Development of KISS1 knockout pigs is characterized by hypogonadotropic hypogonadism, normal growth, and reduced skatole.

Kisspeptin is a major regulator of gonadotropin secretion in pigs. Previously, CRISPR/Cas9 knockout of KISS1 was used to develop a mosaic parental line of pigs to generate offspring that would not need castration due to loss of kisspeptin. The current goal was to characterize growth and reproductive development of F1 pigs from this parental line. Body weights, gonadotropin concentrations and gonadal development were measured from birth through development (boars to 220 d of age, n = 42; gilts to 160 d of age, n = 36). Testosterone, skatole, and androstenone were also measured in boars. Blood samples were collected by jugular venipuncture for quantification of serum hormones, gonadal tissues collected for gross morphology and histology, and a fat biopsy collected (boars) for skatole and androstenone analysis. Body weight did not differ with genotype. There were no differences between KISS1+/+ and heterozygote KISS1+/- animals for most parameters measured. Gonadotropin concentrations were reduced in KISS1-/- boars and gilts compared with KISS1+/+ and KISS1+/- animals (P < 0.05). Concentrations of testosterone in serum and both androstenone and skatole in adipose were less in KISS1-/- boars than in KISS1+/+ and KISS1+/- boars (P < 0.05). Hypogonadism was in all KISS1-/- gilts and boars. These data indicate that knocking out KISS1 causes hypogonadotropic hypogonadism but does not negatively affect growth in pigs. Only one KISS1 allele is needed for normal gonadotropin secretion and gonadal development, and accumulation of compounds in adipose leading to boar taint.

Iliac crest bone graft versus cell-based grafts to augment spinal fusion: a systematic review and meta-analysis.

INTRODUCTION: Despite successful fusion rates with iliac crest bone graft (ICBG), donor-site morbidity and increased operating time remain a considerable limitation and drive the search for alternatives. In this systematic review, grafts with additional cellular supplementation were compared with ICBG for spinal arthrodesis. We compared safety, efficacy and long-term outcomes, thus providing the current and relevant evidence for orthopaedic surgeons to make informed choices regarding this rapidly developing field. METHODS: An electronic literature search was conducted according to the PRISMA guidelines by two independent reviewers for articles published up to 1st March 2023 using PubMed, EMBASE and the Cochrane Central Register of Controlled Trial. Cellular allografts were not included. The following data were extracted: Number of patients, type of graft, fusion assessment method, follow-up duration, fusion rates, clinical outcomes and complications. The methodological quality of evidence (MQOE) was assessed using the Risk of Bias 2 (RoB-2) tool and Risk of Bias In Non-Randomised Studies (ROBINS) tool developed by Cochrane for evaluating bias in randomised and non-randomised studies. RESULTS: Ten studies fulfiled the inclusion criteria, including 465 patients. The mean number of patients per study was 43.8 (std dev. 28.81, range 12-100). Two studies demonstrated cell-based therapy to be significantly more successful in terms of fusion rates compared to ICBG. However, the remaining eight demonstrated equivocal results. No study found that cell-based therapy was inferior. No difference was seen between the two groups in three studies who focused on degenerative cohorts. No difference in functional outcome scores was seen between the groups. A number of different preparation techniques for cell-based grafts were used throughout the studies. CONCLUSION: Cell-based therapy offers a promising alternative to ICBG in spinal fusion surgery, which could help reduce the associated morbidity to patients. This review found that cell-based therapy is non-inferior to iliac crest bone graft and may offer patients an alternative treatment option with fewer complications and reduced post-operative pain. However, the literature to date is limited by heterogeneity of the cell preparation and grafting process. Future research with a unified approach to the cell preparation process is required to fully delineate the potential advantages of this technology.

Risk factors for distal junctional failure in long-construct instrumentation for adult spinal deformity.

