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BACKGROUND Reports of nutritional deficiencies in patients with thalassemia (Thal) are common. Despite its importance, however, nutritionally focused research in Thal has been limited by inadequate sample size, inconsistent methodology, a lack of control comparisons, and few interventional trials. Due to these limitations, clinicians lack evidence-based nutrition recommendations to support clinical decision-making. This systematic review summarizes observed relationships between nutrition and morbidity in Thal published in the last 3 decades. METHODS PubMed, Web of Science, and Embase were screened for articles pertaining to nutrition in Thal using comprehensive search terms. Studies performed in humans, written in English, and published between 1990 and 2020 were included. Over 2100 manuscripts were identified, from which 97 were included. RESULTS Patients with Thal were most often deficient in vitamins A, C, D, selenium, and zinc. Prevalence of nutritional deficiency was positively correlated with age and iron overload. Evidence to support the role of vitamin D and zinc for bone health was observed; zinc was also found to improve glucose metabolism. CONCLUSIONS Due to the risk for multinutrient deficiency, nutritional status should be assessed annually in patients with Thal with prompt nutrient replacement when deficiency is detected. Routine supplementation with vitamin D and zinc is recommended.

Interference from metal hardware (piercings; buttons on clothing; and ingested material, e.g. barium) is well documented in bone health assessments by dual-energy X-ray absorptiometry (DXA). It is unknown if iron in hepatic tissue of highly iron-loaded patients could be mistakenly assessed by DXA as bone, and if this would lead to increased areal bone mineral density (aBMD) lumbar spine Z-scores derived by DXA. Our hypothesis is that iron in the liver of heavily loaded patients will artificially raise aBMD in the spine, and thereby lead to an error in the DXA scan. This study consisted of a retrospective chart review and re-analysis of DXA scans from patients with sickle cell disease and thalassemia combined with prospective DXA and liver iron concentration (LIC) measurements from healthy controls. Patients who previously had both a DXA and LIC measurement were compared with controls. aBMD of individual vertebrae were analyzed and grouped by those that may be covered by the liver (L1 or L1/2) with those typically not (L3/4). Subjects were grouped by diagnosis and LIC severity. Phantoms were created to mimic the geometry of iron loaded liver tissue, and analyzed by DXA. A significant effect was observed in the difference of BMD Z-score of L1 and L 3/ 4 when patients with LIC < 1000 were compared to those with >5000 µg Fe/g wet tissue (p = 0.043). A significant relationship was also observed in the difference in aBMD Z-score of L1 and 3/4 when controls were compared to the high iron group (p = 0.037). These findings were supported by phantom experiments. These results suggest that there is a relationship between hepatic iron and increased L1 aBMD Z-scores in highly iron-loaded patients. Given patients with hemoglobinopathies are at increased risk for osteoporosis, clinicians should maintain a higher index of suspicion when diagnosing low bone mass.

BACKGROUND Nutritional deficiencies in children with cancer at time of diagnosis and during treatment may negatively affect disease outcome and increase treatment-related toxicity. Yet zinc, an essential nutrient important for supporting immune function and known for reducing diarrheal episodes, is rarely assessed in these children. PROCEDURES Fifty children (1 month to 18 years) with recently diagnosed cancer were enrolled in this study. An age and gender matched control group (n = 50) was also recruited. Plasma and urinary zinc, plasma copper, and C-reactive protein (CRP) levels were measured at baseline, 3, and 6 months following diagnosis. A retrospective review of the toxicity profile was performed in the cohort of children with cancer for the first 4 years after initial diagnosis. RESULTS CRP and plasma copper (both acute-phase reactants) were elevated in patients with cancer compared to controls at baseline, both p

Background Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. Methods This 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. Results The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. Conclusions Laronidase seemed to improve growth in participants

BACKGROUND: An association between increasing anaesthetic depth and decreased postoperative survival has been shown in observational studies; however, evidence from randomised controlled trials is lacking. Our aim was to compare all-cause 1-year mortality in older patients having major surgery and randomly assigned to light or deep general anaesthesia.METHODS: In an international trial, we recruited patients from 73 centres in seven countries who were aged 60 years and older, with significant comorbidity, having surgery with expected duration of more than 2 h, and an anticipated hospital stay of at least 2 days. We randomly assigned patients who had increased risk of complications after major surgery to receive light general anaesthesia (bispectral index [BIS] target 50) or deep general anaesthesia (BIS target 35). Anaesthetists also nominated an appropriate range for mean arterial pressure for each patient during surgery. Patients were randomly assigned in permuted blocks by region immediately before surgery, with the patient and assessors masked to group allocation. The primary outcome was 1-year all-cause mortality. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000632897, and is closed to accrual.FINDINGS: Patients were enrolled between Dec 19, 2012, and Dec 12, 2017. Of the 18 026 patients screened as eligible, 6644 were enrolled, randomly assigned to treatment or control, and formed the intention-to-treat population (3316 in the BIS 50 group and 3328 in the BIS 35 group). The median BIS was 47·2 (IQR 43·7 to 50·5) in the BIS 50 group and 38·8 (36·3 to 42·4) in the BIS 35 group. Mean arterial pressure was 3·5 mm Hg (4%) higher (median 84·5 [IQR 78·0 to 91·3] and 81·0 [75·4 to 87·6], respectively) and volatile anaesthetic use was 0·26 minimum alveolar concentration (30%) lower (0·62 [0·52 to 0·73] and 0·88 [0·74 to 1·04], respectively) in the BIS 50 than the BIS 35 group. 1-year mortality was 6·5% (212 patients) in the BIS 50 group and 7·2% (238 patients) in the BIS 35 group (hazard ratio 0·88, 95% CI 0·73 to 1·07, absolute risk reduction 0·8%, 95% CI -0·5 to 2·0). Grade 3 adverse events occurred in 954 (29%) patients in the BIS 50 group and 909 (27%) patients in the BIS 35 group; and grade 4 adverse events in 265 (8%) and 259 (8%) patients, respectively. The most commonly reported adverse events were infections, vascular disorders, cardiac disorders, and neoplasms.INTERPRETATION: Among patients at increased risk of complications after major surgery, light general anaesthesia was not associated with lower 1-year mortality than deep general anaesthesia. Our trial defines a broad range of anaesthetic depth over which anaesthesia may be safely delivered when titrating volatile anaesthetic concentrations using a processed electroencephalographic monitor.FUNDING: Health Research Council of New Zealand; National Health and Medical Research Council, Australia; Research Grant Council of Hong Kong; National Institute for Health and Research, UK; and National Institutes of Health, USA.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 μg/mmol during vaso-occlusive crises to 2.62 μg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

