Subgroups of Idiopathic Clubfoot Can Predict Short-term Outcomes.

BACKGROUND: The Pirani scale is used for the assessment of Ponseti-managed clubfoot. Predicting outcomes using the total Pirani scale score has varied results, however, the prognostic value of midfoot and hindfoot components remains unknown. The purpose was to (1) determine the existence of subgroups of Ponseti-managed idiopathic clubfoot based on the trajectory of change in midfoot and hindfoot Pirani scale scores, (2) identify time points, at which subgroups can be distinguished, and (3) determine whether subgroups are associated with the number of casts required for correction and need for Achilles tenotomy. METHODS: Medical records of 226 children with 335 idiopathic clubfeet, over a 12-year period, were reviewed. Group-based trajectory modeling of the Pirani scale midfoot score and hindfoot score identified subgroups of clubfoot that followed statistically distinct patterns of change during initial Ponseti management. Generalized estimating equations determined the time point, at which subgroups could be distinguished. Comparisons between groups were determined using the Kruskal-Wallis test for the number of casts required for correction and binary logistic regression analysis for the need for tenotomy. RESULTS: Four subgroups were identified based on the rate of midfoot-hindfoot change: (1) fast-steady (61%), (2) steady-steady (19%), (3) fast-nil (7%), and (4) steady-nil (14%). The fast-steady subgroup can be distinguished at the removal of the second cast and all other subgroups can be distinguished at the removal of the fourth cast [ H (3) = 228.76, P < 0.001]. There was a significant statistical, not clinical, difference in the total number of casts required for correction across the 4 subgroups [median number of casts 5 to 6 in all groups, H (3) = 43.82, P < 0.001]. Need for tenotomy was significantly less in the fast-steady (51%) subgroup compared with the steady-steady (80%) subgroup [ H (1) = 16.23, P < 0.001]; tenotomy rates did not differ between the fast-nil (91%) and steady-nil (100%) subgroups [ H (1) = 4.13, P = 0.04]. CONCLUSIONS: Four distinct subgroups of idiopathic clubfoot were identified. Tenotomy rate differs between the subgroups highlighting the clinical benefit of subgrouping to predict outcomes in Ponseti-managed idiopathic clubfoot. LEVEL OF EVIDENCE: Level II, prognostic.

Who Benefits From Allowing the Physis to Grow in Slipped Capital Femoral Epiphysis?

BACKGROUND: The globally acknowledged treatment for mild to moderate slipped capital femoral epiphysis (SCFE) is single screw in situ fixation, also used for prophylactic contralateral fixation. The Free-Gliding Screw (FG; Pega Medical) is a 2-part free-extending screw system designed to allow the growth of the proximal femur. We aimed to analyze the relationship between skeletal maturity and potential growth of the proximal physis and remodeling of the femoral neck using this implant. MATERIALS AND METHODS: Females below 12 years and males below 14 years undergoing in situ fixation for stable SCFE or prophylactic fixation were treated using the implant. Three elements of the modified Oxford Bone (mOB 3 ) score were used to measure maturity (triradiate cartilage, head of the femur, and greater trochanter). Radiographs were analyzed immediately postoperatively and at a minimum of 2 years for a change in screw length, posterior-sloping angle, articulotrochanteric distance, α angle, and head-neck offset. RESULTS: The study group comprised 30 (F:M=12:18) of 39 hips treated with SCFE and 22 (F:M=13:9) of 29 hips managed prophylactically using the free-Gliding screw. In the therapeutic group, chronologic age was a less valuable predictor of future screw lengthening than mOB 3 . An mOB 3 of ≤13 predicted future growth of >6 mm but did not reach statistical significance ( P =0.07). Patients with open triradiates showed a mean screw lengthening of 6.6 mm compared with those with closed triradiates (4.0 mm), but this did not reach significance ( P =0.12). In those with mOB 3 ≤13, the α angle reduced significantly ( P <0.01) and the head-neck offset increased significantly, suggesting remodeling. There was no change in these parameters when mOB 3 ≥14. In the prophylactic group, change in screw length was significant with mOB 3 of ≤13 (mean=8.0 mm, P <0.05), as was the presence of an open triradiate cartilage (mean=7.7 mm, P <0.05). In both cohorts, posterior-sloping angle and articulotrochanteric distance did not change, indicating no slip progression in either treatment or prophylactic groups and minimal effect on the proximal physeal growth relative to the greater trochanter. CONCLUSIONS: Growing screw constructs can halt slip progression while allowing proximal femoral growth in young patients with SCFE. Ongoing growth is better when the implant is used for prophylactic fixation. The results in treated SCFE need to be expanded to demonstrate a clinically meaningful cut-off for significant growth, but SCFE patients with an open triradiate remodel significantly more than those where it is closed. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Optimization of globomycin analogs as novel gram-negative antibiotics.

Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 µM) and 61 (E. coli MIC 0.78 µM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery.

Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.

Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).

Water molecules in protein-ligand interfaces. Evaluation of software tools and SAR comparison.

Targeting the interaction with or displacement of the 'right' water molecule can significantly increase inhibitor potency in structure-guided drug design. Multiple computational approaches exist to predict which waters should be targeted for displacement to achieve the largest gain in potency. However, the relative success of different methods remains underexplored. Here, we present a comparison of the ability of five water prediction programs (3D-RISM, SZMAP, WaterFLAP, WaterRank, and WaterMap) to predict crystallographic water locations, calculate their binding free energies, and to relate differences in these energies to observed changes in potency. The structural cohort included nine Bruton's Tyrosine Kinase (BTK) structures, and nine bromodomain structures. Each program accurately predicted the locations of most crystallographic water molecules. However, the predicted binding free energies correlated poorly with the observed changes in inhibitor potency when solvent atoms were displaced by chemical changes in closely related compounds.

Safety profile of ultrasound enhancing agents in echocardiography.

INTRODUCTION: Ultrasound enhancing agents (UEAs) are often utilized to enhance ultrasound image quality; however, concerns about adverse reactions have limited their use. Moreover, these agents had been either contraindicated or are labeled with a warning in patients with intra-cardiac shunts because of a theoretic risk of systemic microvascular obstruction. This labeling was recently removed in the United States, but data in these patients are lacking. METHODS: Over a 15-month period, patients receiving three different FDA-approved UEAs at our center were prospectively evaluated for clinically significant adverse events (AEs). RESULTS: A total of 5521 UEA administrations were performed (Definity® : 3306, Lumason® : 2137, Optison® : 78). There were 14 AEs (0.25%) reported (Lumason® : 0.05% [n = 1] vs Definity® : 0.39% [n = 13], P = 0.02). Back pain was the most common complaint (n = 9), followed by headache (n = 2), rash (n = 2), dyspnea (n = 2), and palpitations (n = 1). Among the 33 patients known to have intra-cardiac shunts, there were no AEs. Known right-to-left shunts with positive saline bubble study were present in 20 patients (Lumason® : n = 9, Definity® : n = 11). Left-to-right atrial shunts based on color Doppler were present in 10 patients (Lumason® : n = 5, Definity® n = 5). Three patients were known to have ventricular septal defect with left-to-right flow (Definity® : n = 2, Optison® : n = 1). CONCLUSION: Adverse events were significantly higher with Definity® ; however, overall incidences were low, and AEs were minor. Furthermore, no AEs were reported in patients with known intra-cardiac shunts. UEAs showed a good safety profile in our study and should be afforded to all appropriate patients, including those with known intra-cardiac shunts.

Prevalence and orthopedic management of foot and ankle deformities in Charcot-Marie-Tooth disease.

INTRODUCTION: Foot deformities are frequent complications in Charcot-Marie-Tooth disease (CMT) patients, often requiring orthopedic surgery. However, there are no prospective, randomized studies on surgical management, and there is variation in the approaches among centers both within and between countries. METHODS: In this study we assessed the frequency of foot deformities and surgery among patients recruited into the Inherited Neuropathies Consortium (INC). We also designed a survey addressed to orthopedic surgeons at INC centers to determine whether surgical approaches to orthopedic complications in CMT are variable. RESULTS: Foot deformities were reported in 71% of CMT patients; 30% of the patients had surgery. Survey questions were answered by 16 surgeons working in different specialized centers. Most of the respondents were foot and ankle surgeons. There was marked variation in surgical management. DISCUSSION: Our findings confirm that the approaches to orthopedic management of CMT are varied. We identify areas that require further research. Muscle Nerve 57: 255-259, 2018.

Common paediatric conditions of the lower limb.

Growing children are susceptible to a number of disorders to their lower extremities of varying degrees of severity. The diagnosis and management of these conditions can be challenging. With musculoskeletal symptoms being one of the leading reasons for visits to general practitioners, a working knowledge of the basics of these disorders can help in the appropriate diagnosis, treatment, counselling, and specialist referral. This review covers common disorders affecting the hip, the knee and the foot. The aim is to assist general practitioners in recognising developmental norms and differentiating physiological from pathological conditions and to identify when a specialist referral is necessary.

Chelonian perivitelline membrane-bound sperm detection: A new breeding management tool.

