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The following are available online at https://www.mdpi.com/article/ 10.3390/genes14040831/s1, A.A.M.S. received a scholarship from the Philippine Council for Health and Research Development of the Department of Science and Technology (PCHRD-DOST) under the Research Enrichment (Sandwich) Grant of the Accelerated Science and Technology Human Resource Devel- opment Program. O.A.K. was supported by the US National Institutes of Health (NIH)—National Institute on Deafness and Other Communication Disorders (NIDCD) grant T32 DC012280 (to Sue C. Kinnamon and Herman A. Jenkins). This work was supported by the NIH through the NIDCD grants R01 DC019642 (to R.L.P.S.-C. and Ivana V. Yang) and R01 DC013912 (to S.P.G.); and the National Insti- tute of Arthritis and Musculoskeletal and Skin Diseases grant R01 AR068292 (to N.H.-M.). Funding was also provided by Junta de Andalucia, grant Retos en Investigacion PY20_00303 (to J.A.L.-E.)., Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere’s disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere’s disease, and 38 European–American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere’s disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease., Philippine Council for Health and Research Development of the Department of Science and Technology (PCHRD-DOST) under the Research Enrichment (Sandwich) Grant of the Accelerated Science and Technology Human Resource Development Program, US National Institutes of Health (NIH)-National Institute on Deafness and Other Communication Disorders (NIDCD) T32 DC012280, NIH through the NIDCD R01 DC019642, R01 DC013912, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) R01 AR068292, Junta de Andalucia PY20_00303

Idiopathic scoliosis (IS) is a spinal disorder affecting up to 3% of otherwise healthy children. IS has a strong familial genetic component and is believed to be genetically complex due to significant variability in phenotype and heritability. Previous studies identified putative loci and variants possibly contributing to IS susceptibility, including within ECM, cilia and actin networks, but the genetic architecture and underlying mechanisms remains unresolved. Here, we used whole exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (MAF C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of a second cohort of unrelated IS individuals and controls identified several severe mutations in KIF7 in affected individuals only. Subsequently, we generated a mutant zebrafish model of kif7 using CRISPR-Cas9. kif7(co63/co63) zebrafish displayed severe scoliosis, presenting in juveniles and progressing through adulthood. We observed no deformities in the brain, Reissner fiber, or central canal cilia in kif7(co63/co63) embryos, although alterations were seen in Hh pathway gene expression. This research suggests defects in KIF7-dependent Hh signaling may drive pathogenesis in a subset of individuals with IS.

Medial collateral ligament (MCL) injuries are typically managed non-operatively, with high rates of clinical success. However, patients who present with medial knee laxity with valgus stress testing of a fully extended knee, anteromedial rotatory instability, associated tibial plateau fracture, or multiligament injury or those who continue to be symptomatic after non-operative treatment may benefit from surgical intervention. Patients with a history of total knee arthroplasty who suffer MCL and posterior oblique ligament (POL) injuries represent a challenging patient population and often require surgical attention. In this Technical Note, we describe the preoperative assessment, decision making, and surgical technique for anatomic reconstruction of the superficial MCL and POL with an Achilles allograft in young, active patients with medial-sided knee injuries after total knee arthroplasty.

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.

Idiopathic scoliosis (IS) is defined as a structural lateral spinal curvature ≥ 10° in otherwise healthy children and is the most common pediatric spinal deformity. IS is known to have a strong genetic component; however, the underlying etiology is still largely unknown. Animal models have been used historically to both understand and develop treatments for human disease, including within the context of IS. This intended audience for this review is clinicians in the fields of musculoskeletal surgery and research.In this review article, we synthesize current literature of genetic animal models of IS and introduce considerations for researchers.Due to complex genetic and unique biomechanical factors (i.e., bipedalism) hypothesized to contribute to IS in humans, scoliosis is a difficult condition to replicate in model organisms.We advocate careful selection of animal models based on the scientific question and introduce gaps and limitations in the current literature. We advocate future research efforts to include animal models with multiple characterized genetic or environmental perturbations to reflect current understanding of the human condition.

Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.

