Representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering therapies in Type 2 diabetes.

AIMS: Our aim was to investigate the proportional representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering drugs or strategies in Type 2 diabetes, noting that these are among the most significant pieces of evidence used to formulate the guidelines on which clinical practice is largely based. METHODS: We searched for cardiovascular outcome trials in Type 2 diabetes published before January 2015, and extracted data on the ethnicity of participants. These were compared against expected values for proportional representation of South Asian individuals, based on population data from the USA, from the UK, and globally. RESULTS: Twelve studies met our inclusion criteria and, of these, eight presented a sufficiently detailed breakdown of participant ethnicity to permit numerical analysis. In general, people of South Asian origin were found to be under-represented in trials compared with UK and global expectations and over-represented compared with US expectations. Among the eight trials for which South Asian representation could be reliably estimated, seven under-represented this group relative to the 11.2% of the UK diabetes population estimated to be South Asian, with the representation in these trials ranging from 0.0% to 10.0%. CONCLUSIONS: Clinicians should exercise caution when generalizing the results of trials to their own practice, with regard to the ethnicity of individuals. Efforts should be made to improve reporting of ethnicity and improve diversity in trial recruitment, although we acknowledge that there are challenges that must be overcome to make this a reality.

Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

The impact of COVID-19 on the mental health of radiography staff and managers in Northern Ireland, UK: The radiography managers' perspective.

INTRODUCTION: Increasing evidence suggests that the COVID-19 pandemic has influenced the mental health of health professionals, including radiographers. Less is known about the effect of the pandemic on the mental health of radiography managers. Radiography managers have led their teams through the pandemic, making unpopular decisions to safeguard staff and patients. This study explores radiography managers' perceptions regarding the impact of the COVID-19 pandemic on the mental health of themselves and their staff. METHODS: Ethical approval was obtained from the NHS Research Ethics Committee (ID 287032). Eleven interviews were conducted with therapeutic and diagnostic radiography managers between March-April 2021. Written information was also included from a paediatric diagnostic radiography manager. Data was analysed independently by 2 researchers using thematic analysis. RESULTS: Three central themes emerged: 1) Factors perceived to have negatively influenced mental health, which included changing PPE guidance, restructuring of work conditions, social isolation, challenges to patient care and lack of quality vacation leave. 2) Factors perceived to have positively influenced mental health, which included witnessing staff resilience and team camaraderie. 3) Support provided for mental health. CONCLUSION: Managers felt that they had implemented appropriate strategies to support their staff throughout the first year of the pandemic and expressed feeling responsible for the wellbeing of their staff. Strong empathy was evident towards staff and their experiences. Despite the availability of mental health support services, managers felt that resources were underutilised by radiography teams. IMPLICATIONS FOR PRACTICE: Managers should be proactive in communicating their appreciation for their staff in an era where remote working can add to disconnect between staff and management. Mental health support services should be promoted and continually reviewed, to ensure that appropriate support services are maintained.

Impact of COVID-19 on service delivery in radiology and radiotherapy.

INTRODUCTION: The COVID-19 pandemic has had a profound impact on radiography services globally. The reshaping of service delivery continues to impact patient management and the experience of the radiography workforce should be evaluated to determine how effective service delivery can be maintained in the ongoing and post-pandemic world. METHODS: A mixed methods approach was adopted. Questionnaires, designed using Qualtrics (Qualtrics, Provo, UT) online survey software, were used to survey radiographers throughout Northern Ireland (NI). Semi-structured interviews were conducted with radiography service managers in the NHS and private sector in NI. All interviews were digitally recorded, transcribed and coded independently by 2 researchers. RESULTS: A total of 106 Radiographers completed the online survey i.e. 82 Diagnostic and 24 Therapeutic. Variations were reported regarding staff concern for contracting COVID-19 and passing it on. Clinical workload was reported to fluctuate during the early period of the pandemic, however, both diagnostic and therapeutic radiographers reported workloads which were higher than normal at the time of the data collection. Nine service managers participated in the interviews plus two band 8 superintendent radiographers. Staff faced many challenges whilst delivering services due to COVID-19. The two most frequently cited challenges included issues related to (i) Implementation of PPE and (ii) Changes to work practices. CONCLUSION: A pre-prepared pandemic plan should be established and stress tested for the future. The plan should be devised in consultation with both the public and private sector to determine the very best use of resources. IMPLICATIONS FOR PRACTICE: The radiography workforce has worked continuously throughout the pandemic and needs to be supported to deal with the potential increase in demand for services in the post-pandemic world.

