改良胰管空肠端侧吻合术在胰十二指肠切除术中的应用价值分析

目的探讨胰十二指肠切除术中应用改良胰管空肠端侧吻合术的价值。方法将40例行胰十二指肠切除术患者根据吻合术式不同分为套入式胰肠端侧吻合术组(对照组20例)和改良胰管空肠端侧吻合术组(观察组20例),观察2组胰肠吻合时间和术后并发症发生情况。结果观察组胰肠吻合时间平均(10.4±1.6)min,明显短于观察组(20.5±1.8)min,P<0.01;观察组术后并发症发生率10%(2/20)明显低于对照组50%(10/20),P<0.05。结论在胰十二指肠切除术中,改良胰管空肠端侧吻合术是一种可靠、安全的吻合术式,吻合时间,术后并发症发生率低,值得临床继续研究和探讨。     

两种胰肠吻合术式与胰瘘关系探讨

目的分析比较粘合式胰肠吻合方式与双层套入式吻合方式发生胰瘘并发症的差异。方法对1999年1月至2006年1月期间57例胰十二指肠切除术病例资料进行回顾性分析研究,依据术中胰肠吻合方式的不同,分为粘合式胰肠吻合组和双层套入式吻合组,比较两组间手术时间、出血量、平均住院时间和胰瘘发生率的差异。结果无手术死亡。两组手术时间、出血量和平均住院时间无统计学差异。套入式吻合组发生胰肠吻合口瘘1例(2.9%)、单纯性胰瘘6例(17.6%),粘合式吻合组无胰瘘发生。两组胰肠吻合口瘘差异无统计学意义(P>0.05),套入式吻合组单纯性胰瘘显著高于粘合式吻合组(P<0.05)。胰瘘经保守治疗均治愈。结论胰肠吻合术式对胰瘘发生率有一定的影响,粘合式胰肠吻合术式可以有效地降低胰瘘发生率。     

封闭式单层胰肠吻合技术在胰十二指肠切除术中的效果分析

目的探讨封闭式单层胰肠吻合技术在胰十二指肠切除术中的应用效果。方法回顾性分析我院2014年1月至2015年5月期间行胰十二指肠切除术的85例患者的临床资料,其中行封闭式单层胰肠吻合术28例,胰管空肠黏膜端侧吻合术27例,端端套入式胰肠吻合术30例。比较3组间的胰肠吻合时间、腹腔引流管拔管时间、术后住院时间、胰瘘发生率的差异。结果 1胰肠吻合时间(min)在封闭式单层胰肠吻合组明显少于胰管空肠黏膜端侧吻合组(12.51±2.96比25.65±3.35,P0.05)和端端套入式胰肠吻合组(12.51±2.96比23.73±5.27,P0.05)。2腹腔引流管拔管时间(d)在封闭式单层胰肠吻合组明显少于端端套入式胰肠吻合组(7.65±1.30比11.15±3.47,P0.05),但与胰管空肠黏膜端侧吻合组间比较差异无统计学意义(7.65±1.30比8.36±2.29,P0.05)。3术后住院时间(d)在3组间比较差异均无统计学意义(9.52±3.96比11.97±3.53比12.27±3.78,P0.05)。4封闭式单层胰肠吻合组发生1例A级胰瘘,胰管空肠黏膜端侧吻合组发生A、B级胰瘘各1例,端端套入式胰肠吻合组发生A级胰瘘1例、B级胰瘘2例,胰瘘发生率在3组间比较差异无统计学意义(P0.05)。结论从本组有限的数据初步得出,封闭式单层胰肠吻合技术是一种相对安全的胰肠吻合方式,其操作简单,手术时间较短。     

