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.

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.

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.

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.

Glenoid labrum ossification and mechanical restriction of joint motion: extraosseous manifestations of melorheostosis.

We report a case of a 47-year-old man who presented with progressive loss of motion and pain in the right shoulder. Radiographs of the shoulder demonstrated dense ossification in the glenoid and humeral head with extension into the periarticular soft tissues. CT and MRI scans confirmed the radiographic findings and also revealed ossification of the glenoid labrum. A radiographic diagnosis of melorheostosis, an uncommon benign sclerosing bone dysplasia, was made. Because of the patient's severe symptomatology, he underwent total shoulder arthroplasty. Histological analysis of the resected masses was consistent with melorheostosis with a few areas covered by a cartilage cap. This case illustrates several uncommon but important features of melorheostosis, including mechanical obstruction of joint motion requiring joint replacement, ossification of the glenoid labrum, and cartilage-covering portions of the intra-articular masses, not to be confused with cartilage-producing tumors.

Aminoglycoside resistance with homogeneous and heterogeneous populations of antibiotic-resistant ribosomes.

Aminoglycosides bind to rRNA in the small subunit of the bacterial ribosome. Mutations in the decoding region of 16S rRNA confer resistance to specific subsets of aminoglycoside antibiotics. The two major classes of 2-deoxystreptamine aminoglycosides are the 4,5- and the 4,6-disubstituted antibiotics. Antibiotics of the 4,5-disubstituted class include neomycin, paromomycin, and ribostamycin. Gentamicins and kanamycins belong to the 4,6-disubstituted class of aminoglycosides. Structural studies indicated the potential importance of position 1406 (Escherichia coli numbering) in the binding of ring III of the 4,6-disubstituted class of aminoglycosides to 16S rRNA. We have introduced a U1406-to-A mutation in a plasmid-encoded copy of E. coli 16S rRNA which has been expressed either in a mixture with wild-type ribosomes or in a strain in which all rRNA is transcribed from the plasmid-encoded rrn operon. High-level resistance to many of the 4,6-disubstituted aminoglycosides is observed only when all the rRNA contains the U1406-to-A mutation. In contrast to the partial dominance of resistance observed with other mutations in the decoding region, there is a dominance of sensitivity with the 1406A mutation. Chemical footprinting experiments indicate that resistance arises from a reduced affinity of the antibiotic for the rRNA target. These results demonstrate that although position 1406 is an important determinant in the binding and action of the 4,6-disubstituted aminoglycosides, other rRNA mutations that perturb the binding of ring I of both classes of 2-deoxystreptamine aminoglycosides confer higher levels of resistance as well as a partial dominance of resistance.

Magnetic resonance imaging of the foot and ankle.

Magnetic resonance (MR) imaging of the foot and ankle is playing an increasingly important role in the diagnosis of a wide range of foot and ankle abnormalities, as well as in planning for their surgical treatment. For an optimal MR study of the foot and ankle, it is necessary to obtain high-resolution, small-field-of-view images using a variety of pulse sequences. The most common indication for MR imaging of the foot and ankle is for the evaluation of tendon and bone abnormalities, such as osteomyelitis, occult fractures, and partial and complete tears of the Achilles, tibialis posterior, and peroneal tendons. Magnetic resonance imaging has also been shown to be helpful in the diagnosis of several soft-tissue abnormalities that are unique to the foot and ankle, such as plantar fasciitis, plantar fibromatosis, interdigital neuromas, and tarsal tunnel syndrome.

Percutaneous CT guided resection of osteoid osteoma of the tibial plafond.

Osteoid osteomas of the foot and ankle are relatively rare and notoriously difficult to diagnose. Juxta-articular osteoid osteomas are more difficult to treat and often have a significant delay in diagnosis. We report a case of a juxta-articular osteoid osteoma of the tibial plafond. Once the diagnosis was made, excisional biopsy was performed percutaneously under computed tomography (CT) guidance as an outpatient in the radiology suite. The patient had complete resolution of symptoms and remains pain free at two years follow-up. CT guided resection can be a lower morbidity and more cost effective technique to treat this lesion than traditional methods.

