Social Decision-Making Analysis: A General Approach to Inform Decisions on Resources in the Public Sector.

OBJECTIVES: Public expenditure aims to achieve social objectives by improving a range of socially valuable attributes of benefit (arguments in a social welfare function). Public expenditure is typically allocated to public sector budgets, where budget holders are tasked with meeting a subset of social objectives. METHODS: Decision makers require an evidence-based assessment of whether a proposed investment is likely to be worthwhile given existing levels of public expenditure. However, others also require some assessment of whether the overall level and allocation of public expenditure are appropriate. This article proposes a more general theoretical framework for economic evaluation that addresses both these questions. RESULTS: Using a stylized example of the economic evaluation of a new intervention in a simplified UK context, we show that this more general framework can support decisions beyond the approval or rejection of single projects. It shows that broader considerations about the level and allocation of public expenditure are possible and necessary when evaluating specific investments, which requires evidence of the range of benefits offered by marginal changes in different types of public expenditure and normative choices of how the attributes of benefit gained and forgone are valued. CONCLUSIONS: The proposed framework shows how to assess the value of a proposed investment and whether and how the overall level of public expenditure and its allocation across public sector budgets might be changed. It highlights that cost-benefit analysis and cost-effectiveness analysis can be viewed as special cases of this framework, identifying the weakness with each.

Impact of prevention in primary care on costs in primary and secondary care for people with serious mental illness.

A largely unexplored part of the financial incentive for physicians to participate in preventive care is the degree to which they are the residual claimant from any resulting cost savings. We examine the impact of two preventive activities for people with serious mental illness (care plans and annual reviews of physical health) by English primary care practices on costs in these practices and in secondary care. Using panel two-part models to analyze patient-level data linked across primary and secondary care, we find that these preventive activities in the previous year are associated with cost reductions in the current quarter both in primary and secondary care. We estimate that there are large beneficial externalities for which the primary care physician is not the residual claimant: the cost savings in secondary care are 4.7 times larger than the cost savings in primary care. These activities are incentivized in the English National Health Service but the total financial incentives for primary care physicians to participate were considerably smaller than the total cost savings produced. This suggests that changes to the design of incentives to increase the marginal reward for conducting these preventive activities among patients with serious mental illness could have further increased welfare.

Investigating the relationship between social care supply and healthcare utilization by older people in England.

Since 2010, adult social care spending in England has fallen significantly in real terms whilst demand has risen. Reductions in social care supply may also have impacted demand for NHS services, particularly for those whose care is provided at the interface of the health and care systems. We analyzed a panel dataset of 150 local authorities (councils) to test potential impacts on hospital utilization by people aged 65 and over: emergency admission rates for falls and hip fractures ("front-door" measures); and extended stays of 7 days or longer; and 21 days or longer ("back-door" measures). Changes in social care supply were assessed in two ways: gross current expenditure (per capita 65 and over) adjusted by local labor costs and social care workforce (per capita 18 and over). We ran negative binomial models, controlling for deprivation, ethnicity, age, unpaid care, council class, and year effects. To account for potential endogeneity, we ran instrumental variable regressions and dynamic panel models. Sensitivity analysis explored potential effects of funding for integrated care (the Better Care Fund). There was no consistent evidence that councils with higher per capita spend or higher social care staffing rates had lower hospital admission rates or shorter hospital stays.

Plan, recruit, retain: a framework for local healthcare organizations to achieve a stable remote rural workforce.

BACKGROUND: Recruiting and retaining a skilled health workforce is a common challenge for remote and rural communities worldwide, negatively impacting access to services, and in turn peoples' health. The research literature highlights different factors facilitating or hindering recruitment and retention of healthcare workers to remote and rural areas; however, there are few practical tools to guide local healthcare organizations in their recruitment and retention struggles. The purpose of this paper is to describe the development process, the contents, and the suggested use of The Framework for Remote Rural Workforce Stability. The Framework is a strategy designed for rural and remote healthcare organizations to ensure the recruitment and retention of vital healthcare personnel. METHOD: The Framework is the result of a 7-year, five-country (Sweden, Norway, Canada, Iceland, and Scotland) international collaboration combining literature reviews, practical experience, and national case studies in two different projects. RESULT: The Framework consists of nine key strategic elements, grouped into three main tasks (plan, recruit, retain). Plan: activities to ensure that the population's needs are periodically assessed, that the right service model is in place, and that the right recruits are targeted. Recruit: activities to ensure that the right recruits and their families have the information and support needed to relocate and integrate in the local community. Retain: activities to support team cohesion, train current and future professionals for rural and remote health careers, and assure the attractiveness of these careers. Five conditions for success are recognition of unique issues; targeted investment; a regular cycle of activities involving key agencies; monitoring, evaluating, and adjusting; and active community participation. CONCLUSION: The Framework can be implemented in any local context as a holistic, integrated set of interventions. It is also possible to implement selected components among the nine strategic elements in order to gain recruitment and/or retention improvements.