机器人辅助胰腺手术的消化道重建:胰肠吻合还是胰胃吻合

目的 总结分析机器人辅助胰腺切除术中胰肠吻合术与胰胃吻合术的临床特点与手术技巧,分析比较两种吻合方式的优劣.方法 回顾性分析2010年3月至2012年2月上海瑞金医院应用达芬奇机器人辅助手术系统行24例胰腺吻合术的临床资料.结果 24例胰腺吻合术均在达芬奇机器人辅助手术系统下完成,无中转开腹.其中男10例,女14例,平均年龄( 48.58±13.31)岁,术中切除肿瘤平均大小( 2.74±1.31)cm,胰管平均直径(3.58±1.69 )mm,胰腺吻合口平均完成时间( 57.71±13.10) min,其中行胰肠吻合术12例,胰胃吻合术12例,术后并发胰漏者9例(37.5％)、胰腺吻合口出血者2例(8.3％)、胃排空延迟者1例(4.2％),均经过保守治疗后康复.术后平均住院时间为( 23.88±8.02)d,胰腺吻合口旁引流管留置时间为(18.83±7.23)d,肛门排气恢复时间为( 2.38±1.24)d.进一步研究发现,与胰肠吻合术组比较,胰胃吻合术组吻合时间长、术后胰漏发生率较高(P＜0.05),但两组术后住院时间、吻合口引流时间、肛门排气时间差异无统计学意义.结论 在机器人辅助手术系统下完成胰胃吻合或胰肠吻合均是安全可行的,具体吻合方式的选择应综合考虑手术方式与外科医师的手术经验.     

三种胰肠吻合术式与胰瘘的关系

目的 比较分析胰管空肠黏膜吻合术、改良式胰肠套入吻合术和胰肠套入吻合术发生胰瘘的差异.方法 回顾性分析我院2000年1月～2007年1月间行3种胰肠吻合术共127例的临床资料,比较不同吻合术术后胰瘘的发生率.结果 胰管空肠黏膜吻合术、改良式胰肠套入吻合术和胰肠套入吻合术术后的胰瘘发生率分别为1.5%、2.7%、13.6%.主胰管外引流与无外引流者的胰瘘发生率有非常显著性差异(P＜0.01),胰肠套入式吻合与另两种吻合术术后胰瘘发生率均有显著性差异(P＜0.01,P＜0.05).结论 主胰管外引流对减少胰瘘发生有重要意义.胰管空肠黏膜吻合术优于胰肠套入式吻合术.胰管纤细时改良式胰肠套入吻合术对减少胰瘘的发生是有效的.     

胰十二指肠切除术后胰胃吻合术与胰肠吻合术的营养状况比较

目的比较胰十二指肠切除术后胰胃吻合术与胰肠吻合术患者的远期营养状况。方法回顾性分析2006年4月至2010年12月间在中山大学附属第一医院胃肠胰腺外科接受胰十二指肠切除术的37例患者的临床资料,其中胰胃吻合者19例,胰空肠吻合者18例。比较两组患者的体质量指数（BMI）以及白蛋白、前白蛋白和转铁蛋白等营养参数。结果胰胃吻合组和胰空肠吻合组的手术时间、术中失血量、术后胰瘘发生率、围手术期死亡率及术后住院时间的差异均无统计学意义（均P〉0．05）。术后1个月,胰胃吻合组和胰肠吻合组的BMI分别为（17．1±7．0）和（19．0±4．8）kg／m2。白蛋白分别为（30．1±0．5）和（32．1±1．3）g／L,转铁蛋白分别为（1．89±0．57）和（2．01±0．61）g／L,前白蛋白分别为（0．18±0．05）和（0．18±0．09）g／L。较术前均略有下降,但两组间差异并无统计学意义（均P〉0．05）。术后6个月,两组的上述营养参数均恢复到术前或高于术前水平,但两组间差异仍无统计学意义（均P〉0．05）。结论胰十二指肠切除术后胰胃吻合和胰空肠吻合对患者术后营养状况的影响无明显差别。     

胰十二指肠切除术肠胰吻合术式的探讨

目的探讨胰十二指肠切除后的肠胰吻合的合理术式.方法回顾分析1996年1月-2003年12月施行的108例胰十二指肠切除手术行套入捆绑式肠胰吻合者的临床资料.结果手术时间为3.5～4.5h.无围手术期死亡.无胰瘘发生;1例糖尿病患者术后第8天发生胆瘘经引流自愈;切口裂开2例,经行切口减张缝合后愈合;2例术后发生胃瘫,经保守治疗治愈.结论套入捆绑式肠胰吻合手术方式能够较好的预防胰瘘,且手术时间明显缩短.     