The lessons learned working in diagnostic and therapeutic radiography departments through the COVID-19 pandemic in Northern Ireland, UK. What can we do differently the next time?

INTRODUCTION: Following the emergence of the COVID-19 pandemic in January 2020, a radical restructure of NHS services occurred, prioritising the acute needs of infected patients. This included suspending routine procedures, leading to an inevitable resurgence in the future, placing increased demands on the NHS, including diagnostic and therapeutic radiographers. With radiography departments already experiencing staff shortages due to COVID-19 related illnesses and vulnerable staff shielding, there is a need to implement plans within radiography departments to ensure their sustainability in the future. METHODS: A mixed methods study was undertaken in Northern Ireland, involving distribution of a survey to diagnostic and therapeutic radiographers alongside conducting interviews with radiography department managers. RESULTS: 106 radiographers completed the survey, with 9 radiography managers and 2 band eight superintendents participating in interviews. Over 60% of participants felt that morale declined in their departments, with the majority feeling that the pandemic had a negative impact on their physical or mental health and wellbeing. Managers felt that to improve staff morale and motivation, incentives need to be offered including remuneration, flexible working and support for professional development. CONCLUSION: Whilst predicting when the next wave of a COVID-19 variant or the next pandemic will occur is impossible, preparation and planning will help manage the situation better. This requires identifying clinical areas for expansion/retraction and having access to additional staff to meet the demands on the service to ensure all patients receive care not just those acutely ill. IMPLICATIONS FOR PRACTICE: This study has identified key lessons learned from the pandemic within the radiography departments. This will enable preparation and strategic planning for future pandemics.

Phosphoinositide 3-kinases and membrane traffic.

Phosphoinositide 3-kinases (PI 3-kinases) and their 3-phosphoinositide products were identified initially as components of intracellular signalling pathways emanating from cell surface receptors. A new role for 3-phosphoinositides in the constitutive movement o f proteins from one intracellular compartment to another was proposed with the discovery of homology between the product of a yeast gene important for vacuolar sorting, Vps34p, and a mammalian PI 3-kinase. Recent studies have implicated PI 3-kinase as an essential component in membrane traffic at specific steps o f the trans-Golgi-network-endosomal pre-lysosomal system. Evidence largely emerging from the insulin-stimulated glucose transport system suggests that PI 3-kinase may also mediate the effects o f growth factors on membrane traffic events. These studies suggest a possible link between growth-factor-stimulated and constitutive membrane traffic in the endosomal system.

Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat.

AIMS/HYPOTHESIS: Use of the second-generation antipsychotic drugs (SGAs) results in the development of obesity and a type 2 diabetes-like syndrome. We hypothesised that, in addition to the insulin resistance associated with the obesity, the SGAs might have acute effects on glucose metabolism that could contribute to the derangements in glucose metabolism. METHODS: We investigated the effects of therapeutically relevant levels of three different antipsychotic medications (haloperidol, quetiapine and clozapine) on glucose tolerance, measures of insulin resistance and hepatic glucose production, and on insulin and glucagon secretion in rats. RESULTS: We found that these drugs induce impaired glucose tolerance in rats that is associated with increased insulin secretion (clozapine>quetiapine>haloperidol) but is independent of weight gain. However, Akt/protein kinase B activation is normal, and at these levels of drug there was no effect on insulin action in fat cells or soleus muscle, and no effect on insulin sensitivity as evaluated by insulin tolerance tests. We show that clozapine induces increased glucose levels following pyruvate and glycerol challenges, indicating an increase in hepatic glucose output (HGO). Increased HGO would in turn increase insulin release and would explain the apparent phenotype mimicking insulin resistance. We provide evidence that this effect could at least in part be mediated by a stimulation of glucagon secretion. CONCLUSIONS/INTERPRETATION: Our findings indicate that SGAs can cause acute derangements in glucose metabolism that are not caused by a direct induction of insulin resistance but act via an increase in glucagon secretion and thus stimulation of hepatic glucose production.

