同种异体骨复合氨基胍对兔桡骨缺损愈合的影响

目的探讨同种异体松质骨和iNOS选择性抑制剂氨基胍(AG)复合物对兔桡骨中段骨缺损愈合的影响。材料和方法制备同种异体松质骨并和氨基胍复合。制备兔桡骨骨缺损动物模型。左侧前肢植入同种异体松质骨,右侧前肢植入氨基胍和同种异体松质骨复合物。术后2、4、8、12周,行肉眼观察、X线片、骨密度检查和组织学切片检查。术后12周,用材料性能试验机行三点弯曲试验。并与正常桡骨比较。结果氨基胍和同种异体松质骨复合物在骨缺损愈合过程中成骨量、成骨速度、时间均优于单纯同种异体松质骨。术后12周骨缺损基本得到修复。结论iNOS选择性抑制剂氨基胍可促进骨缺损愈合。     

移植骨复合骨髓基质干细胞修复兔股骨缺损

目的观察同种异体骨复合骨髓基质干细胞对兔股骨大段缺损修复情况,探讨其修复骨缺损的可行性。方法将24只大耳兔随机分为2组,造成股骨大段缺损,对照组植入打孔同种异体骨,实验组植入打孔同种异体骨＋明胶海绵＋骨髓基质干细胞。术后2个月行X线片观察、病理组织学检查及骨密度测试。结果①放射学检查：对照组在异体骨结合部可见骨痂通过,实验组整个异体骨段均可见明显骨痂形成。②病理组织学检查：对照组可见少量内骨痂及外骨痂且被大量纤维结缔组织所分隔,实验组异体骨有坏死后弧形吸收窝,可见内外骨痂生长,髓腔内充满大量骨母细胞。③平均骨密度值测定：实验组高于对照组及正常股骨,差异有显著性（P〈0．05）。结论同种异体骨复合骨髓基质干细胞用于修复兔股骨大段缺损,较单纯异体骨成骨量大、迅速,能够对骨缺损进行有效的修复。     

猕猴组织工程化骨异体植入修复骨缺损T淋巴细胞亚群的检测

目的　通过对T淋巴细胞亚群的检测 ,从免疫学方面探讨同种异体细胞来源的组织工程化骨植入猕猴体内修复长段骨缺损的可行性。方法　用骨髓基质干细胞 (MSCs)经诱导分化为成骨样细胞后与生物衍生骨材料复合培养 ,体外构建组织工程化骨 ,植入 15只异体猕猴体内桥接桡骨 2 .5cm节段骨缺损作为实验组 ;用单纯生物衍生骨材料桥接对侧同样大小骨缺损作为对照组 ;分别于术后 1、2、3、6、12周抽取静脉血和作双侧局部组织取材 ,样本应用流式细胞术检测T淋巴细胞亚群CD3 /CD4 /CD45 、CD3 /CD8 /CD45 和CD2 8 阳性率。结果　术后第 1、2、3、6、12周实验组和对照组T淋巴细胞亚群CD3 /CD4 /CD45 、CD3 /CD8 /CD45 和CD2 8 阳性率两者差异均无显著性 (P >0 .0 5 )。结论　生物衍生骨材料和猕猴MSCs复合构建组织工程化骨植入异体猕猴体内其术后 12周内免疫反应水平低 ,可用以修复猕猴节段骨缺损。     

以生物衍生材料为支架的组织工程骨移植早期兔外周血T淋巴细胞亚群的变化

目的检测体外构建的组织工程骨移植后兔外周血T细胞亚群的变化，对移植组织进行组织学观察，探讨以生物衍生材料作为骨组织工程支架材料的可行性。方法组织工程骨以兔骨膜来源的成骨细胞为种子细胞，经抗原自消化、部分脱钙、冻干后的异体骨为支架材料于体外构建。将健康新西兰白兔48只制成1cm长桡骨缺损模型后，随机分成A～D4组，每组12只，分别用部分脱钙冻干骨（partial demineralized freeze—dried bone，PDFDB）、组织工程骨、自体骨、同种异体骨植入兔桡骨节段性缺损。术后1、2、4周取材，用流式细胞仪检测4种材料移植早期兔外周血T淋巴细胞亚群的变化；通过常规组织学检测观察2、4、8、12周时4种材料的成骨作用。结果B组术后2周材料孔隙内有成骨细胞和成软骨细胞，可见骨、软骨混合性新生物形成，周边分布有破骨细胞，部分网架呈蚕食状被破坏吸收。术后4周，形成的新生骨过渡为编织骨。A、B组材料植入后1、2周外周血CD4^＋和CD8^＋T细胞较术前明显升高（P〈0．05）；术后4周CD4^＋T细胞较术前轻度偏高，但无统计学差异（P〉0．05）。C组术后CD4^＋和CD8^＋T细胞升高不明显（P〉0．05）。D组术后1、2、4周外周血CD4^＋和CD8^＋T细胞较术前及其他各组同期均明显增高（P〈.．05）。结论PDFDB为支架材料构建的细胞一材料复合物移植后外周血T淋巴细胞增高，但不影响其良好的修复骨缺损能力，生物衍生骨可作为支架材料应用于骨组织工程研究。     

