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Musculoskeletal Diseases - Top 30 Publications

Muscle involvement in systemic sclerosis: points to consider in clinical trials.

SSc is clinically and pathogenetically heterogeneous. Consensus standards for trial design and outcome measures are needed. International experts experienced in SSc clinical trial design and a researcher experienced in systematic literature review screened the PubMed and Cochrane Central Register of Controlled Trials in order to develop points to consider when planning a clinical trial for muscle involvement in SSc. The experts conclude that SSc-associated muscle involvement is heterogeneous and lacks a universally accepted gold-standard for measuring therapeutic response. Although outcome studies are currently limited by the inability to clearly distinguish active, reversible muscle inflammation from irreversible muscle damage and extramuscular organ involvement, strong consideration should be given to enrolling patients with a myopathy that features several elements of likely reversibility such as muscle weakness, biopsy-proven active inflammation, an MRI indicating muscle inflammation and a baseline serum creatinine kinase above three times the upper limit of normal to prevent floor effect. Randomized controlled trials are preferred, with a duration of at least 24 weeks. Outcome measures should include a combination of elements that are likely to be reversible, such as muscle weakness, biopsy-proven active inflammation, creatinine kinase/aldolase and a quality of life questionnaire. The individual measurements might require a short pre-study for further validation. A biological sample repository is recommended.

Points to consider for designing trials in systemic sclerosis patients with arthritic involvement.

Although musculoskeletal involvement is quite common in SSc (arthritic in particular), there have been few trials and even fewer controlled trials of therapeutic agents in arthritis in SSc. In addition, there have been only three outcome measures that have been validated for use in trials of SSc arthritis: the HAQ Disability Index, the Cochin Hand Function Scale and the Hand Mobility in SSc scale. The purpose of this article is to present evidence-based points to consider for the design of trials in SSc patients with musculoskeletal involvement (joints in particular). In addition, we make an argument for including outcome variables that can be validated within a given trial for use in future trials.

Severe hypokalemic paralysis and rhabdomyolysis occurring after binge eating in a young bodybuilder: Case report.

Severe hypokalemia can be a potentially life-threatening disorder and is associated with variable degrees of skeletal muscle weakness.

Conservative treatment for equinus deformity in children with cerebral palsy using an adjustable splint-assisted ankle-foot orthosis.

A novel splint, the assisting ankle-foot orthoses (AFO), was developed to provide adjustable sustained stretching to improve conservative treatment for equinus deformities in children with cerebral palsy (CP). The treatment effect was validated by follow-up visits.

Cervical epidural analgesia complicated by epidural abscess: A case report and literature review.

Spinal epidural abscess is an uncommon complication in clinical practice. If the abscess is large enough, the patient will rapidly develop neurologic signs of spinal injury, and urgent neurosurgical intervention may be required.

Chemoradiotherapy for Solitary Skeletal Muscle Metastasis from Oesophageal Cancer: Case Report and Brief Literature Review.

The incidence of skeletal muscle metastasis from oesophageal cancer is very low, and the treatment strategy has not been established.

Comparison of Cold Atmospheric Plasma Devices' Efficacy on Osteosarcoma and Fibroblastic In Vitro Cell Models.

Cold atmospheric plasma (CAP) attenuates tumor cell proliferation and induces apoptosis in various cell lines. While exerting marginal effects on non-neoplastic cells this unfolds promising applications in cancer therapy. The aim of the study was to analyse the effects of different CAP sources and application times on osteosarcoma (OS) cells and non-malignant fibroblast cell proliferation.

Separate the Sheep from the Goats: Use and Limitations of Large Animal Models in Intervertebral Disc Research.

Approximately 5,168 large animals (pigs, sheep, goats, and cattle) were used for intervertebral disc research in identified studies published between 1985 and 2016. Most of the reviewed studies revealed a low scientific impact, a lack of sound justifications for the animal models, and a number of deficiencies in the documentation of the animal experimentation. The scientific community should take suitable measures to investigate the presumption that animal models have translational value in intervertebral disc research. Recommendations for future investigations are provided to improve the quality, validity, and usefulness of animal studies for intervertebral disc research. More in vivo studies are warranted to comprehensively evaluate the suitability of animal models in various applications and help place animal models as an integral, complementary part of intervertebral disc research.

Global Alignment and Proportion (GAP) Score: Development and Validation of a New Method of Analyzing Spinopelvic Alignment to Predict Mechanical Complications After Adult Spinal Deformity Surgery.

