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Significant comorbidities were excluded in the placebo- controlled studies reporting that characteristic buy antabuse 250mg line symptoms of pregnancy. Studies Currently Being Conducted We identified no trials in progress that would meet inclusion criteria for this review that would potentially change conclusions cheap antabuse 500mg with mastercard symptoms 24. Summary of the evidence by key question Key Question 1 proven antabuse 500mg treatment tinea versicolor. What is the comparative efficacy and effectiveness of newer diabetes medications, TZDs, and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of a Drugs evidence Conclusion Amylin Evidence in children agonists: Insufficient No data on children were reported, although people as young as 16 years were Pramlintide for eligible for study enrollment in 2 included trials (% of children enrolled was not 19, 20 Type 1 reported) diabetes Evidence in adults Low HbA1c was either slightly improved or no different with the addition of pramlintide 30 or 60 mcg/meal to a flexible-dose insulin regimen compared with placebo plus 20 flexible-dose insulin regimen over 29 weeks (between-group difference: 0. Low Greater reduction in HbA1c when pramlintide 60 mcg 3 or 4 times a day was added to fixed-dose insulin therapy (decreased from baseline by 0. What is the comparative efficacy and effectiveness of newer diabetes medications, TZDs, and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of a Drugs evidence Conclusion Amylin Evidence in children agonists: Insufficient Children and adolescents ≤ 18 years were not enrolled in any of the included Pramlintide for studies Type 2 diabetes Evidence in adults Insufficient No included studies focused on health outcomes as the primary outcomes. One study reported some health outcomes among the adverse events. Moderate Greater reduction in HbA1c with pramlintide doses from 75 mcg to 120 mcg given 2 or 3 times daily added to fixed- or stable doses of insulin compared with placebo and insulin (range 0. Low No statistically significant difference for reduction in HbA1c between the addition of pramlintide 120 mcg at meals to glargine or detemir compared with rapid acting insulin analog at 24 weeks (1. Low No change in weight reported with the addition of pramlintide 120 mcg at meals to glargine or detemir, compared with a 4. Saxagliptin inhibitors: Insufficient We found no head-to-head studies of sitagliptin and saxagliptin meeting inclusion Sitagliptin vs. Saxagliptin DPP-IV Sitagliptin: Evidence in children inhibitors: Insufficient Children and adolescents ≤ 18 years were not included in any of the published Sitagliptin studies on effectiveness or efficacy. Sitagliptin: Evidence in adults Insufficient All studies focused on intermediate outcomes with none focusing on health outcomes as primary outcomes. Some studies reported some health outcomes such as all-cause mortality or number of people with macrovascular disease among secondary outcomes or adverse events. Insufficient No studies provided data on efficacy/effectiveness for follow up beyond 2 years. Low (for both Sitagliptin monotherapy resulted in slightly less HbA1c reduction than either comparisons) metformin monotherapy over 54 weeks (between group difference −0. Low Sitagliptin monotherapy resulted in slight weight gain, compared with slight weight loss for those treated with metformin monotherapy over 54 weeks (between group difference −1. Low Sitagliptin monotherapy resulted in slightly less weight gain compared with glipizide monotherapy over 12 weeks (+0. Moderate Greater reduction in HbA1c with sitagliptin 100 mg/d monotherapy than with placebo (WMD −0. What is the comparative efficacy and effectiveness of newer diabetes medications, TZDs, and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of a Drugs evidence Conclusion Moderate Less weight loss with sitagliptin 100 mg/d monotherapy than with placebo (WMD 0. Low Studies comparing add-on of sitagliptin to other hypoglycemic agents (metformin, pioglitazone, or glimepiride) found sitagliptin-treated subjects to have either more weight gain, less weight loss, or similar changes in weight compared to placebo- treated subjects. Moderate Overall, in patients with inadequate glycemic control on 1 (metformin, pioglitazone, or glimepiride) or 2 hypoglycemic agents, the addition of sitagliptin resulted in greater reduction