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Background and Purpose:  Hip dysplasia can present challenges for total hip arthroplasty (THA) due to anatomic abnormalities. We aimed to assess the association of age, sex, osteotomies prior to THA, and fixation method on 5- and 10-year revision-free implant survival and patient-reported outcome measures (PROMs) of THAs in patients with hip dysplasia., Methods: Using Dutch Arthroplasty Register data, we studied hip dysplasia patients receiving primary THAs in 2007-2021 (n = 7,465). THAs were categorized by age, pelvic osteotomy prior to THA (yes/no), and fixation (cemented, uncemented, hybrid, reverse hybrid). Kaplan-Meier and multivariable Cox models were used to determine 5- and 10-year revision-free implant survival and adjusted hazard ratios including 95% confidence intervals (CIs). Reasons for revision and PROMs were compared within the categories., Results:  We found a 10-year revision-free implant survival of 94.9% (CI 94.3-95.5). Patients younger than 50 years had a 10-year implant survival of 93.3% (CI 91.9-94.7), Patients with prior pelvic osteotomy had a 10-year implant survival of 92.0% (CI 89.8-94.2). Fixation method and sex were not associated with implant survival. Patients with a prior pelvic osteotomy had more revisions due to cup loosening and reported lower PROM scores than patients without earlier osteotomy., Conclusion:  5- and 10-year revision-free implant survival rates of THA for hip dysplasia are 96.4% and 94.9%. Age and prior osteotomies were associated with decreased implant survival rates in patients with hip dysplasia, while fixation method was not. Prior osteotomies were also associated with reduced PROM scores.

The acetabular rim extension (ACE-X) implant is a custom-made three-dimensionally printed titanium device designed for the treatment of canine hip dysplasia. In this study, 34 dogs (61 hips) underwent ACE-X implantation, and assessments were conducted using computed tomography, force plate analysis, Ortolani's test, and the Helsinki chronic pain index (HCPI) questionnaires at five intervals: the pre-operative day, the surgery day, and the 1.5-month, 3-month, and 12-month follow-ups. Statistically significant increases in femoral head coverage with a negative Ortolani subluxation test were observed immediately after surgery and persisted throughout the study. Osteoarthritis (OA) scores remained stable, but osteophyte size significantly increased between the surgery day and the 12-month follow-up, especially in hips with a baseline OA score of 2 compared to those with a score of 1. The force plate data showed no significant changes during the study. The HCPI demonstrated a significant decrease in pain score from pre-operative value to six-week follow-up and gradually decreased over time. Major complications were identified in six hips (9.8%) of four dogs. In conclusion, the ACE-X implant effectively increased femoral head coverage, eliminated subluxation, and provided long-term pain relief with minimal complications, benefiting over 90% of the study population. The study supports the ACE-X implant as a valuable alternative treatment for canine hip dysplasia.

Study Design: Cross-sectional., Objective: The aim of this study was to describe morphologic changes of the annulus fibrosus (AF) and nucleus pulposus (NP) in children during growth using magnetic resonance imaging., Summary of Background Data: Little is known of intervertebral disk (IVD) maturation as opposed to degeneration, such as changes in relative AF/NP proportions and orientation during growth. Studies suggest that IVD plays a role in the etiology of pediatric spinal deformities. Therefore, understanding the morphologic development of the AF and NP during growth is key., Materials and Methods: An existing database of children aged 0 to 18 that had magnetic resonance imaging for indications unrelated to the spine were analyzed. The AF/NP were segmented semiautomatically from T1 to L5. The parameters: mean IVD height, cross-sectional area, slenderness (height/width ratio), volume (ratio), and relative position of the centroid of the NP within the IVD in three directions ( x , y , z ) were extracted, and compared between age, sex, and spinal level., Results: IVD height increased modestly and predominantly in the low-thoracic and lumbar spine during the first 5 to 10 years of life. Cross-sectional area and thus volume increased steadily at all levels throughout growth. IVD slenderness decreased sharply in the first years of life and remains relatively stable throughout the remainder of growth. IVDs were smaller and more slender in females, especially in the mid-thoracic spine at early adolescence. In the upper-thoracic and mid-thoracic spine the NP comprises 10% to 12% of total IVD volume during growth, this percentage increases in the low-thoracic and lumbar spine towards 20% to 25%. In the anterior-posterior direction, the position of the nucleus increasingly shifts with age, possibly in line with the developing sagittal profile of the spine., Conclusion: This study describes the development of thoracic and lumbar IVDs during growth and may be used as a reference for future studies on the role of IVD in the etiology of disk-related disorders., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hip dysplasia causes major disability in dogs. Treatment options are limited to palliative treatment (e.g., pain relief, physical exercise, lifestyle changes, and weight control) or invasive surgeries such as pelvic osteotomies and total hip arthroplasty. Hence, a strong unmet need exists for an effective and dog-friendly solution that enhances the quality of life of man's best friend. We fill this treatment gap by offering a minimally traumatic and extraarticular, dog-specific, 3-dimensional-printed, hip implant (3DHIP) that restores hip joint stability. The surgical treatment using a 3DHIP implant is less invasive than osteotomies and can be performed bilaterally in one surgical session. The 3DHIP implant extends the dorsal acetabular rim of the dysplastic hip joint thereby increasing coverage of the femoral head and inhibiting joint subluxation with fast recovery. Sufficient access to the dorsal acetabular rim and ventral border of the iliac body together with optimal fitting and fixation of the implant are key steps for a successful 3DHIP implantation and imply the need for a specific approach. The present article aims to showcase this innovative surgical technique with tips and tricks as a surgical manual for implantation of the 3DHIP implant in dogs affected by hip dysplasia.