The restoration of normal sagittal alignment is a critical goal in adult spinal deformity surgery to achieve favorable outcomes and prevent mechanical complications. Schwab sagittal modifiers have been accepted as targets for appropriate alignment, but addressing these targets does not always prevent high mechanical complication or revision rates. This may be because the linear absolute numerical parameters do not cover the whole pelvic incidence spectrum and the distribution of lordosis, pelvic anteversion, and negative malalignment are not considered as potential causes of failure. The aim of the present study was to develop and validate a score based on pelvic-incidence-based proportional parameters to better predict mechanical complications.

Results of Porous-Coated Anatomic Total Hip Arthroplasty without Cement at 25 to 30 Years: A Concise Follow-up of a Previous Report.

The purpose of this study was to update the results of a prospective series of 100 primary cementless total hip arthroplasty (THA) procedures that were performed between 1983 and 1986 with use of the Porous Coated Anatomic (PCA) system. This is one of the first prospective studies of cementless primary THA with a minimum of 25 years of follow-up. Twenty-one patients (22 hips) of the original series were alive and had clinical and radiographic follow-up at a minimum of 25 years postoperatively. Twenty-three percent (23) of all hips and 50% (11) of the hips among the living cohort had undergone revision for loosening and/or osteolysis of the acetabular component, and 7% (7) of all hips and 4.5% (1) of the hips among the living cohort were revised for loosening and/or osteolysis of the femoral component. Only 4 femoral stems were revised for isolated loosening (without osteolysis). The PCA femoral component proved to be durable at a minimum of 25 years postoperatively, while the acetabular component was less durable.

Acetabular Reconstructions with Impaction Bone-Grafting and a Cemented Cup in Patients Younger Than 50 Years of Age: A Concise Follow-up, at 27 to 35 Years, of a Previous Report.

We present an update of 19 acetabular reconstructions, performed with a cemented total hip arthroplasty and impaction bone-grafting, in situ at the time of our previous report. At a mean follow-up of 30 years (range, 27 to 35 years), no additional patients were lost to follow-up. Two patients (3 reconstructions) died for reasons unrelated to the hip surgery. Five reconstructions (5 patients) were revised, 4 for aseptic loosening and 1 for septic loosening, after a mean of 24 years (range, 22 to 27 years), leaving 11 surviving hips (11 patients) that were clinically and radiographically evaluated. Kaplan-Meier survival at 30 years was 0.40 (95% confidence interval [CI], 0.23 to 0.56) for revision for any reason, 0.56 (95% CI, 0.35 to 0.73) for aseptic loosening, and 0.53 (95% CI, 0.33 to 0.69) for radiographic loosening. Competing risk analysis showed that Kaplan-Meier analysis overestimates the revision risk by 18% for revision for any reason and 22% for aseptic loosening. Cemented impaction bone-grafting is a reasonable long-term solution for demanding primary and revision acetabular reconstructions in young patients with acetabular bone defects.

Quality of Life of Patients with Spinal Metastasis from Cancer of Unknown Primary Origin: A Longitudinal Study of Surgical Management Combined with Postoperative Radiation Therapy.

Patients with spinal metastasis from cancer of unknown primary origin have limited life expectancy and poor quality of life. Surgery and radiation therapy remain the main treatment options, but, to our knowledge, there are limited data concerning quality-of-life improvement after surgery and radiation therapy and even fewer data on whether surgical intervention would affect quality of life.

Condyle-Specific Matching Does Not Improve Midterm Clinical Outcomes of Osteochondral Allograft Transplantation in the Knee.

Condyle-specific matching for osteochondral allograft transplantation (OCA) pairs donor and recipient condyles in an attempt to minimize articular incongruity. While the majority of cartilage defects are located on the medial femoral condyle, lateral femoral condyles are more commonly available as a graft source. The purpose of this study was to compare the clinical outcomes of patients treated with non-orthotopic (lateral-to-medial condyle or medial-to-lateral condyle) OCA with those treated with traditional orthotopic (medial-to-medial condyle or lateral-to-lateral condyle) OCA. We hypothesized that clinical outcomes would be similar between groups at midterm follow-up.

Analysis of SNP-SNP interactions and bone quantitative ultrasound parameter in early adulthood.

Osteoporosis individual susceptibility is determined by the interaction of multiple genetic variants and environmental factors. The aim of this study was to conduct SNP-SNP interaction analyses in candidate genes influencing heel quantitative ultrasound (QUS) parameter in early adulthood to identify novel insights into the mechanism of disease.

Identification and Management of TP53 Gene Carriers Detected Through Multigene Panel Testing.

