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Successful Treatment of Refractory Ischemic Diabetic Foot Ulcers by Combination Therapy of Autologous Platelet-rich Gel and Topical β Adrenergic Receptor Blocker: a Case Report

  • History and clinical findings: A 76 year-old woman with 8-year history of diabetes mellitus and hypertension was admitted with gangrene of left great toe, 3rd, 4th and 5th toes. Twenty months ago, She started to receive hemodialysis due to end-stage renal disease . She did not have any history of reactive airway disease nor bradycardia that would contraindicate the use of topical beta-blocker. The X-ray of left lower limb and foot showed calcification of left superficial femoral artery, popliteal artery, anterior tibial artery, posterior tibial artery, dorsal foot artery and digital artery, as well as osteolytic destruction at distal end of metatarsal bone, and lateral dislocation of the 4th and 5th toes. Color Doppler ultrasound of bilateral lower extremity arteries showed obvious calcification of bilateral superficial femoral arteries, thrombosis of left popliteal artery, severe stenosis of left anterior tibial artery, occlusion of left posterior tibial artery, right anterior tibial artery and posterior tibial artery. Computed tomographic angiography (CTA) of bilateral lower limb arteries revealed moderate stenosis of left superficial femoral artery, occlusion of left popliteal artery, left posterior tibial artery and dorsal pedal artery, occulusion of right posterior tibial artery, but right dorsal pedal artery was visible. Diagnosis, treatment and follow-up : Diagnosis of diabetic foot (left, grade 4 ) and diabetic lower extremity arterial occlusion (left, stage 4) was made. Based on multidisciplinary team ( MDT) discussion, the patient was unable to undergo vascular bypass surgery, and left lower extermity amputation also was not suitable because of right atrial thrombosis.Therefore, conservative treatment was recommended. The specific scheme used clopidogrel for antiplatelet agglutination, Low Molecular Weight Heparin (Clexane) and warfarin for anticoagulation, lipo-alprostadil for vasodilation, as well as local debridement and ultrasonic debridement.The treatments were given for up to 9 weeks, but with no significant clinical response. So the patient was treated with vacuum-assisted closure and autologous platelet-rich gel therapy for the next 7 weeks, then applied with 1 drop of timolol maleate 0.5% ophthalmic solution per cm2 wound area every other day for another 6 weeks, the wound rapidly healed and re-epithelialized basically. The follow-up for 5 weeks showed that the wound healed completely without any discomfort. No side effect was found.
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  • [1] JIANG Y, WANG X, XIA L, et al. A cohort study of diabetic patients and diabetic foot ulceration patients in China. Wound Repair Regen,2015,23(2): 222–230. doi: 10.1111/wrr.12263
    [2] XU Z, RAN X. Diabetic foot care in China: challenges and strategy. Lancet Diabetes Endocrinol,2016,4(4): 297–298. doi: 10.1016/S2213-8587(16)00051-6
