The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Goal Attainment Scaling for haemophilia (GAS-Hem): testing the feasibility of a new patient-centric outcome measure in people with haemophilia.

INTRODUCTION: To address the need for a patient-reported outcome that can measure clinically and personally meaningful change in people with haemophilia (PwH) on prophylaxis, an approach based on Goal Attainment Scaling (GAS) was developed: the GAS-Hem. AIM: To establish real-world feasibility of GAS-Hem in PwH. METHODS: Patients aged 5-65 years were enroled from four North American centres for a 12-week study. The primary outcome was the proportion of participants who completed GAS-Hem interviews at baseline, 6 and 12 weeks. GAS-Hem scores were obtained by subject- and clinician-rated goal attainment at Weeks 6 and 12, and compared with quality of life (QoL) measures and annualized bleed rate (ABR) for construct validity. Goals were evaluated qualitatively for content validity. Responsiveness was calculated using standardized response means (SRM). RESULTS: Forty-two participants set 63 goals. Participants preferred to define (37/63) their own goals or further individualize (23/63) from the GAS-Hem menu. Thirty of the 37 self-defined goals were matched to goals on the GAS-Hem menu. The most common goal areas were: weight, exercise and nutrition (n = 17); leisure activities (n = 8); and joint problems (n = 7). Both participant- and clinician-rated GAS-Hem scores at 6 weeks (n = 40) and 12 weeks (n = 41) demonstrated satisfactory goal attainment (SRM [subject-rated] at 12 weeks for adult and paediatric groups was 1.25 and 1.16, respectively). Correlations of GAS-Hem scores with QoL measures and ABR were uniformly small. CONCLUSION: GAS-Hem was feasible and tapped constructs not captured by ABR or QoL measures.

Impact of pain and functional impairment in US adults with haemophilia: Patient-reported outcomes and musculoskeletal evaluation in the pain, functional impairment and quality of life (P-FiQ) study.

INTRODUCTION: Standardized and disease-specific patient-reported outcome (PRO) instruments assessing pain, functional impairment and health-related quality of life (HRQoL) in people with haemophilia (PWH) have been used in studies, but infrequently in comprehensive care settings for individual assessment or treatment planning. AIM: To assess the impact of pain and functional impairment on HRQoL in PWH. METHODS: P-FiQ enrolled 381 adult PWH with a history of joint pain/bleeding and included 5 PROs and a clinical joint evaluation (Hemophilia Joint Health Score v2.1 [HJHS]). RESULTS: Median age was 34 years; 49.9% reported a history of joint procedure or surgery. On EQ-5D-5L, most reported problems with mobility (61.4%), usual activities (53.2%) and pain/discomfort (76.1%). On Brief Pain Inventory v2 Short Form, median worst pain (range 0-10) was 6, least pain 1, average pain 3 and current pain 2. Ankles were most frequently reported as the most painful joints (37.4%), followed by knees (23.7%) and elbows (18.9%). On International Physical Activity Questionnaire, 51% reported no activity in the prior week. On SF-36v2 health survey, median subscores were worse for 4 physical health domains vs 4 mental health domains. Among Hemophilia Activities List domains (range 0 [worst]-100 [best]), functions of the legs (median, 66.7) and lying/sitting/kneeling/standing (median, 67.5) were most impacted and self-care least impacted (median, 100.0). On HJHS, ankle scores (median, 6.0; range, 0-40) were worse than elbow/knee scores (median, 4.0/4.0). Results were consistent across PROs/HJHS. CONCLUSION: Data demonstrate challenges of predominantly ankle/knee pain and lower extremity functional impairment in US adult PWH, affecting HRQoL across PROs/HJHS.

Prophylaxis use among males with haemophilia B in the United States.