Successful use of National Cancer Registry data to monitor the effective use of imatinib for treating chronic myeloid leukaemia.

UNLABELLED: Imatinib is a tyrosine kinase inhibitor, which selectively antagonises the BCR-ABL molecular pathway which causes chronic myeloid leukaemia (CML). Imatinib was first approved by the Scottish Medicines Consortium (SMC) in January 2002 with the recommendation that its use be audited. The cost of the drug has major financial implications for health resources. METHODS: All imatinib usage since its first prescription in Scotland in September 2000 to July 2003 was audited through pharmacy records and through the Scotland Leukaemia Registry (SLR), an existing national registry of patients with CML. RESULTS: One hundred and four patients in Chronic Phase (CP), 36 in Accelerated Phase (AP) and five in Blast Phase (BP) received imatinib. The median duration of therapy was not reached for CFP 17 months for AFP and two months for BP patients. Major (complete) cytogenetic response rates were 74% (63%) and 38% (24%) respectively for CP and APR Overall survival for all CP patients from the start of imatinib therapy was 94% at one year, 91% at two years and 83% at three years. An audit of the effectiveness of the SLR as an auditing agency, showed complete registration in 95% of cases. CONCLUSIONS: We believe such data collection should be an important ongoing resource for assessing outcomes in a rare form of leukaemia but one which already has major implications for health economics and will continue to do so given the future development of dual tyrosine kinase inhibitors for imatinib resistant cases.

TRUFU: Therapeutic radiographer undertaking follow up for prostate cancer patients.

INTRODUCTION: A study was proposed to examine the impact to patients and the Oncology review team, of extending the role of the Therapeutic Radiographer to undertake follow up review of prostate cancer patients who have completed a radical course of external beam radiotherapy treatment. METHOD: A total of 30 patients attending for routine radiotherapy follow up were included in an observational study. Patients were assigned for review with a Doctor or a Therapeutic Radiographer using 1:1 randomisation and a number of time points were recorded and analysed. RESULTS: Of the 44 patients screened, 30 patients were recruited. Average time from scheduled appointment time to departure from clinic was 36 min for both the doctor and Therapeutic Radiographer. The average length of Consultation was 19 min for the Therapeutic Radiographer and 10 min for the Doctor. Average length of wait for patients from scheduled appointment time to being taken for review was 17 min for the Therapeutic Radiographer and 25 min for the Doctor. Of the patients who completed questionnaires, 23/28 had no preference of reviewer, 2/28 declared a preference to be seen by a doctor, whilst 3/28 stated a preference for review with a Therapeutic Radiographer. CONCLUSION: The results of the study are encouraging and should be further investigated in an attempt of developing what would be a very rewarding aspect of the Therapeutic Radiographers role.

Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways.

Leptin is produced in adipose tissue and acts in the hypothalamus to regulate food intake. However, recent evidence also indicates a potential for direct roles for leptin in peripheral tissues, including those of the immune system. In this study, we provide direct evidence that macrophages are a target tissue for leptin. We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin. Leptin also stimulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine phosphorylation of JAK2 and STAT3 in these cells. We investigated the effects of leptin on hormone-sensitive lipase (HSL), which acts as a neutral cholesterol esterase in macrophages and is a rate-limiting step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macrophages, and these effects were additive with the effects of cAMP and were blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase. These results indicate that leptin and insulin regulate cholesterol-ester homeostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidence of atherosclerosis found associated with obesity and type 2 diabetes.

