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Background: Removal of the metaphyseal screw from tension band plate constructs after correction of angular deformity in patients treated with hemiepiphysiodesis has been suggested as an alternative to removing the plate and both screws. While this has the potential benefit of easier implant removal and reinsertion in the event of rebound, there is debate in the literature regarding the benefits and risks of leaving the epiphyseal screw and plate in place., Methods: Patients treated with hemiepiphysiodesis at the distal femur and/or proximal tibia with tension band plates and screws who underwent subsequent removal of the metaphyseal screw after correction were included. Charts and radiographs were reviewed for the need for metaphyseal screw reinsertion, subsequent removal of deep implants, and evidence of physeal tethering. Tethering was defined as progressive overcorrection in the treated bone segment after removal of the metaphyseal screw with the mechanical axis moving one full mechanical axis zone or more. Patients with tethering were compared with those without., Results: A total of 215 patients with 387 limbs treated met inclusion criteria. Of those, 175 patients were treated for idiopathic genu valgum, while 40 were treated for other conditions. Fifty-nine individuals (27%) underwent replacement of the metaphyseal screw for repeat angular correction. Fifty-one percent of patients underwent secondary procedures for reasons other than metaphyseal screw reinsertion (74 symptomatic implant removal, 7 elective implant removal, 29 due to tethering). There were 44 cases of tethering in 36 patients (17%). In cases of tethering, 7 patients were treated with observation, 11 with implant removal only, 16 with hemiepiphysiodesis on the opposite side, and 2 with osteotomy. Patients with tethering were significantly younger, more likely to be male, and more likely to have had the metaphyseal screw removed more than once ( P < 0.05)., Conclusion: Removal of only the metaphyseal screw after hemiepiphysiodesis has high rates of tethering and further surgery for iatrogenic deformity correction and implant removal. This technique is not recommended., Level of Evidence: Therapeutic Level III, case-control study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA) is a membrane transporter that creates and maintains intracellular Ca 2+ stores. In the heart, SERCA is regulated by an inhibitory interaction with the monomeric form of the transmembrane micropeptide phospholamban (PLB). PLB also forms avid homo-pentamers, and the dynamic exchange of PLB between pentamers and SERCA is an important determinant of cardiac responsiveness to exercise. Here, we investigated two naturally occurring pathogenic variants of PLB: a cysteine substitution of Arg9 (R9C) and an in-frame deletion of Arg14 (R14del). Both variants are associated with dilated cardiomyopathy. We previously showed that the R9C mutation causes disulfide crosslinking and hyperstabilization of pentamers. While the pathogenic mechanism of R14del is unclear, we hypothesized this mutation may also alter pentamer stability. Immunoblots revealed a significantly increased pentamer: monomer ratio for R14del-PLB compared to WT-PLB. We quantified homo-oligomerization and SERCA-binding in live cells using fluorescence resonance energy transfer (FRET) microscopy. R14del-PLB showed an increased affinity for homo-oligomerization and decreased binding affinity for SERCA compared to WT. The data suggest that, like R9C, the R14del mutation stabilizes PLB in pentamers, decreasing its ability to regulate SERCA. The R14del mutation reduced the rate of PLB unbinding from pentamers after transient elevations of Ca 2+ , limiting the recovery of PLB-SERCA complexes. A computational model predicted that hyperstabilization of PLB pentamers by R14del impairs the ability of cardiac Ca 2+ handling to respond to changing heart rates between rest and exercise. We postulate that impaired responsiveness to physiological stress contributes to arrhythmogenesis in human carriers of the R14del mutation., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.L.R. is a member of the scientific advisory board of Neurodon LLC. Neurodon did not have any role in this study., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Intramedullary rodding of lower extremity long bones in patients with osteogenesis imperfecta (OI) is a widely accepted technique for fracture treatment and prevention. Previous small studies with short to medium-term follow-up have shown that telescoping rods have longer survival times compared with static rods. However, there are no long-term studies (10 or more years) longitudinally evaluating the results of these procedures. The purpose of this study was to compare the rod survival duration and number of procedures in patients treated with static versus telescoping rods with 10 years minimum follow-up., Methods: This was a multicenter retrospective comparative study of patients with a diagnosis of OI who had intramedullary nailing of the femur and/or tibia. Each bone included in the study had a 10-year minimum follow-up, only one type of rod utilized over the follow-up period, and no rod replacement surgeries outside of the primary hospital system. Patient demographics, clinical data, and details of each procedure were obtained. Groups were compared using univariate analysis with a 2-independent samples t test for continuous variables, χ 2 for categorical variables, and the Kaplan-Meier method for survival analysis., Results: A total of 119 bones in 52 patients met inclusion criteria. Average follow up was 13.1 (range: 10.2 to 18.4) years. There were no differences between groups in follow-up length, Sillence type, bisphosphonate use, or age at first-rod placement. There were significantly more tibias treated in the static rod group compared with the telescopic rod group. The average survival length was significantly longer for telescopic rods, 5.8 ± 3.9 years versus 4.0±3.6 years for static rods. On average, bones treated with telescopic rods had significantly fewer surgeries compared with static rods (2.2 ± 0.8 vs 3.3 ± 1.6)., Conclusion: At long term follow up, bone segments in patients with OI treated with telescopic rods required fewer surgeries and had longer implant survival times compared with those treated with static rods. When available, surgeons should consider telescopic rods as the initial implant choice in this patient population., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The mechanism(s) underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) is unknown. Herein we observe elevation in circulating phenylacetylglutamine (PAGln), a known CVD-associated GMM, in individuals living with alcohol use disorder. In a male murine binge-on-chronic alcohol model, we confirm gut microbial reorganization, elevation in PAGln levels, and the presence of cardiovascular pathophysiology. Fecal microbiota transplantation from pair-/alcohol-fed mice into naïve male mice demonstrates the transmissibility of PAGln production and the CVD phenotype. Independent of alcohol exposure, pharmacological-mediated increases in PAGln elicits direct cardiac and vascular dysfunction. PAGln induced hypercontractility and altered calcium cycling in isolated cardiomyocytes providing evidence of improper relaxation which corresponds to elevated filling pressures observed in vivo. Furthermore, PAGln directly induces vascular endothelial cell activation through induction of oxidative stress leading to endothelial cell dysfunction. We thus reveal that the alcohol-induced microbial reorganization and resultant GMM elevation, specifically PAGln, directly contributes to CVD., Competing Interests: Competing interests: Z.W. reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Z.W. also reports having received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, a fully owned subsidiary of Quest Diagnostics and Procter & Gamble. C.M.T. consults for Abbott Laboratories. S.L.H. reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, being a paid consultant for Procter & Gamble and Zehna Therapeutics, having received research funds from Procter & Gamble, Zehna Therapeutics, and Roche Diagnostics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab and Procter & Gamble. All other authors: Z.L., M.G., A.Z., X.F., K.M., M.M., X.S.L., Z.Y., J.M., T.T., K.C., M.H., L.H., K.G., T.T.V., D.W., A.M.G., P.Q., C.A.M., J.M.B., D.J.L., D.A.W., and T.E.S. have no competing interests., (© 2024. The Author(s).)