Outcomes of postoperative septic arthritis after anterior cruciate ligament reconstruction.

Arthroscopically guided reconstruction of the anterior cruciate ligament is a common orthopaedic procedure. While many associated complications have been described in the literature, postoperative septic arthritis has received little attention. Although rare after anterior cruciate ligament reconstruction, septic arthritis can have devastating consequences. From a group of 831 consecutive patients, we report 4 (0.48%) who sustained septic arthritis. All patients had similar symptoms and were treated by the same surgeon in the same manner. All underwent immediate arthroscopic lavage, open incision, drainage of associated wounds, debridement with graft retention, and treatment with intravenous and then oral antibiotics. The patients underwent an average of 2.75 procedures after the diagnosis to eradicate the infection and restore knee motion. All patients were evaluated at an average of 3 years after surgery. We found that previous knee surgery and meniscal repair were risk factors for the development of postoperative septic arthritis. The infection was successfully eradicated, the ligament graft was preserved, and knee stability and mobility were adequately restored in all patients. However, the clinical outcome of these patients appeared to be inferior to that of patients who had undergone uncomplicated anterior cruciate ligament reconstruction. This inferior outcome appeared to be secondary to damage to the articular cartilage from the infection.

MR arthrography of the adult acetabular capsular-labral complex: correlation with surgery and anatomy.

OBJECTIVE: Our purpose was to describe the appearance of the acetabular capsular-labral complex on MR arthrography and to correlate this appearance with surgical findings in adult patients and with gross anatomic findings in cadavers. SUBJECTS AND METHODS: MR arthrography of the hip joint was performed in 40 patients and six cadavers. All patients underwent subsequent arthrotomy of the hip. MR arthrography consisted of a T1-weighted three-dimensional gradient-echo sequence in both the coronal oblique and sagittal oblique planes after intraarticular injection of a 2 mmol/l solution of gadopentetate dimeglumine. The normal and pathologic appearance of the capsular-labral complex was assessed, and the labra were evaluated on the basis of morphology, signal intensity, presence of a tear, and attachment to the acetabulum. MR arthrography findings were correlated with the surgical results in all patients and with the anatomic sections of the cadaveric hip joint specimens. RESULTS: MR arthrography images of the T-weighted three-dimensional gradient-echo sequences allowed visualization of the anatomic structures. The normal labrum was triangular, without any sublabral sulcus, and of homogeneous low signal intensity. A recess between the labrum and the joint capsule could be identified in instances in which no thickened labrum was present. Labral lesions included labral degeneration, a tear, or a detached labrum either with or without thickening of the labrum. The sensitivity for detection and correct staging of labral lesions with MR arthrography in the patient study was 91%; the specificity, 71%; and the accuracy, 88%. CONCLUSION: MR arthrography with T1-weighted three-dimensional gradient-echo sequences allows excellent assessment of the normal and pathologic acetabular capsular-labral complex.

Basis for prokaryotic specificity of action of aminoglycoside antibiotics.

The aminoglycosides, a group of structurally related antibiotics, bind to rRNA in the small subunit of the prokaryotic ribosome. Most aminoglycosides are inactive or weakly active against eukaryotic ribosomes. A major difference in the binding site for these antibiotics between prokaryotic and eukaryotic ribosomes is the identity of the nucleotide at position 1408 (Escherichia coli numbering), which is an adenosine in prokaryotic ribosomes and a guanosine in eukaryotic ribosomes. Expression in E.coli of plasmid-encoded 16S rRNA containing an A1408 to G substitution confers resistance to a subclass of the aminoglycoside antibiotics that contain a 6' amino group on ring I. Chemical footprinting experiments indicate that resistance arises from the lower affinity of the drug for the eukaryotic rRNA sequence. The 1408G ribosomes are resistant to the same subclass of aminoglycosides as previously observed both for eukaryotic ribosomes and bacterial ribosomes containing a methylation at the N1 position of A1408. The results indicate that the identity of the nucleotide at position 1408 is a major determinant of specificity of aminoglycoside action, and agree with prior structural studies of aminoglycoside-rRNA complexes.