PURPOSE: The aim of this study is to identify risk factors associated with postoperative DJF in long constructs for ASD. METHODS: A retrospective review was performed at a tertiary referral spine centre from 01/01/2007 to 31/12/2016. Demographic, clinical and radiographic parameters were collated for patients with DJF in the postoperative period and compared to those without DJF. Survival analyses were performed using univariate logistic regression to identify variables with a p value < 0.05 for inclusion in multivariate analysis. Spearman's correlations were performed where applicable. RESULTS: One hundred two patients were identified. 41 (40.2%) suffered DJF in the postoperative period, with rod fracture being the most common sign of DJF (13/65; 20.0%). Mean time to failure was 32.4 months. On univariate analysis, pedicle subtraction osteotomy (p = 0.03), transforaminal lumbar interbody fusion (p < 0.001), pre-op LL (p < 0.01), pre-op SVA (p < 0.01), pre-op SS (p = 0.02), postop LL (p = 0.03), postop SVA (p = 0.01), postop PI/LL (p < 0.001), LL correction (p < 0.001), SVA correction (p < 0.001), PT correction (p = 0.03), PI/LL correction (p < 0.001), SS correction (p = 0.03) all proved significant. On multivariate analysis, pedicle subtraction osteotomy (OR 27.3; p = 0.03), postop SVA (p < 0.01) and LL correction (p = 0.02) remained statistically significant as independent risk factors for DJF. CONCLUSION: Recently, DJF has received recognition as its own entity due to a notable postoperative incidence. Few studies to date have evaluated risk factors for DJF. The results of our study highlight that pedicle subtraction osteotomy, poor correction of lumbar lordosis, and sagittal vertical axis are significantly associated with postoperative occurrence of DJF.

Changing Demographic Trends in spine trauma: The presentation and outcome of Major Spine Trauma in the elderly.

INTRODUCTION: Major trauma has seen a demographic shift in recent years and it is expected that the elderly population will comprise a greater burden on the major trauma service in the near future. However, whether a similar trend exists in those undergoing operative intervention for spinal trauma remains to be elucidated. AIMS: To compare the presentation and outcomes of patients ≥65 years of age sustaining spine trauma to those <65 years at a national tertiary referral spine centre. METHODS: The local Trauma Audit Research Network (TARN) database was analysed to identify spinal patients referred to our institution, a national tertiary referral centre, between 01/2016 and 05/2019. Patients were divided into a young cohort (16-64 years old) and an elderly cohort (> 64 years old). No explicit distinction was made between major and minor spine trauma cases. Variables analysed included patient demographics, injury severity, mortality, interventions, mechanism of injury and length of hospital stay. RESULTS: A total of 669 patients were admitted of which 480 patients underwent operative intervention for spinal trauma. Within the elderly cohort, this represented 75.3% of cases. Among the younger population, road traffic collisions were the most common mechanism of injury (37.1%), while low falls (<2 m) (57.4%) were the most common mechanism among the older population. Patients ≥65 years old had significantly longer length of stay (21 days [1-194] v 14 days [1-183]) and suffered higher 30-day mortality rates (4.6% [0-12] v 0.97% [0-4]). CONCLUSION: Orthopaedic spinal trauma in older people is associated with a significantly higher mortality rate as well as a longer duration of hospitalization. Even though severity of injury is similar for both young and old patients, the mechanism of injury for the older population is of typically much lower energy compared to the high energy trauma affecting younger patients.

Timing of surgical fixation in traumatic spinal fractures: A systematic review.

BACKGROUND: The optimal timing of fracture fixation following spinal injury is controversial. Many spinal fractures occur as part of polytrauma requiring a complex management strategy. Whilst the decision to stabilize unstable spinal column injuries is without debate, the duration between injury and definitive fixation can impact on the incidence of post-operative complications. This study was designed to systemically summarize and compare the complication profile of early vs late stabilization of spinal injuries, in an attempt to unveil an appropriate treatment protocol for traumatic spinal fractures. METHODS: A comprehensive search strategy was performed on the PubMed, Cochrane, and Google Scholar databases using key words. The search strategy provided 1120 results. Forty-six articles were reviewed for full-text. Reference lists were analysed for potential additional texts. RESULTS: Sixteen articles met the inclusion criteria and were included for systematic review. Studies were controversial and the overall result was inconclusive. Several studies favour early stabilisation to reduce post-surgical complication rates, especially in cases of patients with high Injury Severity Scale (ISS) scores. However, this is challenged by a small number of studies reporting a higher mortality rate in the early-stabilisation cohort. CONCLUSION: Due to limited studies and a small overall cohort, the authors would cautiously recommend the early surgical fixation of unstable spine fractures in the stable trauma patient. For severely injured patients, the discordance among literature warrants the need for further investigation.

A systematic review of the presentation of scan-negative suspected cauda equina syndrome.