改良套入式胰肠端端吻合对胰十二指肠切除术后胰瘘的影响

目的 探讨改良套入式胰肠端端吻合对胰十二指肠切除术后胰瘘的影响.方法 回顾性分析2001年1月至2011年1月山东省肿瘤医院施行396例胰十二指肠切除术患者的临床资料.根据吻合方式分为2组:改良组235例,经典组161例.两组患者均由同一术者带领的医疗小组完成手术,消化道重建以Child吻合为基本术式.改良组采用改良套入式胰肠端端吻合,经典组采用经典套入式胰肠端端吻合,两组患者在术中及术后的处理均相同.比较两组患者术中出血量、手术时间、术后胰瘘和住院时间.计量资料采用t检验,计数资料采用x2检验,胰瘘的分析采用Fisher确切概率法.结果 改良组和经典组患者术中平均出血量、平均手术时间、平均住院时间分别为(383 ±56)ml、(7.2±1.0)h、(21 ±3)d和(381±39)ml、(7.0±0.5)h、(22 ±5)d,两组比较,差异无统计学意义(t=0.388,1.680,± 1.835,P＞0.05).396例患者均无手术死亡发生,胰瘘总发生率为7.6％(30/396).改良组患者术后无一例胰瘘发生,经典组患者术后发生胰瘘30例(胰肠吻合口瘘4例、单纯性胰瘘26例),两组比较,差异有统计学意义(P＜0.05).经典组中发生胰瘘的患者通过保持引流通畅、使用生长抑素及胃肠外营养等保守治疗后痊愈.结论 改良套入式胰肠端端吻合能显著降低胰十二指肠切除术后胰瘘的发生率.     

改良的套入式端侧吻合在胰肠吻合术中的临床应用

目的：探讨改良的套入式端侧吻合在胰肠吻合术中临床应用的可行性。 方法：回顾2004年2月—2012年11月实施的31例胰十二指肠切除术（PD）患者的临床资料,其中男19例,女12例,平均年龄58（16~76）岁;胰头癌16例,壶腹癌5例,胆总管下段癌8例,十二指肠肿瘤2例,均采用胰十二指肠切除术及改良的套入式端侧胰肠吻合术,分析消化道重建后的恢复及并发症发生情况。 结果：全组手术时间160~260 min,术中出血100~500 mL,总并发症发生率为12.9%,其中腹水2例,胰瘘2例,均给予保守治疗而治愈;无手术死亡,患者均治愈出院。 结论：改良的套入式端侧吻合技术在胰十二指肠切除术的胰肠吻合术中具有操作简单,手术时间短,术后并发症少等优点,是胰肠吻合的一种有效改进。     

套入式端侧吻合加Prolene线连续缝合在胰肠吻合术中的应用

胰肠吻合口瘘是胰十二指肠切除术(pancreati-coduodenectomy,PD)后最常见和最严重的并发症之一,治疗困难,预后较差,病死率较高[1].目前常采用套入式胰肠吻合术,其中胰肠端侧套入式吻合优于胰肠端端套入式吻合[2].采用胰肠端侧吻合加外层Prolene线连续缝合的PD 31例,总结报道如下……     

Vasopressor hormone response following mesenteric traction during major abdominal surgery