Nutrition is increasingly being seen by care providers as important for patients with thalassemia. However, the definition of optimal nutritional support and the means to provide that support remain elusive. This review focuses on the relationships between nutritional status and three common comorbidities in patients with thalassemia: low bone mass, growth deficiency, and diabetes. The association between low bone mass and specific nutrient deficiencies (e.g., vitamin D, zinc) is clear, while the role of nutritional adequacy for young patients with growth deficiencies requires careful analysis to distinguish it from chronic anemia and endocrine insufficiency. Correction of isolated nutritional deficiencies in small cohorts of patients with thalassemia has shown some promise at improving both bone health and linear growth in the short term. However, the long-term safety and acceptability of these practices need to be evaluated. On the whole, there are few well-designed, adequately powered studies of the role of general dietary or specific micronutrients in the cause, treatment, or prevention of these commonly observed morbidities in thalassemia. Until these data are gathered, it is suggested that patients with thalassemia be monitored frequently and that their nutritional deficiencies be corrected when observed in order to advance their overall health and quality of life.

Background: Patients with Thal (Thalassemia) are presumed to be inactive for many of the same reasons as healthy adults, though there are limited published data to support this claim. The primary aim of this study was to compare physical activity patterns in subjects with Thal to healthy controls as well as to explore the effects of transfusion therapy on physical activity in transfusion dependent patients with Thal. Methods: 37 Thal (23 Thal major, 14 Thal intermedia, 21 Female, 27.3±10.1 years) and 30 healthy controls (17 Female, 28.0 ± 13.7 years) wore an ActiGraph accelerometer for one to two weeks. Results: Thal subjects recorded a significantly fewer total number of steps per day and lower total energy expenditure compared to healthy controls (p=0.001). None of the adult Thal subjects met the recommended 10,000 steps/day as opposed to 27% of healthy adult controls (p=0.004). Thal spent significantly less time in moderate (p=0.03) to vigorous (p=0.005) activities and more time in sedentary activity (p=0.006). Conclusion: It is now clear that Thal spend significantly less time in physically demanding activities than age-matched healthy controls, a result that has long been assumed though not previously documented. Further research is needed to define an appropriate physical activity regimen best suited for patients with Thal while examining its effect on mental and physical health. J O U R N A L O F H E M A T O L O G Y A N D O N C O L O G Y R E S E A R C H ISSN NO: 2372-6601 Research DOI : 10.14302/issn.2372-6601.jhor-15-776 Corresponding author Ellen B. Fung, PhD RD CCD, Department of Hematology, UCSF Benioff Children's Hospital, Oakland, 747 52 Street, Oakland, CA 94609, Phone: 510-428-3885 x 4939, Fax: 510-450-5877 , efung@mail.cho.org

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children's Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency.

BackgroundLow calcium intake during pregnancy may cause maternal skeletal calcium mobilization to meet fetal needs. The Recommended Dietary Allowance (RDA) for calcium in nonpregnant, pregnant, or lactating women aged 19-50 y is 1000 mg/d; most women in the United States report consuming 60-80% of the calcium RDA. An insufficient calcium intake could increase maternal bone loss during pregnancy and reduce bone recovery postpartum.ObjectivesThe aim of this study was to determine the effect of maternal calcium supplementation on peripheral cortical and trabecular bone loss during pregnancy and bone gain postpartum.MethodsA total of 64 women were enrolled in the study at 16 wk of gestation and randomly assigned to receive 1000 mg Ca/d or placebo for the remainder of the pregnancy. Measurements were performed at 16, 26, and 36 wk of pregnancy and at 4 and 12 mo postpartum for serum 25-hydroxyvitamin D and markers of bone turnover. Trabecular and cortical bone mineral density (BMD) and content were assessed at the tibia and radius by peripheral quantitative computed tomography.ResultsMean±SD daily calcium intake at baseline was 733±350 mg; only 25% of the women met the RDA. Thirty women (47% of those enrolled) remained in the study at 12 mo postpartum. After controlling for baseline bone value, serum 25-hydroxyvitamin D concentrations, length of breastfeeding, and body mass index, the calcium group had significantly greater increases in radial total BMD (P=0.02) and tibial cortical BMD (P=0.03) at 12 mo postpartum than the placebo group. Trabecular and total BMD at the tibia trended toward higher values (P&nbsp

Patients with thalassemia are frequently deficient in key micronutrients. Attempts to correct these inadequacies through nutritional supplementation have been met with some success, although disparities between intake and circulating levels continue to be observed. This study employed a convenience sample of 41 well-nourished transfusion dependent patients with thalassemia to identify possible mechanisms behind nutritional deficiencies. Each subject completed a Block 2005© Food Frequency Questionnaire (FFQ), through which macro and micronutrient intake was quantified. Fasting blood was drawn to assess vitamins A, C, D, E, copper, selenium, zinc and hematologic parameters. Dietary intake was found to be inadequate compared to Institute of Medicine (IOM) recommendations for many of the fat-soluble vitamins, as well as calcium and zinc. Circulating deficiencies of vitamins C, D, copper, zinc and γ tocopherol were also present in over 20% of patients. Many individuals who consumed an adequate dietary intake had deficient levels of circulating nutrients, which suggest alternative etiologies of nutrient excretion or loss, in addition to higher micronutrient requirements. Liver iron concentration displayed a significant negative relationship with vitamins C (r=-0.62, p

Transfusion-independent patients with thalassemia intermedia (TI) develop fatal iron overload from excessive iron absorption triggered by ineffective erythropoiesis. More information about iron pharmacokinetics and nonheme, dietary iron absorption in such patients is needed to optimize management. To obtain more information, different forms of supplemental nonheme iron sources (ferritin and ferrous sulfate) were compared in 4 TI (hemoglobin Abbreviations: CRP C-reactive protein; Hb hemoglobin; IDA iron-deficient anemia; ICP inductively coupled plasma; IE ineffective erythropoiesis; SCD sickle cell disease; sTf transferrin saturation; TI thalassemia intermedia; TIBC total iron binding capacity; TM thalassemia major; Tf transferrin