Human small intestine facilitative fructose/glucose transporter (GLUT5) is also present in insulin-responsive tissues and brain. Investigation of biochemical characteristics and translocation.

A recent study by C.F. Burant et al. (13) demonstrates that GLUT5 is a high-affinity fructose transporter with a much lower capacity to transport glucose. To characterize the potential role of GLUT5 in fructose and glucose transport in insulin-sensitive tissues, we investigated the distribution and insulin-stimulated translocation of the GLUT5 protein in human tissues by immunoblotting with an antibody to the COOH-terminus of the human GLUT5 sequence. GLUT5 was detected in postnuclear membranes from the small intestine, kidney, heart, four different skeletal muscle groups, and the brain, and in plasma membranes from adipocytes. Cytochalasin-B photolabeled a 53,000-M(r) protein in small intestine membranes that was immunoprecipitated by the GLUT5 antibody; labeling was inhibited by D- but not L-glucose. N-glycanase treatment resulted in a band of 45,000 M(r) in all tissues. Plasma membranes were prepared from isolated adipocytes from 5 nonobese and 4 obese subjects. Incubation of adipocytes from either group with 7 nM insulin did not recruit GLUT5 to the plasma membrane, in spite of a 54% insulin-stimulated increase in GLUT4 in nonobese subjects. Thus, GLUT5 appears to be a constitutive sugar transporter that is expressed in many tissues. Further studies are needed to define its overall contribution to fructose and glucose transport in insulin-responsive tissues and brain.

Insulin-like growth factors require phosphatidylinositol 3-kinase to signal myogenesis: dominant negative p85 expression blocks differentiation of L6E9 muscle cells.

Phosphatidylinositol 3 (PI 3)-kinases are potently inhibited by two structurally unrelated membrane-permeant reagents: wortmannin and LY294002. By using these two inhibitors we first suggested the involvement of a PI 3-kinase activity in muscle cell differentiation. However, several reports have described that these compounds are not as selective for PI 3-kinase activity as assumed. Here we show that LY294002 blocks the myogenic pathway elicited by insulin-like growth factors (IGFs), and we confirm the specific involvement of PI 3-kinase in IGF-induced myogenesis by overexpressing in L6E9 myoblasts a dominant negative p85 PI 3-kinase-regulatory subunit (L6E9-delta p85). IGF-I, des(1-3)IGF-I, or IGF-II induced L6E9 skeletal muscle cell differentiation as measured by myotube formation, myogenin gene expression, and GLUT4 glucose carrier induction. The addition of LY294002 to the differentiation medium totally inhibited these IGF-induced myogenic events without altering the expression of a non-muscle-specific protein, beta1-integrin. Independent clones of L6E9 myoblasts expressing a dominant negative mutant of the p85-regulatory subunit (delta p85) showed markedly impaired glucose transport activity and formation of p85/p110 complexes in response to insulin, consistent with the inhibition of PI 3-kinase activity. IGF-induced myogenic parameters in L6E9-delta p85 cells, ie. cell fusion and myogenin gene and GLUT4 expression, were severely impaired compared with parental cells or L6E9 cells expressing wild-type p85. In all, data presented here indicate that PI 3-kinase is essential for IGF-induced muscle differentiation and that the specific PI 3-kinase subclass involved in myogenesis is the heterodimeric p85-p110 enzyme.

High level overexpression of glucose transporter-4 driven by an adipose-specific promoter is maintained in transgenic mice on a high fat diet, but does not prevent impaired glucose tolerance.

