Genomic sister-disorders of neurodevelopment: an evolutionary approach

Genomic sister-disorders are defined here as diseases mediated by duplications versus deletions of the same region. Such disorders can provide unique information concerning the genomic underpinnings of human neurodevelopment because effects of diametric variation in gene copy number on cognitive and behavioral phenotypes can be inferred. We describe evidence from the literature on deletions versus duplications for the regions underlying the best-known human neurogenetic sister-disorders, including Williams syndrome, Velocardiofacial syndrome, and Smith–Magenis syndrome, as well as the X-chromosomal conditions Klinefelter and Turner syndromes. These data suggest that diametric copy-number alterations can, like diametric alterations to imprinted genes, generate contrasting phenotypes associated with autistic-spectrum and psychotic-spectrum conditions. Genomically based perturbations to the development of the human social brain are thus apparently mediated to a notable degree by effects of variation in gene copy number. We also conducted the first analyses of positive selection for genes in the regions affected by these disorders. We found evidence consistent with adaptive evolution of protein-coding genes, or selective sweeps, for three of the four sets of sister-syndromes analyzed. These studies of selection facilitate identification of candidate genes for the phenotypes observed and lend a novel evolutionary dimension to the analysis of human cognitive architecture and neurogenetic disorders

Acetabular reconstruction with femoral head autograft in primary total hip arthroplasty through a direct anterior approach is a reliable option for patients with secondary osteoarthritis due to developmental dysplasia of the hip

BACKGROUND Developmental dysplasia is challenging to treat with total hip arthroplasty via the direct anterior approach (DAA). Reconstructing the former anatomy while restoring the acetabular bone stock for future revisions in this young patient collective combined with the known advantages of the DAA would be desirable. The purpose of this study was to analyze the feasibility, radiographic outcome and clinical outcome of primary uncemented total hip arthroplasty with bulk femoral head autograft for acetabular augmentation through a DAA with a minimal follow-up of 12 months. METHODS A retrospective, consecutive series from March 2006 to March 2018 of 29 primary total hip arthroplasty with acetabular augmentation with bulk femoral head autograft through a direct anterior approach was identified. All complications, reoperations and failures were analyzed. Radiographic and clinical outcome was measured. RESULTS 24 patients (29 hips) with a mean age of 43 (18-75) years and a mean follow-up of 35 months (12-137) were included. Surgical indication was secondary osteoarthritis for developmental dysplasia of the hip (Hartofilakidis Grade A (n = 19), B (n = 10)) in all cases. We noted no conversion of the approach, no dislocation and no acetabular loosening. The center of rotation was significantly distalized by a mean of 9 mm (0-23) and significantly medialized by a mean of 18 mm (6-29). The bone graft was fully integrated after 12 months in all cases. CONCLUSION Acetabular reconstruction with femoral head autograft in primary THA through a direct anterior approach seems to be a reliable option for the treatment of secondary osteoarthritis in patients with DDH Hartofilakidis grade A and B. Prospective cohort studies with a large sample population and a long-term follow-up are necessary to confirm our findings

Mid-term migration pattern of a calcar-guided short stem: A five-year EBRA-FCA-study

BACKGROUND Short-term results of several short-stem designs have indicated early axial migration. Mid- and long-term results for most designs are lacking. The objective of this study was to evaluate the mid-term migration pattern of a calcar-guided short stem five years postoperative. METHODS Implant migration of 191 calcar-guided short stems was assessed by Ein-Bild-Roentgen-Analysis Femoral-Component- Analysis (EBRA-FCA) 5 years after surgery. Migration pattern of the whole group was analyzed and compared to the migration pattern of implants potentially being "at hazard" with a subsidence of more than 1.5 mm at 2 years postoperatively. Influence of preoperative Dorr types (A vs. B vs. C), age (70 years), gender (female vs. male), weight (90 kg), BMI (30) and uni-vs. bilateral procedures on mid-term migration pattern was analyzed. Additionally outcome of varus- and valgus stem alignment was assessed. RESULTS Mean axial subsidence was 1.5 mm (SD 1.48 mm) at final follow-up. Two years after surgery 73 short stems were classified "at hazard". Of these stems, 69 cases showed secondary stabilisation in the following period, whereas 4 cases presented unstable with more than 1 mm of further subsidence. Stem revision was not required neither in the group of implants with early stabilisation nor the group with pronounced early onset migration. Male gender and heavy-weight patients had a significant higher risk for axial migration, as well as extensive valgus stem alignment, whereas for Dorr type B, compared to A, no statistical difference could be observed. CONCLUSIONS In most cases, even in the group of stems being "at hazard", settling could be documented. While different Dorr types did not show a statistically significant impact on axial migration, particularly in male and heavy-weight patients the risk of continuous subsidence is increased. In those 4 cases with further migration, undersizing of the stem could be recognized. At present, clinical consequences are still uncertain

Comparison of Muscle Fat Fraction Measurements in the Lower Spine Musculature with Non-Contrast-Enhanced CT and Different MR Imaging Sequences

