Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 83

Clinical neurology in lung transplantation CHRISTOPHER H. WIGFIELD1* AND ROBERT B. LOVE2 Department of Surgery, Section of Cardiac & Thoracic Surgery, University of Chicago, Chicago, IL, USA

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Department of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaulkee, Wi, USA

INTRODUCTION Outcomes, for both single and bilateral sequential lung transplantation have significantly improved over the last decade (Arcasoy and Kotloff, 1999; Hertz et al., 2002; Orens et al., 2006). The vast majority of lungs for transplantation are procured from certified brain dead donors. Results of lung transplantation suggest satisfactory survival, but outcomes still remain inferior when compared with other solid organs transplanted. Widened application of lung transplantation has included older recipients and candidates with a range of other comorbidities (Rosengard et al., 2002; Collaborative Transplant Study, 2013). Surgical challenges and the presence of comorbid conditions more frequently require prolonged intensive care unit (ICU) stays for recipients. Consequently, an increased relative risk for neurologic complications occurs. Potential pharmaceutical adverse effects, and metabolic derangements may present with neurologic sequelae. The relatively low incidence and insidious nature of most of these neurologic complications requires clinical awareness and diagnostic acumen. Generically, solid organ transplantation is associated with approximately 30–60% of recipients developing neurologic complications, and the prevalence may be higher in lung transplant recipients (Wijdicks, 1999a, b). Early recognition allows appropriate management strategies to be incorporated into the critical care management of these patients, resulting in best possible outcomes for these patients. This chapter initially provides a brief review of the evaluation required for lung transplant candidates, then describes selected aspects of the operative management

and discusses the clinical challenges common in lung transplant recipients. We define expected outcomes and frequent complications and discuss observed clinical neurology associated with lung transplantation.

BACKGROUND The standard criteria for lung transplantation from brain dead donors has been widened to include extended criteria donors (ECD) and these are now frequently utilized to meet the increasing demand for lung transplantation (Weill, 2002; Wigfield et al., 2009). Such ECD allografts generally do not fulfill one or more of ideal pulmonary function parameters or systemic donor criteria (Botha et al., 2006). The scarcity of donors and the urgent nature of the pulmonary transplant process frequently results in marked deterioration of candidates awaiting lung transplantation. This in turn results in a multitude of critical care issues and both central and peripheral nervous system vulnerability. A recent review suggested a comparatively high prevalence of morbidities due to neurologic derangements following lung transplantation with previously underestimated impact on long-term survival (Wijdicks, 1999a). In view of the paucity of information reported for neurology in pulmonary transplant recipients, we provide an overview of clinically important neurologic issues encountered. This chapter considers neurologic syndromes and specific impairments affecting the quality of life of recipients after transplantation in the likely sequence of occurrence. A synopsis of the current clinical standards for lung transplantation, for recipient selection and donor criteria follows.

*Correspondence to: C. Wigfield, M.D., M.D., F.R.C.S. (C/Th), Assistant Professor, Director of Lung Transplantation, The University of Chicago Medicine, Department of Surgery, Section of Cardiac & Thoracic Surgery, MC 5040, STE E500, 5841 S Maryland Ave, Chicago, Illinois 60637, USA. Tel: þ1-773-702-3551, Fax: þ1-773-702-4187, E-mail: [email protected]

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LUNG TRANSPLANT CANDIDATE EVALUATION

regimen, early screening as well as sound surveillance protocols for the recipients (Pochettino et al., 2000).