Background: Skeletal and joint disease persists and slowly worsens in individuals with mucopolysaccharidosis type I (MPS I) despite treatment with hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT). Surrogate biomarkers are crucial for efficient testing of the effects of new and adjunctive therapies on bones and joints in MPS I. Methods: As part of a 9-year observational study of individuals with MPS I, hip, and spine radiographs, and range-of-motion (ROM) were measured annually in years 7-9 and height in years 1-9. Fasting morning plasma and urine samples of inflammatory and bone biomarkers were measured by ELISAs in years 1 and 2. A novel summary score for skeletal disease (i.e. hip and spine radiographs and height Z-score standardized by age and sex) and joint disease (i.e. ROM in shoulders, elbows, and knees) were calculated. Linear regression, adjusting for age, was used to test for associations of change in biomarkers over the first year with the annualized change in summary bone and ROM score, and height Z-score over years 7-9 and 1-9 respectively. Sensitivity analyses removed biomarkers greater than 3 standard deviations from the mean. Results: The cohort included eighteen participants (MPS IH N=14, MPS IA N=4), age 5-16 years, who were 6.7±3.0 years since HCT (MPS IH) or 7.1±2.8 years since ERT initiation (MPS IA). Sensitivity analysis showed an association between increasing interleukin-6 and more rapid worsening of ROM (-31 pg/ml: 95%CI -45 to -18 pg/ml p Conclusions: We have identified two potential candidate surrogate biomarkers of change in skeletal or joint disease over time. Once validated, these biomarkers may prove useful in determining early efficacy of skeletal or joint directed therapies in MPS I.

Purpose Low magnitude mechanical stimulation (LMMS) has been used successfully to promote bone formation in certain patient populations. This study evaluated the feasibility and effectiveness of LMMS on improving bone mineral density (BMD) in patients with Rett syndrome. Methods A 12-month crossover pilot study design of 6 months of intervention with LMMS and 6 months without was studied in 14 subjects divided in two subgroups. BMD was assessed using Dual Energy X-ray Absorptiometry (DXA). The levels of 25-hydroxy vitamin D (25OHD), Parathyroid Hormone (PTH), Insulin-Like Growth Factor 1 (IGF-1), and circulating markers of bone resorption (NTx) were analyzed in blood samples. Health questionnaires and diet logs were obtained at 0, 6, and 12 months. Results Of the 11 subjects who completed the protocol, 9 had an adherence of > 65% and showed an increase in spine BMD Z-scores from the intervention (Z: -2.51) compared to non-intervention period (Z: -2.27) of 0.23 SD (p=0.048). Following intervention, favorable trends were also observed for IGF-1 (p=0.06) and right distal femur BMD Z-scores (p=0.07). Conclusions These preliminary results are promising for a larger, placebo-controlled randomized study of subjects with Rett syndrome.

Osteoporosis has been described in animal models of mucopolysaccharidosis (MPS). Whether clinically significant osteoporosis is common among children with MPS is unknown. Therefore, cross-sectional data from whole body (WB; excluding head) and lumbar spine (LS) bone mineral density (BMD) compared with sex-, chronologic age–, and ethnicity-matched healthy individuals (Zage), height-for-age (HAZ) Z-score (ZHAZ) and bone mineral content (BMC) measured by dual-energy X-ray absorptiometry (DXA) in 40 children with MPS were analyzed. A subset of these children (n = 24) was matched 1:3 by age and sex to a group of healthy children (n = 72) for comparison of BMC adjusted for Tanner stage, race, lean body mass, height, and bone area. Low BMD Z-score was defined as Z-score of −2 or less. In children with MPS, 15% had low WB Zage and 48% had low LS Zage; 0% and 6% had low WB ZHAZ and low LS ZHAZ, respectively. Adjusted WB BMC was lower in MPS participants (p = 0.009). In conclusion, children with MPS had deficits in WB BMC after adjustments for stature and bone area. HAZ adjustment underestimated bone deficits (i.e., overestimated WB BMD Z-scores) in children with MPS likely owing to their abnormal bone shape. The influence of severe short stature and bone geometry on DXA measurements must be considered in children with MPS to avoid unnecessary exposure to antiresorptive treatments.

PURPOSE: Skeletal disease causes significant morbidity in mucopolysaccharidoses (MPS), and bone remodeling processes in MPS have not been well characterized. The objective of this study was to determine if biomarkers of bone turnover are abnormal in children with specific MPS disorders (i.e. MSP-I, MPS-II, and MPS-VI) compared to healthy children. METHODS: A cross-sectional study was performed of serum biomarkers of bone formation (bone-specific alkaline phosphatase [BSAP], osteocalcin) and urine biomarkers of bone resorption (pyridinoline, deoxypyridinoline) in MPS and healthy controls. Measures of physical function and pain were obtained using the Children’s Health Questionnaire (CHQ). RESULTS: The cohort consisted of 39 children with MPS (MPS-I = 26; MPS-II = 11; MPS-VI = 4) and 51 healthy children. Adjusting for sex and Tanner stage group, MPS individuals had statistically significant increases for osteocalcin ( p< 0.001), with trends toward higher BSAP (p = 0.054) and urinary pyridinoline (p = 0.084). These biomarkers were not significantly associated with CHQ bodily pain and physical-function scores. CONCLUSION: Osteocalcin was increased in children with MPS disorders, with trends for increases in BSAP and urinary pyridinoline, suggesting that bone remodeling is altered in children with MPS. Future studies to assess the ability of these biomarkers to quantify and monitor MPS skeletal disease in response to therapy are needed.

Ganglion cysts are soft tissue swellings occurring most commonly in the hand or wrist. Apart from swelling, most cysts are asymptomatic. Other symptoms include pain, weakness, or paraesthesia. The two main concerns patients have are the cosmetic appearance of the cysts and the fear of future malignant growth. It has been shown that 58% of cysts will resolve spontaneously over time. Treatment can be either conservative or through surgical excision. This review concluded that nonsurgical treatment is largely ineffective in treating ganglion cysts. However, it advised to patients who do not surgical treatment but would like symptomatic relief. Compared to surgery, which has a lower recurrence rate but have a higher complication rate with longer recovery period. It has been shown that surgical interventions do not provide better symptomatic relief compared to conservative treatment. If symptomatic relief is the patient’s primary concern, a conservative approach is preferred, whilst surgical intervention will decrease the likelihood of recurrence.

This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from β-thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase-3/7, 48% higher caspase-8 and 88% higher caspase-9 activities and 428% more nucleosomal DNA fragmentation than control subjects. Only neutrophils correlated significantly with apoptotic markers. Previously, we showed that over the treatment year, hepatic iron declined; we now show that the ratio of Bax/Bcl-2 (BCL2), (-27·3%/year), and caspase-9 activity (-13·3%/year) declined in both treatment groups, suggesting that chelation decreases body iron and indicators of PBL apoptosis.

