An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.

Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.

Mouse models of neutropenia reveal progenitor-stage-specific defects.

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.

cellHarmony: cell-level matching and holistic comparison of single-cell transcriptomes.

To understand the molecular pathogenesis of human disease, precision analyses to define alterations within and between disease-associated cell populations are desperately needed. Single-cell genomics represents an ideal platform to enable the identification and comparison of normal and diseased transcriptional cell populations. We created cellHarmony, an integrated solution for the unsupervised analysis, classification, and comparison of cell types from diverse single-cell RNA-Seq datasets. cellHarmony efficiently and accurately matches single-cell transcriptomes using a community-clustering and alignment strategy to compute differences in cell-type specific gene expression over potentially dozens of cell populations. Such transcriptional differences are used to automatically identify distinct and shared gene programs among cell-types and identify impacted pathways and transcriptional regulatory networks to understand the impact of perturbations at a systems level. cellHarmony is implemented as a python package and as an integrated workflow within the software AltAnalyze. We demonstrate that cellHarmony has improved or equivalent performance to alternative label projection methods, is able to identify the likely cellular origins of malignant states, stratify patients into clinical disease subtypes from identified gene programs, resolve discrete disease networks impacting specific cell-types, and illuminate therapeutic mechanisms. Thus, this approach holds tremendous promise in revealing the molecular and cellular origins of complex disease.

Cross-platform single cell analysis of kidney development shows stromal cells express Gdnf.

The developing kidney provides a useful model for study of the principles of organogenesis. In this report we use three independent platforms, Drop-Seq, Chromium 10x Genomics and Fluidigm C1, to carry out single cell RNA-Seq (scRNA-Seq) analysis of the E14.5 mouse kidney. Using the software AltAnalyze, in conjunction with the unsupervised approach ICGS, we were unable to identify and confirm the presence of 16 distinct cell populations during this stage of active nephrogenesis. Using a novel integrative supervised computational strategy, we were able to successfully harmonize and compare the cell profiles across all three technological platforms. Analysis of possible cross compartment receptor/ligand interactions identified the nephrogenic zone stroma as a source of GDNF. This was unexpected because the cap mesenchyme nephron progenitors had been thought to be the sole source of GDNF, which is a key driver of branching morphogenesis of the collecting duct system. The expression of Gdnf by stromal cells was validated in several ways, including Gdnf in situ hybridization combined with immunohistochemistry for SIX2, and marker of nephron progenitors, and MEIS1, a marker of stromal cells. Finally, the single cell gene expression profiles generated in this study confirmed and extended previous work showing the presence of multilineage priming during kidney development. Nephron progenitors showed stochastic expression of genes associated with multiple potential differentiation lineages.

The Perils of Riding Motocross: A Summary of this Extensive, Prospective Study.

Background: Motocross is a high-risk form of motorbiking where serious injuries occur regularly, although little data have been collected to illustrate this relationship. Over 5 years, teams from RJAH Oswestry and RSH sought to demonstrate the impact of Motocross on orthopaedic presentation and workload. Method: Data were collected prospectively over 5 years including 615 orthopaedic injuries associated with both recreational and competitive motocross. Results: An increase in injury and operation frequency was observed, young males were identified as the highest risk participant. This was evident over winter and weekends, during the competitive racing season. A variety of injuries have been implicated, some with life threatening or disabling consequences. Conclusion: Motocross has seen exponential growth in popularity with increases in injuries and operations. This implicates major impacts on finances and healthcare, especially at times of seasonal vulnerability. The authors encourage event organisers to explore the avenues of rider safety in this increasingly popular sport.

Management of traumatic anterior shoulder dislocation in the 17- to 25-year age group: a dramatic evolution of practice.

