Clinical accuracy of a patient-specific femoral osteotomy guide in minimally-invasive posterior hip arthroplasty.

INTRODUCTION: Patient specific guides can be a valuable tool in improving the precision of planned femoral neck osteotomies, especially in minimally invasive hip surgery, where bony landmarks are often inaccessible. The aim of our study was to validate the accuracy of a novel patient specific femoral osteotomy guide for THR through a minimally invasive posterior approach, the direct superior approach (DSA). METHODS: As part of our routine preoperative planning 30 patients underwent low dose CT scans of their arthritic hip. 3D printed patient specific femoral neck osteotomy guides were then produced. Intraoperatively, having cleared all soft tissue from the postero-lateral neck of the enlocated hip, the guide was placed and pinned onto the posterolateral femoral neck. The osteotomy was performed using an oscillating saw and the uncemented hip components were implanted as per routine. Postoperatively, the achieved level of the osteotomy at the medial calcar was compared with the planned level of resection using a 3D/2D matching analysis (Mimics X-ray module, Materialise, Belgium). RESULTS: A total of 30 patients undergoing uncemented Trinity acetabular and TriFit TS femoral component arthroplasty (Corin, UK) were included in our analysis. All but one of our analysed osteotomies were found to be within 3 mm from the planned height of osteotomy. In one patient the level of osteotomy deviated 5 mm below the planned level of resection. CONCLUSION: Preoperative planning and the use of patient specific osteotomy guides provides an accurate method of performing femoral neck osteotomies in minimally invasive hip arthroplasty using the direct superior approach. LEVEL OF EVIDENCE: IV (Case series).

Ability-Based Balancing Using the Gross Motor Function Measure in Exergaming for Youth with Cerebral Palsy.

OBJECTIVE: To test if the gross motor function measure (GMFM) could be used to improve game balancing allowing youth with cerebral palsy (CP) with different physical abilities to play a cycling-based exercise videogame together. Our secondary objective determined if exergaming with the GMFM Ability-Based algorithm was enjoyable. MATERIALS AND METHODS: Eight youth with CP, 8-14 years of age, GMFM scores between 25.2% and 87.4% (evenly distributed between Gross Motor Function Classification System levels II and III), competed against each other in head-to-head races, totaling 28 unique race dyads. Dyads raced three times, each with a different method of minimizing the distance between participants (three balancing algorithms). This was a prospective repeated measures intervention trial with randomized and blinded algorithm assignment. The GMFM Ability-Based algorithm was developed using a least squares linear regression between the players' GMFM score and cycling cadence. Our primary outcome was dyad spread or average distance between players. The GMFM Ability-based algorithm was compared with a control algorithm (No-Balancing), and an idealized algorithm (one-speed-for-all [OSFA]). After each race, participants were asked "Was that game fun?" and "Was that game fair?" using a five-point Likert scale. RESULTS: Participants pedaled quickly enough to elevate their heart rate to an average of 120 ± 8 beats per minute while playing. Dyad spread was lower when using GMFM Ability-Based balancing (4.6 ± 4.2) compared with No-Balancing (11.9 ± 6.8) (P < 0.001). When using OSFA balancing, dyad spread was (1.6 ± 0.9), lower than both GMFM Ability-Based (P = 0.006) and No-Balancing (P < 0.001). Cycling cadence positively correlated to GMFM, equal to 0.58 (GMFM) +33.29 (R2adj= 0.662, P = 0.004). Participants rated the games a median score 4/5 for both questions: "was that game fun?" and "was that game fair?." CONCLUSION: The GMFM Ability-Based balancing decreased dyad spread while requiring participants to pedal quickly, facilitating interaction and physical activity.

A Comparison of 2-Year Outcomes in Patients Undergoing Tibiofemoral or Patellofemoral Matrix-Induced Autologous Chondrocyte Implantation.