Perivitelline membrane (PVM)-bound sperm detection has recently been incorporated into avian breeding programs to assess egg fertility, confirm successful copulation, and to evaluate male reproductive status and pair compatibility. Due to the similarities between avian and chelonian egg structure and development, and because fertility determination in chelonian eggs lacking embryonic growth is equally challenging, PVM-bound sperm detection may also be a promising tool for the reproductive management of turtles and tortoises. This study is the first to successfully demonstrate the use of PVM-bound sperm detection in chelonian eggs. Recovered membranes were stained with Hoechst 33342 and examined for sperm presence using fluorescence microscopy. Sperm were positively identified for up to 206 days post-oviposition, following storage, diapause, and/or incubation, in 52 opportunistically collected eggs representing 12 species. However, advanced microbial infection frequently hindered the ability to detect membrane-bound sperm. Fertile Centrochelys sulcata, Manouria emys, and Stigmochelys pardalis eggs were used to evaluate the impact of incubation and storage on the ability to detect sperm. Storage at -20°C or in formalin were found to be the best methods for egg preservation prior to sperm detection. Additionally, sperm-derived mtDNA was isolated and PCR amplified from Astrochelys radiata, C. sulcata, and S. pardalis eggs. PVM-bound sperm detection has the potential to substantially improve studies of artificial incubation and sperm storage, and could be used to evaluate the success of artificial insemination in chelonian species. Mitochondrial DNA from PVM-bound sperm has applications for parentage analysis, the study of sperm competition, and potentially species identification.

Structure-guided design of a selective BCL-X(L) inhibitor.

The prosurvival BCL-2 family protein BCL-X(L) is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X(L) will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X(L)-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X(L) and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X(L) and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X(L) from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X(L) for their sustained growth.

Experimental and Computational Studies of the Diastereoselective Alkylations of 3-Substituted γ-Sultams.

We report that chiral 3-substituted γ-sultam α-carbanions undergo diastereoselective alkylation reactions with alkyl halides to predominantly produce trans-3,5-disubstituted γ-sultam products. Quantum mechanical calculations provided a stereoelectronic rationale for the observed diastereoselectivity.

Interventions for congenital talipes equinovarus (clubfoot).

BACKGROUND: Congenital talipes equinovarus (CTEV), which is also known as clubfoot, is a common congenital orthopaedic condition characterised by an excessively turned in foot (equinovarus) and high medial longitudinal arch (cavus). If left untreated it can result in long-term disability, deformity and pain. Interventions can be conservative (such as splinting or stretching) or surgical. The review was first published in 2012 and we reviewed new searches in 2013 (update published 2014). OBJECTIVES: To evaluate the effectiveness of interventions for CTEV. SEARCH METHODS: On 29 April 2013, we searched CENTRAL (2013, Issue 3 in The Cochrane Library), MEDLINE (January 1966 to April 2013), EMBASE (January 1980 to April 2013), CINAHL Plus (January 1937 to April 2013), AMED (1985 to April 2013), and the Physiotherapy Evidence Database (PEDro to April 2013). We also searched for ongoing trials in the WHO International Clinical Trials Registry Platform (2006 to July 2013) and ClinicalTrials.gov (to November 2013). We checked the references of included studies. We searched NHSEED, DARE and HTA for information for inclusion in the Discussion. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating interventions for CTEV. Participants were people of all ages with CTEV of either one or both feet. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in included trials and extracted the data. We contacted authors of included trials for missing information. We collected adverse event information from trials when it was available. MAIN RESULTS: We identified 14 trials in which there were 607 participants; one of the trials was newly included at this 2014 update. The use of different outcome measures prevented pooling of data for meta-analysis even when interventions and participants were comparable. All trials displayed bias in four or more areas. One trial reported on the primary outcome of function, though raw data were not available to be analysed. We were able to analyse data on foot alignment (Pirani score), a secondary outcome, from three trials. Two of the trials involved participants at initial presentation. One reported that the Ponseti technique significantly improved foot alignment compared to the Kite technique. After 10 weeks of serial casting, the average total Pirani score of the Ponseti group was 1.15 (95% confidence interval (CI) 0.98 to 1.32) lower than that of the Kite group. The second trial found the Ponseti technique to be superior to a traditional technique, with average total Pirani scores of the Ponseti participants 1.50 lower (95% CI 0.72 to 2.28) after serial casting and Achilles tenotomy. A trial in which the type of presentation was not reported found no difference between an accelerated Ponseti or standard Ponseti treatment. At the end of serial casting, the average total Pirani scores in the standard group were 0.31 lower (95% CI -0.40 to 1.02) than the accelerated group. Two trials in initial cases found relapse following Ponseti treatment was more likely to be corrected with further serial casting compared to the Kite groups which more often required major surgery (risk difference 25% and 50%). There is a lack of evidence for different plaster casting products, the addition of botulinum toxin A during the Ponseti technique, different types of major foot surgery, continuous passive motion treatment following major foot surgery, or treatment of relapsed or neglected cases of CTEV. Most trials did not report on adverse events. In trials evaluating serial casting techniques, adverse events included cast slippage (needing replacement), plaster sores (pressure areas) and skin irritation. Adverse events following surgical procedures included infection and the need for skin grafting. AUTHORS' CONCLUSIONS: From the limited evidence available, the Ponseti technique produced significantly better short-term foot alignment compared to the Kite technique and compared to a traditional technique. The quality of this evidence was low to very low. An accelerated Ponseti technique may be as effective as a standard technique, according to moderate quality evidence. Relapse following the Kite technique more often led to major surgery compared to relapse following the Ponseti technique. We could draw no conclusions from other included trials because of the limited use of validated outcome measures and lack of available raw data. Future randomised controlled trials should address these issues.