BACKGROUND: Anterior shoulder dislocation in the young patient is a common problem, yet there is no universal agreement on its management. METHODS: In this study, we comprehensively surveyed all members of the British Elbow and Shoulder Society (BESS) to ascertain their preferred methods of treating young patients with traumatic, anterior shoulder dislocation. We then repeated exactly the same survey 7 years later to find out whether practices had changed and if any consensus of opinion had been reached. RESULTS: The number of surgeons indicating their preferred stabilization procedure was arthroscopic more than quadrupled from only 16% in 2002 to 71% in 2009, while the numbers of those preferring an open technique fell in a correspondingly dramatic manner. The numbers who now potentially offer stabilization surgery to first-time dislocators virtually doubled from 35% to 68%. There was also a big rise in the use of magnetic resonance imaging (MRI) arthrograms as an investigation prior to surgery and in the use of bio-absorbable anchors during surgical stabilization. There remain, however, aspects of treatment and rehabilitation where little consensus exists. CONCLUSION: Rarely in the history of orthopaedic surgery has such a dramatic and widespread change in operative technique occurred in such a short space of time. Rarer still has such a change been prospectively documented.

Joint replacement surgery for elbow tumours: a systematic review of outcomes.

BACKGROUND: Tumour resection followed by joint reconstruction is a surgical option in the appropriate patient. The evidence for such reconstructive surgery of the elbow joint is limited. The aim of this study is to review the literature to evaluate the outcomes of joint replacement surgery in tumours of the elbow. METHODS: A systematic review of PUBMED and EMBASE databases was conducted. Case series and comparative studies reporting results after total elbow arthroplasty, modular endo-prosthetic replacement and custom prosthesis were eligible for inclusion. RESULTS: Eleven eligible studies were identified (n = 134). At mean follow-up of 44 months, the overall revision rate was 14% and complication rate was 28%. The mean Mayo Elbow Performance Score was 75, with 56% of patients reporting good or excellent outcomes. The mean post-operative range of motion was 97°. DISCUSSION: Elbow prosthesis reconstruction after tumour resection can provide good functional outcomes at mid-term follow-up. The complication and revision rates are comparable to other indications for elbow replacement surgery. Further prospective studies are required to compare outcomes between different elbow arthroplasty options after tumour resection.

An analysis of virtual fracture clinics in orthopaedic trauma in the UK during the coronavirus crisis.

Virtual fracture clinics (VFC) are advocated by new orthopaedic (British Orthopaedic Association) and National Health Service (NHS) guidelines in the United Kingdom. We discuss benefits and limitations, reviewing the literature, as well as recommendations on introducing a VFC service during the coronavirus pandemic and into the future.A narrative review identifying current literature on virtual fracture clinic outcomes when compared to traditional model fracture clinics in the UK. We identify nine relevant publications related to VFC.The Glasgow model, initiated in 2011, has become the benchmark. Clinical efficiency can be improved, reducing the number of emergency department (ED) referrals seen in VFC by 15-28% and face-to-face consultations by 65%. After review in the VFC, 33-60% of patients may be discharged. Some studies have shown no negative impact on the ED; the time to discharge was not increased. Patient satisfaction ranges from 91-97% using a VFC service, and there may be cost-saving benefits annually of £67,385 to £212,705. Non-attendance may be reduced by 75% and there are educational opportunities for trainees. However, evidence is limited; 28% of patients prefer face-to-face consultations and not all have access to internet or email (72%).We propose a pathway integrating the VFC model, whilst having senior orthopaedic decision makers available in the ED, during normal working hours, to cope with the pandemic. Beyond the pandemic, evidence suggests the Glasgow model is viable for day-to-day practice. Cite this article: EFORT Open Rev 2020;5:442-448. DOI: 10.1302/2058-5241.5.200041.

Indications and outcome in total elbow arthroplasty: A systematic review.