Calcium (Ca 2+ ) dysregulation is a hallmark feature of cardiovascular disease. Intracellular Ca 2+ regulation is essential for proper heart function and is controlled by the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA2a). Another-regulin (ALN) is a newly discovered cardiomyocyte-expressed SERCA2a inhibitor, suggesting cardiomyocyte Ca 2+ -handling is more complex than previously appreciated. To study the role of ALN in cardiomyocytes, we generated ALN null mice (knockout, KO) and found that cardiomyocytes from these animals displayed enhanced Ca 2+ cycling and contractility compared to wildtype (WT) mice, indicating enhanced SERCA2a activity. In vitro and in vivo studies show that ALN is post-translationally modified via phosphorylation on Serine 19 (S19), suggesting this contributes to its ability to regulate SERCA2a. Immunoprecipitation and FRET analysis of ALN-WT, phospho-deficient ALN (S19A), or phosphomimetic ALN (S19D) revealed that S19 phosphorylation alters the SERCA2a-ALN interaction, leading to relief of its inhibitory effects. Adeno-associated virus mediated delivery of ALN-WT or phospho-mutant ALN-S19A/D in ALN KO mice showed that cardiomyocyte-specific expression of phospho-deficient ALN-S19A resulted in increased SERCA2a inhibition characterized by reduced rates of cytoplasmic Ca 2+ clearance compared to ALN-WT and ALN-S19D expressing cells, further supporting a role for this phosphorylation event in controlling SERCA2a-regulation by ALN. Levels of ALN phosphorylation were markedly increased in cardiomyocytes in response to Gα q agonists (angiotensin II, endothelin-1, phenylephrine) and Gα q -mediated phosphorylation of ALN translated to increased Ca 2+ cycling in cardiomyocytes from WT but not ALN KO mice. Collectively, these results indicate that ALN uniquely regulates Ca 2+ handling in cardiomyocytes via integration of neuroendocrine signaling with SERCA2a activity., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Medial epicondyle fractures are a common pediatric injury. When operative, cannulated partially threaded screws, with or without a washer, are commonly utilized. These implants may need to be removed after full healing if symptomatic. There is mixed evidence regarding the influence of a washer on rates of implant removal, and the influence of screw size has not been studied. We aim to determine the rate of symptomatic deep implant removal for each fixation type and identify factors associated with the need for removal., Methods: This was an IRB-reviewed, retrospective, case-cohort study. Patients treated at our institution between January 1, 2004 and December 31, 2019, age 18 years old or younger, with a medial epicondyle fracture managed operatively with 4.0 or 4.5 mm cannulated screws with or without washers were included. Patients with multiple operative ipsilateral elbow fractures and those who underwent implant removal for reasons other than pain or irritation were excluded. Removal rates were compared between screw sizes (4.0 vs 4.5 mm), as well as with and without a washer using a Cox proportional hazards model., Results: In total, 151 patients met the inclusion criteria, 54 with symptomatic hardware removed and 97 without symptomatic hardware removed. A significantly higher number of patients treated with 4.5 mm screws compared with 4.0 mm screws underwent removal of symptomatic deep implants (50% vs 30%, P = 0.033). In a multivariable Cox regression model adjusting for age and ulnar nerve status, when no washer was used, the hazard ratio (HR) for symptomatic hardware removal for 4.5 mm screws was 2.92 times the HR for 4.0 mm screws (95% CI: 1.35-6.29). When a 4.0 mm screw was used, the HR for symptomatic hardware removal for a washer was 3.24 times the HR without a washer (95% CI: 1.53-6.84)., Conclusion: Implant removal rates are influenced by screw size and the use of a washer. These results may help guide implant choice and counsel families regarding the rate of symptomatic implant removal., Level of Evidence: Level III-therapeutic level, case-control study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The phospholamban (PLN) pathogenic gene variant, p.Arg14del (PLN-R14del), can lead to dilated and arrhythmogenic cardiomyopathy, resulting in heart failure. PLN-R14del cardiomyopathy has been conceptualized as a disease caused by sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) superinhibition. However, recent studies raised controversy regarding the effect of PLN-R14del on SERCA activity and revealed a prominent role for abnormal PLN protein distribution and sarco/endoplasmic reticulum disorganization as underlying disease mechanism. Strategies targeting sarco/endoplasmic reticulum malformation may, therefore, prove more effective than SERCA activity modulation. This review reassesses the disease mechanisms of PLN-R14del cardiomyopathy and emphasizes the importance of dissecting the underlying molecular mechanisms to uncover targets for innovative treatments., Competing Interests: This work was supported by grants from the Netherlands Heart Foundation (CVON PREDICT2, grant 2018-30; CARMA, grant 01-003-2022-0358); the Leducq Foundation (Cure-PLaN), EU Horizon grant Geremy, the Netherlands Heart Institute, the PLN Foundation. It was also supported by National Institutes of Health grant HL171221 to Dr Makarewich. Dr de Boer has received grant support from the Netherlands Heart Foundation (grants 2017-21; 2017-11; 2018-30; 2020B005; 01-003-2022-0358) and the European Research Council (ERC CoG 818715); has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; has had speaker engagements with and/or received fees from and/or served on an advisory board for Abbott, AstraZeneca, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; and received travel support from Abbott, Cardior Pharmaceuticals GmbH, and Novo Nordisk. Dr van der Meer has received grant support from the European Research Council (ERC CoG 101045236, DISSECT-HF); has received consulting fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, AstraZeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi Sankyo, Boehringer Ingelheim, and Ionis. Dr Silljé has received research grants from AstraZeneca, Novo Nordisk and Ionis Pharmaceuticals. Dr Stege has reported that she has no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Supracondylar humerus fractures are a common pediatric orthopedic injury requiring surgery. These patients are typically seen 4 weeks post-op for cast and pin removal followed by an 8-12-week post-op motion check. Our study aimed to limit the number of in-office visits by conducting this last motion check by telehealth. This was a single-surgeon series of consecutive surgically treated supracondylar humerus fractures. The primary outcome was the number of patients who completed their range of motion check remotely. Loss to follow-up at the telehealth visit was compared to a prior cohort for whom the range of motion visit was performed in person. Secondary outcomes included number of patients missing work/school for the in-person vs. telehealth visits and satisfaction with the in-person and telehealth visits. Twenty-two patients were enrolled during the study period. Sixteen (73%) successfully completed their telehealth follow-up, which was similar to the prior in-person cohort. Significantly more parents/children had to take a day off from work/school to attend the in-person visit. No patient required a subsequent in-person visit or referral to physical therapy. A total of 100% of patients reported excellent satisfaction with their telehealth visit. Overall satisfaction was similar comparing the in-person vs. telehealth visits (84% vs. 100% reporting excellent satisfaction, P  = 0.12). Telehealth is a viable option for the postoperative care of surgically treated supracondylar humerus fractures. This approach limits in-office visits and decreases the need for parents/children to miss work/school while maintaining excellent satisfaction scores., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The p.Arg14del variant of the PLN (phospholamban) gene causes cardiomyopathy, leading to severe heart failure. Calcium handling defects and perinuclear PLN aggregation have both been suggested as pathological drivers of this disease. Dwarf open reading frame (DWORF) has been shown to counteract PLN regulatory calcium handling function in the sarco/endoplasmic reticulum (S/ER). Here, we investigated the potential disease-modulating action of DWORF in this cardiomyopathy and its effects on calcium handling and PLN aggregation., Methods: We studied a PLN-R14del mouse model, which develops cardiomyopathy with similar characteristics as human patients, and explored whether cardiac DWORF overexpression could delay cardiac deterioration. To this end, R14 Δ/Δ (homozygous PLN-R14del) mice carrying the DWORF transgene (R14 Δ/Δ DWORF Tg [R14 Δ/Δ mice carrying the DWORF transgene]) were used., Results: DWORF expression was suppressed in hearts of R14 Δ/Δ mice with severe heart failure. Restoration of DWORF expression in R14 Δ/Δ mice delayed cardiac fibrosis and heart failure and increased life span >2-fold (from 8 to 18 weeks). DWORF accelerated sarcoplasmic reticulum calcium reuptake and relaxation in isolated cardiomyocytes with wild-type PLN, but in R14 Δ/Δ cardiomyocytes, sarcoplasmic reticulum calcium reuptake and relaxation were already enhanced, and no differences were detected between R14 Δ/Δ and R14 Δ/Δ DWORF Tg . Rather, DWORF overexpression delayed the appearance and formation of large pathogenic perinuclear PLN clusters. Careful examination revealed colocalization of sarcoplasmic reticulum markers with these PLN clusters in both R14 Δ/Δ mice and human p.Arg14del PLN heart tissue, and hence these previously termed aggregates are comprised of abnormal organized S/ER. This abnormal S/ER organization in PLN-R14del cardiomyopathy contributes to cardiomyocyte cell loss and replacement fibrosis, consequently resulting in cardiac dysfunction., Conclusions: Disorganized S/ER is a major characteristic of PLN-R14del cardiomyopathy in humans and mice and results in cardiomyocyte death. DWORF overexpression delayed PLN-R14del cardiomyopathy progression and extended life span in R14 Δ/Δ mice, by reducing abnormal S/ER clusters., Competing Interests: Disclosures The UMCG, which employs several of the authors, has received research grants and fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. R.A. de Boer received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. The other authors report no conflicts.

Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria [translocase of the outer mitochondrial membrane (TOMM) complex, translocase of the inner mitochondrial membrane (TIMM) complex, OXPHOS complexes, mitoribosomes]. These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines but also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress, and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.

Background: Achondroplasia is the most prevalent form of skeletal dysplasia, affecting more than 250,000 individuals. Lower extremity angular deformities, particularly genu varum, are common in children with achondroplasia, often resulting in pain and limitation of function. The authors aim to determine the utility of lower extremity growth modulation with hemiepiphysiodesis in children with achondroplasia for correction of coronal plane deformities about the knee., Methods: The authors performed a retrospective chart review of a single center from 1/1/2000 to 12/31/2020 to identify pediatric patients with achondroplasia treated with hemiepiphysiodesis as their initial procedure at the distal femur and/or proximal tibia. Patients with adequate records and who had completed their treatment were included. Data collected included duration of treatment, complications, need for osteotomy, and radiographic measurements including initial and final mechanical axis deviation, knee mechanical axis zone, mechanical lateral distal femoral angle and medial proximal tibia angle., Results: Ten patients with 17 limbs met our criteria. Nine patients (15 limbs) were treated for genu varum and 1 patient (2 limbs) was treated for genu valgum. Prior to treatment, the mechanical axis fell in zone 3 in 59% of limbs and zone 2 in 41%. Average correction in mechanical axis deviation was 26.1 mm. Average change in mechanical lateral distal femoral angle was 10.3 degrees per limb, and average change in medial proximal tibia angle was 7.1 degrees per limb. Average treatment duration was 909 days. At final follow up, 81% (14/17) of limbs had the mechanical axis in zone 1, with the remaining 18% (3/17) in zone 2. No patient/limb underwent subsequent distal femur or proximal tibia osteotomy for coronal plane alignment., Conclusions: Children with achondroplasia can successfully be treated with hemiepiphysiodesis to correct coronal plane deformities at the distal femur and proximal tibia. Using this technique, no patient in our series required an osteotomy for genu varum/valgum., Level of Evidence: Therapeutic level IV, Case series., Competing Interests: P.M.S. has received royalties from Orthofix, Lewisville, TX 75056, and OrthoPediatrics, Warsaw, IN 46582. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Ongoing efforts to generate a complete and accurate annotation of the genome have revealed a significant blind spot for small proteins (<100 amino acids) originating from short open reading frames (sORFs). The recent discovery of numerous sORF-encoded proteins, termed microproteins, that play diverse roles in critical cellular processes has ignited the field of microprotein biology. Large-scale efforts are currently underway to identify sORF-encoded microproteins in diverse cell-types and tissues and specialized methods and tools have been developed to aid in their discovery, validation, and functional characterization. Microproteins that have been identified thus far play important roles in fundamental processes including ion transport, oxidative phosphorylation, and stress signaling. In this review, we discuss the optimized tools available for microprotein discovery and validation, summarize the biological functions of numerous microproteins, outline the promise for developing microproteins as therapeutic targets, and look forward to the future of the field of microprotein biology., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Background Cardiomyopathy is a leading health threat in Duchenne muscular dystrophy (DMD). Cytosolic calcium upregulation is implicated in DMD cardiomyopathy. Calcium is primarily removed from the cytosol by the sarcoendoplasmic reticulum calcium ATPase (SERCA). SERCA activity is reduced in DMD. Improving SERCA function may treat DMD cardiomyopathy. Dwarf open reading frame (DWORF) is a recently discovered positive regulator for SERCA, hence, a potential therapeutic target. Methods and Results To study DWORF's involvement in DMD cardiomyopathy, we quantified DWORF expression in the heart of wild-type mice and the mdx model of DMD. To test DWORF gene therapy, we engineered and characterized an adeno-associated virus serotype 9-DWORF vector. To determine if this vector can mitigate DMD cardiomyopathy, we delivered it to 6-week-old mdx mice (6×10 12 vector genome particles/mouse) via the tail vein. Exercise capacity, heart histology, and cardiac function were examined at 18 months of age. We found DWORF expression was significantly reduced at the transcript and protein levels in mdx mice. Adeno-associated virus serotype 9-DWORF vector significantly enhanced SERCA activity. Systemic adeno-associated virus serotype 9-DWORF therapy reduced myocardial fibrosis and improved treadmill running, electrocardiography, and heart hemodynamics. Conclusions Our data suggest that DWORF deficiency contributes to SERCA dysfunction in mdx mice and that DWORF gene therapy holds promise to treat DMD cardiomyopathy.