    [3] GARIMELLA P S, WANG W, LIN S F, et al. Incident diabetic foot ulcers and mortality in hemodialysis patients. Hemodial Int,2017,21(1): 145–147. doi: 10.1111/hdi.12490
    [4] AL-THANI H, EL-MENYAR A, KOSHY V, et al. Implications of foot ulceration in hemodialysis patients: a 5-year observational study. J Diabetes Res, 2014, 2014: 945075[2020-03-12]. https://doi.org/10.1155/2014/945075.
    [5] LEV-TOV H, DAHLE S, MOSS J, et al. Successful treatment of a chronic venous leg ulcer using a topical beta-blocker. J Am Acad Dermatol, 2013, 69(4): e204-e205[2020-03-12]. https://doi.org/10.1016/j.jaad.2013.06.003.
    [6] 袁南兵, 王椿, 王艳, 等. 自体富血小板凝胶在糖尿病难治性皮肤溃疡中的初步应用. 四川大学学报(医学版),2007,38(5): 900–903.
    [7] THOMAS B, KURIEN J S, JOSE T, et al. Topical timolol promotes healing of chronic leg ulcer. J Vasc Surg Venous Lymphat Disord,2017,5(6): 844–850. doi: 10.1016/j.jvsv.2017.04.019
    [8] ALSAAD A M S, ALSAAD S M, FATHADDIN A, et al. Topical timolol for vasculitis ulcer: a potential healing approach. JAAD Case Rep,2019,5(9): 812–814. doi: 10.1016/j.jdcr.2019.07.016
    [9] BRAUN L R, LAMEL S A, RICHMOND N A, et al. Topical timolol for recalcitrant wounds. JAMA Dermatol,2013,149(12): 1400–1402. doi: 10.1001/jamadermatol.2013.7135
    [10] MOHAMMADI A A, BAKHSHAEEKIA A, ALIBEIGI P, et al. Efficacy of propranolol in wound healing for hospitalized burn patients. J Burn Care Res,2009,30(6): 1013–1017.
    [11] 中华医学会糖尿病学分会, 中华医学会感染病学分会, 中华医学会组织修复与再生分会. 中国糖尿病足防治指南(2019版)(Ⅳ). 中华糖尿病杂志,2019,11(5): 316–327. doi: 10.3760/cma.j.issn.1674-5809.2019.05.003
    [12] YANG H, CHEN F, JIAO H, et al. Management of tunneled-cuffed catheter-related right atrial thrombosis in hemodialysis patients. J Vasc Surg,2018,68(5): 1491–1498. doi: 10.1016/j.jvs.2018.02.039
    [13] STAVROULOPOULOS A, ARESTI V, ZOUNIS C. Right atrial thrombi complicating haemodialysis catheters. A meta-analysis of reported cases and a proposal of a management algorithm. Nephrol Dial Transplant,2012,27(7): 2936–2744. doi: 10.1093/ndt/gfr739
    [14] LI Y, GAO Y, GAO Y, et al. Autologous platelet-rich gel treatment for diabetic chronic cutaneous ulcers: a meta-analysis of randomized controlled trials. J Diabetes,2019,11(5): 359–369. doi: 10.1111/1753-0407.12850
    [15] 中华医学会糖尿病学分会, 中华医学会感染病学分会, 中华医学会组织修复与再生分会. 中国糖尿病足防治指南(2019版)(Ⅱ). 中华糖尿病杂志,2019,11(3): 161–189.
    [16] 李兰, 冉兴无. 自体富血小板凝胶治疗糖尿病皮肤慢性难愈合创面机制的研究进展. 感染、炎症、修复,2012,13(1): 53–55. doi: 10.3969/j.issn.1672-8521.2012.01.018
    [17] LI L, CHEN D, WANG C, et al. Autologous platelet-rich gel for treatment of diabetic chronic refractory cutaneous ulcers: a prospective, randomized clinical trial. Wound Repair Regen,2015,23(4): 495–505. doi: 10.1111/wrr.12294
    [18] 孙世怡, 马婧, 冉兴无. β受体阻滞剂治疗糖尿病足溃疡的研究进展. 中国修复重建外科杂志, 2020[2020-03-12]. https://doi.org/10.7507/1002-1892.202002063.
    [19] 高伟, 冉兴无. 钙化防御: 一个临床医师忽略的病变. 中华内科杂志,2017,56(3): 218–220. doi: 10.3760/cma.j.issn.0578-1426.2017.03.016
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Successful Treatment of Refractory Ischemic Diabetic Foot Ulcers by Combination Therapy of Autologous Platelet-rich Gel and Topical β Adrenergic Receptor Blocker: a Case Report