BACKGROUND: Total elbow arthroplasty (TEA) is the established treatment for end-stage rheumatoid arthritis but improved surgical techniques have resulted in expanded indications. The aim of this study is to review the literature to evaluate the evolution of surgical indications for TEA. METHODS: A systematic review of PubMed and EMBASE databases was conducted. Case series and comparative studies reporting results after three types of primary TEA were eligible for inclusion. RESULTS: Forty-nine eligible studies were identified (n = 1995). The number of TEA cases published annually increased from 6 cases in 1980 to 135 cases in 2008. The commonest indication for TEA throughout the review period was rheumatoid arthritis but its annual proportion reduced from 77% to 50%. The mean Mayo Elbow Performance Score significantly improved for all indications. Three comparative studies reported statistically improved functional outcomes in rheumatoid arthritis over the trauma sequelae group. Complication and revision rates varied; rheumatoid arthritis 5.2-30.9% and 11-13%, acute fracture 0-50% and 10-11%, trauma sequelae 14.2-50% and 0-30%, osteoarthritis 50% and 11%, respectively. DISCUSSION: TEA can provide functional improvements in inflammatory arthritis, acute fractures, trauma sequelae and miscellaneous indications. Long-term TEA survivorship appears satisfactory in rheumatoid arthritis and fracture cases; however, further research into alternative surgical indications is still required.

Hand and Wrist Injuries Related to Motocross Injuries: 5 Year Series.

BACKGROUND: The increasingly fashionable sport of motocross is practiced worldwide by millions of people, but there is very little in the literature regarding its associated injuries and their prevention. We therefore present the first comprehensive, prospective study looking at hand and wrist injuries resulting from motocross injuries in the UK. METHODS: Data was prospectively collected over a 5-year period (from 2010 to 2015) at our regional trauma unit. We exclusively looked at motocross riders. Injuries sustained via motorcycle were excluded from our study. RESULTS: During the period studied (five years), 615 injuries were collected, including 240 patients with 265 hand and wrist injuries. Most of injuries were sustained in male patients. The patient's age range was from 4-78 years with most injuries occurring during the spring and summer months. A total of 96 (40%) patients required operative treatment. The most common injury pattern was distal radius fractures (n = 53, 20%), followed by metacarpal fractures (n = 38, 14%) and phalangeal fractures (n = 36, 13.5%). CONCLUSIONS: This study shows the impact and incidence of related hand and wrist injuries. Motocross is a globally fashionable sport. This study shows that the number of annual tournaments and racers have doubled in last 5 years. The number of hand and wrist related injuries and operative requirements have quadruples over the last five years. It is recognized as a high-risk sport despite the use of protective equipment and course adaptions. These injuries can have implications for nearby treating hospitals.

Excised Femoral Heads in Hip Fracture Patients: Is Osteoporosis Worse Than Cancer?

Introduction Annually 80,000 hip fractures are treated at an estimated cost of two billion pounds. The 2011 guidance from the Royal College of Pathologists recommended all specimens where there is fracture through or below the articular surface should be examined to exclude/ identify an underlying cause (pathological fracture). The questions posed in this study are three-fold. Firstly, how does our practice for hip fracture patients comply with the above audit standards? Secondly, what is the prognostic significance of a past medical history of malignancy on survival? Thirdly, is there any other prognostic survival difference attributable to the diagnosis concluded from the histological analysis of the excised femoral head specimens? Methods A retrospective analysis of all hip fractures receiving joint arthroplasty was undertaken between January 2011 and March 2014. Mortality was recorded for a minimum follow-up of 30 months post-operatively. Each excised femoral head was histologically examined by a single consultant histopathologist, and all pre-operative X-rays were reviewed by a consultant radiologist. Histological diagnoses were recorded, and statistical analysis including Kaplan-Meier survival was performed. Results A total of 327 consecutive fractures were identified. Out of 187 specimens sent for analysis, only two revealed metastatic deposits in patients with known disseminated malignancy. A previous medical history of malignancy did not confer a significant increase in mortality over a five-year postoperative period (p = 0.42). A histological diagnosis of osteoporosis significantly increased mortality over a five-year postoperative period (p = 0.004). A comparative analysis found that patients with a histological diagnosis of osteoporosis had the poorest survival. Conclusion A histological femoral head analysis may diagnose previously undiagnosed osteoporosis, allowing the clinician to intervene in a disease process, which if left untreated, can lead to a significant increase in mortality.

