Prevalence, parameters, and pathogenic mechanisms for splice-altering acceptor variants that disrupt the AG exclusion zone.

Predicting the pathogenicity of acceptor splice-site variants outside the essential AG is challenging, due to high sequence diversity of the extended splice-site region. Critical analysis of 24,445 intronic extended acceptor splice-site variants reported in ClinVar and the Leiden Open Variation Database (LOVD) demonstrates 41.9% of pathogenic variants create an AG dinucleotide between the predicted branchpoint and acceptor (AG-creating variants in the AG exclusion zone), 28.4% result in loss of a pyrimidine at the -3 position, and 15.1% result in loss of one or more pyrimidines in the polypyrimidine tract. Pathogenicity of AG-creating variants was highly influenced by their position. We define a high-risk zone for pathogenicity: > 6 nucleotides downstream of the predicted branchpoint and >5 nucleotides upstream from the acceptor, where 93.1% of pathogenic AG-creating variants arise and where naturally occurring AG dinucleotides are concordantly depleted (5.8% of natural AGs). SpliceAI effectively predicts pathogenicity of AG-creating variants, achieving 95% sensitivity and 69% specificity. We highlight clinical examples showing contrasting mechanisms for mis-splicing arising from AG variants: (1) cryptic acceptor created; (2) splicing silencer created: an introduced AG silences the acceptor, resulting in exon skipping, intron retention, and/or use of an alternative existing cryptic acceptor; and (3) splicing silencer disrupted: loss of a deep intronic AG activates inclusion of a pseudo-exon. In conclusion, we establish AG-creating variants as a common class of pathogenic extended acceptor variant and outline factors conferring critical risk for mis-splicing for AG-creating variants in the AG exclusion zone, between the branchpoint and acceptor.

Congenital Titinopathy: Comprehensive characterization and pathogenic insights.

OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization.

This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking glutathione reductase glr1 show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease.

Radiologists' perspectives about evidence-based medicine and their clinical practice: a semistructured interview study.

OBJECTIVES: To describe radiologist's attitudes and perspectives on evidence-based medicine (EBM) and their practice. DESIGN: Face-to-face semistructured interviews, thematic analysis. SETTING: 24 institutions across six Australian states and New Zealand. Transcripts were imported into HyperRESEARCH software and thematically analysed. PARTICIPANTS: 25 radiologists. RESULTS: Six themes were identified: legitimising decisions (validated justification, prioritising patient preferences, reinforcing protocols), optimising outcomes (ensuring patient safety, maximising efficiency), availability of access (requiring immediacy, inadequacy of evidence, time constraints, proximity of peer networks, grasping information dispersion), over-riding pragmatism (perceptibly applicability, preserving the art of medicine, technical demands), limited confidence (conceptual obscurity, reputation-based trust, demands constant practice, suspicion and cynicism), and competing powers (hierarchical conflict, prevailing commercial interests). CONCLUSIONS: Radiologists believe EBM can support clinical decision-making for optimal patient outcomes and service efficiency but feel limited in their capacities to assimilate and apply EBM in practice. Improving access to evidence, providing ongoing education and training supplemented with practical tools for appraising evidence; and developing evidence-based guidelines and protocols may enhance feasibility and promote the confidence and skills among radiologists in applying EBM in radiology practice for better patient care.

Imaging of ankle tendinopathy and tears.

The major muscular prime movers and stabilizers of the foot and ankle originate in the mid to lower leg and send their tendons distally. Most of these tendons, with the exception of the Achilles and plantaris tendons, must negotiate a sharply curved course at the ankle and are stabilized by fibro-osseous tunnels, pulleys, or fibrous retinaculi before eventually inserting at the foot. Knowledge of specific tendon anatomy, contact points and sites of physical and vascular stress, helps to identify those regions susceptible to degeneration or tearing and to optimize the design of imaging protocols. This review covers the imaging modalities used to assess tendons about the ankle and issues related to their usage, normal tendon structure and relevant anatomy, normal imaging appearances and artifacts, and the common degenerative pathological processes which imaging can show.

Fibulotalocalcaneal ligament: magnetic resonance imaging findings with cadaver correlation.