Recommendations to refer candidates considered for lung transplantation have evolved over the last 20 years (Orens et al., 2006). Both the International Society for Heart and Lung Transplantation (ISHLT) and the United Network for Organ Sharing (UNOS) have provided clinical guidelines for potential recipient selection (Shumway et al., 1994; Botha et al., 2006; Orens et al., 2006; Wigfield et al., 2006; UNOS, 2013). A multidisciplinary approach is required to adequately evaluate potential candidates for lung transplantation. To estimate the perioperative risks and survival prospects for individual lung transplant candidates it is essential to provide realistic recommendations. Formal acceptance of candidates on to waiting lists is carried out according to national guidelines and is usually moderated by lung allocation systems, for example, the Lung Allocation Scoring (LAS) system in UNOS in the US (Egan et al., 2006; Iribarne et al., 2009). Referral to transplant centers should be made when pulmonary patients have less than a 50% chance of surviving 24–36 months. A complete evaluation includes detailed pulmonary status and pulmonary circulation assessment, cardiovascular diagnostics, a negative neoplastic workup, selective gastrointestinal and endocrine screening, as well as psychological review and confirming reliable social support. Coping skills and patient education are crucial. Optimization of acceptable comorbidities requires continuous clinical outpatient evaluation and readjustment, in particular the cardiac and pulmonary vascular status updates mandatory (Neuringer et al., 2005; Christie et al., 2008).

LUNG TRANSPLANT PROCEDURE

LUNG ALLOGRAFT PROCUREMENT Donor to recipient matching includes several considerations: organ size comparison, donor history and risk factors, respiratory and systemic physiologic parameters, and several serologic markers are routinely measured to ensure adequate selection viral serology size matching (de Perrot et al., 2004; Wong et al., 2004; Doucette et al., 2007; Humar and Fishman, 2008). ABO compatibility is ensured. Due to ischemia time constraints in pulmonary transplantation, major histocompatibility antigens (MHC Class I and II) are routinely tested retrospectively. This allows for some adjustment of the immunosuppressive regimen (Hadjiliadis et al., 2005; Shah et al., 2008). Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) serology mismatch is tolerated due to the high prevalence in the general population and available therapeutics. This does, however, require a specific antiviral

Some more recent evidence suggests survival benefits for bilateral lung transplantation, even for older candidates with fibrotic lung disease (Hertz et al., 2002; Hartwig et al., 2005; Wigfield et al., 2007). This survival benefit has been more clearly shown for patients with documented, fixed primary or secondary pulmonary hypertension. Surgical approaches for either single or bilateral sequential lung transplantation include lateral thoracotomies or occasionally via median sternotomy. Muscle sparing thoracotomies are advocated to minimize restrictive and neuromuscular impairment during the recovery period. Cardiopulmonary bypass (CPB) or extracorporal membrane oxygenation (ECMO) systems are used for safe facilitation of the implant procedure. It is essential in patients with intolerance to single lung ventilation and hemodynamic instability during pneumonectomies or lung implantation. Concerns regarding mandatory cold ischemic time have been addressed by surgeons with refined protocols. The administration of antegrade pulmonary artery flush solution in conjunction with additional retrograde back bench administration has become routine for most transplant programs. Extracellular and intracellular composition of pulmoplegia solutions have proven adequate preservation in most series (Arcasoy and Kotloff, 1999). Lungs are routinely transported in an inflated state to avoid atelectasis, and stored on ice at approximately 4 C to ensure optimal reduction of residual cellular metabolic rate. Ischemic times up to 6 hours are usually tolerated well, but excessive delays may result in increased incidence of primary graft dysfunction during the reperfusion phase in the recipient.

EXPECTED OUTCOMES AND COMPLICATIONS AFTER LUNG TRANSPLANTATION Expected survival rates after lung transplantation are 78% at 1 year, and 51% at 5 years. Conditional on 30 day mortality, the survival advantage over selected end-stage respiratory diseases has been established (Estenne et al., 2002). Primary graft dysfunction (PGD) has a significant impact on first year survival. Improved outcome after lung transplantation has resulted from refined pharmaceutical immunosuppression with effective suppression of selective lymphocytes via inhibited lymphokine generation (ciclosporin, tacrolimus) and related signal transduction (sirolimus) pathways. Despite the triple agent regimen, rejection