Purpose: To assess whether two-point Dixon (TPD) MRI, true fast imaging with steady-state free precession (TRUFI) MRI and non-contrast-enhanced CT (NECT) can accurately measure muscle fat fraction (FF) in the autochthonous back muscles (AM) and the psoas muscle (PM) compared to multi-point Dixon (MPD) MRI. Method: 29 oncological patients who received MRI including MPD, TPD and NECT imaging in a period of three months were analyzed retrospectively. A sub-cohort of 16 patients additionally underwent TRUFI MRI and were included in a sub-analysis. Region of interest (ROI) measurements for each muscle compartment of the AM and PM were conducted by two examiners. Additionally, the Goutallier classification was used to quantify the amount of fatty infiltration of each muscle. Intermodality correlations were assessed with the Pearson correlation coefficient (r), and interreader and intrareader agreements with the intraclass correlation coefficient (ICC). Results: Good intermodality correlations were found for NECT (r = 0.969), TPD (r = 0.942) and TRUFI (r = 0.904, all P < 0.001) when assessing FF in the AM and slightly lower in the PM. Interreader agreement showed good correlations and low median deviations (1.1 - 4.1 %, depending on the modality). The Goutallier classification of the AM showed good separation between grades with substantial interreader agreement (κ = 0.627, P < 0.001). Conclusions: ROI measurements of the AM in NECT, TPD and TRUFI highly correlate with muscle FF measurements in MPD MRI and may be used to assess sarcopenia in oncological patients. Keywords: Body Composition; Computed Tomography; Fat Fraction; Magnetic Resonance Imaging; Muscles; Sarcopenia

Epicardial Adipose Tissue Attenuation and Fat Attenuation Index: Phantom Study and In-Vivo Measurements With Photon-Counting CT

Background: Epicardial adipose tissue (EAT) attenuation is a vascular inflammation marker predictive of adverse cardiac events. Fat attenuation index (FAI) assesses fat attenuation for predefined coronary segments. Photon-counting detector (PCD) CT employs routine virtual monoenergetic image (VMI) reconstructions. VMI energy level may impact EAT attenuation and FAI measurements. Objective: To assess EAT attenuation and FAI measurements at different monoenergetic keV levels in patients undergoing coronary CTA using a first-generation whole-body dual-source PCD CT scanner. Methods: An anthropomorphic phantom at two sizes with a fat-insert was imaged on a first-generation dual-source PCD CT scanner and, as reference, on a conventional energy-integrating detector (EID) CT scanner at 120 kV. Thirty patients (11 women, 19 men; mean age, 48±10 years; Agatston score ≤60) who underwent an ECG-gated unenhanced calcium-scoring scan and contrast-enhanced coronary CTA by PCD CT were retrospectively evaluated. VMI from 55 to 80 keV at 5 keV increments were reconstructed. EAT attenuation was manually measured on unenhanced and contrast-enhanced images. FAI was calculated using semiautomated software. Results: The phantom fat-insert attenuation was -69 HU for the reference EID CT; closest attenuation for PCT CT was observed at 70 keV for small (-69 HU) and large (-70 HU) phantoms. In patients, EAT attenuation increased for unenhanced acquisition from -111±11 HU at 55 keV to -82±9 HU at 80 keV, and for contrast-enhanced acquisition from -104±11 HU at 55 keV to -81±9 HU at 80 keV. Mean attenuation difference between unenhanced and contrast-enhanced scans decreased with increasing keV level (from 7±12 HU to 1±10 HU). FAI increased from -89±8 HU at 55 keV to -77±12 HU at 80 keV for right coronary artery, -95±11 HU at 55 keV to -85±11 HU at 80 keV for left anterior descending artery, and -87±10 HU at 55 keV to -80±12 HU at 80 keV for circumflex artery. Conclusion: EAT attenuation and FAI measurements using PCD CT are impacted by keV level and contrast enhancement. Use of 70 keV provides fat attenuation approximating conventional polychromatic measurements. Clinical impact: The findings may help standardize evaluation of pericoronary inflammation by PCT CT as a measure of patients' cardiac risk

Lack of Conclusive Evidence of the Benefit of Biologic Augmentation in Core Decompression for Nontraumatic Osteonecrosis of the Femoral Head: A Systematic Review

PURPOSE To assess whether biologic augmentation in addition to core decompression (CD), compared with CD alone, improves clinical and radiographic outcomes in the treatment of nontraumatic osteonecrosis of the femoral head (ONFH). Our hypothesis was that biologic augmentation would reduce the progression of osteonecrosis and therefore also the rate of conversion to total hip arthroplasty (THA). METHODS A systematic review was performed in accordance with the Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) statement. Six databases were searched: Central, MEDLINE, Embase, Scopus, AMED, and Web of Science. Studies comparing outcomes of CD versus CD plus biologic augmentation (with or without structural augmentation), with a reported minimum level of evidence of III and ≥24 months of follow-up, were eligible. Procedural success was conceptualized as (1) avoidance of conversion to THA and (2) absence of radiographic disease progression. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal checklists. A quantitative analysis of heterogeneity was undertaken. RESULTS We included studies reporting on 560 hips in 484 patients. Biologic augmentation consisted of bone marrow stem cells in 10 studies, bone morphogenic protein in 2, and platelet-rich plasma in 1. Three studies used additional structural augmentation. The median maximum follow-up time was 45 months. Only 4 studies reported improvement in all clinical scores in the augmentation group. Seven studies observed a reduction in the rate of radiographic progression, and only 5 found reduced rates of conversion to THA when using augmentation. A high risk of bias and marked heterogeneity was found, with uncertainty about the study designs implemented, analytical approaches, and quality of reporting. CONCLUSION Current evidence is inconclusive regarding the benefit of biologic augmentation in CD for nontraumatic ONFH, because of inconsistent results with substantial heterogeneity and high risk of bias. LEVEL OF EVIDENCE III, systematic review of level I, II, and III studies