INTRODUCTION: Prophylaxis is considered the optimal treatment for persons with moderate to severe haemophilia (factor activity between 1-5% of normal and <1% of normal respectively) in countries where safe factor concentrates are available and economically feasible. Historically, prophylactic treatment has not been well studied in the haemophilia B (HB) population due to difficulties in obtaining a sufficiently large sample. AIM: This study examines the prevalence of prophylaxis use among a robust sample of persons with HB in the United States and its association with specific demographic and clinical characteristics. METHODS: Using data collected between 1998 and 2011 for the Centers for Disease Control and Prevention's Universal Data Collection project, we analysed data on 2428 males with moderate to severe HB aged 2-79 years who were seen at 135 federally funded haemophilia treatment centres. RESULTS: Prevalence of prophylactic treatment in our sample was 35% among children and youth (ages 2-19) and 14% among adults (age 20 and older). Increased HB prophylaxis use was significantly associated with younger age (<40 years), Hispanic ethnicity, severe disease and self-infusion, while decreased use was associated with above-normal body mass index (BMI) in adults. Health care coverage was vital, although type of coverage did not appear to influence access. CONCLUSIONS: Our analysis confirms previous reports of lower prevalence of prophylaxis use among individuals with HB compared to those with haemophilia A and adds to the body of knowledge regarding treatment patterns among a historically understudied population.

Prevalence and impact of obesity in people with haemophilia: Review of literature and expert discussion around implementing weight management guidelines.

Obesity affects more than 35% of Americans, increasing the risk of more than 200 comorbid conditions, impaired quality of life and premature mortality. This review aimed to summarize literature published over the past 15 years regarding the prevalence and impact of obesity in people with haemophilia (PWH) and to discuss implementing general guidelines for weight management in the context of the haemophilia comprehensive care team. Although few studies have assessed the effects of obesity on haemophilia-specific outcomes, existing evidence indicates an important impact of weight status on lower extremity joint range of motion and functional disability, with potentially important effects on overall quality of life. Data regarding bleeding tendency in PWH with coexisting obesity are largely inconclusive; however, some individuals may experience reduced joint bleeds following moderate weight loss. Additionally, conventional weight-based dosing of factor replacement therapy leads to increased treatment costs for PWH with obesity or overweight, suggesting pharmacoeconomic benefits of weight loss. Evidence-based recommendations for weight loss include behavioural strategies to reduce caloric intake and increase physical activity, pharmacotherapy and surgical therapy in appropriate patients. Unique considerations in PWH include bleed-related risks with physical activity; thus, healthcare professionals should advise patients on types and intensities of, and approaches to, physical activity, how to adjust treatment to accommodate exercise and how to manage potential activity-related bleeding. Increasing awareness of these issues may improve identification of PWH with coexisting obesity and referral to appropriate specialists, with potentially wide-ranging benefits in overall health and well-being.

Self-reported prevalence, description and management of pain in adults with haemophilia: methods, demographics and results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.

INTRODUCTION: Haemophilia is characterized by frequent haemarthrosis, leading to acute/chronic joint pain. AIM: To assess self-reported prevalence, description and management of pain in adult males with mild-to-severe haemophilia and history of joint pain/bleeding. METHODS: Participants completed a pain survey and five patient-reported outcome instruments assessing pain, functional impairment and health-related quality of life (HRQoL). RESULTS: Of 381 participants enrolled, median age was 34 years; 77% had haemophilia A, 71% had severe disease and 65% were overweight/obese. Many (56%) were not receiving routine infusions; 30% never received routine infusions. During the prior 6 months, 20% experienced acute pain, 34% chronic pain and 32% both acute/chronic pain. Subjects with both acute/chronic pain (vs. none, acute or chronic) were more likely to be depressed (30% vs. 0-15%), obese (35% vs. 20-29%) and have lower HRQoL (mean EQ-5D visual analog scale, 69 vs. 83-86) and function (median overall Hemophilia Activities List, 60 vs. 88-99). Most common analgesics used for acute/chronic pain during the prior 6 months were acetaminophen (62%/55%) and non-steroidal anti-inflammatory drugs (34%/49%); most common non-pharmacologic strategies were ice (65%/33%) and rest (51%/33%). Hydrocodone-acetaminophen was the most common opioid for both acute/chronic pain (30%); other long-acting opioids were infrequently used specifically for chronic but not acute pain (morphine, 7%; methadone, 6%; fentanyl patch, 2%). CONCLUSION: Patients with chronic pain, particularly those with both acute/chronic pain, frequently experience psychological issues, functional disability and reduced HRQoL. Treatment strategies for acute pain (e.g. routine infusions to prevent bleeding) and for chronic pain (e.g. long-acting opioids) may be underused.