    Corresponding author: RAN Xing-wu, ranxingwu@163.com
  • 1. Diabetic Foot Care Centre, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China
  • 2. Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China
  • 3. Department of Vascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China

doi: 10.12182/20200460601

Abstract:  History and clinical findings: A 76 year-old woman with 8-year history of diabetes mellitus and hypertension was admitted with gangrene of left great toe, 3rd, 4th and 5th toes. Twenty months ago, She started to receive hemodialysis due to end-stage renal disease . She did not have any history of reactive airway disease nor bradycardia that would contraindicate the use of topical beta-blocker. The X-ray of left lower limb and foot showed calcification of left superficial femoral artery, popliteal artery, anterior tibial artery, posterior tibial artery, dorsal foot artery and digital artery, as well as osteolytic destruction at distal end of metatarsal bone, and lateral dislocation of the 4th and 5th toes. Color Doppler ultrasound of bilateral lower extremity arteries showed obvious calcification of bilateral superficial femoral arteries, thrombosis of left popliteal artery, severe stenosis of left anterior tibial artery, occlusion of left posterior tibial artery, right anterior tibial artery and posterior tibial artery. Computed tomographic angiography (CTA) of bilateral lower limb arteries revealed moderate stenosis of left superficial femoral artery, occlusion of left popliteal artery, left posterior tibial artery and dorsal pedal artery, occulusion of right posterior tibial artery, but right dorsal pedal artery was visible. Diagnosis, treatment and follow-up : Diagnosis of diabetic foot (left, grade 4 ) and diabetic lower extremity arterial occlusion (left, stage 4) was made. Based on multidisciplinary team ( MDT) discussion, the patient was unable to undergo vascular bypass surgery, and left lower extermity amputation also was not suitable because of right atrial thrombosis.Therefore, conservative treatment was recommended. The specific scheme used clopidogrel for antiplatelet agglutination, Low Molecular Weight Heparin (Clexane) and warfarin for anticoagulation, lipo-alprostadil for vasodilation, as well as local debridement and ultrasonic debridement.The treatments were given for up to 9 weeks, but with no significant clinical response. So the patient was treated with vacuum-assisted closure and autologous platelet-rich gel therapy for the next 7 weeks, then applied with 1 drop of timolol maleate 0.5% ophthalmic solution per cm2 wound area every other day for another 6 weeks, the wound rapidly healed and re-epithelialized basically. The follow-up for 5 weeks showed that the wound healed completely without any discomfort. No side effect was found.

  • 糖尿病足是糖尿病患者尤其是老年糖尿病患者最严重且痛苦的慢性并发症之一,在我国年发病率高达8.1%[1],虽然在中华医学会糖尿病学分会的引导下,糖尿病足与周围血管病学组带领广大医务工作者经过近20年的努力,并制定了足病相关的指南与共识,我国糖尿病足的大截肢率逐步降至2.14%[2],但是较欧美发达国家仍有较大差距。随着糖尿病发病率以及糖尿病肾病并发症的增加,肾脏替代治疗技术有所进步,终末期肾病透析治疗的糖尿病患者比例明显增加,临床收治的糖尿病足溃疡患者合并血液透析的比例增加,并且治疗困难、预后差[3-4],尤其在同时合并下肢动脉闭塞病变的血液透析患者[4],这也是我国糖尿病足截肢率及死亡率仍较高的主要原因。为了降低血液透析患者的截肢率及死亡率,临床上亟待寻找一些价格合理、疗效较好的治疗方案。自2013年β受体阻滞剂成功用于治疗第1例糖尿病合并慢性静脉功能不全下肢溃疡[5]以来,相关的临床及机制研究正逐渐开展。现报道1例联合应用自体富血小板凝胶及β受体阻滞剂噻吗洛尔,成功治愈难治性缺血性糖尿病足溃疡,且未发现有长期使用的毒副作用,在目前的报道中尚属首次。现报道如下。

    本研究经过四川大学华西医院临床伦理委员会批准〔 批准号:2018年审(485)号〕,患者签署知情同意书后进行。

1.   病例和诊疗方案
  • 患者,女性,76岁,因“反复双足溃烂、感染,发现血糖、血压升高8+年,加重伴左足踇趾、3、4及5趾坏疽1+月”于2019年8月入院。8年前在我院眼科诊断“糖尿病视网膜病变(右增殖期,左非增殖期)”,行右眼底激光光凝治疗;7年前因“右眼玻璃体出血”,在我院行“右眼玻璃体腔灌洗+视网膜激光光凝术”治疗。20个月前(2017年12月)因“冠状动脉粥样硬化性心脏病、 非ST段抬高型心肌梗塞,慢性肾功能不全、尿毒症期”在我院行冠脉造影及支架植入术,同时安置右侧颈内cuff导管并行规律血液透析(每周二、四、六)。入院前1年,因“左足外侧及第2趾烫伤溃破感染”先后两次入我科住院治疗,给予抗感染、降血糖、降压、调血脂、抗血小板聚集、扩血管及清创换药等治疗,左足创面有所好转而出院。出院后一直服用硫酸氢氯吡格雷片75 mg qd,贝前列素钠片40 μg tid以及舒洛地特软胶囊250 LSU bid抗血小板、抗凝和扩血管以及居家自行更换敷料等治疗。1+月前因“左足创面逐渐扩大、变黑、肿胀,伴恶臭,疼痛明显1月”收入我科。