CLINICAL NEUROLOGY IN LUNG TRANSPLANTATION remains an acute threat. The risk of infections, on the other hand, is particularly prominent in lung transplant recipients due to the continuous environmental exposure to airborne pathogens. Acute cellular rejection (ACR) affects a majority of recipients with at least one episode within the first year after lung transplantation. Methylprednisolone augmentation of the standard triple immunosuppressive regimen is frequently sufficient to improve transient impairment of FEV1 and alleviate associated systemic symptoms. Antibody-mediated rejection (AMR) is thought to be a much less frequently involved immunologic mechanism, but is possibly an underestimated contributor. Long-term lung allograft function outcomes, beyond 5 years, are impacted primarily by bronchiolitis obliterans syndrome (BOS) (Speich and van der Bij, 2001; Husain et al., 2006; Silveira and Husain, 2008; Valentine et al., 2008; Belperio et al., 2009). The pathologic substrate of chronic graft impairment, and probably multifactorial in etiology, it has been likened to “chronic rejection.” A lack of efficient therapeutic options has led to occasional indication for retransplantation. Infectious complications and focal neoplastic disorders increase with time elapsed on immunosuppressive medication. The list of pathogens includes communityacquired, nosocomial, and opportunistic infections (Roach et al., 1996). Viremia and fungal infections may present differential diagnostic challenges. Aggressive diagnostic and antimicrobial strategies have to be implemented to afford a chance of cure in this high-risk population. The continued need for surveillance and monitoring of serologic markers has resulted in time consuming subspecialty care. Table 83.1 provides a summary of common complications after lung transplantation.

NEUROLOGIC COMPLICATIONS AFTER LUNG TRANSPLANTATION Perioperative complications A wide range of neurologic injuries are among the operative risks during lung transplantation. Brachial plexus neuropraxia due to inadequate positioning during the operative procedure is preventable and reversible unless prolonged and not recognized intraoperatively. The spectrum of problems includes a diffuse and possibly permanent central nervous system (CNS) insult due to perioperative hypoxemia. CPB-related complications may include diffuse injury and focal deficits and may be either reversible or permanent. The general consensus is that CPB is associated infrequently with cerebrovascular events in this setting.

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Table 83.1 Complications after lung transplantation Primary graft dysfunction (PGD) Acute cellular rejection (ACR) Antibody mediated rejection (AMR) Airway complications Vascular complications Infective complications Bronchiolitis obliterans syndrome Proliferative disorders

Multifactorial acute lung injury after reperfusion MHC complex triggered host CD8-regulated response Humoral rejection with C4D deposition Bronchial anastomotic stenosis, dehiscence Bleeding, pulmonary artery or venous cuff stenosis Pulmonary, bacterial/viral; systemic; opportunistic Clinical syndrome with progressive impairment of FEV1 Post-transplant lymphoproliferative disease (PTLD), malignancies

Phrenic nerve damage during pneumonectomies is a dreaded operative complication. This has to be avoided at all costs in view of the devastating effect on respiratory mechanics in the recipient after lung transplantation. Idiopathic pulmonary fibrosis, cystic fibrosis, and previous chest surgery of the recipient can involve and obscure the phrenic nerve on either side, rendering this difficult to identify and preserve. The recurrent laryngeal nerve is vulnerable to injury predominantly on the left due to the proximity when fashioning the pulmonary artery anastomosis. These nerves can be injured directly or, more frequently, suffer neuropraxia. Proper function postoperatively is essential to promote early extubation, airway control and expectoration. The cough reflex and Hering–Breuer reflex are absent after lung transplantation. Afferent autonomic nerves are severed at the time of preparation of the bronchi for implantation. Reports indicate a possible incidence for airway reinnervation after considerable time evolves, but may not be of clinical importance. Impairment of mucociliary clearance has to be assisted by intense respiratory therapy. A prolonged inability to clear airway secretions is associated with persistent infective lower respiratory tract complications. Vocal cord dysfunction may be transient due to prolonged endotracheal intubation or, rarely, due to vagal branch injury of the recurrent laryngeal nerves. This is more likely encountered on the left due to the proximity of the nerve path to the pulmonary artery ligament and the need to mobilize adjacent structure for save anastomosis of the left pulmonary artery and left main bronchus.