A comparison of two types of ankle supports in men with haemophilia and unilateral ankle pain from arthropathy.

INTRODUCTION: Adults with haemophilia frequently have a painful and disordered gait due to ankle arthropathy. AIM: The aim of this study was to determine if pain and gait parameters were affected by the use of different types of ankle bracing. METHODS: We investigated the gait patterns of 17 men with severe haemophilia without bracing, using a fracture boot (FB) and a carbon fibre floor reaction ankle foot orthosis (CF-AFO). Pain relief was determined in each condition. Gait parameters were measured by means of an electronic, pressure sensitive mat. RESULTS: Both brace types relieved pain. Use of a FB altered gait parameters that are associated with movement of the involved and the uninvolved limb during the gait cycle, whereas the use of a CF-AFO did not affect the gait cycle. CONCLUSION: This study suggests that pain relief from both types of braces is identical but use of a CF-AFO does not alter gait patterns.

Recognizing the need for personalization of haemophilia patient-reported outcomes in the prophylaxis era.

The safety and efficacy of treatment options for patients with haemophilia have significantly improved over the last two decades, particularly with greater utilization of prophylactic approaches. Consequently, it is becoming increasingly difficult to differentiate the treatment benefits of available choices based on standard endpoints such as annualized bleeding rates and joint health scores. Patient-reported outcomes (PROs) have shown limited ability to discriminate between treatment outcomes, in part because of their comprehensive nature; i.e. differences in specific outcomes meaningful to individual patients are masked by a global scoring system based on a fixed set of items, many of which may be unimportant for any given patient. There is a clear need for new outcome measures. Initiatives to develop patient-centric outcomes that capture clinically meaningful change are ongoing. One such approach, goal attainment scaling (GAS), allows patients, in collaboration with a trained clinician, to select goals from a medical condition-specific menu of options and subsequently facilitates quantitative assessment of goal realization. Thus, it is fully personalized and sensitive to small, often idiosyncratic, treatment benefits, such as improvements in functional capacity. In this paper, we present the underlying rationale for GAS and one other novel approach to PRO personalization, and discuss their potential to augment current outcome measures by reliably detecting and quantifying treatment effects in individuals with haemophilia on prophylaxis.

Assessment of neonatal platelet adhesion, activation, and aggregation.

BACKGROUND: Acquired and inherited bleeding disorders may present in the neonatal period with devastating lifelong effects. Diagnosing bleeding disorders in the neonatal population could aid in preventing and treating the associated complications. However, currently available platelet function testing is limited in neonates, owing to difficulties in obtaining an adequate blood volume, a lack of normal reference ranges, and an incomplete understanding of the neonatal platelet functional phenotype. OBJECTIVE: To develop small-volume, whole blood platelet function assays in order to quantify and compare neonatal and adult platelet function. METHODS AND RESULTS: Peripheral blood was obtained from healthy, full-term neonates at 24 h of life. Platelet activation, secretion and aggregation were measured via flow cytometry. Platelet adhesion and aggregation were assessed under static and flow conditions. As compared with adult platelets, peripheral neonatal platelet P-selectin expression and integrin glycoprotein IIbIIIa activation were significantly reduced in response to the G-protein-coupled receptor (GPCR) agonists thrombin receptor activator peptide-6 (TRAP-6), ADP, and U46619, and the immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway agonists collagen-related peptide (CRP) and rhodocytin. Neonatal platelet aggregation was markedly reduced in response to TRAP-6, ADP, U46619, CRP and rhodocytin as compared with adult platelets. The extents of neonatal and adult platelet adhesion and aggregate formation under static and shear conditions on collagen and von Willebrand factor were similar. CONCLUSIONS: As compared with adult platelets, we found that neonatal platelet activation and secretion were blunted in response to GPCR or ITAM agonists, whereas the extent of neonatal platelet adhesion and aggregate formation was similar to that of adult platelets.

Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity.

BACKGROUND: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. OBJECTIVES: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. METHODS/PATIENTS: This was a post hoc analysis of adept(™) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. RESULTS: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. CONCLUSIONS: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.

Use of recombinant activated factor VII in patients with Glanzmann's thrombasthenia: a review of the literature.

Glanzmann's thrombasthenia (GT) is a rare bleeding disorder characterized by a quantitative or qualitative defect of glycoprotein IIb/IIIa on the platelet membrane. Managing bleeding episodes is often difficult, and a variety of modalities have been used, including platelet transfusions, recombinant factor VIIa (rFVIIa), and other supportive care. The aim of this review was to present the clinical experience with rFVIIa bolus infusion (rFVIIa BI) for treatment of bleeding episodes and prevention of bleeding during surgical procedures in patients with GT. A literature search was performed to identify rFVIIa-treated patients with GT. Overall, one international survey, one open-label study, and 40 case reports identified 172 bleeding episodes treated with rFVIIa and 62 procedures covered with rFVIIa. In the international survey, rFVIIa BI was used for 96 bleeding episodes in 59 patients. Recombinant FVIIa was effective in 76 bleeding episodes (79%). Of 34 surgical procedures, 25 procedures received rFVIIa BI with 92% bleeding-prevention efficacy. The open-label study reported 28 patients with 28 rFVIIa BI-treated bleeds, and 26 (93%) bleeding episodes responded to rFVIIa. Published case reports revealed that 25 (69%) of 36 bleeds and 27 (96%) of 28 surgeries responded to rFVIIa BI treatment. Overall, 26 adverse events were reported in 19 patients, including five thromboembolic events in two patients where a possible relationship with rFVIIa could not be excluded. Two large studies and 40 case reports provide a literature base to support the efficacy and safety of rFVIIa BI in patients with GT.

An inventory of healthy weight practices in federally funded haemophilia treatment centres in the United States.

In the haemophilia population, obesity has an adverse effect on health care cost, chronic complications and joint disease. Although staff of federally funded Hemophilia Treatment Centers in the United States (HTCs) anecdotally recognize these outcomes, practices to promote healthy weights have not been reported. This evaluation identifies routine practices among HTCs in body mass index (BMI) assessment, perceptions about need to address obesity and roles in offering evidence-based strategies to promote healthy weights. A telephone survey was developed to assess HTCs practices including patient BMI assessment and counselling, perceptions about the importance of healthy patient weights, and HTCs roles in weight management. Ninety of the 130 federally funded HTCs contacted elected to participate and completed the telephone survey. Of these, 67% routinely calculated BMI and 48% provided results to patients. Approximately one-third classified obesity correctly for children (30%) and adults (32%), using the Centers for Disease Control and Preventions BMI cut-offs. Most HTCs (87%) reported obesity as an issue of 'big' or 'moderate' concern and 98% indicated HTC responsibility to address this issue. Most centres (64%) address patient weight during comprehensive visits. One-third (33%) of centres include a nutritionist; of those without, 61% offer nutrition referrals when needed. Most (89%) HTCs do not have a protocol in place to address healthy weights; 53% indicated that guidelines are needed. HTCs offer services to help improve weight outcomes. Training programmes for calculating and interpreting BMI as well as identifying appropriate guidelines to apply to the HTC patient population are needed.

Detection of cartilage damage in femoroacetabular impingement with standardized dGEMRIC at 3 T.

