Three-dimensional biometrics using weight-bearing imaging shows relationship between knee and hindfoot axial alignment.

BACKGROUND: Existence of a relationship between knee and hindfoot alignments is commonly accepted, but not clearly proven. While studied in the coronal plane using 2D imaging, axial alignment has not been studied yet, likely requiring 3D measurements. We aimed to investigate how knee and hindfoot rotational alignments are related using 3D biometrics and modern 3D weight-bearing technologies. HYPOTHESIS: Hindfoot alignment is correlated with femoral and tibial torsions. PATIENTS AND METHODS: All patients who underwent both weight-bearing CT (WBCT) and low dose biplanar radiographs (LDBR) were selected in this retrospective observational study, resulting in a cohort of 157 lower limbs from 99 patients. Patients' pathologies were stratified in subgroups and those with a history of trauma or surgery affecting lower limb alignment were excluded. Foot Ankle Offset was calculated from WBCT; femoral and tibial torsions and coronal alignment were calculated from LDBR, respectively. RESULTS: Overall, mean Foot Ankle Offset was 1.56% (SD 7.4), mean femoral anteversion was 15.6° (SD 9.5), and mean external tibial torsion was 32.6° (SD 7.6). Moderate negative correlation between Tibial Torsion and Foot Ankle Offset was found in the whole series (rho=-0.23, p=0.003) and for non-pathologic patients (rho=-0.27, p=0.01). Linear models to estimate Tibial Torsion with Foot Ankle Offset and conversely were found, with a low adjusted R2 (3%

A Case-Control Study of 3D vs 2D Weightbearing CT Measurements of the M1-M2 Intermetatarsal Angle in Hallux Valgus.

BACKGROUND: Weightbearing computed tomography (WBCT) 3-dimensional measurements may be reliable in assessing hallux valgus (HV). The objective of this study was to compare 2D and 3D WBCT measurements of the M1-M2 intermetatarsal angle (IMA) in patients with HV and in healthy controls. We hypothesized that 2D and 3D IMA measurements would correlate and have similar reliability in both HV and controls. METHODS: Retrospective multicenter comparative study included WBCT scans from 83 feet (41 HV, 42 controls). IMA was measured on digitally reconstructed radiographs (DRR-IMA). 3D angle (3D-IMA) and its projection on the weightbearing plane (2D-IMA) were calculated from 3D coordinates of the first and second metatarsals. Intraobserver reliability and intermethod correlations were calculated using intraclass correlation coefficients (ICCs). RESULTS: Intraobserver reliability was very strong for DRR-IMA (0.95) and 3D-IMA (0.99). Intermethod correlation between the 3 modalities in HV patients ranged from moderate (DRR vs 2D, 0.48; DRR vs 3D, 0.48) to very strong (2D vs 3D, 0.91). Similarly, intermethod correlation in the control group ranged from moderate (DRR vs 2D, 0.56; DRR vs 3D, 0.60) to very strong (2D vs 3D, 0.92). CONCLUSION: Measurements for IMA are similar using DRR, 3D and 2D projected angles, with very strong intraobserver reliability and moderate to very strong intermethod correlations. This is the first head-to-head comparison between these measurement modalities in HV. Further investigations are warranted before formulating guidelines for the clinical use of 3D angles. LEVEL OF EVIDENCE: Level III, case-control study.

Diagnostic accuracy of measurements in progressive collapsing foot deformity using weight bearing computed tomography: A matched case-control study.