BACKGROUND: A significant proportion of patients presenting with suspected cauda equina syndrome (CES) do not have associated radiological evidence to support the diagnosis, often termed 'scan-negative'. Due to the limited number of studies regarding the matter, there is no clear understanding for this presentation. As a result, no treatment protocol exists for the scan-negative group. The purpose of this review is to assess the potential contributing factors leading to the presentation of suspected CES with normal imaging. METHODS: A systematic review was conducted on PubMed and Cochrane databases. Bibliographies of key articles and Google Scholar were searched for additional results. The search strategy provided 204 results. Of those, 8 had no identifiable causation for suspected CES and were included for systematic review. RESULTS: 6 of 8 studies investigated for a difference in clinical presentation between cohorts that may indicate a normal scan. Studies were either inconclusive and contradictory. Two studies suggest a functional somatic disorder as reasoning for negative MRI, with positive provisional findings. CONCLUSION: A psychogenic hypothesis is plausible and warrants further investigation. The need for additional studies is essential to scheming a potential treatment protocol for the scan-negative population, which currently does not exist.

Pharmacogenetic profiling and individualised therapy in the treatment of degenerative spinal conditions.

Patients presenting with degenerative spinal changes are often poor surgical candidates due to associated co-morbidities, frailty, or sarcopenia. Additionally, surgeries of a degenerative spine can prove difficult due to the distortion of normal surgical anatomy. Therefore, many patients are managed conservatively with a variety of modalities, including over-the-counter and prescription medications. Nevertheless, several patients do not experience adequate relief from pain with analgesic medications, precipitating multiple hospital visits, and usage of resources. As a result, back pain is regarded as a major economic burden, with total costs of associated treatment exceeding $100 billion annually. Pharmacogenetics is a relatively novel method of evaluating an individual's response to analgesic medications, through analysis of germline polymorphisms. It entails obtaining a genetic sample, often via buccal swab or peripheral blood sample, and genetic analysis achieved through either polymerase chain reaction +/- Sanger sequencing, microassays, restriction length fragment polymorphism analysis, or genetic library preparation and next generation sequencing. The potential efficacy of pharmacogenetic analysis has been highlighted across several specialities to date. However, a paucity of evidence exists regarding spine surgery populations. Nevertheless, regular prospective pharmacogenetic analysis may ultimately prove beneficial when concerning degenerative spinal cohorts due to aforementioned surgical and economic considerations. The purpose of this narrative review is to outline how metaboliser profile variants affect the pharmacokinetics of specific analgesia used to treat back pain, and to discuss the current potential and limitations of employing regular pharmacogenetic analysis for spine surgery populations with degenerative conditions.

Preoperative Considerations for the Frail Patient.

Frailty is a common geriatric syndrome, the relevance of which is becoming increasingly apparent in the clinical setting. It is often accompanied by varying degrees of sarcopenia and/or osteoporosis, leading to a decline in physical function, decreased levels of physical activity, and overall poorer health outcomes in older adults. Identifying this cohort of patients before stressor events such as spinal surgery can prove paramount to improving the postoperative outcomes of these patients. This review provides a pertinent descriptive analysis to aid identification of frailty in a clinical setting, in addition to outlining methods of preoperative intervention that may improve postoperative outcomes.

The relationship between radiological paraspinal lumbar measures and clinical measures of sarcopenia in older patients with chronic lower back pain.

Objectives: Sarcopenia is postulated to be an influential factor in chronic low back pain. The aim of this study is to evaluate the relationship between traditional clinical measures of sarcopenia and novel radiographic methods which evaluate overall muscle status, such as adjusted psoas cross-sectional area (APCSA) and degree of fat infiltration (%FI) in paraspinal muscles, in patients with chronic low back pain. Methods: Prospective study performed at our institution from 01/01/19-01/04/19. Inclusion criteria were patients ≥65 years old not requiring surgical intervention presenting to a low back pain assessment clinic. Results: 25 patients were identified (mean age: 73 years, 62% male). On spearman's analyses, %FI shared a significant relationship with hand grip strength (r = -0.37; p=0.03), chair rise (r=0.38; p=0.03), SC (r=0.64; p<0.01), and visual analogue scale scores (r=-0.14; p=0.02). Comparably, a statistically significant correlation was evident between APCSA and %FI (r=-0.40; p=0.02) on analysis. Conclusion: The results of our study demonstrate a statistically significant relationship between APCSA and %FI in the multifidus and erector spinae muscles. Further significant associations of relatability were depicted with traditional clinical measures of sarcopenia. Thus, %FI may be a supplemental indicator of the sarcopenic status of patients presenting with chronic low back pain.