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Neurologic disorders encountered postoperatively

transplantation. Both main bronchi, however, are denervated after transplantation and are affected. Although less abundant in the distal airways, there is a large surface area of respiratory epithelium denervated after transplantation exposed to environmental particles and pathogens. Reinnervation of the bronchial anastomosis has been described in postmortem studies, but this is likely to be the exception and slow to develop. The ability to produce satisfactory expectoration also depends on an intact membranous mucosa, the function of the glottis, the vocal cords and the diaphragm.

Excessive sedation and failure to waken after prolonged anesthesia and intensive care stays are occasionally encountered in this high-risk population. Frequently, diffuse CNS impairment is transient and correlated with retained metabolites of sedative drugs and adverse effects of systemic analgesia. Renal failure and hepatic impairment aggravate the effects due to pharmacokinetic alterations of commonly used CNS depressive drugs in this setting. The respiratory impact is twofold: systemic respiratory drive depression and poor musculoskeletal strength do not allow for optimized respiratory effort and continually impair pulmonary clearance. The risk of recurrent respiratory failure is evident. Further impairment of the CNS secondary to acute chronic hypoxemia and confusional states confounds the clinical dilemma. Aggressive respiratory therapy and bronchopulmonary toilet with early bronchoscopy and differential diagnostic efforts are crucial. Mobilization at the earliest possible stage and assisted deep breathing exercises, the use of incentive spirometers, and occasional utilization of continuous positive airway pressure (CPAP) or biphasic positive airway pressure (BiPAP) ventilation are advocated. To adequately assess the work of breathing clinically and implement effective systematic weaning of ventilatory support is often difficult in patients with cognitive impairment.

Vocal cord impairment may be transient and frequently due to local pressure secondary to double lumen intubation or prolonged endotracheal positioning for delayed extubation. Rarely is a unilateral vocal cord dysfunction permanent in lung transplant recipients. The vagal fibers of the left recurrent laryngeal nerve are more likely to be injured at the time of transplantation unless meticulous dissection avoids the nerve in its course in the mediastinum. Medialization of the affected true vocal cord helps re-establish voice and phonation but crucially may also help prevent nasal drip and aspiration causing upper respiratory tract infections in recipients with immunosuppression. Suspected vocal cord dysfunction should therefore be investigated with laryngoscopy and formal swallow studies.

Sedation and ventilator weaning

Peripheral nerve injury

Weaning patients from the ventilator may occasionally be determined by delayed wakening after prolonged anesthesia or postoperative critical care. Rarely a cerebrovascular event may occur during CPB use. The risk of embolic and ischemic events associated with the use of CPB and ECMO are more frequent than hemorrhagic CNS complications. The preoperative vascular status and pre-existing carotid artery stenoses are likely to increase the risk periopertively. The incidence of diffuse and focal CNS injury after CPB in major cardiac surgery is approximately 6.8%, an even distribution between focal injury, or stupor and coma (categorized as type I injuries) and deterioration in intellectual function, memory deficit, or seizures (categorized as type II injuries) has been described. This in essence applies for patients receiving lung transplantation utilizing cardiopulmonary bypass to facilitate implantation.

Peroneal nerve injury due to pressure on the fibular head during surgery can lead to foot drop and significant impairment of ambulation early after lung transplant. Similarly, excessive abduction of upper extremities during prolonged positioning for the clamshell incision must be avoided to prevent brachial plexus injury.

Absent cough reflex Efferent and afferent fibers of tracheal receptors for the cough reflex remain intact in most lung transplant recipients irrespective of single or sequential bilateral

Recurrent laryngeal nerve injury

Critical illness myopathy/neuropathy Prolonged sedation and use of paralytic pharmaceuticals have long been implicated in development of critical illness myopathy and diffuse peripheral neuropathies. When this occurs in the patients that have been deconditioned prior to transplantation, a prolonged phase of ventilator support and rehabilitation is expected.

Neuromuscular deficits Diaphragmatic impairment may have multiple reasons in lung transplant recipients. Pre-existing dysfunction has to be excluded prior to lung transplantation. The restrictive element of various possible neuromuscular and neuromuscular junction disorders needs to be excluded in potential candidates for lung transplantation.