Spinal Motocross Injuries in the United Kingdom.

BACKGROUND: Motocross is a form of motorcycle racing held on established off-road circuits and has been a recreational and competitive sport across the world for >100 years. In the United Kingdom alone, motocross has grown into a phenomenally ambitious and popular franchise. There are >200 motocross clubs across the country, permitting >900 events annually. PURPOSE: To assess the current trend of spine-related motocross injuries over the past 5 years. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data were prospectively collected over 5 years (August 2010-August 2015) at our regional trauma and spine unit, regardless of whether the rider was performing the sport competitively or recreationally. RESULTS: During the study period, spine-related injuries were identified for 174 patients (age range, 6-75 years) who were directly referred to our department following recreational or competitive motocross, with most injuries being sustained within the early spring and summer months, representing the start of the motocross season. A significant number of injuries were in males (n = 203, 94%), with the majority of injuries occurring within the 21- to 30-year-old age group. A total of 116 (54%) injuries required operative treatment. The most common spinal injury was thoracolumbar burst fracture (n = 95), followed by chance fractures (n = 26). CONCLUSION: This data series emphasizes the prevalence and devastation of motocross-related spinal injuries in the United Kingdom and may serve in administering sanctions and guidelines to governing bodies of motocross. The spinal injuries that occur during motocross have significant capital connotations for regional spinal centers. The recent surge in motocross popularity is correlated with the number of injuries, which have increased over the past 5 years by almost 500%.

Sternoclavicular joint.

The sternoclavicular joint is a saddle shaped, synovial joint and is the only skeletal articulation between the axial skeleton and the upper limb. Here, a reviewis provided of the anatomy, biomechanics, traumatic and atraumatic conditions, and management options for the various conditions described.

The Human Cell Atlas bone marrow single-cell interactive web portal.

The Human Cell Atlas (HCA) is expected to facilitate the creation of reference cell profiles, marker genes, and gene regulatory networks that will provide a deeper understanding of healthy and disease cell types from clinical biospecimens. The hematopoietic system includes dozens of distinct, transcriptionally coherent cell types, including intermediate transitional populations that have not been previously described at a molecular level. Using the first data release from the HCA bone marrow tissue project, we resolved common, rare, and potentially transitional cell populations from over 100,000 hematopoietic cells spanning 35 transcriptionally coherent groups across eight healthy donors using emerging new computational approaches. These data highlight novel mixed-lineage progenitor populations and putative trajectories governing granulocytic, monocytic, lymphoid, erythroid, megakaryocytic, and eosinophil specification. Our analyses suggest significant variation in cell-type composition and gene expression among donors, including biological processes affected by donor age. To enable broad exploration of these findings, we provide an interactive website to probe intra-cell and extra-cell population differences within and between donors and reference markers for cellular classification and cellular trajectories through associated progenitor states.

The Provision of Primary and Revision Elbow Replacement Surgery in the NHS.

BESS Surgical Procedure Guidelines (SPGs). Optimising Surgical Outcomes for Shoulder and Elbow patients. The British Elbow and Shoulder Society (BESS) SPGs are a series of evidence and consensus Best Practice Recommendations developed by BESS surgeons and physiotherapists to help drive quality improvement and achieve the best possible surgical outcomes for UK patients. This SPG on primary and revision elbow replacement surgery is supported and endorsed by both the British Orthopaedic Association (BOA) and the Getting It Right First Time (GIRFT) Programme.

Sequential metatarsal fatigue fractures secondary to abnormal foot biomechanics.

