Ferumoxytol for iron deficiency anemia in patients undergoing hemodialysis. The FACT randomized controlled trial
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BACKGROUND: Patients with chronic kidney disease (CKD) undergoing dialysis often require intravenous iron for iron deficiency anemia (IDA). MATERIALS AND METHODS: The Ferumoxytol for Anemia of CKD Trial (FACT), a randomized, multicenter, open-label, phase 4 study, compared the long-term safety and efficacy of ferumoxytol with iron sucrose for the treatment of IDA in patients with CKD undergoing hemodialysis. Patients with IDA and CKD undergoing hemodialysis were randomized 2:1 to ferumoxytol 1.02 g (2 × 510 mg) or iron sucrose 1.0 g (10 × 100 mg) for a 5-week treatment period (TP). Over 11 months, patients underwent additional 5-week TPs whenever IDA (hemoglobin < 11.5 g/dL and transferrin saturation < 30%) was detected. The primary efficacy endpoint was mean change in hemoglobin from baseline to week 5 for each TP. Adverse events were recorded during the study. RESULTS: Overall, 293 patients received ferumoxytol (n = 196) or iron sucrose (n = 97). Ferumoxytol was noninferior to iron sucrose regarding hemoglobin change from baseline to week 5. The mean change in hemoglobin in the ferumoxytol and iron sucrose groups was 0.5 and 0.4 g/dL, respectively, in TP 1 (least-squares mean difference, 0.13; 95% confidence interval, -0.11 to 0.36) and 0.6 and 0.3 g/dL, respectively, in TP 2 (0.30; 0.06 - 0.55). Treatment-related and serious adverse events were similar in both groups; no new safety signals emerged. CONCLUSION: Long-term administration of ferumoxytol has noninferior efficacy and a similar safety profile to iron sucrose when used to treat IDA in patients with CKD undergoing hemodialysis.
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Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial.

Few trials have examined rates of hypersensitivity reactions (HSRs) with intravenous iron formulations used to treat iron deficiency anemia (IDA). This randomized, multicenter, double-blind clinical trial compared the safety, and efficacy of ferumoxytol versus ferric carboxymaltose (FCM), focusing on rates of HSRs and hypotension as the primary end point. Patients with IDA of any etiology in whom oral iron was unsatisfactory or intolerable received ferumoxytol (n = 997) or FCM (n = 1000) intravenously over ≥15 minutes on days 1 and 8 or 9 for total respective doses of 1.02 g and 1.50 g. Composite incidences of moderate-to-severe HSRs, including anaphylaxis, or moderate-to-severe hypotension from baseline to week 5 (primary safety end point) were 0.6% and 0.7% in the ferumoxytol and FCM groups, respectively, with ferumoxytol noninferior to FCM. No anaphylaxis was reported in either group. The secondary safety end point of incidences of moderate-to-severe HSRs, including anaphylaxis, serious cardiovascular events, and death from baseline to week 5 were 1.3% and 2.0% in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Least-squares mean changes in hemoglobin at week 5 were 1.4 g/dL and 1.6 g/dL in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Incidence of hypophosphatemia was 0.4% for ferumoxytol and 38.7% for FCM.

Correction to: The Ferumoxytol for Anemia of CKD Trial (FACT)-a randomized controlled trial of repeated doses of ferumoxytol or iron sucrose in patients on hemodialysis: background and rationale.

Following publication of the original article [1], the authors reported that one of the authors' name is spelled incorrectly. In this Erratum the incorrect and correct author name are shown. The original publication of this article has been corrected.

The Ferumoxytol for Anemia of CKD Trial (FACT)-a randomized controlled trial of repeated doses of ferumoxytol or iron sucrose in patients on hemodialysis: background and rationale.