Purpose of Review: Congenital pseudarthrosis of the tibia (CPT) is a rare condition closely associated with neurofibromatosis type I. Affected children are born with anterolateral bowing of the tibia which progresses to pathologic fracture, pseudarthrosis, and high risk of refracture even after initial union has been attained. There is currently no consensus on the classification of this disease or consensus on its treatment. The purpose of this review is to (1) review the clinical presentation, etiology, epidemiology, classification, and natural history of congenital pseudarthrosis of the tibia and (2) review the existing trends in treatment of congenital pseudarthrosis of the tibia and its associated complications., Recent Findings: Current treatment protocols focus primarily on combining intramedullary fixation with external or internal fixation to achieve union rates between 74 and 100%. Intramedullary devices should be retained as long as possible to prevent refracture. Cross-union techniques, though technically difficult, have a reported union rate of 100% and no refractures at mid- to long-term follow-up. Vascularized fibular grafting and induced membrane technique can be successful, but at the cost of numerous surgical procedures. Growth modulation is a promising new approach to preventing fracture altogether, though further study with larger patient series is necessary. The primary consideration in treatment of CPT is expected union rate and refracture risk. Combined intramedullary and external or internal fixation, especially with cross-union techniques, show most promise. Perhaps most exciting is further research on preventing fracture through guided growth, which may reduce the morbidity of multiple surgical procedures which have been the mainstay of treatment for CPT thus far., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In the care of open fractures, time to antibiotic administration has been shown to be a critical factor in preventing infection. To help improve outcomes at our institution we designed and implemented an open fracture pathway with the goal of reducing the time from emergency department (ED) arrival to antibiotic administration. Here we evaluate the success of this pathway, propose improvements in the protocol, and provide a framework for initiation at other institutions., Methods: We compared a retrospective prepathway cohort with a prospective postpathway cohort for 1-year pre and postpathway implementation. First, we analyzed the number of patients from outside facilities who had received antibiotics before transfer. For patients who had not received antibiotics before arriving at our institution, we reviewed pathway metrics including time from ED arrival to the ordering and administration of antibiotics, whether the correct antibiotic type was selected, and time to surgical debridement., Results: There were 50 patients in the prepathway cohort and 29 in the postpathway cohort. Prepathway 60.5% of transfers (23 of 38) received antibiotics before transfer, whereas post-pathway 90.0% of transfers (18 of 20) received antibiotics ( P =0.032). For patients who had not received antibiotics before arriving at our institution and were included in pathway metric analysis, there were no differences in demographics or fracture characteristics. Time from ED arrival to antibiotic order decreased from 115.3 to 63.5 minutes ( P =0.016). Time from antibiotic order to administration was similar between groups (48.0 vs. 35.7 min, P =0.191), but the overall time from ED arrival to antibiotic administration decreased from 163.3 to 99.2 minutes ( P =0.004). There were no significant differences in whether the correct antibiotic type was chosen ( P =0.354) or time from ED arrival to surgery ( P =0.783)., Conclusions: This study provides evidence that for pediatric patients presenting with open fractures, a care pathway can successfully decrease the time from ED arrival to antibiotic administration., Level of Evidence: Therapeutic level III-retrospective comparative study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Next-generation sequencing (NGS) has propelled the field of genomics forward and produced whole genome sequences for numerous animal species and model organisms. However, despite this wealth of sequence information, comprehensive gene annotation efforts have proven challenging, especially for small proteins. Notably, conventional protein annotation methods were designed to intentionally exclude putative proteins encoded by short open reading frames (sORFs) less than 300 nucleotides in length to filter out the exponentially higher number of spurious noncoding sORFs throughout the genome. As a result, hundreds of functional small proteins called microproteins (<100 amino acids in length) have been incorrectly classified as noncoding RNAs or overlooked entirely. Here we provide a detailed protocol to leverage free, publicly available bioinformatic tools to query genomic regions for microprotein-coding potential based on evolutionary conservation. Specifically, we provide step-by-step instructions on how to examine sequence conservation and coding potential using Phylogenetic Codon Substitution Frequencies (PhyloCSF) on the user-friendly University of California Santa Cruz (UCSC) Genome Browser. Additionally, we detail steps to efficiently generate multiple species alignments of identified microprotein sequences to visualize amino acid sequence conservation and recommend resources to analyze microprotein characteristics, including predicted domain structures. These powerful tools can be used to help identify putative microprotein-coding sequences in noncanonical genomic regions or to rule out the presence of a conserved coding sequence with translational potential in a noncoding transcript of interest.

Background: Shortening and deformity of the tibia commonly occur during the treatment of congenital pseudarthrosis of the tibia (CPT). The role of osteotomies in lengthening and deformity correction remains controversial in CPT. This study evaluates the approach to and outcome after osteotomy performed in CPT., Methods: We performed an IRB approved retrospective review of consecutive patients with CPT treated at our institution from 2010 through 2019. Patients who underwent osteotomies were included in this study., Results: Nine patients (10 osteotomies-5 proximal metaphyseal and 5 diaphyseal) with a median age at osteotomy of 8.9 years (range: 4 to 21 y) were included. Six patients had neurofibromatosis-1, 1 had cleidocranial dysplasia, and 2 patients had idiopathic CPT. Four osteotomies were performed for deformity correction, 3 osteotomies to allow intramedullary instrumentation, and 3 osteotomies for lengthening. Five osteotomies were preceded by zolendronate treatment before surgery. Nine were fixed with a rod supplemented with external fixation (7) or locking plates (2). One osteotomy was stabilized with locked intramedullary nailing alone. Four osteotomies were supplemented with autologous bone graft, and bone morphogenic protein-2 was utilized in 3 osteotomies. Median time to healing was 222.5 days (range: 124 to 323 d). One osteotomy (locked intramedullary nailing) required grafting at 5.5 months and then healed uneventfully. Median healing index for patients undergoing lengthening was 57.9 days/cm (range: 35 to 81 d/cm). All 3 osteotomies performed for lengthening required a second osteotomy for preconsolidation at a mean of 34 days. Other complications included compartment syndrome requiring fasciotomy (n=2), tibial osteomyelitis (n=1), and fracture distal to cross-union (n=1)., Conclusions: Contrary to much of the established practice, osteotomies may be safely performed in CPT for various indications. All osteotomies healed with only 1 osteotomy requiring secondary bone grafting. Although time to healing of the osteotomy was generally prolonged, this study suggests, somewhat surprisingly, that preconsolidation can occur frequently in lengthening procedures., Level of Evidence: Level IV-case series., Competing Interests: J.E.H. is a clinical advisor for Bonus BioGroup and a consultant for NuVasive Specialized Orthopedics, Orthofix, OrthoPediatrics, OrthoSpin, Smith & Nephew, and WishBone Medical. P.K.M. is a consultant for DePuy Synthes Companies, Novadip, Orthofix, and Smith & Nephew. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Slip progression after in situ fixation of slipped capital femoral epiphysis (SCFE) has been reported as occurring in up to 20% of patients. We review SCFE treated with in situ single screw fixation performed at 2 hospitals over a 15-year period to determine the factors associated with slip progression., Methods: This case-control study reviews SCFE treated with in situ single cannulated screw fixation with minimum follow up of 1 year and full closure of the affected physis. Slip progression (failure) was defined as worsening of the Southwick slip angle of 10 or more degrees or revision surgery for symptomatic slip progression. Univariate and multivariate analyses were performed comparing success and failure groups for patient characteristics, screw type and position, and radiographic measurements., Results: Ninety three patients with 108 slips met all criteria, with 15 hips (14%) classified as having slip progression (failure). All failures had 3 threads or fewer across the physis. Five hips had 2 threads across the physis, and 4 of the 5 were classified as failures. Lower modified Oxford bone scores were found in the failure group, though the difference was small (0.9, P=0.013). Failure was also associated with partially threaded screws (P=0.001). Failed hips were associated with lower initial Southwick angles (32.8 degrees) than successful hips (40.4 degrees) (P=0.047). In the stepwise model for multivariate regression, 4 factors were identified as significant, with lower initial number of threads (P<0.0001), mild initial Southwick category (P=0.0050), male sex (P=0.0061), and partially threaded screw type (P=0.0116) predicting failure., Conclusion: This study is the largest to date evaluating risk factors for slip progression after SCFE fixation, and the first to consider revision surgery for symptomatic slip progression. For stable SCFE, we demonstrate that 4 threads across the physis with a fully threaded screw of 6.5 mm diameter or greater was sufficient to avoid slip progression. We provide a risk stratification for progression of slip showing that in some cases 3 threads across the physis may be sufficient., Level of Evidence: Level III-case-control study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Emerging evidence indicates that a subset of RNA molecules annotated as noncoding contain short open reading frames that code for small functional proteins called microproteins, which have largely been overlooked due to their small size. To search for cardiac-expressed microproteins, we used a comparative genomics approach and identified mitolamban (Mtlbn) as a highly conserved 47-amino acid transmembrane protein that is abundantly expressed in the heart. Mtlbn localizes specifically to the inner mitochondrial membrane where it interacts with subunits of complex III of the electron transport chain and with mitochondrial respiratory supercomplexes. Genetic deletion of Mtlbn in mice altered complex III assembly dynamics and reduced complex III activity. Unbiased metabolomic analysis of heart tissue from Mtlbn knockout mice further revealed an altered metabolite profile consistent with deficiencies in complex III activity. Cardiac-specific Mtlbn overexpression in transgenic (TG) mice induced cardiomyopathy with histological, biochemical, and ultrastructural pathologic features that contributed to premature death. Metabolomic analysis and biochemical studies indicated that hearts from Mtlbn TG mice exhibited increased oxidative stress and mitochondrial dysfunction. These findings reveal Mtlbn as a cardiac-expressed inner mitochondrial membrane microprotein that contributes to mitochondrial electron transport chain activity through direct association with complex III and the regulation of its assembly and function., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Introduction: This study sought to examine prescribing practices for pediatric patients undergoing orthopaedic trauma surgery and assess the effect of state-mandated preoperative informed consent for opioids., Methods: A retrospective single-institution cohort study was done between 2016 and 2018 for surgically managed isolated orthopaedic trauma with cohorting based on the presence of preoperative opioid consent. Analyses examined cohort demographic and procedural factors associated with the number of opioid doses prescribed., Results: A total of 1,793 patients met the study criteria. The proportion of patients prescribed opioids (P = 0.0378) and the number of doses (P < 0.001) were lower in consented patients. Differences were greater among those receiving solution (versus tablets). No cohort differences were observed in refill needs. Nonopioid medications prescribing increased. Multivariate analysis identified multiple factors, including preoperative opioid consent (P = 0.013) associated with fewer prescribed opioid doses., Discussion: After the implementation of preoperative opioid consenting, patients were prescribed fewer opioid doses after pediatric orthopaedic trauma surgery. The increased utilization of nonopioid therapies was also evident. These changes occurred despite a shorter length of hospital stay and without changes in the studied proxies of postoperative pain control. An increased awareness of opioid risks through formal consent discussion may help to facilitate reduced reliance on opioids for children in the postoperative period., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Competing Interests: The authors declare no conflicts of interest.