Boceprevir is a protease inhibitor indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in combination with peginterferon and ribavirin for treatment-naive patients and those who previously failed to improve with interferon and ribavirin treatment.This article provides an overview of the mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of boceprevir.Relevant information was identified through a search of PubMed (1990-July 2012), EMBASE (1990-July 2012), International Pharmaceutical Abstracts (1970-July 2012), and Google Scholar using the key words boceprevir, SCH 503034, non-structural protein 3 (NS3) serine protease inhibitor, and direct-acting antiviral agent (DAA). Additional information was obtained from the US Food and Drug Administration's Web site, review of the reference lists of identified articles, and posters and abstracts from scientific meetings.Clinical efficacy of boceprevir was assessed in 2 Phase III trials, Serine Protease Inhibitor Therapy-2 (SPRINT-2) for treatment-naive patients and Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 (RESPOND-2) for treatment-experienced patients. In SPRINT-2, patients were randomized to receive peginterferon + ribavirin (PR) or peginterferon + ribavirin + boceprevir (PRB); duration of boceprevir therapy varied from 24, 32, to 44 weeks on the basis of HCV RNA results. The primary endpoint was achievement of sustained virologic response (SVR; lower limit of detection, 9.3 IU/mL). The addition of boceprevir was shown to be superior, with overall SVR rates ranging from 63% to 66% compared with 38% with PR (P0.001). Results of SVR in SPRINT-2 were also reorganized to monitor SVRs in black and non-black patients. Treatment-experienced patients were assessed in RESPOND-2; however, null responders were excluded. Patients were again randomized to PR or PRB; duration of boceprevir therapy varied from 32 to 44 weeks on the basis of HCV RNA results. SVR was significantly higher in patients receiving boceprevir (59%-66% vs 21% with PR; P0.001). This benefit was seen in both previous nonresponders (SVR, 40%-52% vs 7% with PR), as well as previous relapsers (SVR, 69%-75% vs 29% with PR). Importantly, SVR could be attained with a shortened course of therapy in almost one half of all treated patients in SPRINT-2 (44%) and RESPOND-2 (46%).Boceprevir was well tolerated in clinical trials and a welcomed addition to our HCV armamentarium.

Patients with thalassemia (Thal) have low bone mass which can lead to fracture and decreased quality of life. There are no noninvasive anabolic therapies available to improve bone health in Thal. A longitudinal cross-over pilot trial was conducted to evaluate the effectiveness of low magnitude whole body vibration (WBV) therapy on bone in 18 patients with Thal (9 adults, 10 male, 22.1 ± 10.7 years). Subjects were asked to stand on a vibrating platform (30 Hz, 0.3 g) for 20 min/day for 6 months. Areal bone mineral density (aBMD) by DXA and volumetric BMD by peripheral quantitative computed tomography (pQCT) was assessed at baseline, 6 and 12 months. Adherence in the first 3 months was greater when compared with the second 3 months (14 ± 6 vs. 10 ± 7 min/day, P=0.007). Intention to treat analysis revealed a significant increase in whole body BMC (2.6%; P = 0.021), BMC/Ht (2.6%, P = 0.02) and aBMD (1.3%; P = 0.036), as well as a net increase in serum markers of bone formation (Osteocalcin/CTx, P = 0.027) in the adult subjects. These preliminary findings suggest that vibration therapy may be an effective nonpharmacologic intervention in Thal. Future research is needed to confirm these findings in a larger sample for longer duration.

Compromised vitamin D status is common in pregnancy and may have adverse impacts on fetal development. The purpose of this study was to investigate the association of infant whole-body bone mineral content (WBBMC) at 8–21 days of age with feto-maternal vitamin D status in a multiethnic population in Oakland, California. This was a cross-sectional study of 120 women and their newborn infants. Maternal and cord blood were collected at delivery. WBBMC was measured by dual-energy X-ray absorptiometry in term-born infants 8–21days post birth. No significant association was observed between unadjusted or size-adjusted WBBMC and feto-maternal vitamin D status analyzed continuously or categorically. In multivariate modeling, unadjusted WBBMC was predicted by bone area (P

Patients with thalassemia have low circulating levels of many nutrients, but the contribution of dietary intake has not been assessed.Our objective was to assess dietary intake in a large contemporary sample of subjects with thalassemia.A prospective, longitudinal cohort study using a validated food frequency questionnaire was conducted.Two hundred and twenty-one subjects (19.7±11.3 years, 106 were female) were categorized into the following age groups: young children (3 to 7.9 years), older children/adolescents (8 to 18.9 years), and adults (19 years or older); 78.8% had β-thalassemia and 90% were chronically transfused. This study took place at 10 hematology outpatient clinics in the United States and Canada.We conducted a comparison of intake with US Dietary Reference Intakes and correlated dietary intake of vitamin D with serum 25-OH vitamin D and dietary iron with total body iron stores.Intake was defined as inadequate if it was less than the estimated average requirement. χ(2), Fisher's exact, and Student's t test were used to compare intake between age categories and logistic regression analysis to test the relationship between intake and outcomes, controlling for age, sex, and race.More than 30% of subjects consumed inadequate levels of vitamin A, D, E, K, folate, calcium, and magnesium. The only nutrients for which90% of subjects consumed adequate amounts were riboflavin, vitamin B-12, and selenium. Dietary inadequacy increased with increasing age group (P0.01) for vitamins A, C, E, B-6, folate, thiamin, calcium, magnesium, and zinc. More than half of the sample took additional supplements of calcium and vitamin D, although circulating levels of 25-OH vitamin D remained insufficient in 61% of subjects. Dietary iron intake was not related to total body iron stores.Subjects with thalassemia have reduced intake of many key nutrients. These preliminary findings of dietary inadequacy are concerning and support the need for nutritional monitoring to determine which subjects are at greatest risk for nutritional deficiency. Future research should focus on the effect of dietary quality and nutritional status on health outcomes in thalassemia.