BACKGROUND: Iron deficiency anemia (IDA) is a common manifestation of chronic kidney disease (CKD), affecting most patients on hemodialysis and imposing a substantial clinical burden. Treatment with iron supplementation increases hemoglobin levels and can reduce the severity of anemia in patients with CKD. While correcting anemia in these patients is an important therapeutic goal, there is a lack of long-term trials directly comparing intravenous iron therapies in patients with CKD receiving hemodialysis. METHODS/DESIGN: The Ferumoxytol for Anemia of CKD Trial (FACT) is a 13-month, open-label, randomized, multicenter, international, prospective study with 2 substudies. Entry criteria for the main study include adults with IDA (defined as hemoglobin <11.5 g/dL [<115.0 g/L] and a transferrin saturation <30%), serum ferritin <800 ng/mL (<1798 pmol/L), and receiving hemodialysis for ≥3 months. Patients are randomized to receive ferumoxytol (1.02 g over 2 doses) or iron sucrose (1.0 g over 10 doses) during the initial 5-week treatment period. Those with persistent/recurrent IDA over the 11-month observation period will receive additional 5-week treatment periods, as appropriate. The primary efficacy endpoint of the main study is the mean change in hemoglobin from Baseline to Week 5 for each treatment period. The secondary efficacy endpoints include the mean change in transferrin saturation from Baseline to Week 5 and the proportion of patients with a hemoglobin increase of ≥1.0 g/dL at any time from Baseline to Week 5. Safety will be assessed through an examination of the adverse event profile over the course of the study. An "oxidative stress" substudy in approximately 100 patients will assess the effects of treatment on biomarkers of oxidative stress/inflammation during the initial 5-week treatment period, and a magnetic resonance imaging substudy in approximately 70 patients will assess the potential for iron deposition in target tissues over 24 months. DISCUSSION: FACT fulfills the need for a long-term comparative trial in patients with IDA and CKD receiving hemodialysis. The efficacy and safety results will provide useful information for guiding therapy in this population. Two hundred ninety-six patients have been enrolled, and completion of the main study is expected soon. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01227616 (registered October 22, 2010); EudraCT number: 2010-022133-28.

Qualitative and quantitative validation of the FACIT-fatigue scale in iron deficiency anemia.

BACKGROUND: Fatigue is a burdensome symptom in iron deficiency anemia (IDA). To capture the severity and impact of fatigue appropriately it must be measured using validated scales. This study evaluated the content validity and psychometric validity of the Functional Assessment of Chronic Illness Therapy - fatigue scale (FACIT-fatigue) in IDA patients. METHODS: Qualitative patient interviews were conducted in the United States to evaluate content validity. The psychometric properties of the FACIT-fatigue scale were investigated using data from a phase 3 clinical trial assessing ferumoxytol in patients with a history of unsatisfactory oral iron therapy or in whom oral iron cannot be used. The statistical analysis assessed the acceptability, reliability, validity and responsiveness of the FACIT-fatigue scale. RESULTS: Qualitative interviews showed that fatigue is a central concern to IDA patients and that the FACIT-fatigue scale sufficiently assessed this construct. Psychometric assessment demonstrated that the FACIT-fatigue scale was stable over time (ICC = 0.87) and internally consistent (α = 0.93). The scale demonstrated convergence with other conceptually relevant scales such as SF-36 Vitality (r = 0.74), and distinguished between known groups [i.e., treatment arms (mean difference (95 % CI) = 3.56 (1.68, 5.43), p <0.001) and high vs. low hemoglobin groups (mean difference (95 % CI) = 5.51 (8.59, 2.44) p <0.001)]. Responsiveness was also demonstrated; significant improvements in FACIT-fatigue scale scores corresponded with significant differences between minimal, moderate, and much improved vitality cohorts (p < 0.05). CONCLUSIONS: This research demonstrated that the FACIT-fatigue scale has sound measurement properties and is an appropriate and interpretable assessment of fatigue among IDA patients with various underlying conditions.

A Phase III, randomized, open-label trial of ferumoxytol compared with iron sucrose for the treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapy.

