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17.1. INTRODUCTION

The goal of immunosuppression in transplant patients is to prevent acute and chronic rejection of the transplanted organ, while avoiding opportunistic infections and the adverse effects of immunosuppressive therapy (see Fig. 17.1). Combinations of immunosuppressants are used to affect different immune-system activators and to provide immunosuppressive synergy, using the lowest effective doses of immunosuppressants to reduce the potential for adverse drug events and drug interactions. Superiority of one regimen over another has not been demonstrated, and immunosuppressive protocols are largely program-specific. Familiarity with the immunosuppressants used in a particular programs' protocol is critical, along with a concordant understanding of therapeutic drug monitoring through serum levels and graft evaluation, adverse drug reaction monitoring, and judicious use of auxiliary medications that prevent and treat the consequences of immunosuppression. However, regimens should be flexible and take into account individual patient characteristics, such as the cause of liver failure, sensitization to histocompatibility antigens, side effects of the medications, exposure to previous

Inadequate Immunosuppression Over Immunosuppression

Inadequate Immunosuppression Over Immunosuppression

Rohit Such Anti Body
Figure 17.1. Balance of immunosuppression.

transplantation, and concomitant drug therapy. Medications used to prevent and treat the unwanted effects of immunosuppression should be chosen carefully, because these medications often interact with immunosuppressive agents. These interactions can often be exploited, however, by using lower doses of immunosuppressants. Some patients are more prone to the effects of immunosuppression than others; for instance, a recipient patient who lacks antibodies to cytomegalovirus (CMV) and receives an organ from a CMV-positive donor is more likely to develop symptomatic CMV than a recipient patient who has CMV antibodies. Finally, patient adherence and compliance to regimens are extremely important, and nonadherence is a common cause of organ rejection. Multidisciplinary transplant teams work collaboratively with patients to increase compliance with complicated medication regimens.

17.2. GLUCOCORTICOIDS

Corticosteroids reduce the capacity of antigen-presenting cells (APC-macrophages, B cells, etc.) to release interleukins 1 (IL-1) and 6 (IL-6), thus inhibiting lymphocyte proliferation and the release of JL-2, IL-3, IL-4, tumor necrosis factor (TNF), interferon alpha (INFa), and interferon gamma (INF7). With the reduction in these cytokines, as well as the inflammatory eicosanoids and adhesion molecules on endothelial cells, the migration and phagocytosis capabilities of leukocytes, especially macrophages, are also inhibited. Lympho-

cytopenia, monopenia, and T-cell lysis also occur with glucocorticoids. The most commonly used corticosteroids in transplant protocols are methylprednisolone (Solu-Medrol®) given intravenously (IV) and prednisone (Deltasone® and others) given orally. Prednisone is absorbed after oral administration and converted hepatically to the active moiety, prednisolone. Methylprednisolone is about 1.25 times more potent than prednisone; it is often used for induction therapy intra-operatively and to treat episodes of acute rejection. In addition to concerns with long-standing corticosteroid therapy that suppresses the hypothalamic-pituitary-adrenal axis, slow discontinuation of therapy is desirable in order to manage cytokine rebound effect, because the receptors for cytokines are up-regulated in the presence of corticosteroids even though production is decreased. Although some programs dose steroids based on body weight, there is no convincing evidence that this is better than an empiric dosing strategy.

o Induction: 1000 mg IV day 1 (intraoperatively), tapering to 20 mg prednisone on day 6. o Maintenance: Usually 20 mg daily, tapering to 5 mg by the end of the first year, even discontinuing by 18-months posttransplant. o Acute rejection: 250-1000 mg IV on days 1, 2, and/or 3 tapering to 20 mg orally (PO) daily by day 6.

• Important Side Effects. Side effects include cushingoid effects such as fluid retention, hypertension, hyperglycemia, moon face, as well as bone demi-neralization and osteoporosis, gastritis, and/or peptic ulcers, cataracts, impaired wound healing, and increased susceptibility to infections.

• Important Drug-Drug Interactions. Interactions include increased metabolism in the presence of hepatic enzyme inducers (e.g., phenytoin, barbiturates, and rifampin) or decreased metabolism in the presence of hepatic enzyme inhibitors (e.g., grapefruit juice, cimetidine, macrolides, and "azole" antifungals [e.g., fluconazole]). Glucocorticoids may interfere with the effectiveness of vaccinations due to their inhibitory effect on leukocytes. Furthermore, steroids may reduce the ability of hypoglycemic agents to control blood glucose in diabetics.