BACKGROUND: We aimed to investigate the diagnostic accuracy of known two-dimensional (2D) and three-dimensional (3D) measurements for Progressive Collapsing Foot Deformity (PCFD) in weight-bearing computed tomography (WBCT). We hypothesized that 3D biometrics would have better specificity and sensitivity for PCFD diagnosis than 2D measurements. METHODS: This was a retrospective case-control study, including 28 PCFD feet and 28 controls matched for age, sex and Body Mass Index. Two-dimensional measurements included: axial and sagittal talus-first metatarsal angles (TM1A and TM1S), talonavicular coverage angle (TNCA), forefoot arch angle (FFAA), middle facet incongruence angle (MF°) and uncoverage percentage (MF%). The 3D Foot Ankle Offset (FAO) was obtained using dedicated semi-automatic software. Intra and interobserver reliabilities were assessed. Receiver Operating Characteristic (ROC) curves were calculated to determine diagnostic accuracy (Area Under the Curve (AUC)), sensitivity and specificity. RESULTS: In PCFD, mean MF% and MF° were respectively 47.2% ± 15.4 and 13.3° ± 5.3 compared with 13.5% ± 8.7 and 5.6° ± 2.9 in controls (p < 0.001). The FAO was 8.1% ± 3.8 in PCFD and 1.4% ± 1.7 in controls (p < 0.001). AUCs were 0.99 (95%CI, 0.98-1) for MF%, 0.96 (95%CI, 0.9-1) for FAO, 0.90 (95%CI, 0.81-0.98) for MF°. For MF%, a threshold value equal or greater than 28.7% had a sensitivity of 100% and specificity of 92.8%. Conversely, a FAO value equal or greater than 4.6% had a specificity of 100% and a sensitivity of 89.2%. All other 2D measurements were significantly different in PCFD and controls (p < 0.001). CONCLUSIONS: MF% and FAO were both accurate measurements for PCFD. MF% demonstrated slightly better specificity. FAO better sensitivity. A combination of threshold values of 28.7% for MF% and 4.6% for FAO yielded 100% sensitivity and specificity.

Evaluation of a Weightbearing CT Artificial Intelligence-Based Automatic Measurement for the M1-M2 Intermetatarsal Angle in Hallux Valgus.

BACKGROUND: Weightbearing cone beam computed tomography (WBCT) has been gaining traction as a useful imaging modality in the diagnosis and follow-up of foot and ankle musculoskeletal pathologies due to the ability to perform quick, low-dose, 3-dimensional (3D) scans. However, the resulting wealth of 3D data renders daily clinical use time-consuming. The aim of this study was to evaluate a new artificial intelligence (AI)-based automatic measurement for the M1-M2 intermetatarsal angle (IMA) in hallux valgus (HV). We hypothesized that automatic and manual measurements would have a strong correlation, and that the AI software would yield better reproducibility and would be faster compared with manual measurements. METHODS: This was a multicenter retrospective comparative case-control study in which a total of 128 feet were included from 93 patients who underwent WBCT scans as part of their routine follow-up: 59 feet with symptomatic HV and 69 controls. The IMA was measured automatically using the AI software and manually on digitally reconstructed radiographs (DRRs). The AI software produced both an automatic 2D (auto 2D) and 3D (auto 3D) measurement. RESULTS: There were strong intermethod correlations between the DRR IMA and the auto 2D (HV, r = 0.61; control, r = 0.60; all P < .0001) and auto 3D (HV, r = 0.63; control, r = 0.52; all P < .0001) measurements, respectively. The intrasoftware reproducibility was very close to 100%. Measurements took 23.6 ± 2.31 seconds and 14.5 ± 1.18 seconds, respectively, when taken manually on DRRs and automatically. Controls demonstrated a mean DRR IMA of 8.6 (95% CI, 8.1-9.1), mean auto 2D of 11.2 (95% CI, 10.7-11.7), and mean auto 3D IMA of 11.0 (95% CI, 10.5-11.5). The HV group demonstrated significantly increased IMA compared with controls (P < .0001), with a mean DRR IMA of 15.4 (95% CI, 14.8-16.1), mean auto 2D of 17.8 (95% CI, 17.2-18.4), and mean auto 3D IMA of 16.8 (95% CI, 16.8-17.4). CONCLUSION: Measurements generated by the WBCT AI-based automatic measurement system for IMA demonstrated strong correlations with manual measurements, with near-perfect reproducibility. Further developments are warranted in order to make this tool more usable in daily practice, particularly with respect to its use in the presence of hardware in the foot. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

3D, Weightbearing Topographical Study of Periprosthetic Cysts and Alignment in Total Ankle Replacement.