组织工程骨膜异体体内成骨修复兔骨缺损的初步观察

目的探讨以兔BMSCs和猪SIS复合构建的组织工程骨膜，在异体兔体内成骨的可行性。方法取新西兰大白兔BMSCs与SIS复合构建组织工程骨膜。选2月龄新西兰大白兔12只，制备双侧桡骨1．5～2．0cm缺损模型。随机选一侧植入组织工程骨膜，作为实验组；另一侧仅植入单纯SIS，作为对照组。术后观察动物一般情况，4周后摄X线片观察，取骨缺损中段标本行HE及Masson染色观察。结果两组动物术后饮食及日常活动基本正常：伤口无红肿、溢脓等：伤肢基本能负重行走。x线片观察：实验组骨缺损处有长条状新生骨形成，密度与正常骨相同，新生骨桥接骨缺损；对照组骨缺损无骨形成征象，骨缺损处密度与周围软组织影相近。组织学观察：实验组骨缺损处有新骨形成，骨组织中可见血管腔及不规则髓腔样结构；未见明显异物巨噬细胞及淋巴细胞浸润征象：对照组骨缺损处仅为胶原瘢痕组织，无骨组织形成。结论以SIS和BMSCs构建的组织工程骨膜在同种异体体内可以成骨，有修复骨缺损的可行性。     

冻干同种异体骨与冻干异种骨移植治疗骨缺损的比较实验研究

目的：对比观察冻干同种异体骨和冻干异种骨骨移植治疗骨缺损的效果。方法：48只中国大白兔一侧桡骨造成1cm骨缺损，随机分为同种异体骨组和异种骨组，每组24只，分别植入两种移植骨，术后4、8、12周分批取材，进行X线片和组织学检查，然后做对比分析。结果：术后4周异种骨组的X线片，Gary X线评分与同种异体骨组有统计学差异，而术后8周同种异体骨组组织学检查以及组织学评分与异种骨组有统计学差异，在其他时期两组比较无统计学差异。结论：冻干异种骨具有很好的成骨效果，可以作为修复骨缺损的移植材料。     

涂层双相陶瓷复合BMSC修复骨缺损的实验观察

目的比较双相陶瓷（Biphasie calcium phosphate，BCP）经低结晶羟基磷灰石（Low crystalline hydroxyapatite，LcHA）涂覆改性后构建的组织工程化骨（LcBCP）与单纯BCP复合骨髓基质干细胞（Bone marrow stromal cells，BMSCs）修复兔桡骨节段性缺损的成骨差异。方法BMSCs复合LcBCP（实验组）修复12只兔左侧桡骨15mm缺损；BMSCs复合BCP（对照组）植入右侧桡骨同样大小缺损，植入后第4、8和12周取材，通过大体形态、组织学、影像学和生物力学检测骨缺损修复效果。结果BMSCs—LcBCP复合物在体内骨缺损处生长良好。X线检测显示实验组连接处骨痂形成，对照组连接处在各个时间点愈合稍差。12周时，实验组骨修复良好，髓腔再通，组织学显示板层骨形成，连接处骨性愈合；对照组连接处尚有较多编织骨形成。实验组和对照组生物力学检测有统计学差异。结论BMSCs—LcBCP复合物可修复兔桡骨节段性缺损，低品态羟基磷灰石涂层有助于增强双相陶瓷的成骨能力。     

