly from 57 +/- 6 U/day to 63 +/- 7 U/day. In the IIT-treated patients using insulin lispro HbA1c fell from 8.4 +/- 0.5% to 6.7 +/- 0.3%, body weight increased from 27.6 +/- 1.0 kg/m2 to 28.7 +/- 1.3 kg/m2, insulin dose from 36 +/- 5 U/day to 50 +/- 7 U/day, urinary albumin concentration was reduced from 23 +/- 4 mg/l to 13 +/- 4 mg/l (all p < 0.05). Blood pressure remained uninfluenced by insulin therapy. CONCLUSION: In our patients, we observed a beneficial long-term effect on metabolic control of IIT-treatment using insulin lispro, which was evident over the complete 3-year observation period, together with an only moderate increase in insulin dose and a clinically acceptable increase in body weight, but a remarkable reduction of microalbuminuria. Thus, clinical outcome was superior to that in patients treated with CT or IIT using human normal insulin.

IgM antibodies identified by a DTT-ameliorated positive crossmatch do not influence renal graft outcome but the strength of the IgM lymphocytotoxicity is associated with DR phenotype.

A positive crossmatch that is rendered negative by treating the serum with the IgM-reducing agent dithiothreitol (DTT) is generally reported not to influence short-term renal graft outcome. Its effect on long-term (> or = 3 years) cadaveric and live-donor transplant function, however, is less clear. We evaluated the effect of IgM antibodies in a DTT-ameliorated positive crossmatch (DTT-APXM) on long-term renal graft outcome in 1,290 consecutive cadaveric renal transplants (8-year survival) and 384 live-donor renal transplants (7-year survival) from patients transplanted between 1990 and 1999. The data show that 1- and 8-year graft survival for cadaveric renal transplants in patients with IgM antibodies (n=72) (DWFG censored = 91% and 65%; DWFG not censored = 90% and 60%) was not significantly different from the group without IgM antibodies (n = 1,218) (DWFG censored = 92% and 71%; DWFG not censored = 87% and 55%) (log-rank = 0.25 for DWFG censored, log-rank = 0.92 for DWFG not censored). The one- and seven-year graft survival for live-donor renal transplants in patients with IgM antibodies seen in a DTT-APXM (n = 22) (DWFG censored = 95% and 83%; DWFG not censored = 95% and 66%) was not significantly different from the group without IgM antibodies (n = 362) (DWFG censored = 94% and 81%; DWFG not censored = 92% and 73%) (log-rank = 0.61 for DWFG censored, log-rank = 0.89 for DWFG not censored). DR phenotype was found to be associated with the strong (>40% cell death) IgM reactivity in both black and white patients. In white patients, DR2 was more frequently seen with a strong IgM crossmatch (48.2%) than in molecularly typed controls (28.5%) (P < 0.03) and concomitant with that DR increase, DR4 was decreased in white patients (6.8%) compared with controls (25.5%) (P < 0.02). In black patients with strong IgM reactivity, DR6 was increased in patients (46.1%) compared with controls (20.5%) (P = 0.07) and concomitant with that DR6 increase, DR5 was decreased in frequency in black patients (7.6%) compared with controls (41%) (P < 0.03). These data show that long-term graft survival in renal transplantation is not negatively influenced by the presence of donor-reactive lymphocytotoxic antibodies in the crossmatch ameliorated by serum DTT treatment. They also suggest that the strength of the IgM antibody response is regulated in part by certain gene (s) of the DR region.

The use of insulin and glucose during resuscitation from hemorrhagic shock increases hepatic ATP.