CLINICAL NEUROLOGY IN LUNG TRANSPLANTATION

Gastric outlet obstruction Gastric outlet obstruction (GOO) can be secondary to vagus manipulation or injury at the time of lung transplantation. Manifestations are usually transient, but occasionally require invasive procedures and supportive measures.

Metabolic confounders of neurostatus in lung transplantation patients Hyponatremia and elevated pCO2 are frequent metabolic derangements requiring supportive measures and normalization. Confusion and narcosis are very detrimental to the pulmonary recovery process. Metabolic deficits may also result from polypharmacy, often administered with a long list of potential adverse affects. Simple analgesia is required, but oversedation due to excessive use of narcotics and morphine derivatives often impacts the recovery. Epidural analgesia can solve some of the associated issues. The loss of neurovascular tone with epidural analgesia can cause systemic hypotension and requires close monitoring.

Encephalopathy The increasing success of organ transplantation has been achieved with refined immunosuppression. Ciclosporin and tacrolimus selectively suppress lymphocyte populations via lymphokine inhibition. Other pharmaceuticals used affect immune signal transduction (sirolimus, leflunomide). Methylprednisolone remains a mainstay of nonspecific immunosuppression via NF-kB pathway inhibition. Calcineurin inhibitor toxicity is now well described and includes neurologic manifestations such as recurrent headaches, resting tremors, and occasional seizures. Steroid-induced CNS/PNS adverse effects have been a major source of morbidity for these patients even without considering the endocrine and metabolic disadvantages. Mental derangements and depressive neuropsychiatric problems associated with high-dose administration are additional challenges in patients whose coping skills are already taxed. Other less frequent medication-related neurologic effects include the posterior reversible encephalopathy syndrome (PRES) which may be under reported in this setting. Essentially, the increased risk of CNS infections and neoplastic growth can result in symptoms determined by focal CNS involvement. Infections that may manifest with CNS mass lesions after transplantation include: Listeria monocytogenes, Aspergillus fumigatus, and Cryptococcus neoformans. Presentation of these may

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include systemic signs of infection or seizures due to focal cerebral effect. New onset of seizure activity in patients on calcineurin inhibitors also requires evaluation of serum concentrations to rule out drug toxicities. Therapeutic ranges for tacrolimus and ciclosporin have to be carefully monitored. Resting tremors and partial complex seizures are a common presenting sign in patients with elevated levels, particularly in the early phase of immunosuppression. With increasing time on an immunosuppressive regimen, the risk of neoplastic processes increases and occasional CNS mass lesions may include lymphoma and post-transplant lymphoproliferative disease (PTLD). Subtle neurologic manifestations, however, require comprehensive differential diagnostic skills best provided by neurologic services, and referrals should be made early. Neuroimaging and indications for cerebrospinal fluid (CSF) evaluation are according to their generic indications but a low threshold is prudent in transplant recipients. This is in view of the complex differential diagnostic spectrum and potential for rapid clinical deterioration. A recent review of a cohort of 120 lung transplant recipients revealed some neurologic complications in 95 patients. Half of these were considered severe including cerebrovascular complications and encephalopathy.

NEUROPSYCHOLOGICAL EFFECTS OF ORGAN TRANSPLANTATION A detailed review of the psychiatric issues after lung transplantation is beyond the scope of this chapter. The individual realities after lung transplantation, however, require complex neuropsychological adaptation. Not all patients are equipped with adequate coping skills. Pretransplant psychiatric issues may be aggravated or resurface due to psychological stressors after the critical care phase. Behavioral tendencies in turn clearly may expose transplant recipients to additional risks. Compliance issues, depression, and poor nutritional habits can have detrimental effects and patient education is crucial for transplant recipients. Strong mental attitude and well-developed coping strategies are helpful and essential to maintain quality of life.