17.3. CALCINEURIN INHIBITORS 17.3.1. Cyclosporine A (CyA)

The activation sequence of lymphocytes is altered by cyclosporin, which blocks humoral and cellular rejection mechanisms by binding to and forming a complex with immunophyllin protein and inhibiting the phosphatase activity of the enzyme calcineurin. This effect prevents the key steps in the G0 and G, (gap) stages of cell cycle needed in initiating gene transcription necessary for the formation of lymphokines, especially IL-1 and IL-2. The result is inhibition of lymphocyte activation by T-helper cells and some loss of cytotoxic T-cell function, seemingly sparing T-suppressor mechanisms. Therapeutic drug levels are used to guide therapy. Target levels vary by organ and time after transplant. For example, in liver transplants, levels of 250-400 ng/mL (monoclonal TDX method) early on, with progressive decrease to maintenance levels of 150-250 ng/ mL after 1 year are desirable. Lower levels are desirable for kidney transplants, due to the drug's nephrotoxicity. An important issue is the maintenance of adequate levels of the drug, due to the very variable (20-60%) bioavailability of CyA; best absorption is attained after a high-fat meal, although the microemulsified forms of CyA (Neoral®, Sangcya®, Gengraf®) are more readily bioavailable than the nonemulsified form (Sandimmune®). An IV formulation (Sandimmune®) is also available.

o Induction: generally not used, may use low doses IV (1-2 mg/kg/24 h). o Maintenance: 4-6 mg/kg/12 h PO.

• Important Side Effects. Side effects include nephrotoxicity, tremors, hirsut-ism, hypertension, gum hyperplasia, posttransplant lymphoproliferative disease (PTLD).

• Important Drug Interactions.

o Drugs that may potentiate nephrotoxicity (e.g., aminoglycosides, vancomycin).

o Drugs that may increase cyclosporine blood levels with potential for toxicity (drugs that inhibit the cytochrome P450 (e.g., "azole" antifungals, macrolides, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, grapefruit juice, diltiazem, verapamil). Sometimes these drugs are used in combination with cyclosporin to create "cyclosporin sparing regimens." o Drugs that may decrease blood levels, leading to the potential for rejection (drugs that induce the cytochrome P450 (e.g., rifampin, anti-epileptics, smoking, charcoal cooked foods)).

17.3.2. Tacrolimus (FK506, Prograf®)

The mechanism of action is similar to that of CyA but complexes with the intracellular protein, FKBP-12, leading to an inhibition of calcineurin; it is more potent than CyA. Therapeutic drug levels of 5-20 ng/mL during therapy are generally regarded as therapeutic in liver transplant patients. Tacrolimus is avail able in both PO and IV formulations; however, the IV formulation is very toxic and its use should be limited to patients not able to tolerate oral intake. It is not recommended to use CyA and tacrolimus simultaneously, as the risk of nephro-toxicity is compounded.

o Maintenance: PO 0.15-0.3 mg/kg/ql2h (every 12 hours), o Acute rejection therapy (AR): Rarely used for this purpose. If so used, increase doses to achieve high trough levels (15-20 ng/mL).

• Important Side Effects. Toxicity is mostly neurologic, renal and endocrine (diabetogenic), similar to that seen with CyA.

• Important Drug Interactions. Since both drugs utilize the cytochrome P-450 enzyme system for metabolism, interactions are similar to those of CyA.

17.4. ANTIMETABOLITES

17.4.1. Azathioprine (Imuran®)

A prodrug that is converted to 6-mercaptopurine, azathioprine produces nonspecific depression of DNA and RNA synthesis by inhibiting purine biosynthesis, in turn inhibiting T- and B-lymphocyte proliferation and differentiation. T lymphocytes are sensitive to inhibition of de novo purine synthesis because they lack efficient salvage pathways to maintain adequate intracellular levels. Azathioprine is frequently used in combination with other immunosuppressants, such as CyA and steroids.

o Induction: Not used this way routinely; may be given at doses of 3-5

mg/kg as preoperative medication on call to operating room (OR), o Maintenance: 1-2 mg/kg/d; adjust dose to white blood cell (WBC) level 5= 4,000.