Analysis of the EPR spectra of transferrin: the importance of a zero-field-splitting distribution and 4th-order terms.

Multi-frequency EPR spectroscopy can provide high-level structural information on high-spin Fe3+ sites in proteins and enzymes. Unfortunately, analysis of the EPR spectra of these spin systems is hindered by the presence of broad distributions in the zero-field-splitting (ZFS) parameters, which reflect conformational heterogeneity of the iron sites. We present the analysis of EPR spectra of high-spin Fe3+ bound to human serum transferrin. We apply a method termed the grid-of-errors to extract the distributions of the individual ZFS parameters from EPR spectra recorded in the high-field limit at a microwave frequency of 275 GHz. Study of a series of transferrin variants shows that the ZFS distributions are as characteristic of the structure of a high-spin Fe3+ site as the ZFS parameters themselves. Simulations based on the extracted ZFS distributions reproduce spectra recorded at 34 GHz (Q band) and 9.7 GHz (X band), including subtle variations that were previously difficult to quantify. The X-band spectrum of transferrin shows a characteristic double peak, which has puzzled researchers for decades. We show that the double peak is uniquely related to the term B4-3O4-3(S) in the spin Hamiltonian. Our method is generally applicable in the analysis of spectra that arise from a broad distribution of parameters.

Prospective payment systems and discretionary coding-Evidence from English mental health providers.

Reimbursement of English mental health hospitals is moving away from block contracts and towards activity and outcome-based payments. Under the new model, patients are categorised into 20 groups with similar levels of need, called clusters, to which prices may be assigned prospectively. Clinicians, who make clustering decisions, have substantial discretion and can, in principle, directly influence the level of reimbursement the hospital receives. This may create incentives for upcoding. Clinicians are supported in their allocation decision by a clinical clustering algorithm, the Mental Health Clustering Tool, which provides an external reference against which clustering behaviour can be benchmarked. The aims of this study are to investigate the degree of mismatch between predicted and actual clustering and to test whether there are systematic differences amongst providers in their clustering behaviour. We use administrative data for all mental health patients in England who were clustered for the first time during the financial year 2014/15 and estimate multinomial multilevel models of over, under, or matching clustering. Results suggest that hospitals vary systematically in their probability of mismatch but this variation is not consistently associated with observed hospital characteristics.

Effects of local authority expenditure on childhood obesity.

BACKGROUND: Under the 2013 reforms introduced by the Health and Social Care Act (2012), public health responsibilities in England were transferred from the National Health Service to local authorities (LAs). Ring-fenced grants were introduced to support the new responsibilities. The aim of our study was to test whether the level of expenditure in 2013/14 affected the prevalence of childhood obesity in 2016/17. METHODS: We used National Child Measurement Programme definitions of childhood obesity and datasets. We used LA revenue returns data to derive three measures of per capita expenditure: childhood obesity (<19); physical activity (<19) and the Children's 5-19 Public Health Programme. We ran separate negative binomial models for two age groups of children (4-5 year olds; 10-11 year olds) and conducted sensitivity analyses. RESULTS: With few exceptions, the level of spend in 2013/14 was not significantly associated with the level of childhood obesity in 2016/17. We identified some positive associations between spend on physical activity and the Children's Public Health Programme at baseline (2013/14) and the level of childhood obesity in children aged 4-5 in 2016/17, but the effect was not evident in children aged 10-11. In both age groups, LA levels of childhood obesity in 2016/17 were significantly and positively associated with obesity levels in 2013/14. As these four cohorts comprise entirely different pupils, this underlines the importance of local drivers of childhood obesity. CONCLUSIONS: Higher levels of local expenditure are unlikely to be effective in reducing childhood obesity in the short term.