Background : We investigated the vasopressor hormone response following mesenteric traction (MT) with hypotension due to prostacyclin (PGI₂) release in patients undergoing abdominal surgery with a combined general and epidural anesthesia. Methods : In a prospective, randomized, placebo-controlled study we administered 400 mg ibuprofen (i.v.) in 42 patients scheduled for abdominal surgery. General anesthesia was combined with epidural anesthesia (T4-L1). Before as well as 5, 15, 30, 45, and 90 min after MT we recorded plasma osmolality, hemodynamics and measured 6-keto-PGFlα (stabile metabolite of PGI₂), TXB₂ (stabile metabolite of thromboxane A₂) active renin, and arginine vasopressin (AVP) plasma concentrations by radioimmunoassay. Catecholamine levels were assessed by high-pressure liquid chromatography (HPLC) with electrochemical detection. Results : Following MT, arterial hypotension occurred along with a substantial PGI₂ release. This was completely abolished by ibuprofen administration. Although plasma levels of 6-keto-PGF_1α (1133 (708) vs. 60 (3) ng/L, median (median absolute deviation), P=0.0001, placebo vs. ibuprofen) remained significantly elevated, blood pressure was restored within 30 min after MT in the placebo group. At the same point in time plasma concentrations of TXB² (164 (87) vs. 58 (1) ng/L, P=0.0001), epinephrine (46 (33) vs. 14 (6) ng/L, P=0.001), AVP (41 ± (18) vs. 12 (7) ng/L, P=0.0004), and active renin (27 (12) vs. 12 (4) ng/L, P = 0.001) were significantly higher in placebo-treated patients. Conclusion : Under combined general and epidural anesthesia arterial hypotension following MT due to endogenous PGI₂ release is associated with enhanced release of AVP, active renin, epinephrine and thromboxane A₂, presumably contributing to hemodynamic stability within 30 min after MT.     

A comparison of the inhibitory effects of four volatile anaesthetics on the metabolism of chlorzoxazone, a substrate for CYP2E1, in rabbits

Background: Halothane inhibits in vitro and in vivo activity of cytochrome P-450 (CYP) 2E1. There are several fluorinated volatile anaesthetics besides halothane, and most of them are defluorinated by CYP2E1. It is unclear whether other fluorinated anaesthetics inhibit the in vivo activity of CYP2E1.
Methods: We compared the inhibitory effects of therapeutic concentrations of four inhalational anaesthetics, halothane, enflurane, isoflurane, and sevoflurane, on chlorzoxazone metabolism in rabbits receiving artificial ventilation.
Results: All four inhalational anaesthetics decreased arterial blood pressure and increased plasma chlorzoxazone concentration. However, no significant differences in the plasma chlorzoxazone concentration were found between the four anaesthetics. The estimated chlorzoxazone clearance increased after beginning inhalation with all four agents, but no significant difference in clearance was noted between agents.
Conclusions: At therapeutic concentrations, the in vivo inhibitory effect on chlorzoxazone metabolism was similar for all four inhalational anaesthetics examined, even though their chemical characteristics and extent of hepatic metabolism differ considerably.     

A Teaspoon Pump for Pumping Blood with High Hydraulic Efficiency and Low Hemolysis Potential

Abstract: Virtually all blood pumps contain some kind of rubbing, sliding, closely moving machinery surfaces that are exposed to the blood being pumped. These valves, internal bearings, magnetic bearing position sensors, and shaft seals cause most of the problems with blood pumps. The original teaspoon pump design prevented the rubbing, sliding machinery surfaces from contacting the blood. However, the hydraulic efficiency was low because the blood was able to "slip around" the rotating impeller so that the blood itself never rotated fast enough to develop adequate pressure. An improved teaspoon blood pump has been designed and tested and has shown acceptable hydraulic performance and low hemolysis potential. The new pump uses a nonrotating "swinging" hose as the pump impeller. The fluid enters the pump through the center of the swinging hose; therefore, there can be no fluid slip between the revolving blood and the revolving impeller. The new pump uses an impeller that is comparable to a flexible garden hose. If the free end of the hose were swung around in a circle like half of a jump rope, the fluid inside the hose would rotate and develop pressure even though the hose impeller itself did not "rotate"; therefore, no rotating shaft seal or internal bearings are required.     