BACKGROUND Bone mineral content (BMC) and density (BMD) have been shown to diminish after fracture and immobilization in adults. Distal radius fractures are common in children, and unlike adults, there is a low incidence of refracture. The primary aim of this study was to assess the change in radial BMC and BMD after upper extremity fracture and casting in healthy pediatric patients. METHODS Patients were recruited at the time of distal radius fractures casting. The nonfractured (non-Fx) distal radius was initially scanned by dual energy x-ray absorptiometry (baseline), and then both arms were scanned at the time of cast removal (CastOff), and 4, 8, 12, 24, and 52 weeks post CastOff. RESULTS Twenty-one patients were enrolled (13 male, 13 Caucasian; 10.4±2.5 y) with an average length of casting of 38±11 days. Eighteen patients (86%) completed all protocol requirements. At CastOff, there was no significant difference in total BMC or BMD between the Fx and non-Fx arms. From CastOff to 24 weeks, the overall change in BMC and BMD for the non-Fx arm was +4.2% and +0.2%, respectively, whereas for the Fx arm, the change was +8.3% and +3.4%, respectively. By 24 weeks, the difference in the overall change in BMD between the Fx and non-Fx arms was statistically significant (greater than instrumental error; P

Background Tranexamic acid reduces blood loss and transfusion requirements in cardiac surgery but may increase the risk of coronary graft thrombosis. We previously reported the 30-day results of a trial evaluating tranexamic acid for coronary artery surgery. Here we report the 1-year clinical outcomes. Methods Using a factorial design, we randomly assigned patients undergoing coronary artery surgery to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary 1-year outcome was death or severe disability, the latter defined as living with a modified Katz activities of daily living score of less than 8. Secondary outcomes included a composite of myocardial infarction, stroke, and death from any cause through to 1 year after surgery. Results The rate of death or disability at 1 year was 3.8% in the tranexamic acid group and 4.4% in the placebo group (relative risk, 0.85; 95% confidence interval, 0.64-1.13; P = .27), and this did not significantly differ according to aspirin exposure at the time of surgery (interaction P = .073). The composite rate of myocardial infarction, stroke, and death up to 1 year after surgery was 14.3% in the tranexamic acid group and 16.4% in the placebo group (relative risk, 0.87; 95% CI, 0.76-1.00; P = .053). Conclusions In this trial of patients having coronary artery surgery, tranexamic acid did not affect death or severe disability through to 1 year after surgery. Further work should be done to explore possible beneficial effects on late cardiovascular events.

Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary β(2) -microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.

Introduction Vaso-occlusive crises (VOCs), the most common acutely painful complication of sickle cell disease (SCD), presumably cause bone infarction. In a preclinical study that exposed sickle cell mice to repeated hypoxia-reperfusion stress-to recapitulate VOCs-the mice over-expressed osteoclast-driven bone resorption markers and suppressed osteoblast-mediated bone formation markers. We hypothesize that bone infarction stems from ongoing hemolysis and inflammation incurred during VOCs, and that the extent of bone degradation can be approximated by increases in concentrations of bone resorption markers in the plasma or urine of adults with SCD. We measured urinary levels of cross-linked carboxyterminal telopeptide (CTX-1, a bone resorption marker) in 52 adults with SCD, both during and after resolution of VOCs. We now report on the association between urinary CTX-1 concentrations and serum markers of hemolysis and inflammation. Methods In the Sickle Cell Pain Markers (SCPM) study, adults with SCD were consecutively recruited from Tulane University Sickle Cell Center of Southern Louisiana (2008-2013). Blood and urine specimens were collected for laboratory analyses and symptoms assessed during vaso-occlusive pain crises (visit 1) and at recovery (visit 2). Self-reported symptoms were graded on a 0-10 scale (0=no symptoms, 10=worst symptoms). We restricted our analyses to subjects with complete data obtained at both visits. Three study participants were re-enrolled in SCPM, but only one subject completed data collection and was included in this analysis. We used paired t-tests and non-parametric Wilcoxon sign rank test to assess for between-visit differences in continuous variables and Fisher's exact test to monitor changes in categorical variables. Urinary CTX-1 concentrations, corrected for urine creatinine levels, were measured using enzyme-linked immunosorbent assays performed by the Research Laboratory Services, a core facility of Maine Medical Center Research Institute, Scarborough, ME. We then compared between-visit changes in urinary CTX-1 levels with changes in serum/plasma markers of hemolysis (hemoglobin, total bilirubin, lactate dehydrogenase and reticulocyte counts) and inflammation (white blood cell count, platelets, fibrinogen, C-reactive protein and erythrocyte sedimentation rates). All data were analyzed using R 3.5.1 software, and results presented in standard box plots, with slopes and 95% confidence intervals (CI). Results Of the 52 adults enrolled in the SCPM study (62% female, 65% hemoglobin SS/ Sb-thalassemia, 35% hemoglobin SC), we analyzed paired data from 31 subjects (60%). The average duration between visits 1 and 2 was 22 days. Mean concentrations of urinary CTX-1-corrected for urine creatinine-significantly decreased from 3.43±1.95 μg/mmol during vaso-occlusive crises to 2.62±1.34 μg/mmol at recovery (Figure). We found a non-significant positive correlation between changes in urinary CTX-1 levels and days between visits (slope 0.048, 95% CI -0.025, 0.121, p-value 0.184). The correlations between changes in urinary CTX-1 concentration and serum/plasma markers of hemolysis and inflammation were not statistically significant. Secondary analyses of all laboratory markers showed significant increases in serum levels of hemoglobin and platelets between visits 1 and 2 (p Conclusions VOCs accelerate bone degradation in adults with SCD. CTX-1 has low intra-individual variability and can reliably approximate the extent of bone resorption that occur during pain crises. The small sample size (n=31 pairs) likely limited our ability to detect a significant association between changes in urinary CTX-1 concentrations and changes in serum/plasma markers of hemolysis and inflammation. Additional studies are required to better understand how CTX-1 concentrations-relative to bone formation markers e.g., bone-specific alkaline phosphatase-can be used to monitor immediate and long-term deleterious effects of recurrent VOCs on the bones of adults with SCD. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Background: Skin and soft tissue infections (SSTIs) have become the second most common type of infection among persons residing in long-term care facilities. Objective: The purpose of this article was to review the latest information on SSTIs among the elderly, including age-related changes, challenges, and treatment strategies in the era of emerging bacterial resistance. Methods: Relevant information was identified through a search of MEDLINE (1970—April 2010), International Pharmaceutical Abstracts (1970—April 2010), and Google Scholar using the terms skin and soft tissue infection, skin and skin structure infection, cellulitis, treatment guidelines , and elderly . Additional publications were found by searching the reference lists of the identified articles. Trials published since 1970 were selected for this review if they prospectively evaluated mostly adults (≥18 years of age), included >50 patients, and reported diagnostic criteria as well as clinical outcomes in patients treated for simple or complicated SSTIs. Results: Fifty-eight of 664 identified studies were selected and included in this review. A search of the literature did not identify any prospective clinical trials that were conducted exclusively in the elderly. Information on the treatment of SSTIs in the elderly was based solely on clinical studies that were conducted in adults in general. As recommended by the Infectious Diseases Society of America (IDSA) 2008 update, SSTIs should be suspected in elderly patients who have skin lesions and present with a decline in functional status, with or without fever. Patients who present with symptoms of systemic toxicity should be hospitalized for further evaluation. Current challenges in the management of SSTIs include the rapid emergence of community-acquired, methicillin-resistant Staphylococcus aureus (CA—MRSA), the emergence of macrolide-resistant streptococci within the past decade, and the lack of a reliable algorithm to differentiate potentially life-threatening SSTIs that require aggressive interventions and prompt hospitalization from those that can be managed in an outpatient setting. S aureus was the most common cause of SSTIs, being isolated in 42.8% (5015/11,723) of wounds, followed by streptococci. Common SSTIs in the elderly such as shingles, diabetic foot infections, infected pressure ulcers, and scabies, and their treatment were also discussed. Based on reviews of published trials, treatment of simple SSTIs generally consisted of administration of agents with activity against S aureus and Streptococcus species such as a penicillinase-resistant β-lactam, a first-generation cephalosporin, or clindamycin. Broadening of the antimicrobial spectrum to include gram-negative and anaerobic organisms should be implemented for complicated SSTIs such as diabetic foot infections and infected pressure ulcers. Local rates of MRSA, CA—MRSA, and macrolide-resistant streptococci should be considered when selecting empiric therapy. Conclusions: A search of the literature did not identify any prospective clinical trials on the treatment of SSTIs in the elderly; therefore, it is recommended to follow treatment based on the current IDSA guidelines. More research and publications are needed to establish proper selection of antimicrobial agents, treatment strategies, and duration of therapy of SSTIs in the elderly population.