Case: An adolescent male developed fat embolism syndrome 24 hours after sustaining a closed right tibial shaft fracture in a football game. The patient was treated with emergent external fixator application due to declining respiratory and mental status and experienced swift recovery after stabilization. He was treated with an intramedullary nail within 1 week of injury., Conclusion: Pediatric fat embolism syndrome is uncommon, and a high index of suspicion is required to facilitate appropriate orthopaedic involvement. External fixation can be performed emergently with minimal fracture manipulation. Rapid provisional fixation appears to have facilitated recovery in this example., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Dillon C. O'Neill et al.)

Aim: To describe the epidemiology and management of appendicular fractures occurring in the neonatal ICU in a large series of patients treated a single, quaternary care neonatal intensive care unit., Methods: Patients <1 years old with appendicular fractures treated from 2012 to 2016 at a quaternary-level NICU were identified. Bivariate testing compared fractures, work-up and management based on designated mechanism (presumed birth-related vs unknown). In patients with unknown mechanism, factors with potential fracture association were analysed in a descriptive fashion., Results: Eighty-five fractures (54 patients) were included. Mechanistic cohorts differed by birthweight (P < .001) and gestational age at birth (P < .001). Presumed birth-related fractures were more commonly upper extremity (P < .001), solitary (P = .001) and radiographically diagnosed in the acute state (<.001). The biochemical profile of the cohorts differed significantly. The prevalence of factors with potential fracture association was high in patients with unknown mechanism. Only one patient required surgery, while all others resolved with minimal orthopaedic intervention., Conclusion: Findings indicate these injuries rarely require operative intervention and that two distinct injury profiles appear to exist based on fracture mechanism. Steroid use, ventilation use, diuretic use, nutritional supplementation and recent bedside procedures were common among patients without known fracture mechanism., Level of Evidence: Level III-Retrospective Cohort Study., (© 2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Pediatric femur fractures are commonly treated with flexible intramedullary nails (FIN). However, there is controversy regarding the effect of patient weight on outcomes and complications. The purpose of this meta-analysis was to review the literature and describe implant choice, analyze complication, and reoperation rates; as well as the report clinical and radiographic outcomes of FIN in pediatric patients weighing ≥40 kg with femoral shaft fractures., Methods: A systematic review was performed of all retrospective and prospective studies focusing on the use of FIN in heavy children in Medline, Cochrane, and Web of Science databases. Data extraction was performed and summarized using descriptive statistics. Quality assessment was performed using the Newcastle-Ottawa Scale. Meta-analysis was performed for complications using pooled data from included studies., Results: The initial search strategy yielded 177 references, and after exclusions, 5 studies were included. The majority of studies were retrospective, and the most commonly used implants in heavier patients were titanium FIN and stainless steel Enders FIN. There were higher rates of radiographic nonunion and malunion, complications, and reoperations for refracture; and nonunion in heavier children treated with FIN. Meta-analysis performed on 4 applicable studies showed the overall complication rate was higher in the heavier patients compared with lighter patients (30.6% vs. 11.1%) with a relative risk of 1.20 [95% confidence interval (CI), 1.02-1.41]. Heavier patients also had higher rates of major complications (relative risk, 1.32; 95% CI, 1.03-1.69) but similar minor complications (relative risk, 1.13; 95% CI, 0.90-1.41)., Conclusions: Heavier children have worse radiographic outcomes and higher complication rates with the use of FIN for femoral shaft fractures. Additional research is needed to determine the effect of FIN material on clinical outcomes in heavier children, and the relationship between weight and other known risk factors for poor outcome in FIN, such as length stability., Level of Evidence: Level III-systematic review of level-III studies.