BACKGROUND: Matrix-induced autologous chondrocyte implantation (MACI) has demonstrated encouraging clinical results in the treatment of knee chondral defects. However, earlier studies suggested that chondrocyte implantation in the patellofemoral (PF) joint was less effective than in the tibiofemoral (TF) joint. PURPOSE: To compare the radiological and clinical outcomes of those undergoing MACI to either the femoral condyles or PF joint. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 194 patients were included in this analysis, including 127 undergoing MACI to the medial (n = 94) and lateral (n = 33) femoral condyle, as well as 67 to the patella (n = 35) or trochlea (n = 32). All patients were evaluated clinically (Knee injury and Osteoarthritis Outcome Score [KOOS], visual analog scale, Short Form-36) before surgery and at 3, 12, and 24 months after surgery, while magnetic resonance imaging (MRI) was undertaken at 3, 12, and 24 months, with the MOCART (magnetic resonance observation of cartilage repair tissue) scoring system employed to evaluate the quality and quantity of repair tissue, as well as an MRI composite score. Patient satisfaction was evaluated. RESULTS: No significant group differences ( P > .05) were seen in demographics, defect size, prior injury, or surgical history, while the majority of clinical scores were similar preoperatively. All clinical scores significantly improved over time ( P < .05), with a significant group effect observed for KOOS activities of daily living ( P = .008), quality of life ( P = .008), and sport ( P = .017), reflecting better postoperative scores in the TF group. While the PF group had significantly lower values at baseline for the KOOS activities of daily living and quality of life subscales, it actually displayed a similar net improvement over time compared with the TF group. At 24 months, 93.7% (n = 119) and 91.0% (n = 61) of patients were satisfied with the ability of MACI to relieve their knee pain, 74.0% (n = 94) and 65.7% (n = 44) with their ability to participate in sport, and 90.5% (n = 115) and 83.6% (n = 56) satisfied overall, in the TF and PF groups, respectively. MRI evaluation via the MOCART score revealed a significant time effect ( P < .05) for the MRI composite score and graft infill over the 24-month period. While subchondral lamina scored significantly better ( P = .002) in the TF group, subchondral bone scored significantly worse ( P < .001). At 24 months, the overall MRI composite score was classified as good/excellent in 98 TF patients (77%) and 54 PF patients (81%). CONCLUSION: MACI in the PF joint with concurrent correction of PF maltracking if required leads to similar clinical and radiological outcomes compared with MACI on the femoral condyles.

Balancing for Gross Motor Ability in Exergaming Between Youth with Cerebral Palsy at Gross Motor Function Classification System Levels II and III.

OBJECTIVE: To test how three custom-built balancing algorithms minimize differences in game success, time above 40% heart rate reserve (HRR), and enjoyment between youth with cerebral palsy (CP) who have different gross motor function capabilities. Youth at Gross Motor Function Classification System (GMFCS) level II (unassisted walking) and level III (mobility aids needed for walking) competed in a cycling-based exercise video game that tested three balancing algorithms. MATERIALS AND METHODS: Three algorithms: a control (generic-balancing [GB]), a constant non-person specific (One-Speed-For-All [OSFA]), and a person-specific (Target-Cadence [TC]) algorithms were built. In this prospective repeated measures intervention trial with randomized and blinded algorithm assignment, 10 youth with CP aged 10-16 years (X ± standard deviation = 12.4 ± 1.8 years; GMFCS level II n = 4, III n = 6) played six exergaming sessions using each of the three algorithms. Outcomes included game success as measured by a normalized game score, time above 40% HRR, and enjoyment. RESULTS: The TC algorithm balanced game success between GMFCS levels similarly to GB (P = 0.11) and OSFA (P = 0.41). TC showed poorer balancing in time above 40% HRR compared to GB (P = 0.02) and OSFA (P = 0.02). Enjoyment ratings were high (6.4 ± 0.7/7) and consistent between all algorithms (TC vs. GB: P = 0.80 and TC vs. OSFA: P = 0.19). CONCLUSION: TC shows promise in balancing game success and enjoyment but improvements are needed to balance between GMFCS levels for cardiovascular exercise.

Interobserver and intraobserver variability of glenoid track measurements.

BACKGROUND: A method of assessing combined glenoid and humeral bone loss in traumatic shoulder instability with an associated treatment protocol was recently published. The aim of this study was to investigate its reliability and reproducibility. METHODS: Seventy-one patients with unilateral anteroinferior shoulder instability underwent computed tomography scans, from which 3-dimensional images were derived. En face views of both glenoid fossae and with 3 views of the humeral head were provided to 4 assessors to determine interobserver reliability. From these measurements, the shoulder was assigned a treatment classification. Two observers repeated their assessments 1 month later to determine intraobserver reliability. For each measurement, the mean coefficient of variability was calculated. RESULTS: Assessment of glenoid bone loss showed good interobserver (4 observers agreeing in 90.1% of cases) and also good intraobserver agreement (94% and 96%). There was a poor level of interobserver reliability regarding the on-track or off-track classification (72%). Intraobserver reliability for this measurement was less variable (90% and 80%). There was a poor level of agreement between observers (65%) regarding treatment classification. The coefficient of variability for the Hill-Sachs lesion measured 19.2%, indicating a high level of variability for this measurement compared with <4% for all other measures. CONCLUSION: Linear bone loss on the glenoid can be measured reliably and reproducibly; however, evaluation of Hill-Sachs lesions demonstrates a high level of variability, and poor interobserver reliability.