• Important Side Effects. Myelosuppression (leukopenia, thrombocytopenia, anemia), skin rash, nausea and vomiting, susceptibility to infections.

• Important Drug Interactions. Allopurinol, other myelosuppressive agents, angiotensin-converting enzyme (ACE) inhibitors.

17.4.2. Mycophenolate Mofetil (Cellcept®)

Mycophenolate is converted to an active form, mycophenolic acid, that blocks the de novo pathway for purine biosynthesis by inhibiting inosine monophosphate dehydrogenase (IMPDH), preventing conversion of inosine monophos-

phate (IMP) to guanosine monophosphate (GMP). This is especially important in T and B lymphocytes, therefore exerting a cytostatic effect in these cells. It is also used in conjunction with steroids and cyclosporine. Azathioprine and mycopheno-late mofetil are not to be taken simultaneously, as the risk of myelosuppression increases dramatically.

I* Dosage. Maintenance: 500-1500 mg PO twice a day (bid), adjusted to WBC and side effects.

• Important Side Effects. Myelosuppression, diarrhea, infections, nausea, and gastric irritation.

• Important Drug Interactions. Acyclovir, gancyclovir and trimethoprim-sulfamethoxazole (Bactrim®; increased myelosuppression), antacids, and binding resins (e.g., cholestyramine, colestipol) cause decreased absorption.

17.5. ANTILYMPHOCYTE ANTIBODY PREPARATIONS 17.5.1. Muromonab-CD3 (Orthoclone OKT3)

A monoclonal antibody directed against the CD3 (T3) receptor present on the surface of T cells, muromonab-CD3 prevents antigen recognition. It also promotes lymphocyte lysis via complement fixation and/or antibody-dependent-cell mediated cytotoxicity. OKT3 is associated with the development of a severe cytokine release syndrome (CRS), resulting in a hyperdynamic state, with fever, tachycardia, and hypotension. This is due to the massive destruction of T cells with release of intracellular products. In the lungs, this produces an increased permeability and can lead to pulmonary edema in extreme instances. Management of this situation includes avoidance of fluid overload in the posttransplant patient, differentiation from septic states, and supportive therapy. It is important to consider that infection may coexist with this hyperdynamic state, and if it does not resolve within 48 hours, infection must be ruled out by usual means. In order to ameliorate this syndrome, premedication with methylprednisolone, diphenhydra-mine, and acetaminophen is indicated. Additionally, patients must have a clear chest X-ray for initiation of therapy, and hemodynamic monitoring is desirable.

The CD3 receptor appears when there is already some immunologic competence. For this reason, it is frequently used for resistant rejection episodes, as T cells are the effector agents of acute allograft rejection. Since OKT3 is a murine antibody, antimurine antibodies limit the effectiveness of repeated courses. OKT3 is also a potent mitogenic factor for T cells, which explains the presence of recurrent rejection following its use, unless other drugs are used. Monitoring of its effectiveness includes CD3 counts at initiation and end of induction or rejection therapy. When treating rejection with antibody preparations, patients should be initially monitored in an ICU setting to avoid complications.

o Induction: 5 mg IV every day (qd) for 7-10 days, o AR therapy: 5 mg IV qd for 10-14 days.

• Important Side Effects. CRS, diarrhea, aseptic meningitis, encephalopathy, seizures, headaches, and infections.

• Important Drug Interactions. Doses of calcineurin inhibitors and other maintenance immunosuppressants should be reduced to avoid overimmuno-suppression, potentially leading to increased risk of infections and/or malignancies.

17.5.2. Antithymocyte Globulins (ATGs)

ATGs are polyclonal antibodies (IgG) purified from the serum of animals immunized with human thymus lymphocytes that are directed against human lymphoid tissues. The two main preparations differ in their origin: Thymoglobu-lin® is derived from rabbit serum, and ATGAM® is derived from horse serum. The main risk associated with their use is anaphylaxis, as they are xenoantibodies. Their effectiveness varies between lots.

o Induction: 15 mg/kg/d IV for 7-14 days (ATGAM®); 1.5 mg/kg/d IV for

7-14 days (Thymoglobulin®). o AR therapy: 10 mg/kg/d IV for 10-14 days (ATGAM®); 1.5 mg/kg/d IV for 10-14 days (Thymoglobulin®).