OBJECTIVE: The objectives of this study were to determine whether the fibulotalocalcaneal (FTC) ligament of the ankle, described in anatomical literature, can be identified on magnetic resonance (MR) imaging studies. METHODS: Magnetic resonance imaging was performed on 6 cadaver ankles, which were then sectioned axially. The posterolateral ankle was inspected on MR imaging and cadaver sections for ligamentous thickening corresponding to the components of the FTC ligament: main stem and talar and peroneocalcaneal laminae. RESULTS: The entire FTC ligament or components of it were seen in 5 (83%) of 6 ankles. In 3 (50%) of 6, all 3 components were present. The main stem of the FTC ligament attached to the posteromedial aspect of the lateral malleolus and then divided inferiorly into 2 laminae: The talar lamina extended horizontally to the talus, and the peroneocalcaneal lamina descended vertically to the calcaneus. CONCLUSIONS: The FTC ligament is a sheetlike extrinsic ligament, which is in continuity with the deep posterior crural fascia of the ankle and is visible on MR imaging.

Opinion: integration of diagnostic and management perspectives for placenta accreta.

The 2007 New South Wales/Queensland Royal Australian and New Zealand College of Obstetricians and Gynaecologists Annual Scientific Meeting convened a panel to discuss multidisciplinary perspectives on the management of placenta accreta, percreta or increta. While it was anticipated that this panel would stimulate discussion, the cohesion between the approaches was underestimated. This document represents an integration of the perspectives of the invited speakers at this presentation, with backgrounds in maternal-fetal medicine, gynaecological oncology, radiology and general obstetrics and gynaecology.

Popliteomeniscal fascicles: anatomic considerations using MR arthrography in cadavers.

OBJECTIVE: This study was performed to examine the normal MR arthrographic anatomy of the popliteomeniscal fascicles with specific reference to the number of popliteomeniscal fascicles, thickness and course of the fascicles, and presence of other posterior attachments from the medial aponeurosis of the popliteus musculotendinous region. MATERIALS AND METHODS: Multiplanar 1.5-T MR arthrography of 10 cadaveric knees was performed using a quadrature knee coil. Specimens were frozen and sectioned in the sagittal (n = 4), axial (n = 3), and coronal (n = 3) planes. MR images and anatomic specimens were correlated by two musculoskeletal radiologists. RESULTS: Three popliteomeniscal fascicles were identified on MR arthrography: anteroinferior and posterosuperior fascicles in all 10 knees and posteroinferior fascicles in four of the knees. The posterosuperior popliteomeniscal fascicle was uniform in thickness, and the anteroinferior popliteomeniscal fascicle was variable in thickness. The anteroinferior popliteomeniscal fascicle formed a conjoined fibular attachment with the popliteofibular ligament. A medial aponeurotic extension from the popliteus musculotendinous region gave rise to the posteroinferior popliteomeniscal fascicle, which extended upward and attached to the inferomedial aspect of the posterior horn of the lateral meniscus. Additional attachments from the medial aponeurosis of the popliteus musculotendinous region to the posterior cruciate ligament, posterior capsule, oblique popliteal ligament, and posterior meniscofemoral ligament of Wrisberg were seen. CONCLUSION: Three popliteomeniscal fascicles were identified on MR arthrographic images. The popliteus muscle-tendon unit forms robust attachments in the superior, inferior, medial, and lateral oblique aspects, highlighting its importance in posterolateral stability of the knee.

Arcuate ligament of the wrist: normal MR appearance and its relationship to palmar midcarpal instability: a cadaveric study.