OBJECTIVE: This study aimed at identifying the optimal threshold value to detect cartilage lesions with Standardized delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) at 3 T and evaluate intra- and inter-observer repeatability. DESIGN: We retrospectively reviewed 20 hips in 20 patients. dGEMRIC maps were acquired at 3 T along radial imaging planes of the hip and standardized to remove the effects of patient's age, sex and diffusion of gadolinium contrast. Two observers separately evaluated 84 Standardized dGEMRIC maps, both by visual inspection and using an average index for a region of interest (ROI) in the acetabular cartilage. A radiologist evaluated the acetabular cartilage on morphologic MR images at exactly the same locations. Using intra-operative findings as reference, the optimal threshold to detect cartilage lesions with Standardized dGEMRIC was assessed and results were compared with the diagnostic performance of morphologic magnetic resonance imaging (MRI). RESULTS: Using z < -2 as threshold and visual inspection of the color-adjusted maps, sensitivity, specificity and accuracy for Observer 1 and Observer 2, were 83%, 60% and 75%, and 69%, 70% and 69%, respectively. Overall performance was 52%, 67% and 58%, when using an average z for the acetabular cartilage, compared to 37%, 90% and 56% for morphologic assessment. The kappa coefficient was 0.76 and 0.68 for intra- and inter-observer repeatability, respectively, indicating substantial agreement. CONCLUSIONS: Standardized dGEMRIC at 3 T is accurate in detecting cartilage damage and could improve preoperative assessment in femoroacetabular impingement (FAI). As cartilage lesions in FAI are localized, visual inspection of the Standardized dGEMRIC maps is more accurate than an average z for the acetabular cartilage.

The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption.

Osteopenia and osteoporosis have increasingly become a recognized morbidity of factor VIII (FVIII) deficiency. Recently, we demonstrated that FVIII knockout (KO) mice had significantly decreased bone mass and bone strength despite the fact that they did not have haemarthroses. The aim of this study was to explore the mechanism of bone disease associated with FVIII deficiency. We compared biochemical markers of bone formation and osteoclastogenesis, inflammatory cytokines, as well as static and dynamic histomorphometry of genetically engineered FVIII KO male mice to those of wild-type (WT) controls. At 20 weeks of age, FVIII KO mice, as well as WT controls, were sacrificed. Serum and bones were obtained at the time of sacrifice to study biochemical markers of bone formation (osteocalcin) and osteoclastogenesis (receptor activator of nuclear factor kappa-ß and osteoprotegerin), levels of inflammatory cytokines (interleukin-1α and interferon-ß) and to perform static and dynamic histomorphometry of tibia cancellous bone. There was no difference in the biochemical markers of bone formation or osteoclastogenesis. However, there were differences in the two bone-associated cytokines studied. In addition, histomorphometric examination revealed cancellous osteopenia in FVIII KO mice as evidenced by decreased bone area and trabecular number and increased trabecular separation. Bone formation parameters were normal in FVIII KO mice. In contrast, osteoclast-lined bone perimeter was increased. These data demonstrate that bone disease in FVIII KO mice is due to an increased rate of bone resorption.

Results from a large multinational clinical trial (guardian™1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: safety and efficacy.

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety and efficacy of turoctocog alfa, a new rFVIII product. The primary objective was to evaluate safety. A total of 150 patients (24 adolescents and 126 adults) with severe haemophilia A (FVIII activity ≤ 1%), with at least 150 exposure days (EDs) to any FVIII product and no history of inhibitors were enrolled, and 146 patients (97%) completed the trial. All patients received prophylaxis with turoctocog alfa for approximately 6 months and had a mean of 85 EDs during the trial. None of the patients developed FVIII inhibitors, there were no indications of early FVIII inhibitor development and no safety concerns were identified. A total of 225 adverse events were reported in 100 (67%) patients, with the most common being events associated with dosing procedures, headaches, and nasopharyngitis. A total of 499 bleeding episodes were reported during the trial, the majority (89%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 81%. The overall median annualized bleeding rate was 3.7 (interquartile range: 8.7) bleeds/patient/year. In conclusion, turoctocog alfa provides a new, safe and effective alternative for prophylaxis and treatment of bleeding episodes in patients with haemophilia A.