• Important Side Effects. Anaphylaxis, serum sickness (usually seen 6-18 days after initiation of therapy), fever, chills, myelosuppression (leukopenia, thrombocytopenia), skin rash, nausea and vomiting, increased risk of infections.

• Important Drug Interactions. None known.

17.5.3. Interleukin 2 (IL-2) Receptor Antagonists

These are humanized monoclonal antibodies directed against the IL-2 receptor present at the lymphocyte surface. By inhibiting IL-2 binding, they inhibit the IL-2-mediated activation of lymphocytes. Because they are humanized chimeric antibodies, they do not elicit the CRS seen with the other antibody preparations. Two main compounds exist in this group: basiliximab (Simulect®) and daclizu-mab (Zenapax®), with similar safety and efficacy profiles. The difference is seen in the half-lives of the compounds, where the receptor saturation for basiliximab and dacluzimab is 36 and 120 days, respectively, at the recommended dosing. Currently the IL-2 receptor antagonists are only approved for use as induction agents in patients receiving renal transplant; however, they may be of benefit in other solid organ transplants.

o Induction: Basiliximab -* 20 mg IV given anywhere from preopera-tively to within 2 hours of implantation, and repeated 4 days after transplantation; dacluzimab -» 1 mg/kg given anywhere from preoperative^ to within 24 hours of implantation, and repeated at 14-day intervals for four more doses.

• Important Side Effects. Potential for anaphylaxis, increased risk of infections.

• Important Drug Interactions. None reported.

17.6. SIROLIMUS (RAPAMUNE®)

Sirolimus has a structure similar to that of macrolide antibiotics and acts by forming a complex that binds the target of rapamycin [sirolimus] (TOR) protein, which in turn inactivates the proteins that bind tacrolimus (FKBP) and/or cyclo-sporine (cyclophyllin), therefore exerting a synergistic effect with these medications. It effectively prevents cytokine-driven T-cell proliferation, inhibiting progression from to S phases of the cell cycle. There is some evidence that sirolimus also inhibits antibody production. Even though serum levels (range: 812 ng/mL) can be obtained, these levels have not been correlated with either safety or efficacy.

o Induction: 5-mg PO loading dose, followed by 2 mg PO qd afterwards, o Maintenance: 2 mg PO qd.

• Important Side Effects. Thrombocytopenia, leukopenia, hyperlipidemia, increased susceptibility to infections.

• Important Drug Interactions. None reported to date, however, studies have shown that when cyclosporin is given concurrently with sirolimus, peak levels of cyclosporin are reduced. The manufacturer suggests separating doses with CyA by about 4 hours for best absorption, peak levels, and synergistic effects.

17.7. IMMUNOSUPPRESSIVE REGIMENS

Immunosuppressive medications can either be used alone or in combination for maintenance immunosuppression in any given patient; however, a multidrug approach is desirable for optimal immunosuppression. Using different immuno-suppressive agents with different mechanisms of action and side effects has the advantage of enhancing immunosuppression and potentially minimizing adverse events associated with aggressive monotherapy. As Table 17.1 shows, some combinations or regimens are most likely to be useful in a given organ transplant model. Between transplant centers, there is great variability in dosing regimens, the type of transplant, as well as how well the donor organ HLA matches with the recipient. Most patients receive a triple-drug regimen for maintenance of immunosuppression, consisting of a calcineurin inhibitor, a steroid, and an antimetabolite; a fine line exists between under- and overimmunosuppression. In general, the level of immunosuppression is more likely to be aggressive in heart transplants, followed by lung, liver, pancreas, and kidney transplants. However, in renal and pancreatic transplants, cumulative rejection episodes can damage the graft and lead to chronic rejection. At the same time, these organs, especially the kidney, are more susceptible to the side effects (nephrotoxicity) of maintenance medications such a CyA and tacrolimus. Furthermore, rejection episodes are usually treated with higher doses of steroids and greater increases in baseline immunosuppression for organs such as liver or pancreas compared to kidney.