Iron deficiency anemia (IDA) is the most common form of anemia worldwide. Although oral iron is used as first-line treatment, many patients are unresponsive to or cannot take oral iron. This Phase III, open-label, non-inferiority study compared the efficacy and safety of ferumoxytol, a rapid, injectable intravenous (IV) iron product with low immunological reactivity and minimal detectable free iron, with IV iron sucrose in adults with IDA of any cause. Patients (N = 605) were randomized 2:1 to receive ferumoxytol (n = 406, two doses of 510 mg 5 ± 3 days apart) or iron sucrose (n = 199, five doses of 200 mg on five nonconsecutive days over 14 days) and followed for 5 weeks. Ferumoxytol demonstrated noninferiority to iron sucrose at the primary endpoint, the proportion of patients achieving a hemoglobin increase of ≥2 g dL(-1) at any time from Baseline to Week 5 (ferumoxytol, 84.0% [n = 406] vs. iron sucrose, 81.4% [n = 199]), with a noninferiority margin of 15%. Ferumoxytol was superior to iron sucrose (2.7 g dL(-1) vs. 2.4 g dL(-1) ) in the mean change in hemoglobin from Baseline to Week 5 (the alternative preplanned primary endpoint) with P = 0.0124. Transferrin saturation, quality-of-life measures, and safety outcomes were similar between the two treatment groups. Overall, ferumoxytol demonstrated comparable safety and efficacy to iron sucrose, suggesting that ferumoxytol may be a useful treatment option for patients with IDA in whom oral iron was unsatisfactory or could not be used.

Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron.

Although oral iron is the initial treatment approach for iron deficiency anemia (IDA), some patients fail to respond to or cannot tolerate oral iron. This double-blind safety and efficacy study of the intravenous (IV) iron, ferumoxytol, randomized patients with a history of unsatisfactory oral iron therapy, or in whom oral iron could not be used, to ferumoxytol (n = 609) or placebo (n = 203). The proportion of patients achieving the primary endpoint (hemoglobin increase ≥2.0 g/dL at Week 5) was 81.1% with ferumoxytol versus 5.5% with placebo (P < 0.0001). The mean increase in hemoglobin from Baseline to Week 5, a secondary endpoint (also the alternative preplanned primary efficacy endpoint for other health authorities), was 2.7 versus 0.1 g/dL (P < 0.0001). Achievement of a hemoglobin ≥12 g/dL, time to a hemoglobin increase ≥2.0 g/dL, and improvement in the Functional Assessment of Chronic Illness Therapy Fatigue score also significantly favored ferumoxytol over placebo at Week 5 (P < 0.0001). Ferumoxytol treatment-emergent adverse events were mainly mild to moderate. Ferumoxytol was effective and well tolerated in patients with IDA of any underlying cause in whom oral iron was ineffective or could not be used. This trial was registered at www.clinicaltrials.gov as #NCT01114139.

Safety and efficacy of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min.

For the majority of patients with iron deficiency anemia (IDA), a full course of intravenous (IV) iron is 1 g. Most IV irons require 5-10 administrations of 100-300 mg. We have successfully employed 1 g low molecular weight iron dextran over 1 hr. For further convenience for patients and physicians, we explored the administration of 1.02 g of ferumoxytol over 15 min instead of the approved 2 × 510 mg injections. Sixty patients with IDA, (hemoglobin <11 g/dL, transferrin saturation [TSAT] ≤20%, and ferritin <100 ng/mL) with an inadequate response or intolerance to oral iron, received 1020 mg ferumoxytol over 15 min. Vital signs were measured for 1 hr. Adverse events (AEs) were collected via telephone at 1, 2, and 7 days. Follow-up visits occurred at 4 and 8 weeks for efficacy assessments. The primary endpoint was safety and tolerability. Secondary efficacy endpoints included mean change in hemoglobin, TSAT, and red cell distribution width. No serious adverse events (SAEs) occurred. Fifty-eight patients received the planned dose. Twenty-six out of sixty (43.3%) patients reported AEs of which 13 were mild and transient during infusion. All resolved within minutes. Fourteen patients reported self-limited arthralgias, myalgias, and/or headache within 24-48 hr. At Baseline, the mean hemoglobin was 9.4 g/dL. The mean increments at Week 4 and 8 were 2.1 and 2.6 g/dL, respectively. Ferumoxytol, administered as 1.02 g infusion over 15 min was well tolerated with no SAEs and demonstrated excellent efficacy. If corroborated in future studies this represents an improved method of treating IDA.