BACKGROUND: We investigated the association between hindfoot residual malalignment assessed on weightbearing computed tomography (WBCT) images and the development of periprosthetic cysts (PPCs) after total ankle replacement (TAR). We hypothesized that PPCs would be found predominantly medially in the varus configuration and laterally in the valgus configuration. METHODS: Cases of primary TAR with available WBCT imaging of the ankle were included in this retrospective study. The location of the PPC was marked and the following volumes were calculated: total (TCV), medial (MCV), central (CCV), and lateral (LCV) cyst volumes. Hindfoot alignment was measured as Foot and Ankle Offset (FAO), with 95% confidence intervals (95% CIs) calculated to define varus (<95% CI) and valgus (>95% CI) groups. Cyst volumes were compared between these 2 groups. The American Orthopaedic Foot & Ankle Society (AOFAS) score at the time of the WBCT was also retrieved. Receiver operating characteristic (ROC) curves were used to determine FAO thresholds for predicting an increased risk of PPC. RESULTS: Forty-eight TARs (mean follow-up, 44.6 months) were included, 81% of which had at least 1 PPC. The mean FAO was 0.12% (95% CI, -1.12 to 1.36). Patients with greater residual malalignment (P < .001) and those with longer follow-up (P < .001) presented with increased TCV. In varus cases, the MCV was greater than the LCV (P = .042), with a threshold FAO value of -2.75% or less predicting an increased MCV. In valgus cases, the LCV was greater than the MCV (P = .049), with a FAO threshold value of 4.5% or more predicting an increased LCV. CONCLUSION: In this series, the PPC volume after primary TAR significantly correlated with postoperative hindfoot malalignment and longer follow-up. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

Relationship Between Chronic Lateral Ankle Instability and Hindfoot Varus Using Weight-Bearing Cone Beam Computed Tomography.

BACKGROUND: Varus hindfoot deformity may increase the risk of chronic lateral ankle instability (CLAI). Our aim was to analyze hindfoot alignment (HFA) in patients with CLAI using weight-bearing cone beam computed tomography (WBCT) to assess this risk. METHODS: This retrospective, comparative analysis was carried out using an existing WBCT database (Talas, CurveBeam LLC), including data sets for 370 consecutive feet (189 patients) obtained between July 2016 and October 2018 at a single institution. The software provided semiautomated measurement of HFA, given as foot ankle offset (FAO). Univariate analysis was conducted to compare feet with and without CLAI against sex, age, body mass index, and FAO. Significant variables were included in a multivariable logistic model with random effects to take into account correlation between feet of the same patient. RESULTS: Forty-three feet had CLAI (34 patients). FAO (P = .0009) was significant for CLAI by univariate analysis. Mean FAO was -2.2% ± 5.5% (varus) and + 2.6% ± 4.7% (valgus) with and without CLAI history, respectively. Multivariable logistic regression adjusted for sex and age demonstrated a 35% increased odds ratio (OR) of CLAI per 1% reduction in FAO value (varus) (adjusted OR=0.64, 95% confidence interval [CI]: 0.49-0.84; P = .001) and no significant effect of sex (adjusted OR=0.52; P = .617) or age (adjusted OR=0.94; P = .165) after adjustment for FAO. CONCLUSION: A positive relationship was found between varus HFA and the risk to have CLAI. Systematic recording of FAO measurements from WBCT images along with clinical data regarding CLAI history proved successful at quantifying the risk of CLAI. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Cell-cycle regulation of non-enzymatic functions of the Drosophila methyltransferase PR-Set7.