Bilayered extracellular matrix derived scaffolds with anisotropic pore architecture guide tissue organization during osteochondral defect repair.

While some clinical advances in cartilage repair have occurred, osteochondral (OC) defect repair remains a significant challenge, with current scaffold-based approaches failing to recapitulate the complex, hierarchical structure of native articular cartilage (AC). To address this need, we fabricated bilayered extracellular matrix (ECM)-derived scaffolds with aligned pore architectures. By modifying the freeze-drying kinetics and controlling the direction of heat transfer during freezing, it was possible to produce anisotropic scaffolds with larger pores which supported homogenous cellular infiltration and improved sulfated glycosaminoglycan deposition. Neo-tissue organization in vitro could also be controlled by altering scaffold pore architecture, with collagen fibres aligning parallel to the long-axis of the pores within scaffolds containing aligned pore networks. Furthermore, we used in vitro and in vivo assays to demonstrate that AC and bone ECM derived scaffolds could preferentially direct the differentiation of mesenchymal stromal cells (MSCs) towards either a chondrogenic or osteogenic lineage respectively, enabling the development of bilayered ECM scaffolds capable of spatially supporting unique tissue phenotypes. Finally, we implanted these scaffolds into a large animal model of OC defect repair. After 6 months in vivo, scaffold implantation was found to improve cartilage matrix deposition, with collagen fibres preferentially aligning parallel to the long axis of the scaffold pores, resulting in a repair tissue that structurally and compositionally was more hyaline-like in nature. These results demonstrate how scaffold architecture and composition can be spatially modulated to direct the regeneration of complex interfaces such as the osteochondral unit, enabling their use as cell-free, off-the-shelf implants for joint regeneration. STATEMENT OF SIGNIFICANCE: The architecture of the extracellular matrix, while integral to tissue function, is often neglected in the design and evaluation of regenerative biomaterials. In this study we developed a bilayered scaffold for osteochondral defect repair consisting of tissue-specific extracellular matrix (ECM)-derived biomaterials to spatially direct stem/progenitor cell differentiation, with a tailored pore microarchitecture to promote the development of a repair tissue that recapitulates the hierarchical structure of native AC. The use of this bilayered scaffold resulted in improved tissue repair outcomes in a large animal model, specifically the ability to guide neo-tissue organization and therefore recapitulate key aspects of the zonal structure of native articular cartilage. These bilayer scaffolds have the potential to become a new therapeutic option for osteochondral defect repair.

Scaffold microarchitecture regulates angiogenesis and the regeneration of large bone defects.

Emerging 3D printing technologies can provide exquisite control over the external shape and internal architecture of scaffolds and tissue engineering (TE) constructs, enabling systematic studies to explore how geometric design features influence the regenerative process. Here we used fused deposition modelling (FDM) and melt electrowriting (MEW) to investigate how scaffold microarchitecture influences the healing of large bone defects. FDM was used to fabricate scaffolds with relatively large fibre diameters and low porosities, while MEW was used to fabricate scaffolds with smaller fibre diameters and higher porosities, with both scaffolds being designed to have comparable surface areas. Scaffold microarchitecture significantly influenced the healing response following implantation into critically sized femoral defects in rats, with the FDM scaffolds supporting the formation of larger bone spicules through its pores, while the MEW scaffolds supported the formation of a more round bone front during healing. After 12 weeksin vivo, both MEW and FDM scaffolds supported significantly higher levels of defect vascularisation compared to empty controls, while the MEW scaffolds supported higher levels of new bone formation. Somewhat surprisingly, this superior healing in the MEW group did not correlate with higher levels of angiogenesis, with the FDM scaffold supporting greater total vessel formation and the formation of larger vessels, while the MEW scaffold promoted the formation of a dense microvasculature with minimal evidence of larger vessels infiltrating the defect region. To conclude, the small fibre diameter, high porosity and high specific surface area of the MEW scaffold proved beneficial for osteogenesis and bone regeneration, demonstrating that changes in scaffold architecture enabled by this additive manufacturing technique can dramatically modulate angiogenesis and tissue regeneration without the need for complex exogenous growth factors. These results provide a valuable insight into the importance of 3D printed scaffold architecture when developing new bone TE strategies.

The impact of the SARS-CoV-2 pandemic on referral characteristics in a national tertiary spinal injuries unit.