High fat feeding is associated with impaired insulin action, an obese body composition, and down-regulation of glucose transporter-4 (GLUT4) expression in adipocytes. We recently showed that overexpression of GLUT4 selectively in adipocytes of transgenic mice using the aP2 (fatty acid-binding protein) promoter/enhancer results in enhanced glucose tolerance and adipocyte hyperplasia. Here, we fed these GLUT4-overexpressing transgenic mice a high fat (55%) or a low fat (10%) diet for 13-15 weeks to determine the role of alterations in GLUT4 expression in adipocytes in the development of insulin resistance and obesity, which are characteristic of high fat consumption. In nontransgenic mice, high fat feeding results in 45-50% reduction of GLUT4 levels in white and brown adipose tissue, with a parallel decrease in insulin-stimulated glucose transport. In transgenic mice receiving the low fat diet, GLUT4 is overexpressed 20-fold in white and 4-fold in brown adipose tissue. Glucose transport in epididymal adipocytes is increased 20-fold in the basal state and 6-fold in the insulin-stimulated state. Even after transgenic mice are fed a high fat diet, GLUT4 expression and glucose transport in their adipocytes remains 14- to 30-fold greater than that in nontransgenic mice receiving the same diet. Despite these marked effects at the adipose cell level, glucose tolerance is not improved, probably due to insulin resistance in skeletal muscle and liver, where the transgene is not expressed. During the low fat diet, transgenic mice have 80% more body lipid than nontransgenics. High fat feeding increases body lipid 76% and adipocyte size 65% in nontransgenic mice, but has no effect in transgenic mice. Thus, overexpression of GLUT4 selectively in adipocytes protects against a further increase in adiposity. Furthermore, by using a heterologous promoter, high level overexpression of GLUT4 can be maintained even under metabolic conditions where it is normally down-regulated in adipocytes. This overexpression results in markedly increased glucose transport at the cellular level, but adipose-specific GLUT4 overexpression does not prevent the decrease in glucose tolerance associated with high fat feeding.

The alpha-isoform of class II phosphoinositide 3-kinase is more effectively activated by insulin receptors than IGF receptors, and activation requires receptor NPEY motifs.

Little is known about the physiological role and mechanism of activation of class II phosphoinositide 3-kinases (PI3Ks), although it has been shown that the PI3K-C2alpha isoform is activated by insulin. Using chimaeric receptor constructs which can be activated independently of endogenous receptors in transfected cells, we found that PI3K-C2alpha activity was stimulated to a greater extent by insulin receptors than IGF receptors in 3T3-L1 adipocytes. Activation of PI3K-C2alpha required an intact NPEY motif in the receptor juxtamembrane domain. We conclude that PI3K-C2alpha is a candidate for participation in insulin-specific intracellular signalling.

The use of [125I]C1q subcomponent for the measurement of complement binding antibodies on cell surfaces.

An assay using 125I-labelled human C1q has been developed for the measurement of complement fixing antibodies bound to cell monolayers or cell suspensions. The method has been adapted for use either during or after sensitisation of the cells with antiserum, is simple to perform and does not require require prelabelling of the target cells.

Selective screening device for the early detection of normal or delayed cognitive development in infants at risk for later mental retardation.

The present study tested the predictive validity at 3 years of age of a screening device for the early identification of later cognitive delay. The screening device, administered between 3 and 7 months of age, is based on the infant's differential fixation "to novel" over previously shown pictures. The sample was composed of 62 infants suspected to be at risk for later mental retardation. The prevalence of delayed cognitive development (IQ less than or equal to 70) at 3 years of age was 13%. Novelty preference scores correctly identified six of eight (75%) of the delayed children. The test identified 49 of 54 (91%) of the normal children. Validity for predicting cognitive delay was 55%. Validity for the prediction of normality was 96%. The screening device proved to be equally sensitive, specific, and valid when the sample was divided into infants born at term or born preterm. The results of the present study and of a previous study indicate that detection of cognitive delay based on early novelty preferences is as easily accomplished for infants who will later be mildly delayed (IQ scores 60 to 70) as it is for those who will later be severely delayed (IQ scores less than or equal to 50). Moreover, such results are in contrast to those obtained with conventional tests tapping sensorimotor development.

Monoclonal antibodies that recognize the native human thyrotropin receptor.