Microspheres Based Detoxification System: A New Method in Convective Blood Purification

Abstract: A variety of protein-bound or hydrophobic substances, accumulating as a result of pathologic conditions such as exogenous or endogenous intoxications, are removed poorly by conventional detoxification methods because of low accessibility (hemodialysis), insufficient adsorption capabilities (hemosorption), low efficiency (peritoneal dialysis), or economic limitations (high-volume plasmapheresis). Combining advantages of existing methods with microspheric technology, a module-based system was designed. Major operating parameters of the latter can be modified to allow for adjustment to individual clinical situations. An extracorporeal blood circuit including a plasmafilter is combined with a secondary high-velocity plasma circuit driven by a centrifugal pump. Different microspheric adsorbers can be combined in one circuit or applied in sequence. Thus, a prolonged treatment can be tailored using specially designed selective adsorber materials. Comparing this system with existing methods (high-flux hemodialysis, molecular adsorbent recycling system), results from our in vitro studies and animal experiments demonstrate the superior efficiency of substance removal.     

Tissue perfusion in relation to cardiac output during continuous positive-pressure ventilation and administration of propranolol or verapamil

Background : Our objective was to determine whether administration of propranolol or verapamil modifies the hemodynamic adaptation to continuous positive-pressure ventilation (CPPV), in particular the regional distribution of cardiac output (CO).
Methods : General hemodynamics and regional blood flows assessed by microsphere technique (15 (μm) were recorded in 16 anesthetized pigs during spontaneous breathing (SB) and CPPV with 8 cm H₂O end-expiratory pressure (CPPV8) before and after intravenous administration of propranolol (0.3 mg · kg⁻¹ followed by 0.15 mg · kg⁻¹ · h⁻¹, n=8) or verapamil (0.1 mg · kg⁻¹ followed by 0.3 mg · kg⁻¹ · h⁻¹, n=8).
Results : CPPV8 depressed CO by 25% without shifts in its relative distribution with the exception of a noteworthy increase in adrenal perfusion. Propranolol increased arterial blood pressure, and due to a fall in heart rate, CO dropped by 25%. The kidneys and, to a lesser extent, the splanchic region and central nervous system received increased fractions of the remaining CO at the expense of skeletal muscle flow. Similar patterns were seen during SB and CPPV8 such that the combination of propranolol and CPPV8 depressed CO by 50%. The circulatory effects of verapamil were less evident but myocardial perfusion tended to increase.
Conclusions : The combination of propranolol or verapamil with CPPV does not result in any specific hemodynamic interaction in anesthetized pigs, except that the combined effect of propranolol and CPPV may severely reduce CO.     

Volatile anaesthetics reduce adhesion of blood platelets under low-flow conditions in the coronary system of isolated guinea pig hearts

Background : Inhibitory effects of volatile anaesthetics on platelet aggregation have been demonstrated in several studies. However, the influence of volatile anaesthetics on intracoronary platelet adhesion has not been elucidated so far.
Methods : Isolated hearts of guinea pigs were perfused with buffer in the absence or presence of volatile anaesthetics (0.5 and 1 MAC) at constant coronary flow rates of 5 ml/min for 25 min, then 1 ml/min for 30 min and again 5 ml/min for 10 min. Before, during and after low-flow perfusion, a bolus of human platelets was applied into the coronary system. To simulate thrombogenic conditions, 0.3 U/ml human thrombin was infused during low-flow perfusion and reperfusion. The number of platelets sequestered to the endothelium was calculated from the difference between coronary in- and output of platelets. The myocardial production of lactate and consumption of pyruvate and coronary perfusion pressure were also determined.
Results : At a flow rate of 5 ml/min only about 3% of the applied platelets did not emerge from the coronary system, in any group. In contrast, 13.1±1.2% (mean±SEM) of infused platelets became adherent in low-flow perfusion in the control group without anaesthetic. The adherence was reduced with each 1 MAC isoflurane (to 6.2±1.2%), sevoflurane (to 4.4±0.9%) or halothane (to 3.2±1.5%) (each P <0.05 vs. control). Volatile anaesthetic, 0.5 MAC, did not inhibit platelet adhesion to a statistically significant extent in any case. Perfusion pressure and metabolic parameters were not statistically different between the control and the hearts exposed to anaesthetics.
Conclusion : Volatile anaesthetics in a concentration of 1 MAC can reduce the adhesion of platelets in the coronary system under reduced flow conditions. This action does not arise from vasodilation or inhibition of ischaemic stress.     