in HbA1c than the addition of placebo (between group difference −0. DPP-IV Saxagliptin: Evidence in children inhibitors: Insufficient We found no studies including children and adolescents ≤ 18 years Saxagliptin Saxagliptin: Evidence in adults Insufficient All studies focused on intermediate outcomes with none focusing on health outcomes as primary outcomes. Some studies reported some health outcomes such as all-cause mortality or cardiac death among secondary outcomes or adverse events. Insufficient No studies provided data on efficacy or effectiveness for follow up beyond 24 weeks. Insufficient We found no active-control studies meeting inclusion/exclusion criteria for saxagliptin. Moderate Greater reduction in HbA1c with saxagliptin monotherapy compared to placebo (between group difference −0. Low for each Saxagliptin added on to either metformin, a thiazolidinedione, or glyburide comparison; resulted in greater HbA1c reduction than placebo added on to metformin, a Moderate thiazolidinedione, or glyburide (between group difference ranges were−0. Liraglutide agonists: Low In the 1 included head-to-head trial (N=464), liraglutide 1. What is the comparative efficacy and effectiveness of newer diabetes medications, TZDs, and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of a Drugs evidence Conclusion GLP-1 Exenatide: Evidence in children agonists: Insufficient No included study examined children or adolescents with type 2 diabetes. Exenatide Exenatide: Evidence in adults Insufficient Except for one study reporting quality of life, no included studies examined the impact of treatment with exenatide on health outcomes (such as MI, death, stroke, or renal failure). Moderate Four active-control trials compared exenatide to insulin, with both groups also receiving oral diabetes agents, and all found no difference between groups for reduction in HbA1c (range for exenatide 10 mcg twice daily −1. In 1 of the trials, the substitution of exenatide for insulin did not improve HbA1c compared to continuing insulin. Moderate Active-control studies demonstrated significant weight loss in exenatide groups compared to weight gain with insulin (treatment difference range 4. Low One active-control trial found no significant difference in improvement in HbA1c between exenatide and glibenclamide (-1. Low One trial comparing exenatide to rosiglitazone with all participants on background metformin therapy, found no significant difference in improvement in HbA1c (- 0. Moderate Greater reduction in HbA1c with exenatide than with placebo, both when added overall; High to various oral agents and as monotherapy. However, statistical heterogeneity 2 was high for the pooled analysis (I =74%), and a sensitivity analysis removing a single study resulted in significant weight loss for exenatide 5mcg compared to placebo (weighted mean difference −0. No significant differences were seen between exenatide and insulin glargine. GLP-1 Liraglutide: Evidence in children agonists: Insufficient No included study examined children or adolescents with type 2 diabetes. Liraglutide Liraglutide: Evidence in adults Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications, TZDs, and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of a Drugs evidence Conclusion Insufficient No included studies focused on health outcomes as the primary outcomes. Some studies reported a health outcome among other secondary outcomes or in the adverse events section. Insufficient Three active-control trials comparing liraglutide to glimepiride demonstrated improvement in HbA1c in both treatment groups. Results indicate either no significant difference between treatment groups (2 trials) with liraglutide 0. Low Greater reduction in HbA1c in 1 good quality active-control trial comparing liraglutide 1. Moderate Greater reduction in HbA1c with liraglutide than with placebo, both when added to various oral agents and as monotherapy (liraglutide 0.
Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study generic 500 mg antabuse visa medicine x 2016. Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records buy 500 mg antabuse amex medicine werx. Differences in lipid profiles of patients given rosiglitazone followed by pioglitazone buy generic antabuse 250mg on line treatment yeast uti. Multicenter retrospective assessment of thiazolidinedione monotherapy and combination therapy in patients with type 2 diabetes: comparative subgroup analyses of glycemic control and blood lipid levels. Thiazolidinediones Page 103 of 193 Final Report Update 1 Drug Effectiveness Review Project 173. Thiazolidinediones: comparison of long-term effects on glycemic control and cardiovascular risk factors. Treating diabetes: Cardiovascular benefits of antidiabetes drugs. A comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones. Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month, open-label, observational, primary care study. Johannes CB, Koro CE, Quinn SG, Cutone JA, Seeger JD. The risk of coronary heart disease in type 2 diabetic patients exposed to thiazolidinediones compared to metformin and sulfonylurea therapy. Impact of oral antihyperglycemic therapy on all- cause mortality among patients with diabetes in the Veterans Health Administration. Pioglitazone initiation and subsequent hospitalization for congestive heart failure. Cancer risks in thiazolidinedione users compared to other anti-diabetic agents. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Coronary heart disease outcomes in patients receiving antidiabetic agents. Risk of hospitalization for heart failure associated with thiazolidinedione therapy: a medicaid claims-based case-control study. Bajaj M, Suraamornkul S, Hardies LJ, Pratipanawatr T, DeFronzo RA. Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus. Clinical evaluation of pioglitazone in patients with type 2 diabetes using alpha-glucosidase inhibitor and examination of its efficacy profile. Effects of pioglitazone and insulin on tight glycaemic control assessed by the continuous glucose monitoring system: A monocentric, parallel-cohort study. Thiazolidinediones Page 104 of 193 Final Report Update 1 Drug Effectiveness Review Project 188. Kiayias JA, Vlachou ED, Theodosopoulou E, Lakka-Papadodima E. Rosiglitazone in combination with glimepiride plus metformin in type 2 diabetic patients. Lipid response to pioglitazone in diabetic patients: clinical observations from a retrospective chart review. Comparison of glycemic and lipid response to pioglitazone treatment in Mexican-Americans and non-Hispanic Caucasians with type 2 diabetes. Effect of pioglitazone on blood proinsulin levels in patients with type 2 diabetes mellitus. Chronic heart failure-related interventions after starting rosiglitazone in patients receiving insulin. Predictors of improved glycaemic control with rosiglitazone therapy in type 2 diabetic patients: A practical approach for the primary care physician. Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones. Orbay E, Sargin M, Sargin H, Gozu H, Bayramicli OU, Yayla A. Addition of rosiglitazone to glimepiride and metformin combination therapy in type 2 diabetes. Osei K, Gaillard T, Kaplow J, Bullock M, Schuster D. Effects of rosglitazone on plasma adiponectin, insulin sensitivity, and insulin secretion in high-risk African Americans with impaired glucose tolerance test and type 2 diabetes. Rosiglitazone is a safe and effective treatment option of new-onset diabetes mellitus after renal transplantation. Rajagopalan R, Rosenson RS, Fernandes AW, Khan M, Murray FT. Association between congestive heart failure and hospitalization in patients with type 2 diabetes mellitus receiving treatment with insulin or pioglitazone: a retrospective data analysis. Real world effectiveness of rosiglitazone added to maximal (tolerated) doses of metformin and a sulfonylurea agent: a systematic evaluation of triple oral therapy in a minority population. Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase. Postmarketing Surveillance Study of the Efficacy and Tolerability of Pioglitazone in Insulin-Resistant Patients with Type 2 Diabetes Mellitus in General Practice. Pioglitazone is effective therapy for elderly patients with type 2 diabetes mellitus. Thiazolidinediones Page 105 of 193 Final Report Update 1 Drug Effectiveness Review Project 203. Effect of rosiglitazone on serum liver biochemistries in diabetic patients with normal and elevated baseline liver enzymes. Long-term glycaemic efficacy and weight changes associated with thiazolidinediones when added at an advanced stage of type 2 diabetes. Reduction in hematocrit and hemoglobin following pioglitazone treatment is not hemodilutional in Type II diabetes mellitus. Improvement of glycemic control after a 3-5 day insulin infusion in type 2-diabetic patients with insulin resistance can be maintained with glitazone therapy. Rosiglitazone in diabetes control in hemodialysis patients with and without viral hepatitis infection: effectiveness and side effects. Treatment with a thiazolidinedione increases eye protrusion in a subgroup of patients with type 2 diabetes. Dorkhan M, Magnusson M, Frid A, Grubb A, Groop L, Jovinge S. Glycaemic and nonglycaemic effects of pioglitazone in triple oral therapy of patients with type 2 diabetes.