The aim of this study was to preoperatively asses the feasibility of drilling a bony recess for the fixation of a cochlear implant in the temporal bone. Even though complications are rare with cochlear implantations, drilling at the site of implantation have resulted in hematoma or cerebrospinal fluid leakage. Mainly in cases with a reduced temporal bone thickness, the risk for complications has increased, such as in paediatric patients., Methods: An in-house designed semi-automatic algorithm was developed to analyse a 3D model of the skull. The feasibility of drilling the recess was determined by a gradient descent method to search for the thickest part of the temporal bone. Feasibility was determined by the residual bone thickness which was calculated after a simulated drilling of the recess at the thickest position. An initial validation of the algorithm was performed by measuring the accuracy of the algorithm on five 3D models with known thickest locations for the recess. The accuracy was determined by a part comparison between the known position and algorithm provided position., Results: In four of the five validation models a standard deviation for accuracy below the predetermined cut-off value of 4.2 mm was achieved between the actual thickest position and the position determined by the algorithm. Furthermore, the residual thickness calculated by the algorithm showed a high agreement (max. 0.02 mm difference) with the actual thickness., Conclusion: With the developed algorithm, a semi-automatic method was created to analyse the temporal bone thickness within a specified region of interest on the skull. Thereby, providing indications for surgical feasibility, potential risks for anatomical structures and impact on procedure time of cochlear implantation. This method could be a valuable research tool to objectively assess feasibility of drilling a recess in patients with thin temporal bones preoperatively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kemper, Markodimitraki, Magré, Simons and Thomeer.)

(1) Background: Complex proximal humerus fractures often result in complications following surgical treatment. A better understanding of the full 3D displacement would provide insight into the fracture morphology. Repositioning of fracture elements is often conducted by using the contralateral side as a reconstruction template. However, this requires healthy contralateral anatomy. The purpose of this study was to create a Statistical Shape Model (SSM) and compare its effectiveness to the contralateral registration method for the prediction of the humeral proximal segment; (2) Methods: An SSM was created from 137 healthy humeri. A prediction for the proximal segment of the left humeri from eight healthy patients was made by combining the SSM with parameters. The predicted proximal segment was compared to the left proximal segment of the patients. Their left humerus was also compared to the contralateral (right) humerus; (3) Results: Eight modes explained 95% of the variation. Most deviations of the SSM prediction and the contralateral registration method were below the clinically relevant 2 mm distance threshold.; (4) Conclusions: An SSM combined with parameters is a suitable method to predict the proximal humeral segment when the contralateral CT scan is unavailable or the contralateral humerus is unhealthy, provided that the fracture pattern allows measurements of these parameters.

Hip dysplasia (HD) is a common orthopedic problem in young dogs. To decrease the laxity of the hip joint related to HD, the surgical treatments are recommended to increase femoral head coverage. ACEtabular rim eXtension (ACE-X) using a personalized 3-dimensional printed titanium shelf implant is a new surgical treatment to increase femoral head coverage and decrease laxity of the dysplastic hip joint, however, the efficacy is less know. Client-owned dogs older than 6 months with clinical signs of coxofemoral joint subluxation and radiographic evidence of HD with no or mild osteoarthritis (OA) were included. The Norberg angle (NA), linear percentage of femoral head overlap (LFO), and percentage of femoral head coverage (PC) were investigated radiographically and with computed tomography (CT) before and after surgery. OA was graded (scores 0-3) according to the maximum osteophyte size measured on CT. In addition, joint laxity (Ortolani) test results, gait analysis, and the Helsinki chronic pain index (HCPI) questionnaire were obtained at preoperative, immediately postoperative and at 1.5- and 3-month evaluations. Acetabular rim extension was performed in 61 hips of 34 dogs; NA, LFO, and PC were significantly higher immediately postoperatively and at the 1.5- and 3-month follow-up examinations compared with preoperative values ( p < 0.05). Osteophyte size gradually increased over time ( p < 0.05). The OA score significantly increased between preoperatively and directly postoperatively, and between preoperatively and at 3-month follow-up ( p < 0.05). The laxity test normalized in 59 out of 61 hips after surgery, and the HCPI questionnaire showed that the pain score decreased significantly at 1.5 and 3 months, postoperatively. The force plate showed no significant improvement during the 3 months follow-up. Although pain reduction by the implant was unclear in short-term results, a personalized shelf implant significantly increased femoral head coverage and eliminated subluxation of the dysplastic hip joint. Further studies are required to study the long-term efficacy of gait, chronic pain, and progression of osteoarthritis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kwananocha, Magré, Willemsen, Weinans, Sakkers, How, Verseijden, Tryfonidou, van der Wal and Meij.)