    入院查体:体温36.7 ℃,脉搏19 min-1,心率98 min-1,血压160/80 mmHg(1 mmHg = 0.133 kPa),慢性病容,焦虑状,消瘦,神志清楚,发育正常,左眼失明,右眼可数指。桶状胸,双肺叩诊过清音,双肺呼吸音低,未闻及干湿啰音;心界不大,心律齐,未闻及病理性杂音。双下肢皮肤变薄,毳毛消失,腓肠肌萎缩;腘动脉、胫后动脉搏动减弱,足背动脉左侧消失,右侧减弱;左足红肿,左足背部内侧、左足跖趾关节、前足掌及第5跖趾关节外侧可见皮肤溃疡,左足拇趾尖、3、4及5趾尖坏疽。

  • 入院后行实验室检查。血常规示:红细胞计数3.67×1012 L−1,血红蛋白103 g/L,白细胞13.57×109 L−1,中性粒细胞比例87.5%;血生化示:血清白蛋白25.0 g/L,血肌酐152.0 μmol/L,估测肾小球滤过率28.69 mL/(min· 1.73 m2),血浆脑钠肽>35 000 pg/mL;红细胞沉降率73.0 mm/1 h,白细胞介素-6(IL-6) 72.55 pg/mL,C反应蛋白74.30 mg/L,降钙素原0.41 ng/mL;糖化血红蛋白A1c 8.1%,糖化血清白蛋白38.97%;凝血图检测显示凝血酶原时间12.6 s、国际标准化比值(INR)1.15、部分凝血活酶时间36.7 s、凝血酶时间20.6 s、纤维蛋白原5.62 g/L及D-二聚体1.29 mg/L FEU。

    足部创面分泌物培养示普通变形杆菌及摩氏摩根氏菌摩根亚种,血培养(3次)阴性;足部病理组织检查示左足凝固性坏死组织,局灶中性粒细胞聚集。

    心电图示窦性心律,左室高电压;超声心动图:右房壁上(靠近下腔静脉口处)探及弱回声团向房内凸入,团块形态不规则,基底部较宽,无明显活动度,未探及明显“蒂”,无血流,心包少量积液,射血分数44%;心脏三维重建增强CT扫描示右心房区域见结节状低密度影,最大横截面为21 mm×15 mm。踝肱指数(ankle-brachial index, ABI)左0.7,右0.73。

    左胫腓骨+左足X片:左胫腓骨骨质疏松,左膝关节退变,左下肢血管壁多发钙化;左足骨质疏松;左足第2~5跖骨远端骨质溶骨性骨质破坏,周围软组织肿胀,内多发气体密度影,趾间关节对合欠佳,第4、5趾向外侧脱位,左足踇趾动脉钙化(图1)。

    Figure 1.  Oblique X-ray of the left knee joint (A,red arrow—vascular calcification) and the positive left foot (B,red arrow—vascular calcification, white arrow—osteolysis at the distal end of the metatarsal bone, yellow arrow—lateral dislocation of the 4th and 5th digits)

    下肢动静脉彩超检查提示左侧部分小腿肌间静脉血栓,双下肢动脉粥样硬化斑(双侧股浅动脉中膜钙化明显);左侧胫前动脉重度狭窄,左侧胫后动脉闭塞,左侧足背动脉呈缺血改变。左侧腘动脉管腔内弱回声部分充填:部分血栓?右侧胫后动脉闭塞,右侧胫前动脉起始段闭塞,远端中度狭窄,可见侧枝动脉供血(图2)。

    Figure 2.  Color Doppler ultrasonography of the left lower extremity

    双下肢动脉CT血管造影术(computed tomographic angiography, CTA)检查:下肢血管粥样硬化,左股浅动脉中度狭窄,右股浅动脉轻度狭窄,左腘动脉重度狭窄、闭塞,左胫后动脉近端闭塞;右胫后动脉重度狭窄、闭塞,双侧胫前及腓动脉管腔节段性狭窄、闭塞;左足背动脉显影不清,右足背动脉可见显影(图3)。