Factors affecting response and tolerability to ferumoxytol in nondialysis chronic kidney disease patients.

BACKGROUND: Ferumoxytol is a unique intravenous (i.v.) iron therapy. This report examines factors affecting hemoglobin response to i.v. ferumoxytol, and the relationship between hematologic parameters, concomitant erythropoiesis-stimulating agents (ESA), and adverse events (AEs) in nondialysis CKD patients. METHODS: A series of post-hoc efficacy and safety analyses were performed using pooled data from two identically designed Phase III studies in 608 nondialysis CKD patients randomized to receive two 510 mg i.v. injections of ferumoxytol within 5 ± 3 days versus oral iron. RESULTS: Ferumoxytol resulted in a significant increase in hemoglobin in the presence and absence of ESA, and across a range of baseline hemoglobin, transferrin saturation, ferritin, and reticulocyte hemoglobin content levels. Adverse event rates with ferumoxytol were similar across quartiles of change in hemoglobin; there were no trends suggesting an increased rate of cardiovascular AEs with higher maximum achieved hemoglobin or faster rate of hemoglobin rise. There was no meaningful difference in the rate of AEs, serious AEs, and cardiovascular AEs between patients receiving or not receiving ESA. CONCLUSIONS: These analyses add to the knowledge of predictors of response and safety outcomes associated with i.v. iron therapy in nondialysis CKD patients.

Intravenous Iron-Induced Hypophosphatemia: An Emerging Syndrome.

Some, but not all, intravenous iron formulations have been recognized to induce renal phosphate wasting syndrome. Most commonly this has been reported following treatment of iron deficiency anemia (IDA) with ferric carboxymaltose (FCM). A search of PubMed identified relevant randomized controlled trials (RCTs), and case studies evaluating hypophosphatemia (HPP) resulting from intravenous iron treatment. While more recent larger comparative RCTs have confirmed that the majority of patients receiving FCM, especially those with normal renal function, may experience severe HPP, complete documentation is hampered by inconsistent reporting of serum phosphate in such trials. Similarly, while case series and RCTs have documented the persistence of HPP for several weeks or even months, the lack of studies lasting beyond 5-6 weeks has constrained full understanding of the duration of effect. Clinical trials have established that the mechanism involves the bone/metabolic axis with the elevation of intact fibroblast growth factor 23 playing the central role. Reports continue to accumulate of the clinical consequences of severe HPP which are, most commonly, bone abnormalities following repetitive dosing. Case reports and studies, however, have also shown that symptomatic hypophosphatemia can occur after a single FCM dose. The frequency of such events remains unknown, in part due to lack of awareness of hypophosphatemia coupled with the fact that the most common acute symptoms of HPP (fatigue and weakness) are the same for IDA and for many of the chronic diseases that cause IDA. Changes to US and European prescribing information for FCM should raise awareness of the potential for HPP and need to monitor patients at risk for it.

Ferumoxytol for the treatment of iron deficiency and iron-deficiency anemia of pregnancy.

INTRODUCTION: A litany of recent evidence supports the morbidity of intra-natal iron-deficiency anemia and its prodrome, iron deficiency. Oral iron administered during second and third trimesters does not get to the developing fetus if the mother is iron deficient. This is especially concerning as the rapidly developing fetal brain is in particular need of iron sufficiency. Intra-natal iron deficiency is associated with autism, schizophrenia and abnormal brain structure. The obstetrical literature reports an unacceptably high incidence of gastrointestinal adverse events with oral iron. The time iron honored standard in the United States for intravenous iron replenishment in gravidas is iron sucrose. While safe and effective, four to seven visits are required to accomplish what newer formulations can achieve with one. METHODS: Ferumoxytol is a superparamagnetic iron oxide linked to polyglucose sorbitol carboxymethylether-binding elemental iron tightly allowing administration of complete replacement doses in 15-30 min. Herein, we report the results of 131 consecutive, non-selected, iron-deficient second- and third-trimester pregnant women who received either 510 mg of intravenous (IV) ferumoxytol twice or 1020 mg once. RESULTS: Hemoglobin and iron parameter increments were highly statistically significant. No adverse events were reported. We report how a single infusion is safe and effective as the same dose over two visits, saving an unnecessary visit and IV placement, while reducing cost. CONCLUSION: Ferumoxytol represents an efficacious and safe method of administration of IV iron which improves convenience for patients and practitioners, and is cost saving due to fewer visits. PLAIN LANGUAGE SUMMARY: One or two infusions of intravenous iron for iron deficiency or iron-deficiency anemia of pregnancy simplifies careThis study was conducted to highlight the inconvenience of multiple doses of IV iron and how administering the same dose in one or two infusions simplifies care. We report how a single infusion is as safe and effective as the same dose over two visits, saving an unnecessary visit and IV placement, while reducing cost. This study supports a growing body of evidence, to date, unreported, with ferumoxytol in pregnancy, reporting improved convenience and decreased costs with higher doses of IV iron in one or two visits.