However buy discount antabuse 500 mg on line in treatment, in HBV-coinfected patients starting ART antabuse 500 mg mastercard treatment urticaria, two HBV drugs should be used in order to reduce the risk of HBV resistance buy antabuse 250mg overnight delivery medications for bipolar. Avoid Combivir or Kivexa in cases of hepatitis B coinfection when no other HBV agent is on board – 3TC alone is not enough for HBV. Last but not least, a wish for parenthood should be considered. There are no absolute contraindications Illness Caution with Active hepatitis B Nevirapine, boosted PIs (beneficial: Tenofovir+ FTC) Active illicit drug use NNRTIs, ritonavir, cobicistat (possibly beneficial: raltegravir) Anemia AZT, possibly also 3TC Arterial hypertension Indinavir Cancer requiring chemotherapy Boosted PIs, boosted INIs (possibly beneficial: raltegravir) Chronic diarrhea, intestinal diseases Lopinavir, fosamprenavir, other PIs Diabetes mellitus PIs Kidney disease Tenofovir, atazanavir, elvitegravir/c Myocardial infarction Abacavir, ddI, PIs (potentially beneficial: nevirapine) Osteoporosis Tenofovir Pancreatitis ddI Polyneuropathy d4T, ddI Psychoses, other CNS illnesses Efavirenz, possibly rilpivirine 6. What to start with 183 Interactions with medications and drugs Interactions are important in when choosing regimens. Whereas interactions between antiretroviral drugs are well known, those with other medications are often less well characterized (see section on interactions). The urgent need for more research was demonstrated in a study investigating the interactions between ART and lipid lowering agents. In healthy volunteers, the measurement of plasma levels showed that levels of simvastatin were elevated by 3059% after concurrent dosing with riton- avir or saquinavir (Fichtenbaum 2002). Several cases of fatal rhabdomyolysis on sim- vastatin, atorvastatin and PIs such as atazanavir or lopinavir have been described (Review: Chauvin 2013). There are even case reports on pravastatin and rosuvastatin (Mikhail 2009, de Kanter 2011), so boosted PIs or INIs such as elvitegravir/c should be utilized with caution. The same applies to several HCV drugs such as daclatasvir. Many other drugs should be avoided in combination with particular antiretroviral drugs, as incalculable interactions may occur. Even drugs that seem unproblematic at first glance can have unfavorable effects. For example, the plasma levels of saquinavir can be reduced by half with administration of garlic capsules (Piscitelli 2002). One noteworthy interaction is between PIs and inhaled or intranasal corticosteroids. This interaction can result in adrenal insuffi- ciency and iatrogenic Cushing’s syndrome (Saberi 2013). Even a seemingly harmless agent such as vitamin C can influence plasma levels. A small study in healthy vol- unteers showed that vitamin C can significantly lower (14%) unboosted indinavir levels (Slain 2005). Coumarin derivative anticoagulants, such as warfarin can also be a problem; ritonavir can significantly lower plasma levels (Llibre 2002). Further typical problem drugs include migraine remedies, prokinetic drugs and sedatives/ hypnotics. One fatal case was described with ergotamine and ritonavir (Pardo 2003). The simultaneous administration of ART and PDE-5 inhibitors (sildenafil, vardenafil, tadalafil) can also be problematic. Drugs or alcohol can interact with ART (Neuman 2006, Mass 2006). For those in sub- stitution programs, the methadone requirement may be significantly increased by certain antiretroviral drugs, such as nevirapine and efavirenz (Clarke 2001). To a lesser extent, this is also true for ritonavir and nelfinavir. There is inconsistent data on lopinavir but it may also require dose adjustments. Raltegravir, seems to have no effects (Anderson 2010). Other interactions have even more dangerous consequences. Several deaths have been reported after simultaneous dosing with ritonavir and amphetamines or MDMA/ecstasy, the popular narcotic gamma hydroxybutyric acid (GHB) or “liquid