17.8. OTHER MEDICATIONS

Patients who are maintained on immunosuppression for allograft survival are susceptible to many opportunistic diseases in addition to chronic diseases (e.g., hypertension, hyperlipidemia, etc.). Many drugs added to the preexisting regimen may interact with the immunosuppressants. Drug interactions should be managed by adjusting the doses of immunosuppressants to targeted levels. The following list of medications may be used in patients prior to or following transplant.

17.8.1. Antivirals

Antiviral drugs are used to prevent and treat viral infections in immunocompromised patients. Antivirals are used prophylactically at smaller doses or at larger doses for active treatment. For example, if the donor organ is positive for a virus (e.g., herpes simplex virus [HSV], CMV, and varicella-zoster virus [VZV]), and the patient is negative for that virus, antiviral medication(s) would be added to the regimen at full treatment doses to prevent the recipient from contracting the virus. Furthermore, if the donor organ is negative and the patient is positive for the virus, or if both the donor organ and the patient are positive, no viral prophylaxis or treatment would be needed (refer to institution-specific protocols).

• Acyclovir (Zovirax®)—Treatment of HSV and VZV (much less active against CMV): 200 mg PO bid for prophylaxis and up to 10 mg/kg PO three times a day (tid).

Legend: CyA = cyclosporine A; AZA = azathioprine; MMF = mycophenolate mofetil; Steroids = glucocorticoids; Tacro = tacrolimus; immunosuppression. aStill experimental.

èMany times, induction and initiation or maintenance therapy overlap.

rapamycin; CNI = calcineurin inhibitors; ISX =

Legend: CyA = cyclosporine A; AZA = azathioprine; MMF = mycophenolate mofetil; Steroids = glucocorticoids; Tacro = tacrolimus; immunosuppression. aStill experimental.

èMany times, induction and initiation or maintenance therapy overlap.

rapamycin; CNI = calcineurin inhibitors; ISX =

• Gancyclovir (Cytovene®)—First-line agent for treatment of invasive CMV disease or CMV prophylaxis: 5 mg/kg IV q 12 h for 2-3 weeks, then 5 mk/kg IV qd for maintenance. Dose needs to be adjusted in renal failure and has dose-related myelosuppression.

• Foscarnet (Foscavir®)—Second-line for treatment of invasive CMV disease: 60 mg/kg IV q 8 h or 90 mg/kg q 12 h for 2-3 weeks; for treatment of acyclovir resistant VZV: 40 mg/kg q 8 h or 60 mg/kg q 12 h for up to 3 weeks. Dose should be adjusted in renal failure as it has additive nephro-toxicity.

• Cidofovir (Vistide®)—Third-line agent for invasive CMV disease: 5 mg/ kg infused over 1 hour once weekly for two doses, then 5 mg/kg every 2 weeks. Due to potential for nephrotoxicity, hydrate the patient with 1 liter of normal saline solution 1 hour, and 2 g probenecid 3 hours prior to start of infusion.

• CMV Hyperimmune Globulin (Cytogam®)—Treatment provides passive immunity to CMV in transplant patients or CMV disease (reactivation of CMV). It is generally used in conjunction with antiviral agents (e.g., acyclovir, gancyclovir). In kidney transplant patients, an initial dose of 150 mg/kg is to be administered within 72 hours of the procedure, then an additional 100 mg/kg dose should be given every 2 weeks, for a total of five doses. In liver, lung, and heart transplant recipients, the initial dose is similar to that in kidney transplant recipients, then a dose of 150 mg/kg is given every 2 weeks (weeks 2-8) and a 100 mg/kg dose is given at weeks 12 and 16 after transplantation, for a total of seven doses. It is to be infused at a rate of 15 mg/kg/h for 30 minutes, and if that is tolerated, the rate can be increased to 30 mg/kg/h for the next 30 minutes, to a final infusion rate of 60 mg/kg/h.

• Immunoglobulin (Gammagard®, Gamimune®, Sandoglobulin®)—

Treatment provides passive immunity against infectious disease when there are no vaccines available, and when patients have antibody deficiencies. Since all products are unique in their production, each product has its own dosing criteria. Gamimune is dosed at 100-200 mg/kg to a maximum of 400 mg/kg once monthly. Gammagard is dosed at 200-400 mg/kg once monthly, and Sandoglobulin is dosed at 200 mg/kg up to a maximum of 300 mg/kg once monthly.