Acute calcific tendinitis of the hip: case report with magnetic resonance imaging findings.

The clinical presentation of acute calcific tendinitis can be quite dramatic. This report describes a patient with this entity who had calcification in an unusual area, accompanied by abnormalities seen on radiography and magnetic resonance imaging. Clinical aspects of acute calcific tendinitis are also reviewed. With recognition of this entity, treatment can be initiated promptly, with dramatic resolution.

MR imaging of tophaceous gout.

OBJECTIVE: MR imaging is not routinely used for evaluation of tophaceous gout. However, gout may present clinically in an atypical, unusual, or confusing manner. A gouty tophus occasionally mimics an infectious or neoplastic process, and MR imaging may be obtained under these circumstances. The purpose of this study was to determine the MR imaging characteristics of intraosseous and soft-tissue tophi. MATERIALS AND METHODS: We identified 13 MR imaging examinations performed during a 27-month period on nine patients with gouty arthritis. All were men 42-70 years old. T1-, proton density-, and T2-weighted spin-echo MR images were obtained for all the examinations. Nine examinations included contrast-enhanced MR images. The findings were then evaluated, as were the corresponding radiographs. RESULTS: Five patients presented with articular involvement, three patients with an isolated soft-tissue mass, and one patient with persistent soft-tissue swelling. The duration of symptoms ranged from 3 months to more than 20 years. Nearly all the tophi were of intermediate signal intensity on T1-weighted images. On T2-weighted images, three sites revealed an overall increase in the signal intensity of the tophi, whereas 10 studies showed a heterogeneous decrease in signal intensity. All but one tophus showed homogeneous enhancement. Erosion of adjacent bone, synovial pannus, joint effusion, soft-tissue edema, and bone marrow edema were common associated findings. CONCLUSION: The MR appearance of tophi in patients with tophaceous gout is constant on T1- but quite variable on T2-weighted images. This variability in signal intensity could be related to calcium within a tophus. Tophaceous gout should be considered in the differential diagnosis when a mass reveals heterogeneously low to intermediate signal intensity, particularly if the adjacent bone shows typical erosive changes or if other joints are involved. When faced with this situation, radiologists may find it helpful to obtain a further clinical history and recommend evaluating the patient's serum urate level.

Accuracy of fat-suppressed three-dimensional spoiled gradient-echo FLASH MR imaging in the detection of patellofemoral articular cartilage abnormalities.

PURPOSE: To determine the accuracy of T1-weighted fat-suppressed (FS) three-dimensional (3D) fast low-angle shot (FLASH) magnetic resonance (MR) imaging for the detection of articular cartilage abnormalities of the patellofemoral joint. MATERIALS AND METHODS: Forty-one patients with suspected internal derangement of the knee were examined with a T1-weighted FS 3D FLASH sequence and subsequently underwent arthroscopy. The patellofemoral articular cartilage was graded blindly on both the MR and arthroscopic images with a modification of the Noyes classification scheme. RESULTS: For the detection of abnormal articular cartilage of the patellofemoral joint with the FS 3D FLASH sequence, sensitivity was 81%, specificity was 97%, and accuracy was 97%. Of the lesions detected on MR images, 77% were graded identically on MR and arthroscopic images. For the remaining 23%, MR imaging and arthroscopic ratings were within one grade of each other. CONCLUSION: T1-weighted FS 3D FLASH imaging is accurate for the detection and grading of articular cartilage abnormalities of the patellofemoral joint.