Investigating the impact of primary care payments on underdiagnosis in dementia: A difference-in-differences analysis.

OBJECTIVE: In England, two primary care incentive schemes were introduced to increase dementia diagnosis rates to two-thirds of expected levels. This study assesses the effectiveness of these schemes. METHODS: We used a difference-in-differences framework to analyse the individual and collective impacts of the incentive schemes: (1) Directed Enhanced Service 18 (DES18: facilitating timely diagnosis of and support for dementia) and (2) the Dementia Identification Scheme (DIS). The dataset included 7529 English general practices, of which 7142 were active throughout the 10-year study period (April 2006 to March 2016). We controlled for a range of factors, including a contemporaneous hospital incentive scheme for dementia. Our dependent variable was the percentage of expected cases that was recorded on practice dementia registers (the "rate"). RESULTS: From March 2013 to March 2016, the mean rate rose from 51.8% to 68.6%. Both DES18 and DIS had positive and significant effects. In practices participating in the DES18 scheme, the rate increased by 1.44 percentage points more than the rate for non-participants; DIS had a larger effect, with an increase of 3.59 percentage points. These combined effects increased dementia registers nationally by an estimated 40 767 individuals. Had all practices fully participated in both schemes, the corresponding number would have been 48 685. CONCLUSION: The primary care incentive schemes appear to have been effective in closing the gap between recorded and expected prevalence of dementia, but the hospital scheme had no additional discernible effect. This study contributes additional evidence that financial incentives can motivate improved performance in primary care.

Structural basis for iron piracy by pathogenic Neisseria.

Neisseria are obligate human pathogens causing bacterial meningitis, septicaemia and gonorrhoea. Neisseria require iron for survival and can extract it directly from human transferrin for transport across the outer membrane. The transport system consists of TbpA, an integral outer membrane protein, and TbpB, a co-receptor attached to the cell surface; both proteins are potentially important vaccine and therapeutic targets. Two key questions driving Neisseria research are how human transferrin is specifically targeted, and how the bacteria liberate iron from transferrin at neutral pH. To address these questions, we solved crystal structures of the TbpA-transferrin complex and of the corresponding co-receptor TbpB. We characterized the TbpB-transferrin complex by small-angle X-ray scattering and the TbpA-TbpB-transferrin complex by electron microscopy. Our studies provide a rational basis for the specificity of TbpA for human transferrin, show how TbpA promotes iron release from transferrin, and elucidate how TbpB facilitates this process.

Directors of public health as 'a protected species': qualitative study of the changing role of public health professionals in England following the 2013 reforms.

Background: The Health and Social Care Act 2012 gave councils in England responsibility for improving the health of their populations. Public health teams were transferred from the National Health Service (NHS), accompanied by a ring-fenced public health grant. This study examines the changing role of these teams within local government. Methods: In-depth case study research was conducted within 10 heterogeneous councils. Initial interviews (n = 90) were carried out between October 2015 and March 2016, with follow-up interviews (n = 21) 12 months later. Interviewees included elected members, directors of public health (DsPH) and other local authority officers, plus representatives from NHS commissioners, the voluntary sector and Healthwatch. Results: Councils welcomed the contribution of public health professionals, but this was balanced against competing demands for financial resources and democratic leverage. DsPH-seen by some as a 'protected species'-were relying increasingly on negotiating and networking skills to fulfil their role. Both the development of the existing specialist public health workforce and recruitment to, and development of, the future workforce were uncertain. This poses both threats and opportunities. Conclusions: Currently the need for staff to retain specialist skills and maintain UKPH registration is respected. However, action is needed to address how future public health professionals operating within local government will be recruited and developed.

Erythroid cell mitochondria receive endosomal iron by a "kiss-and-run" mechanism.