BACKGROUND: Hemorrhagic shock produces a marked decrease in hepatic ATP, adenylate energy charge, and total adenosine nucleotides. This is followed by slow recovery to normal levels after resuscitation. Nucleotide metabolites are increased following shock and resuscitation. Previous experimental work has shown that supraphysiologic doses of insulin have salutary effects in animals with hemorrhagic shock and in cardiac patients. It appears that insulin causes increased availability of glucose and energy-producing substrates. This study examined whether resuscitation with glucose and insulin after hemorrhagic shock would alter the changes previously seen to occur in hepatic ATP levels, adenylate energy charge, or nucleotide metabolites. METHODS: Male Sprague-Dawley rats were bled to a mean arterial blood pressure of 40 mm Hg for 30 min. They were then resuscitated with the shed blood and one of three fluids: (1) lactated Ringer's, (2) lactated Ringer's with 10% glucose, (3) lactated Ringer's with 10% glucose + 6 units/kg regular insulin. Liver biopsies were obtained prior to shock (baseline), after 30 min of shock (shock), and 90 min after resuscitation (90 min). Tissue levels of ATP, ADP, AMP, adenosine, inosine, hypoxanthine, and xanthine were measured. Serum at 90 min was evaluated for potassium, glucose, and tumor necrosis factor alpha (TNF-alpha). RESULTS: The insulin-treated group had significantly increased hepatic ATP and energy charge following resuscitation compared with the other two groups. The insulin group also exhibited significant hypoglycemia. Total adenine nucleotides (ATP, ADP, and AMP) were significantly elevated 90 min postresuscitation in the insulin group. Mean blood pressures throughout the experiment were not significantly different among groups. TNF-alpha was highest in the insulin-treated group, but this was not significant. CONCLUSIONS: Resuscitation with insulin and dextrose significantly increased hepatic ATP and adenylate energy charge after hemorrhagic shock in rats. Total nucleotide pool levels were not different between groups, indicating that there was a shift of the equilibrium away from the metabolites toward ATP and ADP in the insulin-treated group. Insulin treatment had no significant effect on blood pressure or TNF-alpha. However, it caused significant hypoglycemia and hypokalemia.

Realistic expectations for cryoablation of liver tumors.

While cryoablation has been shown to be an effective method of destruction of primary and metastatic liver tumors, there is a disturbingly high incidence of recurrence at the cryoablated site and there are conflicting reports concerning long-term survival. For this reason, resection remains the preferred surgical treatment of liver tumors. However, there is a population of patients who, because of age, pre-existing liver disease, or likely systemic dissemination, present a higher risk for major resection, and for whom cryoablation may be favored. This study examined the safety and effectiveness of cryoablation in patients thought to be at higher risk for conventional hepatic resection, or in whom resection would not eradicate all known disease. Twenty-eight consecutive patients underwent cryoablation, with or without resection, of 39 hepatic tumors for primary (n = 9) or metastatic (n = 19) disease. Their postoperative course and long-term follow-up were examined for complications, survivability, and recurrence of disease. With the use of cryoablation, a major hepatic resection was avoided in 20 patients, 11 of whom were 70 years or older, 4 who likely had disseminated cancer even though the liver was the only site of detectable disease, 2 who were cirrhotic, and 2 with bilobar disease. An additional 7 patients had recurrence of disease in a previously resected liver, for whom additional resection would be hazardous. There was one operative death from an exaggerated systemic inflammatory response syndrome. Seven patients developed complications, including 2 patients with cryoablation-induced coagulopathy. Excluding 2 patients (including the postoperative death) the average hospital length of stay was 6.7 +/- 2.8 days. Seven patients required some intensive care unit (ICU) care. Three patients with primary liver cancer are alive 29 to 47 months after cryoablation. Two patients with metastatic disease are alive without recurrence at 12 and 16 months, and 9 are alive with disease from 13 to 58 months after cryoablation. Fifteen patients developed liver recurrence, 5/27 (19%) at the cryoablated site. Cryoablation appears to be a safe treatment modality for primary and metastatic liver cancer. It is particularly appealing in those patients who may be at higher risk for major hepatectomy because of age, pre-existing liver disease, type of metastatic disease, previous resection, or bilobar tumors. Most disturbing is the high incidence of recurrence at the cryoablated site, which may reflect problems with ultrasound localization or proximity of tumors to major vasculature. Disease-free survival is low. From this standpoint the procedure should be considered palliative, even though all hepatic tumors can be eradicated. However, these limitations should not deter the use of cryoablation in selected patients. There is the potential for long-term survival, just as there is with resection.

Hepatic apoptotic activity following transient normothermic inflow occlusion and reperfusion in the swine model.