BACKGROUND: The SARS-CoV-2 pandemic has had profound implications on healthcare institutions. AIMS: This study aims to assess and compare referral patterns during COVID-19 to corresponding dates for the preceding 3 years (2017-2019), in order to preemptively coordinate the logistics of the surgical unit for similar future experiences. METHODS: Retrospective review for our institution, a national tertiary referral centre for spine pathology. Two distinct time-points were chosen to represent the varied levels of social restriction during the current pandemic: (i) study period 1 (SP1) from 11 November 2020 to 08 June 2020 represents a national lockdown, and (ii) study period 2 (SP2) from 09 June 2020 to 09 September 2020 indicates an easing of restrictions. Both periods were compared to corresponding dates (CP1: 11 March-08 June and CP2 09 June-09 September) for the preceding 3 years (2017-2019). Data collected included age, gender, and mechanism of injury (MOI) for descriptive analyses. MOIs were categorised into disc disease, cyclist, road-traffic-accident (RTA), falls < 2 m, falls > 2 m, malignancy, sporting injuries, and miscellaneous. RESULTS: All MOI categories witnessed a reduction in referral numbers during SP1: disc disease (-29%), cyclist (-5%), RTAs (-66%), falls < 2 m (-39%), falls > 2 m (-17%), malignancy (-33%), sporting injuries (-100%), and miscellaneous (-58%). Four of 8 categories (RTAs, falls < 2 m, malignancy, miscellaneous) showed a trend towards return of pre-lockdown values during SP2. Two categories (disc disease, falls > 2 m) showed a further reduction (-34%, -27%) during SP2. One category (sporting injuries) portrayed a complete return to normal values during SP2 while a notable increase in cyclist-related referrals was witnessed (+ 63%) when compared with corresponding dates of previous years. CONCLUSION: Spinal injury continues to occur across almost all categories, albeit at considerably reduced numbers. RTAs and falls remained the most common MOI. Awareness needs to be drawn to the reduction of malignancy-related referrals to dissuade people with such symptoms from avoiding presentation to hospital over periods of social restrictions.

Methods to Mitigate Industry Influence in Industry Sponsored Research.

Medical and surgical research has always had a long-standing relationship with industry-based funding from sources, such as drug and device companies. Concerns exist surrounding the association between funding sources, outcome from studies and publication bias. Studies demonstrating increased odds ratios associated with positive results in industry sponsored studies across medicine have stimulated Cochrane reviews, literature reviews and other articles to examine this relationship further. In spine surgery in particular, studies with positive results have an odds ratio of 3.3 of being published. This article discusses the biases associated with industry sponsorship, possible ways to reduce such biases and ways to improve transparency in research relationships. This article explores the types of bias that can be encountered at different stages of research including previous trials in spine surgery. The means of improving transparency including the Physician Payment Sunshine Act of 2010 and International Committee of Medical Journal Editors (ICJME) accreditation are discussed. We recognize that physicians undertaking industry sponsored research should be protected and not be liable to perverse incentives. We conclude that mitigating bias in industry sponsored research is a multistep process and needs a multifaceted approach. The main beneficiary of research should be patients and as such a collective effort from medical professionals, health care institutions, journals and industry should approach research, and publications with that in mind.

Impact of Sarcopenia on Degenerative Lumbar Spondylosis.

Sarcopenia is characterized by progressive age-related and systematic loss of skeletal muscle mass, strength, and function. It was classified as an independent disease in 2016; thus, there is a sparsity of research on the association of sarcopenia with lower back pain and spinal diseases. Its prevalence is around 10% worldwide and it has been shown to be detrimental to quality of life in the elderly. Sarcopenia can be clinically identified by assessing muscle mass and physical performance measurements to show reduced strength (eg, grip strength chair rise and knee extensions) or function (eg, walking speed or distance). Radiographic imaging techniques such as computed tomography, ultrasound, or magnetic resonance imaging help diagnose sarcopenia in the lumbar spine by measuring either the cross-sectional area or the fatty infiltrate of the lumbar musculature. The presence of sarcopenia in patients preoperatively may lead to worse postoperative outcomes. Research in the treatment options for sarcopenia presurgery is still in its infancy but exercise (both aerobic and resistance exercise have been found to slow down the rate of decline in muscle mass and strength with aging) and nutrition have been utilized to varying success and show great promise in the future.