Simultaneous intrinsic and extrinsic calibration of a laser deflecting tilting mirror in the projective voltage space.

PURPOSE  : During the past five decades, laser technology emerged and is nowadays part of a great number of scientific and industrial applications. In the medical field, the integration of laser technology is on the rise and has already been widely adopted in contemporary medical applications. However, it is new to use a laser to cut bone and perform general osteotomy surgical tasks with it. In this paper, we describe a method to calibrate a laser deflecting tilting mirror and integrate it into a sophisticated laser osteotome, involving next generation robots and optical tracking. METHODS  : A mathematical model was derived, which describes a controllable deflection mirror by the general projective transformation. This makes the application of well-known camera calibration methods possible. In particular, the direct linear transformation algorithm is applied to calibrate and integrate a laser deflecting tilting mirror into the affine transformation chain of a surgical system. RESULTS  : Experiments were performed on synthetic generated calibration input, and the calibration was tested with real data. The determined target registration errors in a working distance of 150 mm for both simulated input and real data agree at the declared noise level of the applied optical 3D tracking system: The evaluation of the synthetic input showed an error of 0.4 mm, and the error with the real data was 0.3 mm.

Augmented reality assisted laparoscopic partial nephrectomy.

Computer assisted navigation is a widely adopted technique in neurosurgery and orthopedics. However, it is rarely used for surgeries on abdominal organs. In this paper, we propose a novel, noninvasive method based on electromagnetic tracking to determine the pose of the kidney. As a clinical use case, we show a complete surgical navigation system for augmented reality assisted laparoscopic partial nephrectomy. Experiments were performed ex vivo on pig kidneys and the evaluation showed an excellent augmented reality alignment error of 2.1 mm ± 1.2 mm.

Shared protein complex subunits contribute to explaining disrupted co-occurrence.

The gene composition of present-day genomes has been shaped by a complicated evolutionary history, resulting in diverse distributions of genes across genomes. The pattern of presence and absence of a gene in different genomes is called its phylogenetic profile. It has been shown that proteins whose encoding genes have highly similar profiles tend to be functionally related: As these genes were gained and lost together, their encoded proteins can probably only perform their full function if both are present. However, a large proportion of genes encoding interacting proteins do not have matching profiles. In this study, we analysed one possible reason for this, namely that phylogenetic profiles can be affected by multi-functional proteins such as shared subunits of two or more protein complexes. We found that by considering triplets of proteins, of which one protein is multi-functional, a large fraction of disturbed co-occurrence patterns can be explained.

A predicted functional gene network for the plant pathogen Phytophthora infestans as a framework for genomic biology.

BACKGROUND: Associations between proteins are essential to understand cell biology. While this complex interplay between proteins has been studied in model organisms, it has not yet been described for the oomycete late blight pathogen Phytophthora infestans. RESULTS: We present an integrative probabilistic functional gene network that provides associations for 37 percent of the predicted P. infestans proteome. Our method unifies available genomic, transcriptomic and comparative genomic data into a single comprehensive network using a Bayesian approach. Enrichment of proteins residing in the same or related subcellular localization validates the biological coherence of our predictions. The network serves as a framework to query existing genomic data using network-based methods, which thus far was not possible in Phytophthora. We used the network to study the set of interacting proteins that are encoded by genes co-expressed during sporulation. This identified potential novel roles for proteins in spore formation through their links to proteins known to be involved in this process such as the phosphatase Cdc14. CONCLUSIONS: The functional association network represents a novel genome-wide data source for P. infestans that also acts as a framework to interrogate other system-wide data. In both capacities it will improve our understanding of the complex biology of P. infestans and related oomycete pathogens.

Improving phylogenetic inference with a semiempirical amino acid substitution model.