Bariatric Surgery in Some "Central and East-European (former Eastern bloc)"Countries - Current Status and Prediction for the Next Millennium

Background: Obesity is increasing globallly, including in the formerly "Eastern Bloc" countries. Methods: A survey was made of obesity and bariatric surgery. Results: In the 8 East and Central European countries studied, with total population 300 million, roughly 43% of the population was overweight (BMI 25-30), 23% obese (BMI > 30), with about 15 million people morbidly obese (BMI > 40). From 0-10 morbidly obese individuals/100,000/year undergo bariatric surgery. Conclusion: Most countries were found to provide inadequate treatment for obesity.The majority of the morbidly obese are not treated effectively. However, health-care awareness of obesity and bariatric surgeons are slowly increasing.     

Is the recovery profile of mivacurium independent of the rate of decay of its plasma concentration in patients with normal plasma cholinesterase activity?

Background: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. Methods: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg . kg^?1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg . kg^?1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg . kg^?1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. Results: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). Conclusion: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.     

Membranes in Artificial Organs

Abstract: Membrane processes play a pivotal and enabling role in modern replacement therapy for acute and chronic organ failure and in the management of immunologic diseases. In fact, virtually all contemporary extracorporeal blood purification methods employ membrane devices, and the next generation of artificial organs and tissue engineering therapies are almost certain to be similarly grounded in membrane technology. In this short essay, we comment on the similarities and differences among synthetic membranes and their natural counterparts and also provide a critical overview of the demographics and technology of hemodialysis, hemofiltration, apheresis, oxygenation, and emerging membrane technologies and applications.     

Influence of dopexamine hydrochloride on haemodynamics and regulators of circulation in patients undergoing major abdominal surgery

Background: Catecholaminergic support is often used to improve haemodynamics in patients undergoing major abdominal surgery. Dopexamine is a synthetic vasoactive catecholamine with beneficial microcirculatory properties. Methods: The influence of perioperative administration of dopexamine on cardiorespiratory data and important regulators of macro- and microcirculation were studied in 30 patients undergoing Whipple pancreaticduodenectomy. The patients received randomized and blinded either 2 μg · kg^?1 · min^?1 of dopexamine (n=15) or placebo (n=15, control group). The infusion was started after induction of anaesthesia and continued until the morning of the first postoperative day. Endothelin-1 (ET-1), vasopressin, atrial natriuretic peptide (ANP), and catecholamine plasma levels were measured from arterial blood samples. Measurements were carried out after induction of anaesthesia, 2 h after onset of surgery, at the end of surgery, 2 h after surgery, and on the morning of the first postoperative day. Results: Cardiac index (CI) increased significantly in the dopexamine group (from 2.61±0.41 to 4.57±0.78 1 · min^?1 · m^?2) and remained elevated until the morning of the first postoperative day. Oxygen delivery index (DO₂I) and oxygen consumption index (VO₂I) were also significantly increased in the dopexamine group (DO₂I: from 416±91 to 717±110 ml/m² · m²; VO₂I: from 98±25 to 157±22 ml/m² · m²), being significantly higher than in the control group. pHi remained stable only in the dopexamine patients, indicating adequate splanchnic perfusion. Vasopressive regulators of circulation increased significantly only in the untreated control patients (vasopressin: from 4.37±1.1 to 35.9±12.1 pg/ml; ET-1: from 2.88±0.91 to 6.91±1.20 pg/ml). Conclusion: Patients undergoing major abdominal surgery may profit from prophylactic perioperative administration of dopexamine hydrochloride in the form of improved haemodynamics and oxygenation as well as beneficial influence on important regulators of organ blood flow.