Optimal nutritional status is imperative for growth, development, immune function, and bone health. Patients with thalassemia are known to have poor growth, altered puberty, and immune function as well as reduced bone mineral acquisition. The etiology of these comorbidites is typically ascribed to the toxic effects of transfusion-related iron-overload. Recently, our group and others have observed marked nutritional deficiencies in key fat and water-soluble vitamins as well as important essential minerals. Depressed circulating levels of nutrients have been observed despite seemingly adequate dietary intake. This disconnect between intake and circulating levels suggests that patients with thalassemia may have increased needs for certain nutrients due to either poor nutrient absorption, elevated losses, or increased nutrient turnover. Randomized controlled clinical trials are needed to test the efficacy of nutritional therapies toward improving the overall health in thalassemia, as well as decreasing long-term comorbidities such as reduced bone mass.

Enzyme replacement therapy has been successful in alleviating morbidity and improving endurance in Mucopolysaccharidosis (MPS) type I, II, and VI, however little attention has been paid to the effects on bone mineralization. Brief case reports in MPS type III and IV suggest that bone mineral density (BMD) is diminished, but did not account for patient size. In this report, BMD was evaluated by quantitative computed tomography and by dual-energy x-ray absorptiometry (DXA) in separate studies involving 10 patients with MPS type VI (7 Female; 7.0 to 21.0 y) and 4 male patients with MPS II (8.1 to 35.5 y). Vitamin D intake met the current RDA (200 IU) for most, though 25-OH vitamin D was insufficient (< 30 ng/mL) in 87.5% of patients tested. Ht Z-score was low -5.8 +/- 3.6, with height deficits greatest in MPS VI. Spine and whole body BMD Z-scores by DXA were considered normal for chronological age in all MPS II, and after correction for Ht Z-score, in all but one subject with MPS VI. These results suggest that vitamin D insufficiency is quite common in MPS. BMD by DXA is within normal range for most, particularly after correction for short stature. A review of bone health assessment is provided as well as a discussion of these results.

Summary This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23·2 years (range 6·1–75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = −0·73 ± 1·24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12·8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.

Adults with beta thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, > or =6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1-75 yr), were studied. Spine and femur BMD Z-scores < -2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.

Plasma C-reactive protein (CRP) is an inflammatory biomarker that predicts cardiovascular disease. Lowering elevated CRP with statins has reduced the incidence of cardiovascular disease. We investigated whether vitamin C or E could reduce CRP. Healthy nonsmokers (N=396) were randomized to three groups, 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Median baseline CRP was low, 0.85 mg/L. No treatment effect was seen when all participants were included. However, a significant interaction was found, indicating that treatment effect depends on baseline CRP concentration. Among participants with CRP indicative of elevated cardiovascular risk (or =1.0 mg/L), vitamin C reduced the median CRP by 25.3% vs placebo (p=0.02) (median reduction in the vitamin C group, 0.25 mg/L, 16.7%). These effects are similar to those of statins. The vitamin E effect was not significant. In summary, treatment with vitamin C but not vitamin E significantly reduced CRP among individuals with CRPor =1.0 mg/L. Among the obese, 75% had CRPor =1.0 mg/L. Research is needed to determine whether reducing this inflammatory biomarker with vitamin C could reduce diseases associated with obesity. But research on clinical benefits of antioxidants should limit participants to persons with elevations in the target biomarkers.

Background:Understanding and increasing physical activity requires assessment of occupational, home, leisure and sedentary activities.Methods:A physical activity questionnaire was developed using data from a large representative U.S. sample; includes occupational, leisure and home-based domains; and produces estimates of energy expenditure, percent body fat, minutes in various domains, and meeting recommendations. It was tested in 396 persons, mean age 44 years. Estimates were evaluated in relation to percent body fat measured by dual-energy x-ray absorptiometry.Results:Median energy expenditure was 2,365 kcal (women) and 2,960 kcal (men). Women spent 35.1 minutes/day in moderate household activities, 13.0 minutes in moderate leisure and 4.0 minutes in vigorous activities. Men spent 18.0, 22.5 and 15.6 minutes/day in those activities, respectively. Men and women spent 276.4 and 257.0 minutes/day in sedentary activities. Respondents who met recommendations through vigorous activities had significantly lower percent body fat than those who did not, while meeting recommendations only through moderate activities was not associated with percent body fat. Predicted and observed percent body fat correlated at r = .73 and r = .82 for men and women respectively, P < .0001.Conclusions:This questionnaire may be useful for understanding health effects of different components of activity, and for interventions to increase activity levels.