带血运骨膜管移植和骨充填物修复桡骨长段缺损的研究

目的：探讨联合应用带血运骨膜管移植和骨充填物治疗兔桡骨长段缺损的效果。方法：实验分两部分，分别选用幼兔和成年兔各40只，根据填充物的不同分为4组，将兔双侧桡骨干中段切除3cm制成骨长段缺损模型，保留切骨段骨膜，重新重原缝合后作带血运骨膜管移植模型，左侧分别用自体骨，同种异体脱钙骨，磷酸三钙陶瓷和羟基磷灰石进行填充，右侧不行任何填作为对照。观察3个月。通过X线片，髓强度，骨密度和组织学检查等方法，了解骨缺损的修复效果。结果：幼兔术后6周，所有实验组双侧的骨缺损均得到修复，术后12周，磷酸三钙陶瓷和羟基磷灰石组桡骨抗弯曲强度较差与自体骨组、同种异体脱钙骨组和对照侧比较具有统计学意义（P＜0．05）；骨愈合为膜内成骨和软骨成骨，以膜内成骨为主，成年兔；各组实验侧骨缺损修复率分别为：自体骨组50％；同种异体脱钙骨组40％；磷酸三钙陶瓷和羟基磷灰石组为30％。对照侧骨缺损修复率为42．5％，结论：幼兔单行单血运骨管移植或结合应用骨充填物均可有效修复骨长段缺损，但置换较慢的骨充填物不利于再生骨强度的恢复，成年兔带血运骨膜移植联合应用骨填充物不能有效修复骨长段缺损。     

骨髓间充质干细胞及其复合物修复兔桡骨缺损的实验研究

[目的]通过新西兰大白兔骨髓间充质干细胞离体培养后与去抗原牛松质骨复合植入新西兰大白兔桡骨缺损处，比较修复节段性桡骨缺损的效果，初步探讨治疗骨缺损的组织工程学方法。[方法]新西兰大白兔骨髓间充质干细胞（MSCs）离体培养、纯化、扩增后在等同于细胞培养的条件下与去抗原牛松质骨（BCB）复合培养，制成MSCs／BCB复合物并经电镜扫描证实复合物有细胞生长。制成同种异体新西兰大白兔桡骨干15mm节段性动物模型，MSCs／BCB复合物通过手术移植入动物模型桡骨缺损处，通过X线放射学、组织学、生物力学检测对比实验组与对照组、空白组骨缺损修复情况。[结果]术后2、4、8、12、16周实验组与实验对照组放射学检查评价新骨生成有显著性差异（P〈0．01）。术后组织学检查新骨生成速度、生成量均有显著性差异（P〈0．01）。16周生物力学三点抗弯曲实验载荷、弯曲应力检测，实验组与实验对照组新骨生成有显著性差异（P〈0．01），实验组标本与正常基本一致。空白对照组各时点均无新骨形成，最后缺损由纤维组织充填。[结论]骨髓间充质干细胞（MSCs）是骨组织工程中适宜的种子细胞。去抗原牛松质骨能够与兔骨髓间充质干细胞体外复合培养，移植入异体新西兰大白兔后未见明显免疫排斥反应，是可以选择的细胞载体。MSCs／BCB复合物植入修复兔桡骨缺损能够加速新骨形成，修复效果明显优于单纯BCB植入。     

重组转化生长因子-β复合同种异体骨移植修复骨缺损的实验研究

目的：评价重组转化生长因子－β（TGF－β）复合同种异体骨移植修复骨缺损的效果。方法：用基因重组的方法提取TGF－β,与同种异体骨复合后植入兔桡骨缺损区,采用同体双侧对照方法,进行X线摄片,组织学及放射性核素骨扫描检查,结果：术后8－12周,复合物移植侧移植骨与桡骨断端全部连接,成骨,单纯植骨侧移植骨与桡骨断端无连接,成骨差,结论：重组TGF－β复合同种异体骨移植修复缺损效果良好。β     

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 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.     

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.     

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.     

Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits

Background: It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e. g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic. Methods: PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. on the effects of propofol and fentanyl respectively on PNA were studied. Results: Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg · kg^?1 i. v. and 32 μg · kg^?1 i. v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg · kg^?1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg · kg^?1. The mean ED₅₀s, calculated from dose-response curves, were 5.4 mg · kg^?1, 3.9 μg · kg^?1 and 0.4 mg · kg^?1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg · kg^?1 and 8 μg · kg^?1, respectively. Conclusion: Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.     

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.     

Systemic analgesia adapted to the children's condition

A concept of balanced analgesia using nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), opioids, and corticosteroids can also be used in patients with pre-existing illnesses. NSAIDs are the most effective treatment for acute pain of moderate intensity in children; however, these drugs should be avoided in patients at increased risk for serious side effects, e.g. patients with renal impairment, bleeding tendency, or extreme prematurity. NSAIDs can be given with minimal risks to the younger child with mild to moderate asthma, and, in these patients, the use of steroids can be encouraged; in addition to their antiemetic and analgesic action, a beneficial effect on asthma symptoms can be expected. In the non-intubated child with cerebral trauma, exaggerated sedation caused by opioids and increased bleeding tendency caused by NSAIDs must be avoided. In neonates and small infants, the oral administration of sucrose or glucose is helpful to minimize pain reaction during short uncomfortable interventions.