In erythroid cells, more than 90% of transferrin-derived iron enters mitochondria where ferrochelatase inserts Fe2+ into protoporphyrin IX. However, the path of iron from endosomes to mitochondrial ferrochelatase remains elusive. The prevailing opinion is that, after its export from endosomes, the redox-active metal spreads into the cytosol and mysteriously finds its way into mitochondria through passive diffusion. In contrast, this study supports the hypothesis that the highly efficient transport of iron toward ferrochelatase in erythroid cells requires a direct interaction between transferrin-endosomes and mitochondria (the "kiss-and-run" hypothesis). Using a novel method (flow sub-cytometry), we analyze lysates of reticulocytes after labeling these organelles with different fluorophores. We have identified a double-labeled population definitively representing endosomes interacting with mitochondria, as demonstrated by confocal microscopy. Moreover, we conclude that this endosome-mitochondrion association is reversible, since a "chase" with unlabeled holotransferrin causes a time-dependent decrease in the size of the double-labeled population. Importantly, the dissociation of endosomes from mitochondria does not occur in the absence of holotransferrin. Additionally, mutated recombinant holotransferrin, that cannot release iron, significantly decreases the uptake of 59Fe by reticulocytes and diminishes 59Fe incorporation into heme. This suggests that endosomes, which are unable to provide iron to mitochondria, cause a "traffic jam" leading to decreased endocytosis of holotransferrin. Altogether, our results suggest that a molecular mechanism exists to coordinate the iron status of endosomal transferrin with its trafficking. Besides its contribution to the field of iron metabolism, this study provides evidence for a new intracellular trafficking pathway of organelles.

Mathematical modeling of mutant transferrin-CRM107 molecular conjugates for cancer therapy.

The transferrin (Tf) trafficking pathway is a promising mechanism for use in targeted cancer therapy due to the overexpression of transferrin receptors (TfRs) on cancerous cells. We have previously developed a mathematical model of the Tf/TfR trafficking pathway to improve the efficiency of Tf as a drug carrier. By using diphtheria toxin (DT) as a model toxin, we found that mutating the Tf protein to change its iron release rate improves cellular association and efficacy of the drug. Though this is an improvement upon using wild-type Tf as the targeting ligand, conjugated toxins like DT are unfortunately still highly cytotoxic at off-target sites. In this work, we address this hurdle in cancer research by developing a mathematical model to predict the efficacy and selectivity of Tf conjugates that use an alternative toxin. For this purpose, we have chosen to study a mutant of DT, cross-reacting material 107 (CRM107). First, we developed a mathematical model of the Tf-DT trafficking pathway by extending our Tf/TfR model to include intracellular trafficking via DT and DT receptors. Using this mathematical model, we subsequently investigated the efficacy of several conjugates in cancer cells: DT and CRM107 conjugated to wild-type Tf, as well as to our engineered mutant Tf proteins (K206E/R632A Tf and K206E/R534A Tf). We also investigated the selectivity of mutant Tf-CRM107 against non-neoplastic cells. Through the use of our mathematical model, we predicted that (i) mutant Tf-CRM107 exhibits a greater cytotoxicity than wild-type Tf-CRM107 against cancerous cells, (ii) this improvement was more drastic with CRM107 conjugates than with DT conjugates, and (iii) mutant Tf-CRM107 conjugates were selective against non-neoplastic cells. These predictions were validated with in vitro cytotoxicity experiments, demonstrating that mutant Tf-CRM107 conjugates is indeed a more suitable therapeutic agent. Validation from in vitro experiments also confirmed that such whole-cell kinetic models can be useful in cancer therapeutic design.

Variations in Performance of Mental Health Providers in the English NHS: An Analysis of the Relationship Between Readmission Rates and Length-of-Stay.

Length-of-stay (LOS) for inpatient mental health care is a major driver of variation in resource use internationally. We explore determinants of LOS in England, focusing on the impact of emergency readmission rates which can serve as a measure of the quality of care. Data for 2009/2010 and 2010/2011 are analysed using hierarchical and non-hierarchical models. Unexplained residual variation among providers is quantified using Empirical Bayes techniques. Diagnostic, treatment and patient-level demographic variables are key drivers of LOS. Higher emergency readmission rates are associated with shorter LOS. Ranking providers by residual variation reveals significant differences, suggesting some providers can improve performance.

Exploring the Fe(III) binding sites of human serum transferrin with EPR at 275 GHz.

We report 275 GHz EPR spectra of human serum transferrin. At this high microwave frequency the zero-field splitting between the magnetic sublevels of the high-spin [Formula: see text] sites can be accurately determined. We find the zero-field splitting to be a sensitive probe of the structure of the transferrin iron-binding sites. Signals arising from iron bound to the transferrin N-lobe can clearly be distinguished from signals from iron bound to the C-lobe. Moreover, our spectra show that the structure of the iron site in the N-lobe is influenced by the presence and conformation of the C-lobe. The spectra of a series of N-lobe mutants altering the second-shell interaction of Arg124 with the synergistic anion carbonate reflect conformational changes induced at the iron site.