Background: Despite a validated classification system, high-quality multicenter research databases (CSSG/GSSG), and a recent proliferation in publications, early-onset scoliosis (EOS) surgeons have no consensus on standards for surgical treatment. The 21st-century revolution in EOS care has only accelerated, with the arrival of a classification system, magnetically controlled growing rod, nusinersen, and improved nonoperative care (Mehta or Risser casting and compliance-monitored braces). This dizzying pace of change may have outstripped our ability to develop best-practice standards for EOS surgical indications. To learn where consensus is best (and worst) at this moment, we surveyed EOS world thought-leaders on a collection of representative cases., Methods: A 6-case survey was constructed and sent to 20 EOS world thought-leaders. The cases were selected to be representative of the major treatment categories: idiopathic, neuromuscular, syndromic, congenital, thoracic dysplasia, and spinal muscular atrophy (specifically to assess the impact of nusinersen and parasol deformity on surgical planning). Respondents were queried regarding treatment with specific attention to instrumentation and construct when surgery was selected. Responses regarding surgical timing and technique were analyzed for consensus (defined as >80%). χ analysis was performed to evaluate for differences in treatment preferences based on years of experience., Results: The survey response was 100%. Clinical experience ranged from 8 to 40 years (average 23.9 y). There was no consensus on any case. The greatest variability was on the congenital case; the closest to consensus was on the spinal muscular atrophy case. Three or more approaches were selected for all 6 cases; >4 approaches were selected for 5 cases. There is a trend towards screw fixation for proximal anchors. The management of thoracic dysplasia and parasol deformity is far from consensus., Conclusion: The lack of consensus for surgical treatment of 6 representative EOS cases demands a renewed effort and commitment to develop best-practice guidelines based on multicenter outcome data., Level of Evidence: Level V-Expert Opinion.

Estimating the appropriate tendon length and associated skin incision needed to achieve a plantigrade foot without compromising function are essential steps in open Achilles tendon lengthening. Here we describe a technique using basic surgical instruments referencing anatomic landmarks without the need for radiographs. The center of ankle rotation in the sagittal plane is found referencing the tip of the medial malleolus. This point is translated to the plantar surface of the foot, and a straight instrument in line with the foot is used to make a mark at the posterior calcaneal fat pad. The straight instrument is then rotated (representing the plantar surface of the foot) as if dorsiflexing the ankle along the axis of the transposed tibiotalar joint from a plantar-flexed position to the desired final position and a second mark is made at the posterior heel. The distance between the marks is measured, representing the amount of Achilles lengthening required. The skin incision and tendon limb lengths area a sum of the operative correction and the amount of desired tendon overlap, typically 2 cm of tendon overlap is optimal to allow for suture fixation, ensure tendon healing, and maintain the integrity of the repair. A Z-type lengthening is then performed using this tendon limb length. This technique allows an accurate and simple approach to lengthening the Achilles tendon. In this way the ideal tendon limb length is selected to optimize function while minimizing incision length, associated wound complications, inadequate lengthening, and overlengthening. Level of evidence: Technical note, Level V.

Magnetically controlled intramedullary lengthening nails (MCILN) have revolutionized the field of limb lengthening and deformity correction. They allow for accurate and precise distraction with excellent patient outcomes and satisfaction. Though potentially technically easier than external fixation, general deformity principles and bone and soft-tissue biology must be considered for successful use. MCILN can address deformities of a wide range of etiologies including congenital, posttraumatic, post-infectious, tumor, and many others with excellent healing rates and outcomes as well as better patient satisfaction and similar cost compared to external fixation. Of the approximately 10,000 MCILN that have been implanted (written communication, NuVasive, Inc., San Diego, California), about 749 cases have been reported in the published literature. Applications outside of deformity correction are on the rise, with new uses reported in reconstruction after tumor resection and acute trauma. This review of MCILN summarizes the history, recent advances, and results of MCILN treatment in a multitude of clinical applications.

Background: In an effort to increase health care value, there has been a recent focus on the transition of traditionally inpatient procedures to an outpatient setting. We hypothesized that in the treatment of Gartland extension type II supracondylar humerus fractures (SCHF), outpatient surgery can be performed safely and with similar clinical and radiographic outcomes compared with urgent inpatient treatment with an overall reduction in cost., Methods: We compared a prospective cohort of Gartland type II SCHF treated primarily as outpatients (postprotocol) to a retrospective cohort treated primarily as urgent inpatients (preprotocol), excluding patients with preoperative neurovascular injury, open fracture, additional ipsilateral upper extremity fracture, and prior ipsilateral SCHF. Inpatient versus outpatient treatment was also compared. Outcomes including perioperative factors, complications, readmission, reoperation, postoperative radiographic measurements, and direct hospital costs underwent univariate and multivariate analyses., Results: A total of 220 patients in the postprotocol cohort (88 inpatients and 132 outpatients) and 129 in the preprotocol cohort (97 inpatients and 32 outpatients) were analyzed. There were no differences in operative times, number of pins, conversion to open reductions, readmissions, or reoperations between cohorts or groups, and no cases developed postoperative neurovascular injuries or compartment syndromes. Total complications did not differ between the preprotocol and postprotocol cohorts; however, were higher in the inpatient group (3.8% vs. 0%; P=0.016) in the univariate, but not multivariate analysis. There were no differences in Baumann angle or humerocondylar angle. Significantly more inpatients' anterior humeral line fell outside of the middle third of the capitellum in the univariate, but not multivariate analysis. There were significant reductions in total cost per patient between the preprotocol and postprotocol cohorts (marginal effect, -$215; P<0.0001) and between the inpatient and outpatient groups (marginal effect, -$444; P<0.0001)., Conclusions: Delayed treatment of Gartland type II SCHF in the outpatient setting can be performed safely and with similar clinical and radiographic outcomes to those treated urgently as inpatients with a significant cost reduction., Level of Evidence: Therapeutic level III-retrospective comparative study.

Proteins are critical components of biological membranes and play key roles in many essential cellular processes. Membrane proteins are a structurally and functionally diverse family of proteins that have recently expanded to include a number of newly discovered tiny proteins called microproteins, or micropeptides. These microproteins are generated from small open reading frames, which produce protein products that are less than 100 amino acids in length. While not all microproteins are membrane proteins, this review will focus specifically on this subclass to highlight some of the important biological activities that have been ascribed to these molecules and to emphasize their promise as exciting new players in membrane biology., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The recently-discovered single-span transmembrane proteins endoregulin (ELN), dwarf open reading frame (DWORF), myoregulin (MLN), and another-regulin (ALN) are reported to bind to the SERCA calcium pump in a manner similar to that of known regulators of SERCA activity, phospholamban (PLB) and sarcolipin (SLN). To determine how micropeptide assembly into oligomers affects the availability of the micropeptide to bind to SERCA in a regulatory complex, we used co-immunoprecipitation and fluorescence resonance energy transfer (FRET) to quantify micropeptide oligomerization and SERCA-binding. Micropeptides formed avid homo-oligomers with high-order stoichiometry (n > 2 protomers per homo-oligomer), but it was the monomeric form of all micropeptides that interacted with SERCA. In view of these two alternative binding interactions, we evaluated the possibility that oligomerization occurs at the expense of SERCA-binding. However, even the most avidly oligomeric micropeptide species still showed robust FRET with SERCA, and there was a surprising positive correlation between oligomerization affinity and SERCA-binding. This comparison of micropeptide family members suggests that the same structural determinants that support oligomerization are also important for binding to SERCA. Moreover, the unique oligomerization/SERCA-binding profile of DWORF is in harmony with its distinct role as a PLB-competing SERCA activator, in contrast to the inhibitory function of the other SERCA-binding micropeptides., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fat embolism (FE) occurs frequently after trauma and during orthopaedic procedures involving manipulation of intramedullary contents. Classically characterized as a triad of pulmonary distress, neurologic symptoms, and petechial rash, the clinical entity of FE syndrome is much less common. Both mechanical and biochemical pathophysiologic theories have been proposed with contributions of vascular obstruction and the inflammatory response to embolized fat and trauma. Recent studies have described the relationship of embolized marrow fat with deep venous thrombosis and postsurgical cognitive decline, but without clear treatment strategies. Because treatment is primarily supportive, our focus must be on prevention. In trauma, early fracture stabilization decreases the rate of FE syndrome; however, questions remain regarding the effect of reaming and management of bilateral femur fractures. In arthroplasty, computer navigation and alternative cementation techniques decrease fat embolization, although the clinical implications of these techniques are currently unclear, illustrating the need for ongoing education and research with an aim toward prevention.