Micro-finite element analysis applied to high-resolution MRI reveals improved bone mechanical competence in the distal femur of female pre-professional dancers.

UNLABELLED: Micro-finite element analysis applied to high-resolution (0.234-mm length scale) MRI reveals greater whole and cancellous bone stiffness, but not greater cortical bone stiffness, in the distal femur of female dancers compared to controls. Greater whole bone stiffness appears to be mediated by cancellous, rather than cortical bone adaptation. INTRODUCTION: The purpose of this study was to compare bone mechanical competence (stiffness) in the distal femur of female dancers compared to healthy, relatively inactive female controls. METHODS: This study had institutional review board approval. We recruited nine female modern dancers (25.7±5.8 years, 1.63±0.06 m, 57.1±4.6 kg) and ten relatively inactive, healthy female controls matched for age, height, and weight (32.1±4.8 years, 1.6±0.04 m, 55.8±5.9 kg). We scanned the distal femur using a 7-T MRI scanner and a three-dimensional fast low-angle shot sequence (TR/TE=31 ms/5.1 ms, 0.234 mm×0.234 mm×1 mm, 80 slices). We applied micro-finite element analysis to 10-mm-thick volumes of interest at the distal femoral diaphysis, metaphysis, and epiphysis to compute stiffness and cross-sectional area of whole, cortical, and cancellous bone, as well as cortical thickness. We applied two-tailed t-tests and ANCOVA to compare groups. RESULTS: Dancers demonstrated greater whole and cancellous bone stiffness and cross-sectional area at all locations (p<0.05). Cortical bone stiffness, cross-sectional area, and thickness did not differ between groups (>0.08). At all locations, the percent of intact whole bone stiffness for cortical bone alone was lower in dancers (p<0.05). Adjustment for cancellous bone cross-sectional area eliminated significant differences in whole bone stiffness between groups (p>0.07), but adjustment for cortical bone cross-sectional area did not (p<0.03). CONCLUSIONS: Modern dancers have greater whole and cancellous bone stiffness in the distal femur compared to controls. Elevated whole bone stiffness in dancers may be mediated via cancellous, rather than cortical bone adaptation.

A new method to analyze dGEMRIC measurements in femoroacetabular impingement: preliminary validation against arthroscopic findings.

OBJECTIVE: To validate a new method to analyze delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) measurements in the hip for early assessment of cartilage defects in femoroacetabular impingement (FAI). METHODS: We performed a retrospective review of 10 hips in 10 FAI patients, who underwent hip arthroscopy. T1-weighted images and dGEMRIC T(1) maps were acquired at 1.5 T on coronal planes, including the anterior-superior, superior, posterior-superior hip cartilage. For all slices, a region of interest (ROI) was defined over the central portion of the femoral cartilage, assumed to be healthy, and T1 values (x) were transformed to standard scores (z) using z = (x -µ)/σ, where µ and σ are the average and standard deviation of T1 in the femoral ROI. Diagnostic performance of the resulting standardized dGEMRIC maps was evaluated against intraoperative findings and compared with that of a previously proposed dGEMRIC analysis as well as morphologic assessment. RESULTS: Assuming z = -2 or z = -3 as the threshold between normal and degenerated cartilage, sensitivity, specificity and accuracy were 88%, 51% and 62%, and 71%, 63% and 65%, respectively. By using T1 = 500 ms as single threshold for all dGEMRIC T1 maps, these values became 47%, 58% and 55%, whereas they were 47%, 79% and 70% for morphologic evaluation. CONCLUSIONS: Standardized dGEMRIC can increase the sensitivity in detecting abnormal cartilage in FAI and has the potential to improve the clinical interpretation of dGEMRIC measurements in FAI, by removing the effect of inter- and intra-patient T1 variability.