Accelerated hepatic apoptosis was first described in portal vein-ligated livers but has since been reported in a variety of liver injuries. Because porto-prival states can induce apoptosis we sought to determine whether transient ischemic periods followed by reperfusion would trigger such cell death. The cytokines TNF-alpha and TGF-beta are known to facilitate apoptosis and are released in response to a number of stimuli including ischemia. We also investigated alterations in plasma and tissue levels of these cytokines which might lend support to their role in increased apoptotic activity following ischemia/reperfusion. Female pigs were used as the experimental model. Inflow occlusion of portal and hepatic arterial blood was performed to a portion of the swine liver directing the entire splanchnic flow to the remaining hepatic lobes for a period of 2 h. The livers were then reperfused and plasma and tissue samples taken for determination of apoptotic activity utilizing cell death immunoperoxidase staining of 3'-OH DNA ends generated by fragmentation and ELISA assay of histone-associated DNA fragments. Plasma and tissue levels of TNF-alpha and plasma levels of TGF-beta were determined by ELISA assay. An increase in apoptotic activity following reperfusion was seen at Day 2 and Day 4 compared to preischemic values by the cell death stain. The ELISA cell death assay showed an increase in apoptotic activity at 60 min, Day 2, and Day 4. Moreover, the ELISA cell death assay showed enhanced apoptotic activity in "hyperperfused" hepatic lobes compared to preischemic, or resting, liver. This was also observed when compared to sham-operated animals. Surprisingly, there was no detectable increase in plasma TNF-alpha or TGF-beta levels following ischemia/reperfusion, although homogenized liver TNF-alpha levels were increased at 60 min and Day 2 following reperfusion. We conclude that transient hepatic inflow occlusion followed by reperfusion can induce increased apoptotic activity in the swine model. Furthermore, increased apoptotic activity also occurs in the hyperperfused liver raising the possibility of a locally active factor or global hepatic expression of receptor activity in response to ischemia/reperfusion. This period of ischemia/reperfusion did not produce a detectable increase in circulating cytokine levels, and accelerated apoptosis could not be linked to heightened TNF-alpha or TGF-beta plasma activity. Higher tissue levels of TNF-alpha could reflect enhanced binding to TNF cell surface receptors or amplified receptor expression.

Low falls: an underappreciated mechanism of injury.

OBJECTIVE: This is a retrospective study designed to evaluate the pattern and severity of injuries that result from low falls, defined as falls from less than 20 ft, subsequent mortality, and requirements of hospital resources. Our hypothesis is that many of these injuries, even without cardiopulmonary instability, are worthy of trauma center care. METHODS: The records of all patients entered into the hospital trauma registry at an urban Level I trauma center during the years 1991 through 1997 who suffered low falls and who either died after admission or were hospitalized for at least 3 days were reviewed. Patients suffering isolated hip fractures were excluded. One hundred seventy-six patients constituted the study population. This group accounts for about 2% of all admissions for falls at our institution. Patterns of injury were examined. Age, mechanism of injury, Injury Severity Score (ISS), and cardiopulmonary or neurologic instability on admission were documented. Mortality, length of intensive care unit and hospital stays, as well as billed hospital charges, were reviewed. RESULTS: The majority of patients (62%) were younger than 50 years. Sixty patients had ISS >15 and 116 patients had ISS >9. Sixty patients had multisystem injuries requiring specialty care. Head injuries were found in 81 patients (35%), and vertebral fractures or spinal cord injuries were found in 49 patients (22%), including 9 quadriplegics and 5 paraplegics. There were seven patients with intra-abdominal injuries (five spleen and two bowel injuries). There was one patient with a rupture of the thoracic aorta. Seventeen patients had deteriorating neurologic or pulmonary function on arrival, but the majority (90%) were stable. Of the 159 "stable" patients, 48 suffered head injuries, 7 were quadriplegic, and 3 were paraplegic. All intra-abdominal injuries were in this group. Overall, 14 of 176 patients (8%) died. Seven deaths were in patients older than 60 years, and seven deaths were in younger patients (p = 0.04). The majority of deaths (9 of 14) were from head trauma. Care in the intensive care unit was required in 92 of 176 patients. Nine patients had billed charges exceeding $100,000. CONCLUSION: Low falls can cause significant injuries, most commonly to the head and spine. Based on mechanism of injury alone, patients injured in low falls might not be taken to trauma centers. We have found, however, that many of these patients sustain serious multisystem injuries, even though they are stable initially. Although these patients represent only a fraction of those who fall, our study would support adjustment of triage guidelines to recommend transport of such patients, particularly elderly patients, to trauma centers.

In Flanders fields: the Great War, Antoine Depage, and the resurgence of débridement.