The emergence of viral resistance is one of the greatest challenges in the treatment of HIV infection. Maraviroc is the first member of a new class of antiretroviral medications, the CCR5-receptor antagonists. It is approved by the US Food and Drug Administration (FDA) for use in combination with other antiretroviral agents in treatment-experienced patients infected with multidrug-resistant, CCR5-tropic HIV-1.This article provides an overview of the pharmacology, efficacy, and tolerability of maraviroc in the treatment of HIV-1 infection.Relevant information was identified through a search of MEDLINE (January 2000-May 2008) using the terms maraviroc, UK-427,857, and CCR5-receptor antagonist. Also consulted were abstracts from the International AIDS Society Conference, the Conference on Retroviruses and Opportunistic Infections, and other relevant scientific meetings. Additional publications were found by searching the reference lists of the identified articles and the FDA Web site.Maraviroc is a selective, reversible, small-molecule CCR5-receptor antagonist. In vitro, it has potent anti-HIV-1 activity, with a mean 90% inhibitory concentration of 2.0 nmol/L. It is widely distributed, with a V(d) of approximately 194 L. Maraviroc is moderately metabolized in the liver (65.3%), primarily via the cytochrome P450 3A4 isozyme. It has an elimination t(1/2) of 15.9 to 22.9 hours. Until more data are available, maraviroc should be avoided in patients with severe hepatic insufficiency; dose adjustment does not appear to be necessary on the basis of age, sex, or renal function. In 2 Phase IIb/III studies, maraviroc 300 mg PO QD or BID was found to be more efficacious than placebo in reducing the viral load at 48 weeks in treatment-experienced, CCR5-tropic HIV-1-infected patients receiving an optimized background regimen (difference vs placebo-QD arm: -0.89 log(10) copies/mL [97.5% CI, -1.17 to -0.62]; BID arm: -1.05 log(10) copies/mL [97.5% CI, -1.33 to -0.78]). The proportion of patients with a viral load50 copies/mL was 43.2% in the QD arm and 45.5% in the BID arm, compared with 16.7% in the placebo arm (P0.001, both treatment arms vs placebo). In treatment-naive patients infected with CCR5-tropic virus only, maraviroc 300 mg PO BID was not noninferior to oral efavirenz 600 mg QD (difference = -4.2%; lower bound of the 1-sided 97.5% CI, -10.9 [predefined statistical cutoff for noninferiority, -10]). Maraviroc was generally well tolerated in clinical trials. The most frequently reported (or = 5%) adverse events were upper respiratory tract infection (20.0%), cough (12.7%), pyrexia (12.0%), rash (9.6%), musculoskeletal complaints (8.7%), gastrointestinal and abdominal pain (8.2%), dizziness (8.2%), appetite disorders (7.3%), insomnia (7.0%), herpes infection (6.8%), sinusitis (6.3%), joint complaints (6.1%), bronchitis (5.9%), and constipation (5.4%). The recommended dose of maraviroc differs based on concomitant medications, ranging from 150 to 600 mg BID.When used in combination with other antiretroviral agents, maraviroc appears to be a promising agent for treatment-experienced patients infected with multidrug-resistant, CCR5-tropic HIV-1.

Children with sickle cell anemia (SCA) have low bone mass though bone turnover has not been well described. In this study, growth and pubertal development were assessed twice, 1 year apart, in 80 young subjects with type-SS SCA, while whole body bone mineral content (BMC) and density where measured in a subset (n = 46). Markers of bone turnover were measured at the second visit. Bone formation (alkaline phosphatase) was elevated, whereas bone resorption (deoxypyridinoline) was decreased compared to published data in healthy children. Markers of bone turnover correlated with growth velocity and pubertal development but not with changes in bone mass.

The dual-energy X-ray absorptiometry (DXA) report fulfills the role of transmitting data clearly to the referring clinician. A timely, concise, and informative report is essential to relay the DXA findings and to avoid costly and potentially dangerous misinterpretations by physicians unfamiliar with pediatric densitometry data. A comprehensive DXA report ideally includes five elements: (1) patient demographics, (2) a brief medical history, (3) test results, (4) technical comments, and (5) interpretation and occasionally recommendations. Most often the report is focused on bone densitometry components, but may also include body composition measures. The interpretation & recommendation sections remain the most controversial. Densitometry guidelines from an international panel of experts provide recommendations to guide the imaging specialist on acquisition and interpretation of pediatric scans.

Background: The incidence of invasive fungal infections (IFIs) caused by opportunistic filamentous molds is increasing, along with emerging fungal resistance. Posaconazole, a structural analogue of itraconazole that was approved for marketing in the United States in 2006, appears to be a promising antifungal agent. Objective: This article provides an overview of the pharmacology, efficacy, and tolerability of posaconazole when used for the prophylaxis and treatment of various common and rare fungal infections. Methods: Relevant information was identified through a search of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy using the terms posaconazole and SCH 56592 . Additional resources were found by searching the reference lists of the identified articles and the US Food and Drug Administration Web site. Results: Posaconazole is available as an oral suspension. It is highly distributed to various sites, including bone, the central nervous system, and eye tissue. Its Vd is 2447 L when administered in multiple daily doses (up to 800 mg/d) in the presence of a high-fat meal. Because it is excreted mostly as unchanged drug in the feces (77%), posaconazole can be administered to patients with poor renal function without any dose adjustment. Posaconazole has shown in vitro and in vivo activity against a wide variety of fungi, including those that are rare and relatively resistant. Two clinical trials have compared posaconazole with fluconazole or itraconazole for the prophylaxis of IFIs in immunocompromised patients. The first, a randomized, double-blind trial in 600 recipients of hematopoietic stem cell transplants, found that overall rates of IFI did not differ significantly between posaconazole and fluconazole (5% vs 9%, respectively). The other, a randomized, open-label trial in 602 neutropenic patients, reported significantly fewer IFIs in patients receiving posaconazole compared with those receiving fluconazole or itraconazole (>2% vs >8%, respectively; P = 0.001). An additional 2 trials have investigated posaconazole for the treatment of oropharyngeal candidiasis (OPC) in patients with HIV infection. A randomized, controlled, evaluator-blinded study in 350 HIV-infected patients with OPC found similar 14-day clinical success rates with posaconazole and fluconazole (91.7% and 92.5%, respectively; 95% CI, -6.6l to 5.04), whereas an open-label study in 176 HIV-infected patients with a history of refractory OPC reported a 28-day clinical success rate of 75%. Numerous small studies and case reports have described successful posaconazole treatment of zygomycosis, aspergillosis, fusariosis, endemic dimorphic fungal infection, and superficial and subcutaneous fungal infections that were refractory to conventional antifungal agents or in patients who were unable to tolerate these agents. Posaconazole has been well tolerated. The most common complaints have been gastrointestinal in nature, including nausea (7%-8%) and diarrhea (3%-11%), although these have rarely led to permanent discontinuation of therapy. Other common adverse effects have included vomiting (4%-7%), headache (2%-8%), and liver enzyme elevations (2%-3%). Conclusions: Posaconazole suspension administered at up to 800 mg/d is a reasonable alternative to conventional antifungal agents for the prevention and treatment of IFIs in high-risk populations. It may also be suitable in patients with infections caused by rare or relatively resistant fungi, and those who are unable to tolerate long-term therapy with other antifungal agents.