Tight cell-cycle regulation of the histone H4-K20 methyltransferase PR-Set7 is essential for the maintenance of genome integrity. In mammals, this mainly involves the interaction of PR-Set7 with the replication factor PCNA, which triggers the degradation of the enzyme by the CRL4CDT2 E3 ubiquitin ligase. PR-Set7 is also targeted by the SCFß-TRCP ligase, but the role of this additional regulatory pathway remains unclear. Here, we show that Drosophila PR-Set7 undergoes a cell-cycle proteolytic regulation, independently of its interaction with PCNA. Instead, Slimb, the ortholog of ß-TRCP, is specifically required for the degradation of the nuclear pool of PR-Set7 prior to S phase. Consequently, inactivation of Slimb leads to nuclear accumulation of PR-Set7, which triggers aberrant chromatin compaction and G1/S arrest. Strikingly, these phenotypes result from non-enzymatic PR-Set7 functions that prevent proper histone H4 acetylation independently of H4K20 methylation. Altogether, these results identify the Slimb-mediated PR-Set7 proteolysis as a new critical regulatory mechanism required for proper interphase chromatin organization at G1/S transition.

A role for the serine/arginine-rich (SR) protein B52/SRSF6 in cell growth and myc expression in Drosophila.

Serine-/arginine-rich (SR) proteins are RNA-binding proteins that are primarily involved in alternative splicing. Expression of some SR proteins is frequently upregulated in tumors, and previous reports have demonstrated that these proteins can directly participate in cell transformation. Identifying factors that can rescue the effects of SR overexpression in vivo is, therefore, of potential therapeutic interest. Here, we analyzed phenotypes induced by overexpression of the SR protein B52 during Drosophila development and identified several proteins that can rescue these phenotypes. Using the mechanosensory bristle lineage as a developmental model, we show that B52 expression level influences cell growth, but not differentiation, in this lineage. In particular, B52 overexpression increases cell growth, upregulates myc transcription, and gives rise to flies lacking thoracic bristles. Using a genetic screen, we identified several suppressors of the phenotypes induced by overexpression of B52 in vivo in two different organs. We show that upregulation of brain tumor (brat), a tumor suppressor and post-transcriptional repressor of myc, and downregulation of lilliputian (lilli), a subunit of the superelongation complex involved in transcription elongation, efficiently rescue the phenotypes induced by B52 overexpression. Our results demonstrate a role of this SR protein in cell growth and identify candidate proteins that may overcome the effects of SR protein overexpression in mammals.

ftz-f1 and Hr39 opposing roles on EcR expression during Drosophila mushroom body neuron remodeling.

Developmental axon pruning is a general mechanism that is required for maturation of neural circuits. During Drosophila metamorphosis, the larval-specific dendrites and axons of early γ neurons of the mushroom bodies are pruned and replaced by adult-specific processes. We found that the nuclear receptor ftz-f1 is required for this pruning, activates expression of the steroid hormone receptor EcR-B1, whose activity is essential for γ remodeling, and represses expression of Hr39, an ftz-f1 homologous gene. If inappropriately expressed in the γ neurons, HR39 inhibits normal pruning, probably by competing with endogenous FTZ-F1, which results in decreased EcR-B1 expression. EcR-B1 was previously identified as a target of the TGFß signaling pathway. We found that the ftz-f1 and Hr39 pathway apparently acts independently of TGFß signaling, suggesting that EcR-B1 is the target of two parallel molecular pathways that act during γ neuron remodeling.

The SR protein B52/SRp55 is required for DNA topoisomerase I recruitment to chromatin, mRNA release and transcription shutdown.

DNA- and RNA-processing pathways are integrated and interconnected in the eukaryotic nucleus to allow efficient gene expression and to maintain genomic stability. The recruitment of DNA Topoisomerase I (Topo I), an enzyme controlling DNA supercoiling and acting as a specific kinase for the SR-protein family of splicing factors, to highly transcribed loci represents a mechanism by which transcription and processing can be coordinated and genomic instability avoided. Here we show that Drosophila Topo I associates with and phosphorylates the SR protein B52. Surprisingly, expression of a high-affinity binding site for B52 in transgenic flies restricted localization, not only of B52, but also of Topo I to this single transcription site, whereas B52 RNAi knockdown induced mis-localization of Topo I in the nucleolus. Impaired delivery of Topo I to a heat shock gene caused retention of the mRNA at its site of transcription and delayed gene deactivation after heat shock. Our data show that B52 delivers Topo I to RNA polymerase II-active chromatin loci and provide the first evidence that DNA topology and mRNA release can be coordinated to control gene expression.