Bilateral clubfeet are highly correlated: a cautionary tale for researchers.

BACKGROUND: Congenital talipes equinovarus, or clubfoot, is a common pediatric orthopaedic condition of unknown origin. In many clubfoot clinical trials, interventions are assigned to a patient, but response to treatment is assessed separately in each foot. Trials commonly report x patients with y feet where y is greater than x (eg, 35 patients with 56 feet). However, common statistical tests assume that each data point is independent. Although data from unilateral cases of clubfoot are independent, it is unknown if each foot of patients with bilateral clubfeet are correlated. QUESTIONS/PURPOSES: The purpose of this study was to assess the correlation in the feet of patients with bilateral clubfeet by (1) evaluating the degree of severity between lower limbs of each patient with bilateral clubfeet at baseline; (2) determining if right and left feet of each patient responded to intervention in the same way; (3) determining the proportion of bilateral relapse; and (4) determining the proportion of right and left feet which required the same intervention to correct bilateral relapse. METHODS: We performed a chart review of the records of 33 patients with bilateral clubfeet (66 feet). Baseline severity was assessed using the Pirani score. The number of Ponseti serial casts to correct the deformity, the proportion of patients who underwent bilateral Achilles tenotomy, the proportion of bilateral relapse, and the treatment to correct bilateral relapse were examined. RESULTS: The degree of severity between right (Pirani score mean, 5.2; SD, 0.8) and left (Pirani score mean, 5.2; SD, 0.5) feet for each patient at baseline was highly correlated (r=0.76, p<0.001). Response to intervention between lower limbs was highly correlated for the number of Ponseti casts required for initial correction (right mean, 5.2, SD, 1.1; left mean, 5.2, SD, 1.3) (r=0.89, p<0.001) and the proportion of patients who underwent bilateral Achilles tenotomy (right, 17/18; left, 16/18) (r=0.94, p<0.001). In the nine patients who experienced relapse, eight experienced bilateral involvement. In all cases of bilateral relapse, the right and left foot of each patient required the same intervention to correct the relapse. CONCLUSIONS: In patients with bilateral clubfeet, baseline severity, response to initial Ponseti treatment, Achilles tenotomy, and relapse outcomes were highly correlated in the right and left feet of each patient. Pooling clinical results of patients who present with bilateral clubfeet is statistically inappropriate, since results in two limbs of the same patient do not represent independent observations. These results support analogous work in other specialties suggesting that patients with bilateral presentations should not be analyzed as independent data points. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Is tibialis anterior tendon transfer effective for recurrent clubfoot?