For decades, the advantages of rapid prototyping for clinical use have been recognized. However, demonstrations of potential solutions to treat spinal problems that cannot be solved otherwise are scarce. In this paper, we describe the development, regulatory process, and clinical application of two types of patient specific 3D-printed devices that were developed at an in-house 3D point-of-care facility. This 3D lab made it possible to elegantly treat patients with spinal problems that could not have been treated in a conventional manner. The first device, applied in three patients, is a printed nylon drill guide, with such accuracy that it can be used for insertion of cervical pedicle screws in very young children, which has been applied even in semi-acute settings. The other is a 3D-printed titanium spinal column prosthesis that was used to treat progressive and severe deformities due to lysis of the anterior column in three patients. The unique opportunity to control size, shape, and material characteristics allowed a relatively easy solution for these patients, who were developing paraplegia. In this paper, we discuss the pathway toward the design and final application, including technical file creation for dossier building and challenges within a point-of-care lab.

Lipodystrophies belong to the heterogenous group of syndromes in which the primary defect is a generalized or partial absence of adipose tissue, which may be congenital or acquired in origin. Lipodystrophy should be considered in patients manifesting the combination of insulin resistance (with or without overt diabetes), dyslipidemia and fatty liver. Lipodystrophies are classified according to the etiology of the disease (genetic or acquired) and to the anatomical distribution of adipose tissue (generalized or partial). The mechanism of adipose tissue loss is specific to each syndrome, depending on the biological function of the mutated gene. Mice models, together with cellular studies have permitted clarification of the mechanisms by which human mutations deeply compromise adipocyte homeostasis. In addition, rodent models have proven to be crucial in deciphering the cardiometabolic consequences of the lack of adipose tissue such as NAFLD, muscle insulin resistance and cardiomyopathy. More precisely, tissue-specific transgenic and knockout mice have brought new tools to distinguish phenotypic traits that are the consequences of lipodystrophy from those that are cell-autonomous. In this review, we discuss the mice models of lipodystrophy including those of inherited human syndromes of generalized and partial lipodystrophy. We present how these models have demonstrated the central role of white adipose tissue in energetic homeostasis in general, including insulin sensitivity and lipid handling in particular. We underscore the differences reported with the human phenotype and discuss the limit of rodent models in recapitulating adipose tissue primary default. Finally, we present how these mice models have highlighted the function of the causative-genes and brought new insights into the pathophysiology of the cardiometabolic complications associated with lipodystrophy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Le Lay, Magré and Prieur.)

Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability.

Objective: CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic, and cellular characteristics of CGL3., Design/methods: In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery, and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3., Results: Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol, and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n = 9) were asymptomatic, without any metabolic abnormality. Patients' fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients' fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence., Conclusions: The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.

Type 2 diabetes (T2D) is a major risk factor for heart failure. Diabetic cardiomyopathy (DC) is characterized by diastolic dysfunction and left ventricular hypertrophy. Epidemiological data suggest that hyperglycaemia contributes to the development of DC. Several cellular pathways have been implicated in the deleterious effects of high glucose concentrations in the heart: oxidative stress, accumulation of advanced glycation end products (AGE), and chronic hexosamine biosynthetic pathway (HBP) activation. In the present review, we focus on the effect of chronic activation of the HBP on diabetic heart function. The HBP supplies N-acetylglucosamine moiety (O-GlcNAc) that is O-linked by O-GlcNAc transferase (OGT) to proteins on serine or threonine residues. This post-translational protein modification modulates the activity of the targeted proteins. In the heart, acute activation of the HBP in response to ischaemia-reperfusion injury appears to be protective. Conversely, chronic activation of the HBP in the diabetic heart affects Ca 2+ handling, contractile properties, and mitochondrial function and promotes stress signaling, such as left ventricular hypertrophy and endoplasmic reticulum stress. Many studies have shown that O-GlcNAc impairs the function of key protein targets involved in these pathways, such as phospholamban, calmodulin kinase II, troponin I, and FOXO1. The data show that excessive O-GlcNAcylation is a major trigger of the glucotoxic events that affect heart function under chronic hyperglycaemia. Supporting this finding, pharmacological or genetic inhibition of the HBP in the diabetic heart improves heart function. In addition, the SGLT2 inhibitor dapagliflozin, a glucose lowering agent, has recently been shown to lower cardiac HBP in a lipodystophic T2D mice model and to concomitantly improve the diastolic dysfunction of these mice. Therefore, targeting cardiac-excessive O-GlcNAcylation or specific target proteins represents a potential therapeutic option to treat glucotoxicity in the diabetic heart.