A Systematic Review of Risk Factors Associated With Distal Junctional Failure in Adult Spinal Deformity Surgery.

BACKGROUND: The surgical management of adult spinal deformity (ASD) is a major surgical undertaking associated with considerable perioperative risk and a substantial complication profile. Although the natural history and risk factors associated with proximal junctional kyphosis (PJK) and proximal junctional failure are widely reported, distal junctional failure (DJF) is less well understood. STUDY DESIGN: A systematic review was carried out. OBJECTIVES: The primary objective is to identify the risk factors associated with DJF. The secondary objective is to delineate the incidence rate and causative factors associated with DJF. METHODS: A systematic review of articles in Medline/PubMed and The Cochrane Library databases was performed according to preferred reporting items for systematic reviews and meta-analyses guidelines. Data was collated to determine the prevalence of DJF and overall revision rates, and identify potential risk factors for development of DJF. RESULTS: Twelve studies were included for systematic review. There were 81/2261 (3.6%) cases of DJF. Overall, DJF represented 27.3% of all revision surgeries. Anterior-posterior surgery had a reduced incidence of postoperative DJF [5.0% vs. 8.7%; P=0.08; relative risk (RR)=1.73], as did patients below 60 years of age at the time of surgery (2.9% vs. 3.9%; P=0.09; RR=1.34). There was a higher incidence of DJF among those patients who received interbody fusion (9.9% vs. 5.1%; P=0.06; RR=1.93) compared with those who did not. However, none of these findings reached statistical significance. There were significantly more rates of DJF for fusions ending on L5 compared with constructs fused to the sacrum (11.7% vs. 3.6%; P=0.02; RR=3.28). CONCLUSIONS: Cohorts 60 years and above of age at the time of surgery and patients managed with posterior-only fusion or interbody fusion have increased incidences of DJF. Fusion to L5 instead of the sacrum significantly influences DJF rates. However, the quality of available evidence is low and further high-quality studies are required to more robustly analyze the clinical, radiographic, and surgical risk factors associated with the development of DJF after ASD surgery.

A meta-analysis of the diagnostic accuracy of Hounsfield units on computed topography relative to dual-energy X-ray absorptiometry for the diagnosis of osteoporosis in the spine surgery population.

BACKGROUND: The preoperative identification of osteoporosis in the spine surgery population is of crucial importance. Limitations associated with dual-energy x-ray absorptiometry, such as access and reliability, have prompted the search for alternative methods to diagnose osteoporosis. The Hounsfield Unit(HU), a readily available measure on computed tomography, has garnered considerable attention in recent years as a potential diagnostic tool for reduced bone mineral density. However, the optimal threshold settings for diagnosing osteoporosis have yet to be determined. METHODS: We selected studies that included comparison of the HU(index test) with dual-energy x-ray absorptiometry evaluation(reference test). Data quality was assessed using the standardised QUADAS-2 criteria. Studies were characterised into 3 categories, based on the threshold of the index test used with the goal of obtaining a high sensitivity, high specificity or balanced sensitivity-specificity test. RESULTS: 9 studies were eligible for meta-analysis. In the high specificity group, the pooled sensitivity was 0.652 (95% CI 0.526 - 0.760), specificity 0.795 (95% CI 0.711 - 0.859) and diagnostic odds ratio was 6.652 (95% CI 4.367 - 10.133). In the high sensitivity group, the overall pooled sensitivity was 0.912 (95% CI 0.718 - 0.977), specificity was 0.67 (0.57 - 0.75) and diagnostic odds ratio was 19.424 (5.446 - 69.275). In the balanced sensitivity-specificity group, the overall pooled sensitivity was 0.625 (95% CI 0.504 - 0.732), specificity was 0.914 (0.823 - 0.960) and diagnostic odds ratio was 14.880 (7.521 - 29.440). Considerable heterogeneity existed throughout the analysis. CONCLUSION: In conclusion, the HU is a clinically useful tool to aide in the diagnosis of osteoporosis. However, the heterogeneity seen in this study warrants caution in the interpretation of results. We have demonstrated the impact of differing HU threshold values on the diagnostic ability of this test. We would propose a threshold of 135 HU to diagnose OP. Future work would investigate the optimal HU cut-off to differentiate normal from low bone mineral density.

Regenerative Medicine Modalities for the Treatment of Degenerative Disk Disease.