Adamantinoma.

This is an unusual case of an adamantinoma in an early phase of evolution. It was much smaller than adamantinomas typically seen at presentation, although it was located in the usual anterior tibial cortical region. Slow growth and a prolonged period of symptoms are common with adamantinoma and were also observed in this patient. The multifocal presentation within the same bone is unusual. This case illustrated the need to consider adamantinoma in the differential diagnosis of any pre-tibial cortical lesion despite the small size, benign presentation, or the longevity of symptoms.

Localized anterior arthrofibrosis (cyclops lesion) after reconstruction of the anterior cruciate ligament: MR imaging findings.

OBJECTIVE: A localized form of anterior arthrofibrosis, the so-called cyclops lesion, has recently been reported to be a significant cause of loss of knee extension after reconstruction of the anterior cruciate ligament (ACL) of the knee. The purpose of this study was to characterize the MR appearance of this lesion. SUBJECTS AND METHODS: Five patients who had arthroscopic verification of a focal nodule of fibrous tissue in the intercondylar notch anterior to the reconstructed ACL (the cyclops lesion) and who had an MR examination after ACL reconstruction but before repeat arthroscopy and excision of the cyclops lesion were included in this study. The MR images were evaluated for the presence of soft tissue in the intercondylar notch anterior to the reconstructed ACL. If present, this tissue was graded as 1, 2, or 3, depending on its anterior extent along the femoral condyle. RESULTS: MR images of all five patients showed abnormal soft tissue with signal characteristics consistent with fibrous tissue anterior to the reconstructed ACL in the intercondylar notch. The abnormal tissue was grade 2 or 3 in all patients. CONCLUSION: MR imaging shows soft tissue with signal characteristics consistent with fibrous tissue anterior to the reconstructed ACL in the intercondylar notch in patients with localized anterior arthrofibrosis. Although the sensitivity and specificity of MR imaging for the cyclops lesion are yet to be determined, visualization of such fibrous tissue on MR images in a patient with clinical symptoms suggestive of localized anterior arthrofibrosis may be helpful in confirming the diagnosis.

Denervation hypertrophy of muscle: MR features.

OBJECTIVE: Denervation hypertrophy is an entity well recognized in the neurology literature, but with little mention in the radiology literature. Denervation hypertrophy occurs when a muscle paradoxically enlarges rather than atrophies in response to loss of innervation. The purpose of this report is to describe the MR appearance of true hypertrophy and pseudohypertrophy of muscle following denervation. MATERIALS AND METHODS: The clinical data and MRI findings in three patients with muscle enlargement due to denervation hypertrophy are reviewed retrospectively. Two women and one man aged 19-80 years were included. Denervation resulted from spinal stenosis in one patient, a herniated thoracic disc in another, and spina bifida with a tethered cord in the third. RESULTS: True hypertrophy of a single muscle was seen in one patient and pseudohypertrophy of two muscles was present in one patient. One patient had one muscle with true hypertrophy and one muscle with pseudohypertrophy. Electromyographic examination was performed and was consistent with denervation in two patients. Biopsy confirmation of denervation was obtained in two patients. All five abnormal muscles exhibited increased volume, well defined margins, and normal contour. In true hypertrophy the enlarged muscle was isointense with normal muscle on all MRI sequences. In pseudohypertrophy the MRI appearance was consistent with an excessive amount of fat interspersed throughout normal muscle. CONCLUSION: Magnetic resonance in these cases established muscle hypertrophy rather than neoplasm as the cause of a palpable mass. If muscle hypertrophy or pseudohypertrophy is seen on an MR examination of an enlarged extremity, the possibility of an underlying neurologic process should be considered.

CT of dystrophic calcification in subcutaneous soft tissues secondary to chronic insulin injection.

We describe a case of massive dystrophic subcutaneous calcification in the anterior thighs of a long-term insulin-dependent diabetic.