    Figure 3.  CT angiography of lower extremity(A) and CT angiography of both shank and ankle(B)

  • 自体富血小板凝胶(autologous platelet-rich gel, APG)的制备参考文献[6]。抽取患者适量外周静脉血,通过二次差速离心,分离、浓缩制得富含血小板血浆(platelet-rich plasma, PRP),然后将PRP与凝血酶-钙剂按照体积比(V/V)10∶1比例混合,凝固形成APG。

  • 根据临床症状、体征,实验室检查及辅助检查,患者诊断为“糖尿病足伴坏疽(左足4级);血液透析导管相关右心房血栓;2型糖尿病,糖尿病外周血管病(左侧腘动脉、左侧胫前动脉、左侧胫后动脉、右股浅动脉中重度狭窄、闭塞伴钙化), 糖尿病周围神经病变,糖尿病眼底视网膜病变(右增殖期,左非增殖期),糖尿病肾脏病G5期维持血液透析状态;冠状动脉粥样硬化性心脏病支架置入术后,窦性心律,左室稍大,心功能Ⅱ级;高血压3级很高危组”。入院后进行常规基础治疗(包括适当的控制血糖、血压、调脂以及全身抗生素治疗,扩血管以及营养神经等,同时对创面进行清创、负压吸引治疗等),并给予硫酸氢氯吡格雷片75 mg qd抗血小板聚集,华法林纳片2.5 mg qd与依诺肝素纳注射液0.4 mL bid抗凝及脂微球前列地尔注射液10 μg bid扩血管治疗;足溃疡创面经过标准护理足部创面清洁,当无脓性分泌物时,创面局部给予APG治疗;当可见健康肉芽生长,溃疡边缘可见上皮爬行时,局部再给予β受体阻滞剂马来酸噻吗洛尔治疗。鉴于噻吗洛尔局部吸收后可能导致心血管、呼吸以及内分泌系统等副作用[7],因此参考文献[7-10]文献使用方法,拟定以下给药方案:每两天1次、每次每1 cm2创面面积给予1滴0.5%噻吗洛尔滴注,将整个创面完全覆盖,然后待噻吗洛尔吸收、创面完全干燥后再用油纱或速愈乐敷料遮盖,最后用纱布包扎,直至创面完全愈合。

2.   局部创面治疗经过和结果
  • 入院后第1周到第9周,经足部创面标准的伤口护理,包括局部清创及超声清创水刀治疗,但是足部情况未见明显好转。第10周起,给予创面负压吸引联合APG治疗,共3次,创面有所缩小;第17周,在创面局部给予0.5%马来酸噻吗洛尔,6周后创面基本愈合,随访5周,创面完全愈合,患者无任何不适,见图4。在整个治疗过程中,监测患者生命体征(体温、血压、呼吸频率和心率)平稳,未发现任何由噻吗洛尔吸收导致的不良事件(心动过缓或气喘)发生。