Hypophosphatemia Associated with Intravenous Iron Therapies for Iron Deficiency Anemia: A Systematic Literature Review.

BACKGROUND: Iron deficiency anemia (IDA) is a prevalent yet underdiagnosed condition with a significant impact on quality of life. Oral iron supplementation is often poorly tolerated or yields inadequate response, requiring the use of intravenous iron (IVI) in some patients. Administration of certain IVI preparations has been associated with decreases in serum phosphate levels and clinically significant hypophosphatemia, which has been reported to lead to adverse events including serious fatigue and osteomalacia. OBJECTIVE: The purpose of this study was to systematically assess the prevalence, clinical consequences, and reporting of treatment-emergent hypophosphatemia within literature investigating IVI therapies marketed in the United States (US). METHODS: A systematic literature review (SLR) was conducted using the PubMed database to identify publications reporting serum phosphate levels or rates of hypophosphatemia within adult IDA patient populations receiving current US-marketed IVIs. RESULTS: The SLR yielded 511 unique publications, with 40 records meeting the final inclusion criteria. Most studies did not report phosphate monitoring methodology or an explicit definition of hypophosphatemia. Hypophosphatemia rates ranged from 0.0% to 92.1% for ferric carboxymaltose (FCM), 0.0% to 40.0% for iron sucrose, 0.4% for ferumoxytol, and 0.0% for low-molecular-weight (LMW) iron dextran. Randomized controlled studies described hypophosphatemia as "asymptomatic" or did not report on other associated sequelae. Eleven case reports detailed treatment-emergent hypophosphatemia in patients treated with FCM. Patients with acute hypophosphatemia primarily developed severe fatigue; those with repeated FCM dosing developed chronic hypophosphatemia associated with osteomalacia and bone deformities. CONCLUSION: Studies analyzed in this SLR reported a range of hypophosphatemia rates, with the highest consistently seen in patients treated with FCM. Across the clinical literature, there appeared to be minimal standardization of phosphate monitoring and definitions of hypophosphatemia. Although multiple cases have documented serious clinical consequences of hypophosphatemia associated with certain IVIs, current trials neither consistently nor adequately assess the frequency and severity of treatment-emergent hypophosphatemia and may underestimate its prevalence.

Health-related quality of life in patients with iron deficiency anemia: impact of treatment with intravenous iron.

Most physicians appear to be aware of the health consequences of advanced anemia, especially in the acute setting, frequently responding with a not inconsequential therapeutic default of transfusion. In contrast, the profound impact that chronic anemia, of any degree, may have on a patient's performance is underappreciated. The focus of this review is to 1) delineate the consistent and broad impact of anemia on patient quality of life as documented by multiple well-validated patient-reported outcome instruments and 2) demonstrate the essential normalization of the debilitation as assessed by these instruments following the administration of intravenous iron.

Randomized trial of intravenous iron-induced hypophosphatemia.