The increasing use of multigene panel tests may reveal an unexpected pathogenic variant in the tumor protein p53 (TP53) gene among individuals who do not meet clinical criteria for Li-Fraumeni syndrome (LFS). Among a registry-based sample of individuals with a pathogenic (P) or likely pathogenic (LP) variant in TP53, we sought to characterize the original clinical context in which genetic testing was performed, the personal and family history and whether they met clinical LFS criteria, and the follow-up care following diagnosis among those in whom this information was available.

WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells.

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly.

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

Influence of Hip Abductor Strength on Functional Outcomes Before and After Total Knee Arthroplasty: Post Hoc Analysis of a Randomized Controlled Trial.

Total knee arthroplasty (TKA) is associated with declines in hip abductor (HA) muscle strength; however, a longitudinal analysis demonstrating the influence of TKA on trajectories of HA strength change has not been conducted.

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements.

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A-D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A-B 22q11.2 deletion carry inversions of LCR22B-D or LCR22C-D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects.

The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs.

Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

The effect of pneumococcal conjugate vaccines on incidence and microbiology associated with complicated acute otitis media.

The objectives of this study were to investigate the incidence of complicated acute otitis media (cAOM) as well as the associated microbiology before and after introduction of the 7- and 13-valent pneumococcal conjugate vaccines (PCV-7 and -13), respectively. CAOM comprises "heavy" AOM (AOM demanding hospitalization), mastodismus (M) and acute mastoiditis (AM).

Otologic manifestations of Larsen syndrome.

To describe and discuss otologic manifestations of Larsen syndrome, based on a case report and a systematic review of the literature.

Tuberculosis of the spine with severe angular kyphosis: mean 34-year post-operative follow-up shows that prevention is better than salvage.

To address the natural history of severe post-tuberculous (TB) kyphosis, with focus upon the long-term neurological outcome, occurrence of restrictive lung disease, and the effect on life expectancy.

Accuracy of CT-navigated pedicle screw positioning in the cervical and upper thoracic region with and without prior anterior surgery and ventral plating.

We aimed to retrospectively assess the accuracy and safety of CT navigated pedicle screws and to compare accuracy in the cervical and thoracic spine (C2-T8) with (COMB) and without (POST) prior anterior surgery (anterior cervical discectomy or corpectomy and fusion with ventral plating: ACDF/ACCF).

Comparison of the outcome of total ankle arthroplasty for osteoarthritis with moderate and severe varus malalignment and that with neutral alignment.

The purpose of this study was to compare the clinical and radiographic outcomes of total ankle arthroplasty (TAA) in patients with pre-operatively moderate and severe arthritic varus ankles to those achieved for patients with neutral ankles.

Revision total knee arthroplasty for failed high tibial osteotomy and unicompartmental knee arthroplasty have similar patient-reported outcome measures in a two-year follow-up study.

Little is known about the relative outcomes of revision of unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) to total knee arthroplasty (TKA). The aim of this study is to compare the outcomes of revision surgery for the two procedures in terms of complications, re-revision and patient-reported outcome measures (PROMs) at a minimum of two years follow-up.

Do varus or valgus outliers have higher forces in the medial or lateral compartments than those which are in-range after a kinematically aligned total knee arthroplasty? limb and joint line alignment after kinematically aligned total knee arthroplasty.

The aims of this study were to determine the proportion of patients with outlier varus or valgus alignment in kinematically aligned total knee arthroplasty (TKA), whether those with outlier varus or valgus alignment have higher forces in the medial or lateral compartments of the knee than those with in-range alignment and whether measurements of the alignment of the limb, knee and components predict compartment forces.

Appropriate hinge position for prevention of unstable lateral hinge fracture in open wedge high tibial osteotomy.

Open wedge high tibial osteotomy (OWHTO) for medial-compartment osteoarthritis of the knee can be complicated by intra-operative lateral hinge fracture (LHF). We aimed to establish the relationship between hinge position and fracture types, and suggest an appropriate hinge position to reduce the risk of this complication.

Five-year follow-up of a prospective randomised trial comparing ceramic-on-metal and metal-on-metal bearing surfaces in total hip arthroplasty.

The primary aim of this independent prospective randomised trial was to compare serum metal ion levels for ceramic-on-metal (CoM) and metal-on-metal (MoM) bearing surfaces in total hip arthroplasty (THA). Our one-year results demonstrated elevation in metal ion levels above baseline with no significant difference between the CoM and MoM groups. This paper reviews the five-year data.