OBJECTIVE: To describe the magnetic resonance (MR) imaging and gross anatomic appearance of the scaphocapitate (SC) ligament and triquetrohamocapitate (THC) ligament, which are the radial and ulnar limbs of the composite arcuate ligament, a critical volar midcarpal stabilizing ligament. DESIGN: T1 spin-echo and 3D gradient-echo MR imaging in the standard, coronal oblique, and axial oblique planes were performed both before and following midcarpal arthrography in seven cadaveric wrists. The seven specimens were then sectioned in selected planes to optimally visualize the SC and THC ligaments. These specimens were analyzed and correlated with their corresponding MR images. RESULTS: The SC and THC ligaments can be visualized in MR images as structures of low signal intensity that form an inverted "V" joining the proximal and distal carpal rows. The entire ligamentous complex is best visualized with coronal and axial oblique MR imaging but can also be seen in standard imaging planes. CONCLUSION: SC and THC ligaments together form the arcuate ligament of the wrist. Their function is crucial to the normal functioning of the wrist. Palmar midcarpal instability (PMCI) is a resulting condition when abnormalities of these ligaments occur. Dedicated MR imaging in the coronal and axial imaging planes can be performed in patients suspected of having PCMI.

Preservation of limbic and paralimbic structures in aging.

Patterns of gray matter (GM) loss were measured in 223 healthy subjects spanning eight decades. We observed significant clusters of accelerated loss in focal regions of the frontal and parietal cortices, including the dorsolateral frontal cortex, pre- and postcentral gyrus, and the inferior and superior parietal lobes. The rate of loss in these clusters was approximately twice that of the global average. By contrast, clusters of significant GM preservation were found in limbic and paralimbic structures, including the amygdala, hippocampus, thalamus, and the cingulate gyrus. In these clusters, GM loss was attenuated significantly relative to the global rate. The preservation of these structures is consistent with the functional importance of the thalamo-limbic circuits in sensory integration, arousal, emotion, and memory, and lends credence to the idea that later-maturing cortical regions are more vulnerable to age-related morphologic changes. Moreover, the limbic findings act as a frame of reference to explore further the effects of stress and learning on these structures in an evidence-based manner across age.

Visual risk factors for hip fracture in older people.

OBJECTIVES: To determine the association between poor vision and risk of hip fracture in the Blue Mountains Eye Study. DESIGN: Prospective population-based cohort study. SETTING: Two post code areas in the Blue Mountains, west of Sydney, Australia. PARTICIPANTS: Three thousand six hundred fifty-four community-dwelling Australians aged 49 and older. MEASUREMENTS: At baseline, subjects had an extensive eye examination, including refraction, contrast sensitivity and visual field testing, photographs of the lens and retina, and an interview. Hip fractures during the 5-year follow-up were identified by self-report and review of medical records and were radiologically confirmed. RESULTS: For 2-year follow-up (17 hip fractures), the adjusted hazard ratio (HR) for risk of hip fracture in those with corrected visual acuity worse than 20/60 was 8.4 (95% confidence interval (CI) = 1.5-48.5, population attributable risk (PAR) = 27%); for presence of posterior subcapsular cataract, the adjusted HR was 5.0 (95% CI = 1.1-23.0, PAR = 24%); and for visual field loss, the adjusted HR was 5.5 (95% CI = 1.0-29.8, PAR = 55%). In those aged 75 and older, visual acuity worse than 20/60 gave an adjusted HR of 40.6 (95% CI = 5.6-292.5, PAR = 49%). Visual impairment of any type did not predict risk of hip fracture after a 2-year follow-up. CONCLUSION: Visual impairment is strongly associated with risk of hip fracture in the next 2 years but not over a longer period of time.

The accuracy of self-reported fractures in older people.

Self-report is often used in large-scale studies. Therefore, it is important to determine the accuracy of self-report. In the Blue Mountains Eye Study, a population-based study of 3,654 older, community-dwelling Australians, subjects were asked about fracture history at the 5-year follow-up interview. All reported non-rib and vertebral fractures were radiologically confirmed. Hospital radiology records were searched for fracture records of people who reported no fractures in the 5-year period. Of 2,326 subjects who came to the interview, 272 subjects reported 318 fractures sustained since 1990. Overall, 34.6% of fracture reports could not be confirmed, mainly due to no record of treatment. Among self-reported fractures, false positive rates were 10.7% for all fractures and 4.8% for hip, 2.2% for wrist, 19.4% for ankle, and 6.6% for shoulder fractures. Sensitivity and specificity of fracture reports was high, with the lowest sensitivity for shoulder fractures (82.4%). Self-report of major osteoporotic fractures is reasonably accurate but may be improved by obtaining more details about treatment.