BACKGROUND: Hypophosphatemia can complicate intravenous iron therapy, but no head-to-head trials compared the effects of newer intravenous iron formulations on risks and mediators of hypophosphatemia. METHODS: In a randomized, double-blinded, controlled trial of adults with iron deficiency anemia from February 2016 to January 2017, we compared rates of hypophosphatemia in response to a single FDA-approved course of ferric carboxymaltose (n = 1,000) or ferumoxytol (n = 997). To investigate pathophysiological mediators of intravenous iron-induced hypophosphatemia, we nested within the parent trial a physiological substudy (ferric carboxymaltose, n = 98; ferumoxytol, n = 87) in which we measured fibroblast growth factor 23 (FGF23), calcitriol, and parathyroid hormone (PTH) at baseline and 1, 2, and 5 weeks later. RESULTS: The incidence of hypophosphatemia was significantly higher in the ferric carboxymaltose versus the ferumoxytol group (<2.0 mg/dl, 50.8% vs. 0.9%; <1.3 mg/dl, 10.0% vs. 0.0%; P < 0.001), and hypophosphatemia persisted through the end of the 5-week study period in 29.1% of ferric carboxymaltose-treated patients versus none of the ferumoxytol-treated patients (P < 0.001). Ferric carboxymaltose, but not ferumoxytol, increased circulating concentrations of biologically active FGF23 (mean within-patient percentage change from baseline to week 2 peak: +302.8 ± 326.2% vs. +10.1 ± 61.0%; P < 0.001), which was significantly associated with contemporaneous hypophosphatemia, renal phosphate wasting, and decreased serum calcitriol and calcium, and increased PTH concentrations. CONCLUSIONS: Ferric carboxymaltose rapidly increases biologically active FGF23 in patients with iron deficiency anemia. Paralleling hereditary and other acquired syndromes of hypophosphatemic rickets/osteomalacia, ferric carboxymaltose-induced FGF23 elevation triggers a pathophysiological cascade of renal phosphate wasting, calcitriol deficiency, and secondary hyperparathyroidism that frequently culminates in hypophosphatemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02694978FUNDING. AMAG Pharmaceuticals, Inc.Role of the funding source: This study was supported by AMAG Pharmaceuticals, Inc. The academic investigators designed the clinical trial, performed the analyses, and authored the manuscript with input from the coauthors from AMAG Pharmaceuticals, Inc.

Bio-informatic trends for the determination of miRNA-target interactions in mammals.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate mRNAs through a sequence-specific mechanism. By virtue of their structure and mechanism of action, computational methods have been devised to investigate the encoding of miRNA genes and the targets of miRNA action. A variety of assumptions have predicated the implementation of these various computational solutions. Evolutionary sequence conservation, secondary structure, and folding energetics are some of the assumptions that have been used. The success of these different computational solutions has been evaluated for both elucidation of new miRNAs and deducing targets of miRNA action. While the focus is on search techniques for new miRNAs, we have compared the programs miRseeker, miRScan, PalGrade, ProMiR, and miRAlign as examples of implementation of these techniques. For these programs, a benchmark comparison between theoretical estimation and actual identification is possible. We have also compared the target prediction programs TargetScanS, PicTar, DIANA-microT, miRanda, and RNAhybrid. However, it is difficult to rigorously assess the benchmark performance of these programs due to the difficulty in confirming their theoretical predictions.

Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny.

During the last decade, a variety of critical biological processes, including early embryo development, cell proliferation, differentiation, apoptosis, and metabolic regularity, have been shown to be genetically regulated by a large gene family encoding a class of tiny RNA molecules termed microRNAs (miRNAs). All miRNAs share a common biosynthetic pathway and reaction mechanisms. The sequence of many miRNAs is found to be conserved, in their mature form, among different organisms. In addition, the evolutionary appearance of multicellular organisms appears to correlate with the appearance of the miRNA pathway for regulating gene expression. The miRNA pathway has the potential to regulate vast networks of gene products in a coordinate manner. Recent evidence has not only implicated the miRNA pathway in regulating a vast array of basic cellular processes but also specialized processes that are required for cellular identity and tissue specificity. A survey of the literature shows that some miRNA pathways are conserved virtually intact throughout phylogeny while miRNA diversity also correlates with speciation. The number of miRNA genes, the expression of miRNAs, and target diversities of miRNAs tend to be positively correlated with morphological complexities observed in animals. Thus, organismal complexity can be estimated by the complexity of the miRNA circuitry. The complexity of the miRNA gene families establishes a link between genotypic complexity and phenotypic complexity in animal evolution. In this paper, we start with the discussion of miRNA conservation. Then we interpret the trends in miRNA conservation to deduce miRNA evolutionary trends in metazoans. Based on these conservation patterns observed in each component of the miRNA regulatory system, we attempt to propose a global insight on the probable consistency between morphological evolution in animals and the molecular evolution of miRNA gene activity in the cell.