17.8.2. Antibacterials

Patients on immunosuppressive regimens are at increased risk of developing bacterial infections, especially depending on the organ transplanted. Bacterial translocation with normal flora can cause clinically relevant bacterial infections. The most common cause of mortality following liver transplantation is infection.

• Trimethoprim-sulfamethoxazole (Bactrim®, Septra®) is used for prophylaxis of Pneumocystis carinii pneumonia (PCP), given as one double-strength (DS) tablet three times a week (Monday, Wednesday, Friday). Trimethoprim-sulfamethoxazole is also used to treat PCP. Alternatives for prophylaxis include pentamidine and dapsone.

• Other: Macrolides, penicillins, cephalosporins, and quinolones are not normally used for prophylaxis, but rather as treatments for presumed infections.

17.8.3. Antifungals

Patients on immunosuppression regimens are often at risk for developing fungal overgrowth, especially Candida sp. Patients may develop oral thrush, fungal esophagitis, or a vaginal yeast infection and need prophylaxis with antifungal medications; patients may also develop unusual fungal infections that do not normally occur in the general population.

• Fluconazole (Diflucan®): For treatment of Candida overgrowth, 100-200 mg PO daily. Prophylaxis: 100 mg daily to 100 mg weekly, depending on aggressiveness of immunosuppression.

• Clotrimazole troche (Mycelex®): For prophylaxis of Candida overgrowth, one 10 mg troche 4-5 times daily.

• Nystatin (Mycostatin®): For prophylaxis of fungal oral infections, 5 ml swish and spit, three to four times daily.

• Amphotericin B (Fungizone®, Abelcet®, Ambisome®): For the treatment of fungal infections caused by resistant Candida sp., cryptococcus, histomyces, blastomyces, and aspergillus. Due to the differences in ampho-tericin B preparations, the dosing will vary. The conventional amphotericin B (Fungizone®) is dosed at 0.5-1.0 mg/kg to a maximum of 1.5 mg/kg once daily infusion. The lipid formulations (Abelcet® and Ambisome®) of amphotericin B have less nephrotoxic effects, but there is no clinical difference between them. Abelcet® is dosed at 5 mg/kg once daily infusion, and Ambisome® is dosed at 1-5 mg/kg (depending on the sensitivity of the microorganism) once daily infusion.

17.8.4. Antihypertensives

Patients on immunosuppressive (especially CyA, tacrolimus, and glucocorticoids) regimens may develop hypertension that needs to be controlled with medications. Usually, calcium channel blockers (CCBs) are used, although there is place in therapy for angiotensin-converting enzyme (ACE) inhibitors. Non-

dihydropyridine CCBs diltiazem and verapamil interact with cyclosporin and tacrolimus, necessitating a lower dose of calcineurin inhibitor. However, verapamil may be nephroprotective when given before cyclosporin.

17.8.5. Hypoglycemic Agents

Patients on immunosuppression may already have previous history of diabetes mellitus, which may be worsened by some medications or may develop during maintenance therapy (e.g., glucocorticoids and/or tacrolimus). It may be necessary to initiate patients on hypoglycemic agents such as sulfonylureas, meglitinides, thiazolidinediones ("glitazones"), metformin, alpha-glucosidase inhibitors (e.g., acarbose or miglitol), or even insulin to maintain tighter control of blood glucose levels.

17.8.6. Lipid-Lowering Agents

A growing number of patients are starting to experience the effects of hyperlipidemia, especially since allograft survival has increased due to better immunosuppressive medications. In general, for patients who have plasma lipid abnormalities, agents such as HMG-CoA reductase inhibitors (for increased low-density [LDL] lipoprotein cholesterol), fibric acid derivatives (for increased triglycerides), bile acid-binding resins (for increased LDL and triglycerides), and niacin (for decreased high-density lipoprotein [HDL], and increased LDL and triglycerides) should be initiated to prevent the consequences of hyperlipidemia. For patients with mixed hyperlipidemia, a tailored program of blood lipid reduction may be necessary. Drug interactions with immunosuppressive regimens should be monitored closely.

17.8.7. Supplements

Patients may experience electrolyte abnormalities in addition to vitamin and nutritional deficits that may need to be supplemented.

Part

Late Postoperative Complications and Outcomes

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