Monoclonal antibodies have been produced that recognize the native human thyrotropin receptor by using a sensitive screening protocol based on flow cytofluorimetry combined with recombinant eukaryotic cells expressing high levels of the full-length functional receptor. The more standard screening method of ELISA preferentially selected antibodies that only reacted with the denatured receptor. Mice were immunized with recombinant receptor produced in either eukaryotic or prokaryotic systems; after screening and cloning, three stable hybridoma lines were established. An IgM antibody (7B5) produced in response to the eukaryotic material recognized only the native receptor (by flow cytofluorimetry) and did not react with denatured material on ELISA or immunoblotting, suggesting that its epitope is conformational. In contrast, two IgG1 antibodies (2C11 and 3B12) produced in response to the prokaryotic material recognized both native and denatured receptor (by flow cytofluorimetry, immunoprecipitation and immunoblotting). The use of different recombinant constructs in the immunoblotting procedure allowed the epitopes for both the IgG1 antibodies to be assigned to the region 125-369. None of the antibodies stimulated production of cAMP by recombinant cells expressing the full-length functional receptor, but one of the IgG1 antibodies (2C11) did inhibit binding of radiolabelled thyrotropin to these same cells. These antibodies, and others that can now be produced with this screening protocol, will help define the relationship between structure and function of this important receptor.

Identification of an important thyrotrophin binding site on the human thyrotrophin receptor using monoclonal antibodies.

A thyrotrophin (TSH) binding site has been identified on the extracellular domain of the human thyrotrophin receptor (hTSHR) using monoclonal antibodies that recognise the native hTSHR. These antibodies were produced by immunising BALB/c mice with denatured recombinant material, selected by their reaction with recombinant hTSHR expressed on heterologous cell lines using flow cytofluorimetric analysis, and characterised by immunoblotting and immunoprecipitation. The epitopes the monoclonal antibodies recognise were determined using multiple overlapping synthetic peptides. All of the antibodies reacted with epitopes within the region 335-390; these epitopes must be accessible on the external surface of the native hTSHR. None of the antibodies stimulated cAMP production of recombinant hTSHR cell lines. The epitopes of two antibodies (residues 337-342 and 355-358) are in the small peptide thought to be removed by proteolytic processing of hTSHR. A further five different antibodies (determined from their variable region sequences) all reacted with residues 381-384 emphasising the immunogenicity of this region. The functional importance of residues 381-384 as a TSH binding site was shown by the fact that some of these monoclonal antibodies caused inhibition of radiolabelled TSH binding of 80-90% at 1 microg/ml and greater than 50% inhibition at 0.1 microg/ml (0.65 nM--i.e. comparable in effectiveness with TSH itself). Residues 381-384 may form part of the target regions recognised by inhibitory autoantibodies found in Graves' disease.

Progress with interferon in CML--results of the MRC UK CML III study.

527 patients with CML were entered into the multicentre randomised MRC CML III study comparing IFN-alpha n1 to standard chemotherapy, either busulphan or hydroxyurea. Haematologic response to IFN as assessed by the level of control of the WCC predicted cytogenetic response to IFN. Cytogenetic response (< 80% Ph + ve) was seen in 22% of all patients randomised, 11% showing major or complete responses. Major cytogenetic response rate was 18% in Sokal low risk patients, 15% in intermediate risk patients but only 4% in high risk patients. Mantel Byar analyses allowing for time to response showed a survival advantage for cytogenetic responders compared to non-responders. In addition, cytogenetic non-responders to IFN did significantly better than chemotherapy-treated patients. Median survival for all patients was 61 months in the IFN treated groups and 41 months in the no-IFN group. For Ph + ve patients only, the median survival was 63 months compared to 43 months. Sub-group analysis comparing busulphan or hydroxyurea treatment in the IFN and no-IFN treatment arms showed a significant advantage for IFN-compared to busulphan, but no significant difference between IFN and hydroxyurea treated patients, although there was a trend favouring IFN. A proposed overview of all randomised trials comparing IFN to hydroxyurea should, by virture of larger numbers, enable a more accurate assessment of the probable benefit of IFN compared to hydroxyurea therapy.