Objectives The purpose of this study was to evaluate the spatial relationship of the anterior horns of the menisci and the tibial tunnel during all-epiphysial drilling of skeletally immature specimens and identify any iatrogenic damage or destabilisation to the meniscus and meniscal root. Methods Four skeletally immature cadaveric knee specimens (aged 9–11 years) were used to create three-dimensional models from CT images. All-epiphysial anterior cruciate ligament (ACL) tibial tunnel drilling was performed in 14 specimens (aged 7–11 years), entering the joint surface at the ACL footprint and avoided the proximal tibial physis. The anterior meniscal roots and horns were closely inspected visually and probed for stability, prior to drilling. After drilling, the meniscus and attachment points were re-evaluated for damage to the meniscus, meniscus root and probed to evaluate for destabilisation. Results All-epiphysial tunnels entered the joint at the anatomic ACL tibial footprint. Direct visual inspection of the menisci demonstrated an absence of damage to either meniscus or anterior horn regions in all specimens. Probing and traction of the medial and lateral meniscal tissue did not demonstrate evidence of instability or destabilisation of the anterior horn or meniscus root before or after drilling. All tunnels were circumferentially intact at the joint surface, with no evidence of superior tunnel perforation due to shallow tunnel angle. Conclusion In this study, tunnel placement did not produce damage to either meniscus, nor noticeably destabilise the meniscal roots. This study also demonstrated that drill holes can be placed within the ACL footprint without entering the joint on the proximal tibia surface anterior to the ACL attachment, although the ‘safe zone' for drill hole placement is limited. All-epiphysial ACL tibial tunnels can create a large aperture at the tibial joint surface, but these tunnels can be placed at the anatomic footprint of the ACL, without causing gross anterior medial or lateral meniscus horn or root injury.

Adolescent idiopathic scoliosis (AIS) is a lateral spinal curvature &gt, 10° with rotation that affects 2–3% of healthy children across populations. AIS is known to have a significant genetic component, and despite a handful of risk loci identified in unrelated individuals by GWAS and next-generation sequencing methods, the underlying etiology of the condition remains largely unknown. In this study, we performed exome sequencing of affected individuals within 23 multigenerational families, with the hypothesis that the occurrence of rare, low frequency, disease-causing variants will co-occur in distantly related, affected individuals. Bioinformatic filtering of uncommon, potentially damaging variants shared by all sequenced family members revealed 1448 variants in 1160 genes across the 23 families, with 132 genes shared by two or more families. Ten genes were shared by &gt, 4 families, and no genes were shared by all. Gene enrichment analysis showed an enrichment of variants in cytoskeletal and extracellular matrix related processes. These data support a model that AIS is a highly polygenic disease, with few variant-containing genes shared between affected individuals across different family lineages. This work presents a novel resource for further exploration in familial AIS genetic research.

Negative pressure wound therapy is becoming more commonly used to prevent wound complications in joint arthroplasty, although few studies have assessed its outcomes compared with those of a traditional dry sterile dressing. This retrospective study assessed complications that required return to the operating room in a cohort of patients who received a dry sterile dressing (n=159) vs negative pressure wound therapy (n=32). There were significantly more overall complications ( P =.0293) in the dry sterile dressing group (23.3%) compared with the negative pressure wound therapy group (6.3%); however, these findings were not statistically significant when each individual complication was compared separately. The infection rate in the dry sterile dressing group and the negative pressure wound therapy group was 5.7% and 0%, respectively ( P =.3607). A larger, prospective study is needed to confirm the lower infection rate and before any definitive conclusions can be reached. [ Orthopedics . 2018; 41(6):e837–e840.]