Calcium (Ca 2+ ) dysregulation is a hallmark of heart failure and is characterized by impaired Ca 2+ sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca 2+ -ATPase (SERCA). We recently discovered a micropeptide named DWORF ( DW arf O pen R eading F rame) that enhances SERCA activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Here we show that DWORF has a higher apparent binding affinity for SERCA than PLN and that DWORF overexpression mitigates the contractile dysfunction associated with PLN overexpression, substantiating its role as a potent activator of SERCA. Additionally, using a well-characterized mouse model of dilated cardiomyopathy (DCM) due to genetic deletion of the muscle-specific LIM domain protein (MLP), we show that DWORF overexpression restores cardiac function and prevents the pathological remodeling and Ca 2+ dysregulation classically exhibited by MLP knockout mice. Our results establish DWORF as a potent activator of SERCA within the heart and as an attractive candidate for a heart failure therapeutic., Competing Interests: CM CAM has filed a provisional patent application to use DWORF for treatment of heart failure (Application #62/324,706), AM, GS, SB, OR, EC, AV, SR No competing interests declared, RB RB-D has filed a provisional patent application to use DWORF for treatment of heart failure (Application #62/324,706), EO ENO has filed a provisional patent application to use DWORF for treatment of heart failure (Application #62/324,706), (© 2018, Makarewich et al.)

Aims: For this retrospective cohort study, patients aged ≤ 30 years (very young) who underwent total hip arthroplasty (THA) were compared with patients aged ≥ 60 years (elderly) to evaluate the rate of revision arthroplasty, implant survival, the indications for revision, the complications, and the patient-reported outcomes., Patients and Methods: We retrospectively reviewed all patients who underwent primary THA between January 2000 and May 2015 from our institutional database. A total of 145 very young and 1359 elderly patients were reviewed. The mean follow-up was 5.3 years (1 to 18). Logistic generalized estimating equations were used to compare characteristics and the revision rate. Survival was evaluated using Kaplan-Meier curves and hazard rates were created using Cox regression., Results: The overall revision rate was 11% (16/145) in the very young and 3.83% (52/1359) in the elderly groups (odds ratio (OR) 2.58, 95% confidence interval (CI) 1.43 to 4.63). After adjusting for the American Society of Anesthesiologists (ASA) score, gender, and a history of previous surgery in a time-to-event model, the risk of revision remained greater in the very young (adjusted hazard ratio (HR) 2.48, 95% CI 1.34 to 4.58). Survival at ten years was 82% (95% CI, 71 to 89) in the very young and 96% (95% CI, 94 to 97) in the elderly group (p < 0.001). The very young had a higher rate of revision for complications related to metal-on-metal (MoM) bearing surfaces (p < 0.001). At last follow-up, the very young group had higher levels of physical function (p = 0.002), lower levels of mental health (p = 0.001), and similar levels of pain (p = 0.670) compared with their elderly counterparts., Conclusion: The overall revision rate was greater in very young THA patients. This was largely explained by the use of MoM bearings. Young patients with non-MoM bearings had high survivorship with similar complication profiles to patients aged ≥ 60 years. Cite this article: Bone Joint J 2018;100-B:867-74.

Micropeptide regulator of β-oxidation (MOXI) is a conserved muscle-enriched protein encoded by an RNA transcript misannotated as non-coding. MOXI localizes to the inner mitochondrial membrane where it associates with the mitochondrial trifunctional protein, an enzyme complex that plays a critical role in fatty acid β-oxidation. Isolated heart and skeletal muscle mitochondria from MOXI knockout mice exhibit a diminished ability to metabolize fatty acids, while transgenic MOXI overexpression leads to enhanced β-oxidation. Additionally, hearts from MOXI knockout mice preferentially oxidize carbohydrates over fatty acids in an isolated perfused heart system compared to wild-type (WT) animals. MOXI knockout mice also exhibit a profound reduction in exercise capacity, highlighting the role of MOXI in metabolic control. The functional characterization of MOXI provides insight into the regulation of mitochondrial metabolism and energy homeostasis and underscores the regulatory potential of additional micropeptides that have yet to be identified., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cardiac energy is produced primarily by oxidation of fatty acids and glucose, with the relative contributions of each nutrient being sensitive to changes in substrate availability and energetic demand. A major contributor to cardiac metabolic flexibility is pyruvate dehydrogenase (PDH), which converts glucose-derived pyruvate to acetyl-CoA within the mitochondria. PDH is inhibited by phosphorylation dependent on the competing activities of pyruvate dehydrogenase kinases (PDK1-4) and phosphatases (PDP1-2). A single high-fat meal increases cardiac PDK4 content and subsequently inhibits PDH activity, reducing pyruvate utilization when abundant fatty acids are available. In this study, we demonstrate that diet-induced increases in PDK4 are reversible and characterize a novel pathway that regulates PDK4 degradation in response to the cardiac metabolic environment. We found that PDK4 degradation is promoted by CoA (CoASH), the levels of which declined in mice fed a high-fat diet and normalized following transition to a control diet. We conclude that CoASH functions as a metabolic sensor linking the rate of PDK4 degradation to fatty acid availability in the heart. However, prolonged high-fat feeding followed by return to a low-fat diet resulted in persistent in vitro sensitivity of PDH to fatty acid-induced inhibition despite reductions in PDK4 content. Moreover, increases in the levels of proteins responsible for β-oxidation and rates of palmitate oxidation by isolated cardiac mitochondria following long-term consumption of high dietary fat persisted after transition to the control diet. We propose that these changes prime PDH for inhibition upon reintroduction of fatty acids., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Self-adherent elastic wrap dressings are a convenient option to manage pediatric hand and finger injuries. However, when improperly applied, they have the potential to cause devastating complications. We detail in this report 5 cases of dressing-induced ischemic injury to the hand in pediatric patients with a review of the literature. All patients were treated by the senior author between 2007 and 2015 and were retrospectively reviewed for initial injury, frequency of dressing changes, presence of pain, time to evaluation by the orthopedic hand team, treatment, and outcome. Patients' families were contacted for clinical updates and to obtain current photographs. Age at injury ranged from 11 months to 3 years with 2 girls and 3 boys. Only 1 of 5 patients complained of pain or discomfort during the onset of their ischemic injury. Treatment of the ischemic injury included local wound care without surgery in 3 cases (including sympathetic block in 1) and surgical intervention with partial or complete digital amputation in 2 cases. At final follow-up, 2 of the 5 patients reported currently being bothered by the appearance of the injured hand; however, none had persistent pain or difficulty using the hand. Through these examples, health care professionals can be educated on the potentially disastrous complications of improper dressing application in the pediatric population and can be encouraged to share this information with patients' families., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Introduction: We conducted a retrospective study in patients with minimal or no radiographically evident knee osteoarthritis to determine whether presenting signs and symptoms were predictive of knee pathology that was evident on MRI and could be treated with nonarthroplasty knee surgery or could alter nonsurgical treatment., Methods: We reviewed records of patients for whom sports medicine orthopaedic surgeons had ordered an MRI of the knee. Univariate analysis identified factors that were associated with positive MRI findings (eg, surgically treatable lesion, meniscal tear) or a finding that could alter treatment. We used multivariate logistic regression to determine independent predictors of evidence of pathology on MRI., Results: Of the 434 patients in the study, 281 (64.7%) had evidence of knee pathology on MRI. Acute injury, effusion, and ligamentous instability were among the independent predictors of positive MRI results. Patients with evidence of knee pathology on MRI were more likely to have undergone surgery., Discussion: Specific aspects of patient history and physical examination are associated with evidence of knee pathology on MRI., Conclusions: In patients without osteoarthritis, positive findings on knee MRI could be associated with a number of presenting signs and symptoms, and this information could aid physicians in deciding which patients should undergo knee MRIs. Additional prospective research is needed to validate the relationships discovered in our study., Level of Evidence: Level III retrospective study.