BACKGROUND: Tibialis anterior tendon transfer surgery forms a part of Ponseti management for children with congenital talipes equinovarus who, after initial correction, present with residual dynamic supination. Although retrospective studies support good outcomes, prospective longitudinal studies in this population are lacking. QUESTIONS/PURPOSES: We assessed strength, plantar loading, ROM, foot alignment, function, satisfaction, and quality of life in patients with clubfoot that recurred after Ponseti casting who met indications for tibialis anterior tendon transfer surgery, and compared them with a group of patients with clubfoot treated with casting but whose deformity did not recur (therefore who were not indicated for tibialis anterior tendon transfer surgery). METHODS: Twenty children with idiopathic congenital talipes equinovarus indicated for tibialis anterior tendon transfer surgery were recruited. Assessment at baseline (before surgery), and 3, 6, and 12 months (after surgery) included strength (hand-held dynamometry), plantar loading (capacitance transducer matrix platform), ROM (Dimeglio scale), foot alignment (Foot Posture Index(©)), function and satisfaction (disease-specific instrument for clubfoot), and quality of life (Infant Toddler Quality of Life Questionnaire™). Outcomes were compared with those of 12 age-matched children with congenital talipes equinovarus not indicated for tibialis anterior tendon transfer surgery. Followup was 100% in the control group and 95% (19 of 20) in the tibialis anterior transfer group. RESULTS: At baseline, the tibialis anterior tendon transfer group had a significantly worse eversion-to-inversion strength ratio, plantar loading, ROM, foot alignment, and function and satisfaction. At 3 months after surgery, eversion-to-inversion strength, plantar loading, and function and satisfaction were no longer different between groups. Improvements were maintained at 12 months after surgery (eversion-to-inversion strength mean difference, 8% body weight; 95% CI, -26% to 11%; p = 0.412; plantar loading, p > 0.251; function and satisfaction, p = 0.076). ROM remained less and foot alignment more supinated in the tibialis anterior tendon transfer group between baseline and followup (p < 0.001, p < 0.001). CONCLUSIONS: Tibialis anterior tendon transfer surgery was an effective procedure, which at 12-month followup restored the balance of eversion-to-inversion strength and resulted in plantar loading and function and satisfaction outcomes similar to those of age-matched children with congenital talipes equinovarus who after Ponseti casting were not indicated for tibialis anterior tendon transfer.

Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model.

The lack of selective and safe in vivo IRE1α tool molecules has limited the evaluation of IRE1α as a viable target to treat multiple myeloma. Focus on improving the physicochemical properties of a literature compound by decreasing lipophilicity, molecular weight, and basicity allowed the discovery of a novel series with a favorable in vitro safety profile and good oral exposure. These efforts culminated in the identification of a potent and selective in vivo tool compound, G-5758, that was well tolerated following multiday oral administration of doses up to 500 mg/kg. G-5758 demonstrated comparable pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s levels in a multiple myeloma model (KMS-11).

Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors.

A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of Jak1 and Jak2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjusted to gain cellular activity. The crystal structures of two representative inhibitors bound to Jak1 were obtained to enable SAR exploration.

Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors.

The advancement of a series of ligand efficient 2-amino-[1,2,4]triazolo[1,5-a]pyridines, initially identified from high-throughput screening, to a JAK2 inhibitor with pharmacodynamic activity in a mouse xenograft model is disclosed.

Update on clubfoot.

Congental talipes equinovarus, or clubfoot, remains one of the commonest congenital limb deformities. The genetics of this condition are not yet fully understood. It is increasingly being diagnosed on prenatal ultrasound with implications for prenatal counselling. With the widespread acceptance of the Ponseti method of clubfoot treatment major surgical interventions are needed much less frequently and long-term outcomes are improved.

Reliability and sensitivity of radiographic measures of hip dysplasia in childhood Charcot-Marie-Tooth disease.

BACKGROUND: Hip dysplasia is a lack of femoral head coverage and disruption of hip and acetabular alignment and congruency, with severity ranging from mild subluxation in nascent at-risk hips to complete dislocation. Presentation of hip dysplasia in neuromuscular conditions can be sub-clinical or associated with a limp with or without hip pain, abductor and flexor weakness and reduced hip range of motion. Untreated hip dysplasia leads to early onset osteoarthritis requiring hip arthroplasty in early adulthood. Hip dysplasia occurs in 6-20% of children with Charcot-Marie-Tooth disease, however little is known about the reliability and sensitivity of detection on plain film pelvic radiographs. METHODS: 14 common measures of hip dysplasia on anteroposterior pelvis radiographs were independently assessed by 2 orthopaedic specialists in 30 ambulant children with Charcot-Marie-Tooth disease. Hip health was also categorised based on clinical impression to assess the sensitivity of radiographic measures to identify hip dysplasia status. RESULTS: 8 measures (acetabular index, head width, lateral centre-edge angle, lateral uncoverage, medial joint width, migration percentage, neck shaft angle, triradiate status) exhibited 'excellent' reliability between clinical evaluators. 5 of the 30 patients (17%) were identified as having nascent hip dysplasia. Reliable radiographic measures that significantly distinguished between nascent hip dysplasia and healthy hips were acetabular index, lateral centre edge angle, medial joint width and migration percentage. CONCLUSIONS: We have identified a subset of reliable and sensitive radiographic hip measures in children with Charcot-Marie-Tooth disease to prioritise during hip screening to mitigate the deleterious effects of hip dysplasia, pain and disability in adulthood.