Amino acid substitution matrices describe the rates by which amino acids are replaced during evolution. In contrast to nucleotide or codon models, amino acid substitution matrices are in general parameterless and empirically estimated, probably because there is no obvious parametrization for amino acid substitutions. Principal component analysis has previously been used to improve codon substitution models by empirically finding the most relevant parameters. Here, we apply the same method to amino acid substitution matrices, leading to a semiempirical substitution model that can adjust the transition rates to the protein sequences under investigation. Our new model almost invariably achieves the best likelihood values in large-scale comparisons with established amino acid substitution models (JTT, WAG, and LG). In particular for longer alignments, these likelihood gains are considerably larger than what could be expected from simply having more parameters. The application of our model differs from that of mixture models (such as UL2 or UL3), as we optimize one rate matrix per alignment, whereas mixture models apply the variation per alignments site. This makes our model computationally more efficient, while the performance is comparable to that of UL3. Applied to the phylogenetic problem of the origin of placental mammals, our new model and the UL3 mixed model are the only ones of the tested models that cluster Afrotheria and Xenarthra into a clade called Atlantogenata, which would be in correspondence with recent findings using more sophisticated phylogenetic methods.

A new semiempirical codon substitution model based on principal component analysis of mammalian sequences.

Codon substitution models have traditionally been parametric Markov models, but recently, empirical and semiempirical models also have been proposed. Parametric codon models are typically based on 61×61 rate matrices that are derived from a small number of parameters. These parameters are rooted in experience and theoretical considerations and generally show good performance but are still relatively arbitrary. We have previously used principal component analysis (PCA) on data obtained from mammalian sequence alignments to empirically identify the most relevant parameters for codon substitution models, thereby confirming some commonly used parameters but also suggesting new ones. Here, we present a new semiempirical codon substitution model that is directly based on those PCA results. The substitution rate matrix is constructed from linear combinations of the first few (the most important) principal components with the coefficients being free model parameters. Thus, the model is not only based on empirical rates but also uses the empirically determined most relevant parameters for a codon model to adjust to the particularities of individual data sets. In comparisons against established parametric and semiempirical models, the new model consistently achieves the highest likelihood values when applied to sequences of vertebrates, which include the taxonomic class where the model was trained on.

A genomic approach to examine the complex evolution of laurasiatherian mammals.

Recent phylogenomic studies have failed to conclusively resolve certain branches of the placental mammalian tree, despite the evolutionary analysis of genomic data from 32 species. Previous analyses of single genes and retroposon insertion data yielded support for different phylogenetic scenarios for the most basal divergences. The results indicated that some mammalian divergences were best interpreted not as a single bifurcating tree, but as an evolutionary network. In these studies the relationships among some orders of the super-clade Laurasiatheria were poorly supported, albeit not studied in detail. Therefore, 4775 protein-coding genes (6,196,263 nucleotides) were collected and aligned in order to analyze the evolution of this clade. Additionally, over 200,000 introns were screened in silico, resulting in 32 phylogenetically informative long interspersed nuclear elements (LINE) insertion events. The present study shows that the genome evolution of Laurasiatheria may best be understood as an evolutionary network. Thus, contrary to the common expectation to resolve major evolutionary events as a bifurcating tree, genome analyses unveil complex speciation processes even in deep mammalian divergences. We exemplify this on a subset of 1159 suitable genes that have individual histories, most likely due to incomplete lineage sorting or introgression, processes that can make the genealogy of mammalian genomes complex. These unexpected results have major implications for the understanding of evolution in general, because the evolution of even some higher level taxa such as mammalian orders may sometimes not be interpreted as a simple bifurcating pattern.

A method for inferring the rate of occurrence and fitness effects of advantageous mutations.

The distribution of fitness effects (DFE) of new mutations is of fundamental importance in evolutionary genetics. Recently, methods have been developed for inferring the DFE that use information from the allele frequency distributions of putatively neutral and selected nucleotide polymorphic variants in a population sample. Here, we extend an existing maximum-likelihood method that estimates the DFE under the assumption that mutational effects are unconditionally deleterious, by including a fraction of positively selected mutations. We allow one or more classes of positive selection coefficients in the model and estimate both the fraction of mutations that are advantageous and the strength of selection acting on them. We show by simulations that the method is capable of recovering the parameters of the DFE under a range of conditions. We apply the method to two data sets on multiple protein-coding genes from African populations of Drosophila melanogaster. We use a probabilistic reconstruction of the ancestral states of the polymorphic sites to distinguish between derived and ancestral states at polymorphic nucleotide sites. In both data sets, we see a significant improvement in the fit when a category of positively selected amino acid mutations is included, but no further improvement if additional categories are added. We estimate that between 1% and 2% of new nonsynonymous mutations in D. melanogaster are positively selected, with a scaled selection coefficient representing the product of the effective population size, N(e), and the strength of selection on heterozygous carriers of ∼2.5.

OMA 2011: orthology inference among 1000 complete genomes.