The next 20 years: how customer and workforce attitudes will evolve.

Business projects with very long time horizons--such as those involving product R&D, workplace design, and total compensation planning--have to contend with a crucial question: What will be the needs, demands, and desires of consumers and employees decades from now? If you think the answer is "Just more of the same," you're in for a surprise. Howe and Strauss, the authors of Generations, The Fourth Turning, Millennials Rising, and other books, have studied the differences among generations for some 30 years. Their extensive research has revealed a fascinating pattern--one so strong that it supports a measure of predictability. On the basis of historical precedent, they say, we can foresee how the generations that are alive today will think and act in decades to come. Three of those generations will still be vital forces in American society 20 years from now: Boomers, Generation X, and Millennials. Their attitudes and behaviors will have profound effects on the economy, the workplace, and social institutions in general. For example, as aging Boomers eschew high-tech medicine in favor of holistic self-care, natural foods, and mind-body healing techniques, some hospitals are opening new wings featuring alternative medicine and spiritual counseling. Gen Xers, having grown up in an era of failing schools and marriages, will remain alienated, disaffected, and pragmatic as they enter midlife. Already the greatest entrepreneurial generation in U.S. history, they will be highly effective at pushing innovation, efficiency, and mass customization. In contrast, young adult Millennials will favor teamwork, close family relationships, job security, and a bland popular culture. Their unprecedented digital empowerment and talent for organizing will create a political powerhouse and may even revitalize the union movement.

Cost-effectiveness analysis of intravenous ferumoxytol for the treatment of iron deficiency anemia in adult patients with non-dialysis-dependent chronic kidney disease in the USA.

OBJECTIVE: Ferumoxytol has demonstrated superior efficacy compared with oral iron in treating iron deficiency anemia in chronic kidney disease (CKD) patients. However, an economic evaluation of ferumoxytol has not been conducted. The aim of this study was to analyze the cost-effectiveness of treating iron deficiency anemia in adult non-dialysis-dependent CKD patients with ferumoxytol as compared with oral iron, alone or in combination with erythropoietin-stimulating agents (ESAs). METHODS: A decision analytic model compared health outcomes and costs associated with 5-week outpatient treatment of adult non-dialysis-dependent CKD patients with ferumoxytol or oral iron, each as monotherapy or in combination with ESAs in the USA. Direct costs include the following: drug acquisition and administration, adverse events, and medical management. Efficacy was determined as mean increase in hemoglobin (g/dL) from baseline over the 5-week period. Clinical inputs were derived from patient-level data from two Phase III randomized controlled trials of ferumoxytol vs. oral iron in non-dialysis-dependent CKD patients, and cost inputs from RED BOOK™ and Centers for Medicare and Medicaid Services data. Sensitivity analyses were performed to identify cost drivers and assess the stability of results. RESULTS: The 5-week treatment cost was $2,489, $5,216, $1,298, and $4,263 per patient for ferumoxytol, ferumoxytol with ESAs, oral iron, and oral iron with ESAs, respectively. The corresponding incremental costs per g/dL increase in hemoglobin, relative to ferumoxytol alone, were $398, $3,558, and $4,768 per patient. Efficacy was the main driver of cost-effectiveness for all treatments. Adverse event and medical management costs were the principal drivers of oral iron monotherapy costs, while drug acquisition substantially contributed to the overall cost for the remaining treatments. CONCLUSION: These results suggest that ferumoxytol is a cost-effective treatment for iron deficiency anemia in non-dialysis-dependent CKD patients over a 5-week period compared with oral iron with or without ESAs. Ferumoxytol is more cost-effective as monotherapy.