SUMMARY Neurologic complications after lung transplantation may be more frequent than previously reported. The recognition of a range of potentially severe neurologic manifestations including cerebrovascular disease, encephalopathies, and focal CNS lesions depends on early involvement of clinicians with experience in this complex patient group. The liberalization of

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transplant candidate criteria will probably result in more frequent neurologic complications. Timely diagnosis and therapeutic intervention is required for the immunosuppression-related adverse effects. Infectious causes of neurologic deficits, when treated adequately, may result in complete recovery and improved quality of life. Awareness of the potential etiologies and the more frequent specific neurologic patterns in this patient group is essential.

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Husain S, Chan KM, Palmer SM et al. (2006). Bacteremia in lung transplant recipients in the current era. Am J Transplant 6: 3000–3007. Iribarne A, Russo MJ, Davies RR et al. (2009). Despite decreased wait-list times for lung transplantation, lung allocation scores continue to increase. Chest 135: 923–928. Neuringer IP, Chalermskulrat W, Aris R (2005). Obliterative bronchiolitis or chronic lung allograft rejection: a basic science review. J Heart Lung Transplant 24: 3–19. Orens JB, Estenne M, Arcasoy S et al. (2006). International guidelines for the selection of lung transplant candidates: 2006 update – a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 25: 745–755. Pochettino A, Kotloff RM, Rosengard BR et al. (2000). Bilateral versus single lung transplantation for chronic obstructive pulmonary disease: intermediate-term results. Ann Thorac Surg 70: 1813–1818, discussion 8–9. Roach GW, Kanchuger M, Mangano CM et al. (1996). Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 335: 1857–1863. Rosengard BR, Feng S, Alfrey EJ et al. (2002). Report of the Crystal City meeting to maximize the use of organs recovered from the cadaver donor. Am J Transplant 2: 701–711. Shah AS, Nwakanma L, Simpkins C et al. (2008). Pretransplant panel reactive antibodies in human lung transplantation: an analysis of over 10,000 patients. Ann Thorac Surg 85: 1919–1924. Shumway SJ, Hertz MI, Petty MG et al. (1994). Liberalization of donor criteria in lung and heart-lung transplantation. Ann Thorac Surg 57: 92–95. Silveira FP, Husain S (2008). Fungal infections in lung transplant recipients. Curr Opin Pulm Med 14: 211–218. Speich R, van der Bij W (2001). Epidemiology and management of infections after lung transplantation. Clin Infect Dis 33 (Suppl 1): S58–S65. UNOS (2013). United Network for Organ Sharing (UNOS) is the private, non-profit organization that manages the US organ transplant system. www.unos.org. Valentine VG, Bonvillain RW, Gupta MR et al. (2008). Infections in lung allograft recipients: ganciclovir era. J Heart Lung Transplant 27: 528–535. Weill D (2002). Donor criteria in lung transplantation: an issue revisited. Chest 121: 2029–2031. Wigfield CH, Lindsey JD, Anderson J et al. (2006). Organ procurement data evaluation of rejected marginal donors in lung transplantation. Chest 130: 152S. Wigfield CH, Lindsey JD, Steffens TG et al. (2007). Early institution of extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation improves outcome. J Heart Lung Transplant 26: 331–338. Wigfield C, Love R, Dark J (2009). Lung transplantation from non-heart-beating donors – donation after cardiac death

CLINICAL NEUROLOGY IN LUNG TRANSPLANTATION (DCD). In: D Talbot, A Alessandro (Eds.), Organ Donation and Transplantation after Cardiac Death. Oxford University Press, Oxford, pp. 231–254. Wijdicks EFM (1999a). Neurologic Complications in Organ Transplant Recipients Blue Books of Practical Neurology. Butterworth Heinemann, Oxford.

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Wijdicks EFM (1999b). Neurologic Complications in Organ Transplant Recipients Blue Books of Practical Neurology. Butterworth Heinemann, Oxford, ch. 5. Wong JY, Tait B, Levvey B et al. (2004). Epstein–Barr virus primary mismatching and HLA matching: key risk factors for post lung transplant lymphoproliferative disease. Transplantation 78: 205–210.

Clinical neurology in lung transplantation.

Lung transplantation is the only established therapeutic option for several end-stage respiratory diseases. Limited mostly by lack of suitable allogra...
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