OBJECTIVE: The care of traumatic wounds has evolved over hundreds of years, largely as a result of armed conflicts. The lessons learned during World War I in the treatment of extensive soft-tissue injuries proved invaluable in reducing infection and preventing loss of limb and life. Foremost among these was the use of debridement. This report reviews the development of debridement as standard treatment of war wounds and highlights the surgeon largely responsible for its resurgence during one of this century's saddest chapters. SUMMARY BACKGROUND DATA: Before World War I, the care of wounds consisted of minimal exploration and liberal use of then-new antiseptics. For limited injuries, this approach appeared adequate. World War I saw the introduction of devastating weapons that produced injuries that caused extensive devitalization of tissue. Standard treatment of these patients proved woefully inadequate to prevent life-threatening infections. METHODS: This is a historical review of the conditions that occurred during World War I that prompted a change in wound management. One of those responsible for this change was the Belgian surgeon Antoine Depage. His life and contributions to the care of war wounds are profiled. Depage reintroduced the discarded French practice of wound incision and exploration (debridement) and combined it with excision of devitalized tissue. RESULTS: Through the use of debridement, excision, and delayed wound closure based on bacteriologic survey, Depage was able to reduce the incidence of infectious complications of soft-tissue injuries, particularly those involving fractures. CONCLUSIONS: Through his experiences in the Great War, Antoine Depage was able to formulate a treatment plan for wounds of war. All such injuries were assumed to be contaminated and, as such, they required early and careful debridement. Depage thought that wound closure should often be delayed and based his decision to close on the bacteriologic status of the wound. To him, we owe our current management of traumatic wounds.

Influence of the Rh (D) blood group system on graft survival in renal transplantation.

BACKGROUND: The Rh (D) blood group system has not traditionally been considered to be a clinically relevant histocompatibility barrier in transplantation since conflicting results of its clinical importance have been reported. METHODS: We analyzed 786 consecutive primary cadaveric renal transplants performed by transplant centers in our Organ Procurement Organization (OPO) between 1990 and 1997. We also analyzed United Network for Organ Sharing (UNOS) data on 26,469 kidney transplants done from April 1994 to June 1996. RESULTS: Multivariate analysis revealed that Rh identity between the recipient and donor was significantly related to better graft outcome (risk ratio, 0.43; 95% confidence interval, 0.30 to 0.61; P=0.0001). Multivariate analysis of the UNOS data revealed that the Rh -/- group may have a positive influence on graft survival with a risk ratio of 0.43 (P=0.14). CONCLUSION: Multivariate analysis of primary cadaveric renal allografts performed within the Midwest Organ Bank OPO indicates that Rh (D) is a clinically relevant histocompatibility barrier that influences 7-year graft survival.

Ten-year experience in transplantation of A2 kidneys into B and O recipients.

BACKGROUND: This article summarizes our 10-year multicenter experience with transplantation of 50 blood group A2 and A2B kidneys into B and O patients. METHODS: Since 1986, we have transplanted kidneys from 46 cadaver donors and 4 living donors who were blood group A2 (47 donors) or A2B (3 donors) into 19 B and 31 O patients. In 1991, we began allocating these kidneys preferentially to B and O recipients who were selected based on a history of low (< or =4) anti-A IgG isoagglutinin titers. Immunosuppression was no different from that used in ABO-compatible grafts. RESULTS: The 1-month function rate before thus selecting the patients was 68% (19/28), but is now 94% (17/18). Two-year cadaver-donor graft survival with this selection method is 94%, compared with 88% for 640 concurrent and consecutive ABO-compatible transplants (log-rank, 0.15). All four living-related transplants are still functioning, with a mean follow-up of 71 months. Since we began allocating A2 kidneys preferentially to B and O recipients, the percentage of the B patients who received A2 or A2B kidneys has increased from 29% (8/28) to 55% (10/18). CONCLUSIONS: Transplantation of A2 or A2B kidneys into B and O patients is clinically equivalent to that of ABO-compatible transplantation when recipients are selected by low pretransplant anti-A titer histories. This approach increases access of blood group B recipients to kidneys.

Transplantation rate of the blood group B waiting list is increased by using A2 and A2B kidneys.

BACKGROUND: We have increased the transplantation rate for blood group B cadaveric waiting list candidates by transplanting them with A2 and A2B kidneys. METHODS: Since 1991, five of the seven renal transplant programs in our organ procurement organization service area have preferentially transplanted blood group A2 and A2B cadaveric kidneys to B blood group waiting list candidates with histories of low anti-A isoagglutinin titers. RESULTS: Between 1991 and 1997, these five centers performed transplantations on 71 patients from the B cadaveric waiting list. Of those 71 patients, 29% (21 of 71) underwent transplantation with either A2 (n=18) or A2B (n=3) cadaveric kidneys. In 1997 alone, 48% (11 of 23) of the B patient transplant recipients received A2 or A2B kidneys. CONCLUSIONS: Transplantation of A2 and A2B kidneys into B waiting list patients has successfully increased access of B patients to kidneys. Such an allocation algorithm implemented nationally may similarly increase the transplantation rate of B waiting list candidates.