Accurate measurement of liver storage iron is important for the management of iron overload from regular red blood cell transfusion therapy. In clinical trials testing iron chelator efficacy in iron overloaded patients, with different centers involved, it is mandatory to standardize the procedures of liver iron concentration (LIC) measurements. The agreement (precision and bias) of the SQUID biosusceptometer in Oakland/USA (CHO) and Torino/Italy (TOR) was evaluated in comparison to the validated System in Hamburg/Germany (UKE). In a blinded round-robin test, liver iron concentrations were quantified within 1 month by the 3 SQUID biosusceptometer systems, in 20 patients with thalassemia, sickle cell disease or CDA type-1 and in 10 normal subjects. Mean LIC values were determined from 5 vertical scans at each of two, different positions. Prediction of LIC at CHO and TOR in comparison with UKE was excellent, with coefficients of determination between sites of R 2 = 0.97, resulting in inter-site standard deviations of 276 and 315 μg/g liver, respectively. A significant proportional underestimation of 27% was noted for the TOR system. A systematically lower skin–liver distance of 1.0 mm at the TOR site could only account for 10% of the underestimated LIC. Intra-site precision was within an acceptable range for repeated measurements in the majority of iron overloaded subjects.

A natural history study was conducted in 142 Thalassemic (Thal), 199 transfused Sickle Cell Disease (Tx-SCD, n = 199), and 64 non-Tx-SCD subjects to describe the frequency of iron-related morbidity and mortality. Subjects recruited from 31 centers in the US, Canada or the UK were similar with respect to age (overall: 25 +/- 11 years, mean +/- SD) and gender (52% female). We found that Tx-SCD subjects were hospitalized more frequently compared with Thal or non-Tx-SCD (P < 0.001). Among those hospitalized, Tx-SCD adult subjects were more likely to be unemployed compared with Thal (RR = 1.6, 95% CI 1.0-2.5) or non-Tx-SCD (RR = 3.1, 95% CI 1.3-7.3). There was a positive relationship between the severity of iron overload, assessed by serum ferritin, and the frequency of hospitalizations (r= 0.20; P = 0.009). Twenty-three deaths were reported (6 Thal, 17 Tx-SCD) in 23.5 +/- 10 months of follow-up. Within the Tx-SCD group, those who died began transfusion (25.3 vs. 12.4 years, P < 0.001) and chelation therapy later (26.8 vs. 14.2 years, P = 0.01) compared with those who survived. The unadjusted death rate in Thal was lower (2.2/100 person years) compared with that in Tx-SCD (7.0/100 person years; RR = 0.38: 95% CI 0.12-0.99). However, no difference was observed when age at death was considered. Despite improvements in therapy, death rate in this contemporary sample of transfused adult subjects with Thal or SCD is 3 times greater than the general US population. Long term follow-up of this unique cohort of subjects will be helpful in further defining the relationship of chronic, heavy iron overload to morbidity and mortality.

Chronic transfusion therapy has played a central role in extending life expectancy for patients with hemoglobinopathies such as thalassemia. However, this life-saving therapy is associated with numerous complications that now comprise the bulk of management considerations for patients with thalassemia. This review reports on the experience of the Thalassemia Longitudinal Cohort and reviews available literature to establish guidelines for the management of patients with thalassemia.

Iron-overload associated endocrinopathy is the most frequently reported complication of chronic transfusion therapy in patients with thalassaemia (Thal). This study compared iron-overloaded subjects with Thal (n = 142; 54%M; age 25.8 +/- 8.1 years) and transfused sickle-cell disease (Tx-SCD; n = 199; 43%M, 24.9 +/- 13.2 years) to non-transfused SCD subjects (non-Tx-SCD; n = 64, 50%M, 25.3 +/- 11.3 years), to explore whether the underlying haemoglobinopathy influences the development of endocrinopathy. Subjects were recruited from 31 centres in the USA, Canada and the UK. Subjects with Thal had more evidence of diabetes (13% vs. 2%, P < 0.001), hypogonadism (40% vs. 4%, P < 0.001), hypothyroidism (10% vs. 2%, P =

Blood transfusion therapy is life-saving for patients with beta-thalassaemia and sickle cell disease (SCD), but often results in severe iron overload. This pilot study examined whether the biomarkers of tissue injury or inflammation differ in these two diseases. Plasma malondialdehyde (MDA) was significantly increased 1.8-fold in thalassaemia relative to control patients. In contrast, MDA in SCD was not significantly different from controls. In multivariate analysis, the strongest predictors of elevated MDA were liver iron concentration (P < 0.001) and specific diagnosis (P = 0.019). A significant 2-fold elevation of non-transferrin bound iron (NTBI) was observed in thalassaemia relative to SCD. NTBI was not a significant predictor of high MDA in multivariate analysis. SCD patients showed a significant 2.2-fold elevation of the inflammatory marker interleukin (IL)-6 relative to controls, and a 3.6- and 1.7-fold increase in IL-5 and IL-10 relative to thalassaemia. Although alpha-tocopherol was significantly decreased by at least 32% in both thalassaemia and SCD, indicating ongoing oxidant stress and antioxidant consumption, gamma-tocopherol, a nitric oxide-selective antioxidant, was increased 36% in SCD relative to thalassaemia. These results demonstrate that thalassaemia patients have increased MDA and circulating NTBI relative to SCD patients and lower levels of some cytokines and gamma-tocopherol. This supports the hypothesis that the biology of SCD may show increased inflammation and increased levels of protective antioxidants compared with thalassaemia.

Purpose We evaluated bone mineral density (BMD) and risk factors for poor bone mineralization in children with sickle cell anemia (SCA). Patients and Methods Twenty-five children with severe manifestations of SCA (frequent hospitalizations, growth delay, or need for chronic red cell transfusions) were enrolled. Bone density was assessed at lumbar spine and proximal femur with dual-energy X-ray absorptiometry (DXA), and Z-scores were calculated by comparison with age, sex, and ethnicity-specific reference data. Results The median age of the study population was 12.8 years (10.2–19.8 years). Calcium intake was inadequate in 60%, and serum 25-hydroxy vitamin D (25-OHD) level