Degenerative disk disease is a pathologic state associated with axial skeletal pain, radiculopathy, and myelopathy, and will inevitably increase in prevalence in parallel with an aging population. The objective of regenerative medicine is to convert the inflammatory, catabolic microenvironment of degenerative disease into an anti-inflammatory, anabolic environment. This comprehensive review discusses and outlines both in vitro and in vivo efficacy of regenerative treatment modalities for degenerative disk disease, such as; mesenchymal stem cells, gene therapy, tissue engineering, and biologic treatments. To date, clinical applications have been limited secondary to a lack of standardized high quality clinical data. Additional research should focus on determining the optimal cellular makeup and concentration for each of these interventions. Nevertheless, modern medicine provides a new avenue of confronting disease, with methods surpassing traditional methods of removing the pathology in question, as regenerative medicine provides the opportunity to recover from the diseased state.

The diagnostic and prognostic value of artificial intelligence and artificial neural networks in spinal surgery : a narrative review.

In recent years, machine learning (ML) and artificial neural networks (ANNs), a particular subset of ML, have been adopted by various areas of healthcare. A number of diagnostic and prognostic algorithms have been designed and implemented across a range of orthopaedic sub-specialties to date, with many positive results. However, the methodology of many of these studies is flawed, and few compare the use of ML with the current approach in clinical practice. Spinal surgery has advanced rapidly over the past three decades, particularly in the areas of implant technology, advanced surgical techniques, biologics, and enhanced recovery protocols. It is therefore regarded an innovative field. Inevitably, spinal surgeons will wish to incorporate ML into their practice should models prove effective in diagnostic or prognostic terms. The purpose of this article is to review published studies that describe the application of neural networks to spinal surgery and which actively compare ANN models to contemporary clinical standards allowing evaluation of their efficacy, accuracy, and relatability. It also explores some of the limitations of the technology, which act to constrain the widespread adoption of neural networks for diagnostic and prognostic use in spinal care. Finally, it describes the necessary considerations should institutions wish to incorporate ANNs into their practices. In doing so, the aim of this review is to provide a practical approach for spinal surgeons to understand the relevant aspects of neural networks. Cite this article: Bone Joint J 2021;103-B(9):1442-1448.

3D bioprinting of prevascularised implants for the repair of critically-sized bone defects.

For 3D bioprinted tissues to be scaled-up to clinically relevant sizes, effective prevascularisation strategies are required to provide the necessary nutrients for normal metabolism and to remove associated waste by-products. The aim of this study was to develop a bioprinting strategy to engineer prevascularised tissues in vitro and to investigate the capacity of such constructs to enhance the vascularisation and regeneration of large bone defects in vivo. From a screen of different bioinks, a fibrin-based hydrogel was found to best support human umbilical vein endothelial cell (HUVEC) sprouting and the establishment of a microvessel network. When this bioink was combined with HUVECs and supporting human bone marrow stem/stromal cells (hBMSCs), these microvessel networks persisted in vitro. Furthermore, only bioprinted tissues containing both HUVECs and hBMSCs, that were first allowed to mature in vitro, supported robust blood vessel development in vivo. To assess the therapeutic utility of this bioprinting strategy, these bioinks were used to prevascularise 3D printed polycaprolactone (PCL) scaffolds, which were subsequently implanted into critically-sized femoral bone defects in rats. Micro-computed tomography (µCT) angiography revealed increased levels of vascularisation in vivo, which correlated with higher levels of new bone formation. Such prevascularised constructs could be used to enhance the vascularisation of a range of large tissue defects, forming the basis of multiple new bioprinted therapeutics. STATEMENT OF SIGNIFICANCE: This paper demonstrates a versatile 3D bioprinting technique to improve the vascularisation of tissue engineered constructs and further demonstrates how this method can be incorporated into a bone tissue engineering strategy to improve vascularisation in a rat femoral defect model.

Do Equivalence Trials Display Superiority Over the Traditional Comparative Study Methods in Orthopedic Surgery?

Superiority and equivalence trials are 2 commonly encountered methods of designing randomized controlled trials. Traditionally, the goal of a randomized controlled trial is to show superiority. However, in more recent times, there has been a tendency to show equivalence in clinical randomized trials. These differing conclusions at first glance seem to be drawn on the basis of the results of the respective trials. However, to accurately reach these conclusions, there are stark contrasts in the methodologies of these different study types. This article provides a brief overview of superiority and equivalence trials, highlights the differences between the 2, and their relevance to orthopedic surgery.