    Figure 4.  Photographs of refractory diabetic foot ulcers over time

3.   讨论
  • 本例报道患者系老年女性,有多种并发症与合并症,长达20月的血液透析治疗,虽然ABI检查提示左0.7,右0.73,似乎双下肢血供尚可,但根据下肢及足X线、双下肢血管彩超检查结果显示患者下肢动脉完全钙化,因此ABI结果呈现“虚高”,并不能准确评价足部缺血状况。双下肢CTA结果显示,左股浅动脉中度狭窄,左腘动脉重度狭窄、闭塞,左胫后动脉近端闭塞、胫前及腓动脉管腔节段性狭窄、闭塞;左足背动脉显影不清,理论上如果要避免截肢,应该进行腔内球囊扩张、支架置入和/或下肢血管旁路手术,改善左下肢远端血流供应。但由于患者下肢血管病变相当严重且血管钙化非常明显,经皮血管内球囊扩张及支架置入术成功几率低,此外,患者存在双下肢静脉功能不全、且足部远端血管流出道极差,行血管旁路手术治疗效果不佳,因此,经过多学科协作团队(MDT)讨论,建议最佳方案系行左下肢截肢术,以保证患者生命安全[11]。但由于超声心动图检查示右心房占位,诊断“血液透析导管相关右心房血栓”,左下肢截肢手术风险极大,最终建议内科保守治疗。经过查阅文献[12-13],给予硫酸氢氯吡格雷抗血小板聚集,依诺肝素纳注射液、华法林纳片抗凝,及脂微球前列地尔注射液/贝前列腺素钠抗血小板及扩血管治疗以治疗“血液透析导管相关右心房血栓”,同时该治疗方案也有利于患者下肢血供的改善,结果显示经过4.5月治疗后患者右心房血栓显著缩小。同时在第1周到第9周,给予足部创面标准的伤口护理,包括局部清创及超声清创水刀治疗,但足部情况未见明显好转,患者左足疼痛等症状未见缓解;第10周到第16周,开始尝试给予创面负压吸引联合自体富血小板凝胶治疗[14-15],患者症状有所缓解且创面有所缩小,但进展缓慢;因此在第17周开始尝试局部给予0.5%马来酸噻吗洛尔(每平方厘米1滴)[7-9]治疗,两天一次,3周后创面明显缩小,6周后基本愈合,无任何不适。表明联合使用APG与β受体阻滞剂噻吗洛尔治疗可以治愈难愈性缺血性足溃疡。

  • APG促进创面愈合的机制尚未完全阐明,可能有以下几种[16]:① APG所含高浓度生长因子作用于局部巨噬细胞和修复细胞,促进其功能恢复并继续分泌生长因子,保持创面局部高水平生长因子浓度;以及通过调节创面组织基质金属蛋白酶(matrix metalloproteinases, MMPs)及其基质金属蛋白酶抑制剂(tissue inhibitor of metalloproteinase, TIMPs)的平衡,从而改善和修复微环境;② APG可给修复细胞的迁移运动提供空间和支架,易化其正确运动;③ 血小板活化后释放抗菌活性物质,诱导血小板聚集,直接抑制或杀灭病原体;通过趋化和激活白细胞间接发挥抗微生物效应等,从而促进创面愈合,我们的研究结果表明,APG促进糖尿病足溃疡的愈合率高达85.4%[17],但是对于严重肢体缺血,APG促进慢性创面的愈合能力有限,正如该例患者一样,经过3次负压吸引治疗及APG治疗,创面有一定的缓解,但还是难以愈合。

    β受体阻滞剂促进创面愈合的机制尚不清楚,现有研究包括但不限于[18]:① 促进角质形成细胞迁移和再上皮化;② 减轻细胞外信号相关激酶磷酸化和电场定向迁移;③ 增强成纤维细胞迁移;④ 减少局部炎症反应;⑤ 增强血管生成等,进而促进创面愈合。

    此外,从该例患者来看,联合APG与β受体阻滞剂治疗,效果优于单一的APG治疗,是否尚有其他机制,需要进一步的研究。

  • 在血液透析治疗的糖尿病患者,糖尿病足溃疡不但发生率高、治疗困难、预后极差,而且部分患者可能出现更加难以治疗的并发症—钙化防御(calciphylaxis)[19],目前缺乏有效的治疗方案,即使如先进的生物敷料、组织工程皮肤以及血小板凝胶等技术,也难以促进此种创面的愈合,因此临床上寻找有效的治疗方案迫在眉睫。

    局部或全身使用β受体阻滞剂是一种有前途、廉价、无创的新选择,可以促进复杂溃疡和创面的愈合。据我们所知,本病例为第1例联合应用APG及局部β受体阻滞剂噻吗洛尔成功治愈难治性缺血性糖尿病足溃疡的报道,提示联合应用APG及局部β受体阻滞剂噻吗洛尔也许对于难治性缺血性糖尿病足溃疡是一种有效的选择。此外,我们在临床研究中,已经开始着手进行规范化的随机对照研究对这种组合进行验证,以明确真正的临床效果,同时对作用机制也展开相应的研究。试想在不远的将来,可以开发出价格合理且效果上佳的难治性创面产品,用于难治性糖尿病足溃疡的治疗。

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