Purpose To investigate the relation of the at-risk structures (distal femoral physis, lateral collateral ligament, anterolateral ligament, popliteus, and articular cartilage) during all-epiphyseal femoral tunnel drilling. A second purpose was 2-fold: (1) to develop recommendations for tunnel placement and orientation that anatomically reconstruct the anterior cruciate ligament (ACL) while minimizing the risk of injury to these at-risk structures, and (2) to allow for maximal tunnel length to increase the amount of graft in the socket to facilitate healing. Methods Three-dimensional models of 6 skeletally immature knees (aged 7-11 years) were reconstructed from computed tomography and used to simulate all-epiphyseal femoral tunnels. Tunnels began within the ACL footprint and were directed laterally or anterolaterally, with the goal of avoiding injury to at-risk structures. The spatial relation between the ideal tunnel and these structures was evaluated. Full-length tunnels and partial length condyle sockets were simulated in the models using the same trajectories. Results An anterolateral tunnel could be placed to avoid direct injury to lateral structures. The safe zone on the anterolateral aspect of the femur was larger than that of a tunnel with a direct lateral trajectory (median 127 mm 2 vs 83 mm 2 , P = .028). Anterolateral tunnels were longer than direct lateral tunnels (median 30 mm vs 24 mm, P = .041). Safe angles for anterolateral tunnels were 34° to 40° from the posterior condylar axis; direct lateral tunnels were drilled 4° to 9° from the posterior condylar axis. Sockets could be placed without direct injury to structures at risk with either orientation. Conclusions An all-epiphyseal ACL femoral tunnel can be placed without causing direct injury to at-risk structures. A tunnel angled anterolaterally from the ACL origin is longer and has a larger safe zone compared with the direct lateral tunnel. Clinical Relevance The largest safe zone for femoral all-epiphyseal ACL drilling was (1) anterior to the lateral collateral ligament origin, (2) distal to the femoral physis, and (3) proximal to the popliteus tendon origin. A direct lateral tunnel may also be used, but has a smaller safe zone. Sockets or partial length tunnels may have a lower risk of injury to at-risk structures.

Anterior cruciate ligament (ACL) reconstruction failure rates are highest in youth athletes. The role of the anterolateral ligament in rotational knee stability is of increasing interest, and several centers are exploring combined ACL and anterolateral ligament reconstruction for these young patients. Literature on the anterolateral ligament of the knee is sparse in regard to the pediatric population. A single study on specimens younger than age 5 years demonstrated the presence of the anterolateral ligament in only one of eight specimens; therefore, much about the prevalence and anatomy of the anterolateral ligament in pediatric specimens remains unknown. We sought to (1) investigate the presence or absence of the anterolateral ligament in prepubescent anatomic specimens; (2) describe the anatomic relationship of the anterolateral ligament to the lateral collateral ligament; and (3) describe the anatomic relationship between the anterolateral ligament and the physis. Fourteen skeletally immature knee specimens (median age, 8 years; range, 7–11 years) were dissected (12 male, two female specimens). The posterolateral structures were identified in all specimens, including the lateral collateral ligament and popliteus tendon. The presence or absence of the anterolateral ligament was documented in each specimen, along with origin, insertion, and dimensions, when applicable. The relationship of the anterolateral ligament origin to the lateral collateral ligament origin was recorded. The anterolateral ligament was identified in nine of 14 specimens. The tibial attachment point was consistently located in the same region on the proximal tibia, between the fibular head and Gerdy’s tubercle; however, the femoral origin of the anterolateral ligament showed considerable variation with respect to the lateral collateral ligament origin. The median femoral origin of the anterolateral ligament was 10 mm (first interquartile 6 mm, third interquartile 13) distal to the distal femoral physis, whereas its median insertion was 9 mm (first interquartile 5 mm, third interquartile 11 mm) proximal to the proximal tibial physis. The frequency of the anterolateral ligament in pediatric specimens we observed was much lower than other studies on adult specimens; future studies might further investigate the prevalence, development, and functional role of the anterolateral ligament of the knee. This study expands our understanding of the anterolateral ligament and provides important anatomic information to surgeons considering anterolateral ligament reconstruction concomitantly with primary or revision ACL reconstruction in pediatric athletes.

Diabetes is a disease with wide-ranging personal and societal impacts that has been managed medicinally for over half a century. Since the discovery of stem cells, pancreatic islet regeneration has become a central target for clinical application that has the potential to decrease or eliminate the need for insulin administration and adjunctive medications. The discovery of alternative routes to pluripotency that bypass the ethical implications of embryonic stem cells has significantly expanded the horizons of stem cell based therapy. Engraftment of mature insulin producing cells derived from induced pluripotent stem cells may represent the most promising treatment strategy for diabetic patients with impaired β-cell function. These cells are easily accessible and have been shown to closely mimic endogenous β-cell function in vivo. While the risks of oncogenesis and transplant rejection are still of great concern, large strides have been made on both fronts with the application of integration free induction strategies and the ongoing development of microcapsules that cloak implanted cells from an autoimmune response. This review will focus on the progress and remaining obstacles in diabetes related stem cell research, and will specifically discuss approaches using embryonic, induced pluripotent, germline and mesenchymal derived stem cells.