Determinants of hospital length of stay for people with serious mental illness in England and implications for payment systems: a regression analysis.

BACKGROUND: Serious mental illness (SMI), which encompasses a set of chronic conditions such as schizophrenia, bipolar disorder and other psychoses, accounts for 3.4 m (7 %) total bed days in the English NHS. The introduction of prospective payment to reimburse hospitals makes an understanding of the key drivers of length of stay (LOS) imperative. Existing evidence, based on mainly small scale and cross-sectional studies, is mixed. Our study is the first to use large-scale national routine data to track English hospitals' LOS for patients with a main diagnosis of SMI over time to examine the patient and local area factors influencing LOS and quantify the provider level effects to draw out the implications for payment systems. METHODS: We analysed variation in LOS for all SMI admissions to English hospitals from 2006 to 2010 using Hospital Episodes Statistics (HES). We considered patients with a LOS of up to 180 days and estimated Poisson regression models with hospital fixed effects, separately for admissions with one of three main diagnoses: schizophrenia; psychotic and schizoaffective disorder; and bipolar affective disorder. We analysed the independent contribution of potential determinants of LOS including clinical and socioeconomic characteristics of the patient, access to and quality of primary care, and local area characteristics. We examined the degree of unexplained variation in provider LOS. RESULTS: Most risk factors did not have a differential effect on LOS for different diagnostic sub-groups, however we did find some heterogeneity in the effects. Shorter LOS in the pooled model was associated with co-morbid substance or alcohol misuse (4 days), and personality disorder (8 days). Longer LOS was associated with older age (up to 19 days), black ethnicity (4 days), and formal detention (16 days). Gender was not a significant predictor. Patients who self-discharged had shorter LOS (20 days). No association was found between higher primary care quality and LOS. We found large differences between providers in unexplained variation in LOS. CONCLUSIONS: By identifying key determinants of LOS our results contribute to a better understanding of the implications of case-mix to ensure prospective payment systems reflect accurately the resource use within sub-groups of patients with SMI.

UNDERSTANDING VARIATIONS IN RELATIVE EFFECTIVENESS: A HEALTH PRODUCTION APPROACH.

BACKGROUND: Relative effectiveness has become a key concern of health policy. In Europe, this is because of the need for early information to guide reimbursement and funding decisions about new medical technologies. However, ways that effectiveness (does it work?) and efficacy (can it work?) might differ across health systems are poorly understood. METHODS: This study proposes an analytical framework, drawing on production function theory, to systematically identify and quantify the determinants of relative effectiveness and sources of variation between populations and healthcare systems. We consider how methods such as stochastic frontier analysis and data envelopment analysis using a Malmquist productivity index could in principle be used to generate evidence on, and improve understanding about, the sources of variation in relative effectiveness between countries and over time. RESULTS: Better evidence on factors driving relative effectiveness could: inform decisions on how to best use a new technology to maximum effectiveness; establish the need if any for follow-up post-launch studies, and provide evidence of the impact of new health technologies on outcomes in different healthcare systems. CONCLUSIONS: The health production function approach for assessment of relative effectiveness is complementary to traditional experimental and observational studies, focusing on identifying, collecting, and analyzing data at the national level, enabling comparisons to take place. There is a strong case for exploring the use of this approach to better understand the impact of new medicines and devices for improvements in health outcomes.

RELATIVE EFFECTIVENESS IN BREAST CANCER TREATMENT: A HEALTH PRODUCTION APPROACH.