OMA (Orthologous MAtrix) is a database that identifies orthologs among publicly available, complete genomes. Initiated in 2004, the project is at its 11th release. It now includes 1000 genomes, making it one of the largest resources of its kind. Here, we describe recent developments in terms of species covered; the algorithmic pipeline--in particular regarding the treatment of alternative splicing, and new features of the web (OMA Browser) and programming interface (SOAP API). In the second part, we review the various representations provided by OMA and their typical applications. The database is publicly accessible at http://omabrowser.org.

Empirical analysis of the most relevant parameters of codon substitution models.

Traditionally, codon models of evolution have been parametric, meaning that the 61 x 61 substitution rate matrix was derived from only a handful of parameters, typically the equilibrium frequencies, the ratio of nonsynonymous to synonymous substitution rates and the ratio between transition and transversion rates. These parameters are reasonable choices and are based on observations of what aspects of evolution often vary in coding DNA. However, the choices are relatively arbitrary and no systematic empirical search has ever been performed to identify the best parameters for a codon model. Even for the empirical or semi-empirical models that have been presented recently, only the average substitution rates have been estimated from databases of real coding DNA, but the parameters used were essentially the same as before. In this study we attempted to investigate empirically what the most relevant parameters for a codon model are. By performing a principal component analysis (PCA) on 3666 substitution rate matrices estimated from single gene families, the sets of the most co-varying substitution rates were determined. Interestingly, the two most significant principal components (PCs) describe clearly identifiable parameters: the first PC separates synonymous and nonsynonymous substitutions while the second PC distinguishes between substitutions where only one nucleotide changes and substitutions with two or three nucleotide changes. For the third and subsequent PCs no simple descriptions could be found.

The Microbe browser for comparative genomics.

The Microbe browser is a web server providing comparative microbial genomics data. It offers comprehensive, integrated data from GenBank, RefSeq, UniProt, InterPro, Gene Ontology and the Orthologs Matrix Project (OMA) database, displayed along with gene predictions from five software packages. The Microbe browser is daily updated from the source databases and includes all completely sequenced bacterial and archaeal genomes. The data are displayed in an easy-to-use, interactive website based on Ensembl software. The Microbe browser is available at http://microbe.vital-it.ch/. Programmatic access is available through the OMA application programming interface (API) at http://microbe.vital-it.ch/api.

Support patterns from different outgroups provide a strong phylogenetic signal.

It is known that the accuracy of phylogenetic reconstruction decreases when more distant outgroups are used. We quantify this phenomenon with a novel scoring method, the outgroup score pOG. This score expresses if the support for a particular branch of a tree decreases with increasingly distant outgroups. Large-scale simulations confirmed that the outgroup support follows this expectation and that the pOG score captures this pattern. The score often identifies the correct topology even when the primary reconstruction methods fail, particularly in the presence of model violations. In simulations of problematic phylogenetic scenarios such as rate variation among lineages (which can lead to long-branch attraction artifacts) and quartet-based reconstruction, the pOG analysis outperformed the primary reconstruction methods. Because the pOG method does not make any assumptions about the evolutionary model (besides the decreasing support from increasingly distant outgroups), it can detect cases of violations not treated by a specific model or too strong to be fully corrected. When used as an optimization criterion in the construction of a tree of 23 mammals, the outgroup signal confirmed many well-accepted mammalian orders and superorders. It supports Atlantogenata, a clade of Afrotheria and Xenarthra, and suggests an Artiodactyla-Chiroptera clade.

Estimates of positive Darwinian selection are inflated by errors in sequencing, annotation, and alignment.

Published estimates of the proportion of positively selected genes (PSGs) in human vary over three orders of magnitude. In mammals, estimates of the proportion of PSGs cover an even wider range of values. We used 2,980 orthologous protein-coding genes from human, chimpanzee, macaque, dog, cow, rat, and mouse as well as an established phylogenetic topology to infer the fraction of PSGs in all seven terminal branches. The inferred fraction of PSGs ranged from 0.9% in human through 17.5% in macaque to 23.3% in dog. We found three factors that influence the fraction of genes that exhibit telltale signs of positive selection: the quality of the sequence, the degree of misannotation, and ambiguities in the multiple sequence alignment. The inferred fraction of PSGs in sequences that are deficient in all three criteria of coverage, annotation, and alignment is 7.2 times higher than that in genes with high trace sequencing coverage, "known" annotation status, and perfect alignment scores. We conclude that some estimates on the prevalence of positive Darwinian selection in the literature may be inflated and should be treated with caution.