Advances in computational biology and large-scale transcriptome analyses have revealed that a much larger portion of the genome is transcribed than was previously recognized, resulting in the production of a diverse population of RNA molecules with both protein-coding and noncoding potential. Emerging evidence indicates that several RNA molecules have been mis-annotated as noncoding and in fact harbor short open reading frames (sORFs) that encode functional peptides and that have evaded detection until now due to their small size. sORF-encoded peptides (SEPs), or micropeptides, have been shown to have important roles in fundamental biological processes and in the maintenance of cellular homeostasis. These small proteins can act independently, for example as ligands or signaling molecules, or they can exert their biological functions by engaging with and modulating larger regulatory proteins. Given their small size, micropeptides may be uniquely suited to fine-tune complex biological systems., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium-handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and we found that MED12 localizes to transcription factor consensus sequences within calcium-handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes and that MED12 and MEF2 co-occupy promoters of calcium-handling genes. Furthermore, we demonstrated that MED12 enhances MEF2 transcriptional activity and that overexpression of both increases expression of calcium-handling genes in cardiomyocytes. Our data support a role for MED12 as a coordinator of transcription through MEF2 and other transcription factors. We conclude that MED12 is a regulator of a network of calcium-handling genes, consequently mediating contractility in the mammalian heart.

Aims: L-type Ca2+ channels (LTCCs) in adult cardiomyocytes are localized to t-tubules where they initiate excitation-contraction coupling. Our recent work has shown that a subpopulation of LTCCs found at the surface sarcolemma in caveolae of adult feline cardiomyocytes can also generate a Ca2+ microdomain that activates nuclear factor of activated T-cells signaling and cardiac hypertrophy, although the relevance of this paradigm to hypertrophy regulation in vivo has not been examined., Methods and Results: Here we generated heart-specific transgenic mice with a putative caveolae-targeted LTCC activator protein that was ineffective in initiating or enhancing cardiac hypertrophy in vivo. We also generated transgenic mice with cardiac-specific overexpression of a putative caveolae-targeted inhibitor of LTCCs, and while this protein inhibited caveolae-localized LTCCs without effects on global Ca2+ handling, it similarly had no effect on cardiac hypertrophy in vivo. Cardiac hypertrophy was elicited by pressure overload for 2 or 12 weeks or with neurohumoral agonist infusion. Caveolae-specific LTCC activator or inhibitor transgenic mice showed no greater change in nuclear factor of activated T-cells activity after 2 weeks of pressure overload stimulation compared with control mice., Conclusion: Our results indicate that LTCCs in the caveolae microdomain do not affect cardiac function and are not necessary for the regulation of hypertrophic signaling in the adult mouse heart., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Micropeptides function as master regulators of calcium-dependent signaling in muscle. Sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA), the membrane pump that promotes muscle relaxation by taking up Ca 2+ into the sarcoplasmic reticulum, is directly inhibited by three muscle-specific micropeptides: myoregulin (MLN), phospholamban (PLN), and sarcolipin (SLN). The widespread and essential function of SERCA across diverse cell types has raised questions as to how SERCA is regulated in cells that lack MLN, PLN, and SLN. We identified two transmembrane micropeptides, endoregulin (ELN) and another-regulin (ALN), that share key amino acids with their muscle-specific counterparts and function as direct inhibitors of SERCA pump activity. The distribution of transcripts encoding ELN and ALN mirrored that of SERCA isoform-encoding transcripts in nonmuscle cell types. Our findings identify additional members of the SERCA-inhibitory micropeptide family, revealing a conserved mechanism for the control of intracellular Ca 2+ dynamics in both muscle and nonmuscle cell types., (Copyright © 2016, American Association for the Advancement of Science.)

Background: Despite advances in surgical technique, rotator cuff repair retears continue to occur at rates of 10%, 22%, and 57% for small, medium, and large tears, respectively. A common mode of failure in transosseous-equivalent rotator cuff repairs is tissue pullout of the medial mattress stitch. While the medial mattress stitch has been studied extensively, no studies have evaluated a vertical mattress pattern placed near the musculotendinous junction in comparison with a horizontal mattress pattern., Hypothesis: Vertical mattress stitches will have higher load to failure and lower gapping compared with horizontal mattress stitches in a transosseous-equivalent rotator cuff repair., Study Design: Controlled laboratory study., Methods: Double-row transosseous-equivalent rotator cuff repairs were performed in 9 pairs of human male cadaveric shoulders (mean age ± SD, 58 ± 10 years). One shoulder in each pair received a medial-row suture pattern using a vertical mattress stitch, and the contralateral shoulder received a horizontal mattress. Specimens were mounted in a materials testing machine and tested in uniaxial tensile deformation for cyclic loading (500 cycles at 1 Hz to 1.0 MPa of effective stress), followed by failure testing carried out at a rate of 1 mm/s. Construct gapping and applied loads were monitored continuously throughout the testing., Results: Vertical mattress sutures were placed in 5 right and 4 left shoulders. Peak cyclic gapping did not differ between vertical (mean ± SD, 2.8 ± 1.1 mm) and horizontal mattress specimens (3.0 ± 1.2 mm) (P = .684). Vertical mattress sutures failed at higher loads compared with horizontal mattress sutures (568.9 ± 140.3 vs 451.1 ± 174.3 N; P = .025); however, there was no significant difference in failure displacement (8.0 ± 1.6 vs 6.0 ± 2.1 mm; P = .092). Failure stiffness did not differ between the suture patterns (P = .204)., Conclusion: In transosseous-equivalent rotator cuff repairs near the musculotendinous junction, a vertical mattress suture used as the medial stitch has a higher load to failure but no difference in gapping compared with a horizontal mattress pattern., Clinical Relevance: A vertical mattress suture may offer enhanced strength of repair for transosseous-equivalent repairs., (© 2016 The Author(s).)

Combined peripheral nerve injuries present a unique set of challenges to the hand surgeon when considering tendon transfers. They are often associated with severe soft tissue trauma, including lacerations to remaining innervated muscles and tendons, significant scar formation, and substantial sensory loss. In the case of combined nerve injuries, there are typically fewer options for tendon transfers due to fewer tendons of shared function that are expendable as well as associated injuries to tendon or muscle bellies. As such, careful preoperative planning must be performed to make the most of remaining muscle tendon units., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model, the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent-stem-cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)