BACKGROUND: Pharmaceuticals' relative effectiveness has come to the fore in the policy arena, reflecting the need to understand how relative efficacy (what can work) translates into added benefit in routine clinical use (what does work). European payers and licensing authorities assess value for money and post-launch benefit-risk profiles, and efforts to standardize assessments of relative effectiveness across the European Union (EU) are under way. However, the ways that relative effectiveness differs across EU healthcare settings are poorly understood. METHODS: To understand which factors influence differences in relative effectiveness, we developed an analytical framework that treats the healthcare system as a health production function. Using evidence on breast cancer from England, Spain, and Sweden as a case study, we investigated the reasons why the relative effectiveness of a new drug might vary across healthcare systems. Evidence was identified from a literature review and national clinical guidance. RESULTS: The review included thirteen international studies and thirty country-specific studies. Cross-country differences in population age structure, deprivation, and educational attainment were consistently associated with variation in outcomes. Screening intensity appeared to drive differences in survival, although the impact on mortality was unclear. CONCLUSIONS: The way efficacy translates into relative effectiveness across health systems is likely to be influenced by a range of complex and interrelated factors. These factors could inform government and payer policy decisions on ways to optimize relative effectiveness, and help increase understanding of the potential transferability of data on relative effectiveness from one health system to another.

How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH.

Delivery of iron to cells requires binding of two iron-containing human transferrin (hTF) molecules to the specific homodimeric transferrin receptor (TFR) on the cell surface. Through receptor-mediated endocytosis involving lower pH, salt, and an unidentified chelator, iron is rapidly released from hTF within the endosome. The crystal structure of a monoferric N-lobe hTF/TFR complex (3.22-Å resolution) features two binding motifs in the N lobe and one in the C lobe of hTF. Binding of Fe(N)hTF induces global and site-specific conformational changes within the TFR ectodomain. Specifically, movements at the TFR dimer interface appear to prime the TFR to undergo pH-induced movements that alter the hTF/TFR interaction. Iron release from each lobe then occurs by distinctly different mechanisms: Binding of His349 to the TFR (strengthened by protonation at low pH) controls iron release from the C lobe, whereas displacement of one N-lobe binding motif, in concert with the action of the dilysine trigger, elicits iron release from the N lobe. One binding motif in each lobe remains attached to the same α-helix in the TFR throughout the endocytic cycle. Collectively, the structure elucidates how the TFR accelerates iron release from the C lobe, slows it from the N lobe, and stabilizes binding of apohTF for return to the cell surface. Importantly, this structure provides new targets for mutagenesis studies to further understand and define this system.

Measuring the overall performance of mental healthcare providers.

To date there have been no attempts to construct composite measures of healthcare provider performance which reflect preferences for health and non-health benefits, as well as costs. Health and non-health benefits matter to patients, healthcare providers and the general public. We develop a novel provider performance measurement framework that combines health gain, non-health benefit, and cost and illustrate it with an application to 54 English mental health providers. We apply estimates from a discrete choice experiment eliciting the UK general population's valuation of non-health benefits relative to health gains, to administrative and patient survey data for years 2013-2015 to calculate equivalent health benefit (eHB) for providers. We measure costs as forgone health and quantify the relative performance of providers in terms of equivalent net health benefit (eNHB): the value of the health and non-health benefits minus the forgone benefit equivalent of cost. We compare rankings of providers by eHB, eNHB, and by the rankings produced by the hospital sector regulator. We find that taking account of the non-health benefits in the eNHB measure makes a substantial difference to the evaluation of provider performance. Our study demonstrates that the provider performance evaluation space can be extended beyond measures of health gain and cost, and that this matters for comparison of providers.

Human serum transferrin: is there a link among autism, high oxalate levels, and iron deficiency anemia?

It has been previously suggested that large amounts of oxalate in plasma could play a role in autism by binding to the bilobal iron transport protein transferrin (hTF), thereby interfering with iron metabolism by inhibiting the delivery of iron to cells. By examining the effect of the substitution of oxalate for the physiologically utilized synergistic carbonate anion in each lobe of hTF, we sought to provide a molecular basis for or against such a role. Our work clearly shows both qualitatively (6 M urea gels) and quantitatively (kinetic analysis by stopped-flow spectrofluorimetry) that the presence of oxalate in place of carbonate in each binding site of hTF does indeed greatly interfere with the removal of iron from each lobe (in the absence and presence of the specific hTF receptor). However, we also clearly demonstrate that once the iron is bound within each lobe of hTF, neither anion can displace the other. Additionally, as verified by urea gels and electrospray mass spectrometry, formation of completely homogeneous hTF-anion complexes requires that all iron must first be removed and hTF then reloaded with iron in the presence of either carbonate or oxalate. Significantly, experiments described here show that carbonate is the preferred binding partner; i.e., even if an equal amount of each anion is available during the iron loading process, the hTF-carbonate complex is formed.