ecstasy” (Henry 1998, Harrington 1999, Hales 2000). Ritonavir in particular inhibits the metabolism of amphetamines, ketamines or LSD (Antoniou 2002). Clinicians and patients are well advised to have an open conversation about drug use before starting therapy. Marijuana and THC appear to have a low potential for interactions (Kosel 2002). Amphetamines seem to be particularly dangerous and neurotoxic in HIV+ patients (Chana 2006). Many are described in the respective drug chapters and in the Interactions chapter. It is always recommended to check the package insert. Initiation of ART provides a good opportunity to re-evaluate exist- ing prescribed medications. Additive toxicities Although toxicity of newer antiviral agents has been markedly reduced, compared to first generation compounds such as AZT, ddI or d4T, several potential additive toxicities should be considered in the choice of therapy. When treating hepatitis C with interferon and ribavirin, ddI must be avoided. Tenofovir, indinavir, possibly also atazanavir should also be avoided with potentially nephrotoxic drugs. Interactions with the transport of creatinine have been identified with rilpivirine, dolutegravir, and cobici- stat. Although these interactions can cause mild-to-moderate increases in serum cre- atinine concentrations that do not translate into real decreases in glomerular filtra- tion, these interactions must be considered. Lastly, it is not advisable during primary therapy to start with potential allergy-induc- ing agents if anti-infectious prophylaxis with cotrimoxazole or other sulphonamides is necessary. Included here are all NNRTIs and abacavir, but also fosamprenavir and darunavir. Otherwise, it can be diffi- cult to clearly identify the causative agent for a drug-induced exanthema. References Anderson MS, Mabalot Luk JA, Hanley WD, et al. Effect of Raltegravir on the Pharmacokinetics of Methadone. Interactions between recreational drugs and antiretroviral agents. Efficacy of tenofovir disoproxil fumarate/emtricitabine compared with emtricitabine alone in antiretroviral-naive HIV-HBV coinfection in Thailand. Directly observed anti- retroviral therapy improves adherence and viral load in drug users attending methadone maintenance clinics: a randomized controlled trial.
Therefore cheap antabuse online amex medicine cat herbs, JAK2 reduced iron overload with only minimal effects on the RBC and inhibition might have positive clinical consequences in -thalasse- hemoglobin levels buy discount antabuse 250 mg online withdrawal symptoms, indicating that a lower dose of these agents mia patients in whom excessive IE generic antabuse 500 mg with visa medicine 230, causing iron overload and could achieve a reduction in iron absorption and iron overload after splenomegaly, are severe problems. In -thalassemia, these approaches also led to a signiﬁcant improvement of anemia, It has also been shown that chronic stress erythropoiesis, and the IE, extramedullary hematopoiesis, and a signiﬁcant reduction of consequent overproliferation of erythroid progenitors in -thalasse- spleen size associated with improved spleen architecture. Upon depletion of macrophages results were observed using minihepcidins, showing that these in these animals, the number of erythroblasts was signiﬁcantly molecules represent a valid therapeutic approach with a disease reduced, with major improvement of IE, anemia, iron metabolism, modiﬁer’s end point. Furthermore, these approaches by a decreased ability of the erythroid progenitors to differentiate. For this reason, macrophage depletion may Hematology 2014 219 not represent a valid clinical approach. However, speciﬁcally improved therapeutics, advancing the management of these disor- interrupting the interaction between macrophages and erythroblasts, ders and improving the quality of life of the affected patients. Disclosures Ongoing studies to more fully characterize the molecules involved Conﬂict-of-interest disclosures: S. Off-label drug use: None Additional studies support the notion that modulation of IE, in disclosed. In mice, this has been underscored by studies using 2 Stefano Rivella, Department of Pediatrics, Weil Medical College, different drugs, RAP-011 and RAP-536, ligand traps based on the Cornell University, Belfer Research Bldg, 413 East 69th St, Rm extracellular domains of the activin receptor IIA (ActRIIA) and 1202, Box 284, New York, NY 10021. Complexes containing ActRIIA, ActRIIB, or 646-962-0574; e-mail: str2010@med. Tgf type II receptor regulate gene expression primarily by activating the Smad2/3 subfamily of intracellular effectors. Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews signaling in erythroid cells. Slc11a2 is required for intestinal iron absorption and erythropoiesis Gdf11, which is up-regulated in thalassemic erythroid cells and is but dispensable in placenta and liver. Lack of hepcidin gene erythroblasts in animal models of -thalassemia intermedia, with expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. In conclusion, targeting mechanisms of IE or iron 4. Hepcidin regulates cellular iron absorption may trigger a beneﬁcial and synergistic loop that will efﬂux by binding to ferroportin and inducing its internalization. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and Future directions inﬂammation. New agents that decrease iron absorption have the potential to 6. Severe iron deﬁciency anemia in improve the management of iron overload in both HH and transgenic mice expressing liver hepcidin. Suppression of tional iron chelation might be beneﬁcial in accelerating the unload- hepcidin during anemia requires erythropoietic activity. Biochim Biophys -thalassemia intermedia, as indicated by some preliminary obser- Acta. These drugs might improve RBC protein signaling by hemojuvelin regulates hepcidin expression. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. In addition, in the presence of blood hemojuvelin in the regulation of bone morphogenic protein-6 and transfusion, they might further suppress the IE and prevent or hepcidin expression in vivo. Mutations in TMPRSS6 cause iron-refractory iron deﬁciency anemia (IRIDA). Therefore, also in -thalassemia major, these drugs have the 14. Modulators of erythropoiesis: emerging therapies potential to transform the management of this disease. In conclusion, the focus of many investigators is to identify new 15. Beta-thalassemia and polycythemia vera: mechanisms and strategies to prevent or reverse iron overload and targeting chronic stress erythropoiesis. Hopefully, these investigations will lead to new and 2014;51:89-92. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identiﬁca- mediated by down-regulation of hepcidin and up-regulation of ferropor- tion of erythroferrone as an erythroid regulator of iron metabolism. BMP4 and Madh5 regulate the phenotype in a mouse model of beta-thalassemia. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe( / ) mice and erythropoiesis in polycythemia vera and beta-thalassemia. Vemula S, Ramdas B, Hanneman P, Martin J, Beggs HE, Kapur R. Essential role for focal adhesion kinase in regulating stress hematopoi- 33. Curr Opin tissue-iron accumulation in disorders of iron overload with anemia. The role of ineffective erythropoiesis in non-transfusion- 35. Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC. Decreased differentiation of Hepcidin antimicrobial peptide transgenic mice exhibit features of the erythroid cells exacerbates ineffective erythropoiesis in beta-thalasse- anemia of inﬂammation. An activin receptor IIA ligand tool to limit iron overload and improve anemia in beta-thalassemic trap corrects ineffective erythropoiesis in beta-thalassemia. Modiﬁed activin receptor IIB designed small peptides that mimic hepcidin activity in mice and may be ligand trap mitigates ineffective erythropoiesis and disease complica- useful for the treatment of iron overload. Schmidt P, Racie T, Butler JS, Fitzgerald K, Fleming MD. Minihepcidins prevent iron RNAi-therapeutic targeting tmprss6, in conjunction with oral chelator overload in a hepcidin-deﬁcient mouse model of severe hemochromato- therapy, ameliorates anemia and additively diminishes secondary iron sis. Tmprss6 is a genetic Blood (ASH Annual Meeting Abstracts). Ineffective erythropoiesis beta-thalassemia major: a longitudinal study. Freeman2 1Department of Medical & Molecular Genetics, King’s College London School of Medicine, London, United Kingdom; and 2Department of Clinical Immunology, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom The past 40 years have witnessed major advances in deﬁning the cytogenetic aberrations, mutational landscape, epigenetic proﬁles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratiﬁcation guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter ﬂow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status.