Sequential fatigue fractures of the fourth, second, and third metatarsals in the same foot are reported for a military aviator in the absence of abnormal stresses or underlying bone disease. The likely etiological factor is altered foot biomechanics, as identified in pedobarographic assessment. We have reviewed the literature regarding multiple metatarsal stress fractures.

Unusual lesions mimicking impingement syndrome in the shoulder joint - Think medially.

Impingement syndrome is usually caused by irritation of the rotator cuff within the sub acromial space and this includes the coraco-acromial arch (Acromion and Coraco-acromial ligament), the acromio-clavicular joint and occasionally the coracoid. Iatrogenic causes such as sutures, pins, plates or wires left from previous surgery can cause similar symptoms. We present a series of four cases mimicking "classical" impingement symptoms/signs in which the causal pathology was identified outside the sub-acromial space. Magnetic Resonance Imaging (MRI) showed lesions that were present in the supra-spinatus fossa but were causing pressure effects on the sub-acromial space, namely - a ganglion cyst in one case, lipomata in two other cases, and a glomus tumour. A ganglion cyst and glomus tumour mimicking impingement syndrome is a rare reported case to our knowledge. These are unusual causes that should be considered when investigating classical impingement syndrome and particularly those who may have failed to respond to decompression surgery. They highlight the potential value of looking beyond the sub-acromial space for causal lesions and in these cases, at a time when limited ultrasound investigation has become increasingly popular; MRI has clearly played an important and was essential in planning surgery as these lesions would not have been identified on USS. Even though the symptoms were classical.

An epidemiological study of paediatric motocross injuries in the United Kingdom.

PURPOSE: Although off-road motorcycling is one of the most popular sports activities practised by millions of people worldwide, little has been written on motocross injuries and their prevention. In the UK alone, motocross has grown into a phenomenally ambitious and popular franchise. There are >200 motocross clubs across the country holding >900 events annually. The aim of this study is to categorise and quantify the magnitude of motocross paediatric injuries and associated morbidity. METHODS: Data were collected prospectively over 4 years (2010-2014) at our unit. All injuries caused by motocross biking that were referred to our trauma and orthopaedic department were included in this study, regardless of whether the rider was performing the sport competitively or recreationally. RESULTS: During the study period, 130 patients (aged 4-17 years) were identified with a total of 142 injuries, ranging from one to six injuries per patient. Most of the injuries were sustained within the early spring and summer months, representing the start of the motocross season; 76 patients required hospital admission, with 60 (42 %) requiring surgical intervention. CONCLUSION: We present the first epidemiological study of motocross paediatric injuries in the UK. The results from this study highlight the frequency and severity of motocross-related injuries in the paediatric population in the UK. This may assist in providing recommendations and guidelines to governing bodies and to parents. The injuries sustained during motocross have significant resource implications, especially for smaller rural hospitals, as shown by the number of injuries doubling over the past 4 years.

Motocross biking for competition and for recreation: a prospective analysis of 423 injured riders.

BACKGROUND: Motocross is a form of motorcycle racing held on established off-road circuits and has been a recreational and competitive sport across the world for over 100 years. In the UK alone, motocross has grown into a phenomenally ambitious and popular franchise. There are over 200 motocross clubs across the country, permitting over 900 events annually. METHOD: Data were collected prospectively over 4 years (from 2010 to 2014) at our unit. All injuries caused by motocross biking that were referred to our trauma and orthopaedic department were included in this study, regardless of whether the rider was performing the sport competitively or recreationally. RESULTS: During the period studied (4 years), 423 patients were included with a total of 485 injuries, ranging from 1 to 6 injuries per patient. The patient's age range was from 4 to 73 years, with most of the injuries being sustained within the early spring and summer months representing the start of the motocross season. CONCLUSIONS: We present the first epidemiological study of motocross injuries in the UK. Within the growing culture of 'adrenaline sports', motocross has become an exhilarating and extremely fashionable pastime. This study has identified and categorised the spectrum of injuries from upper limb fracture dislocations to life-threatening head and chest injuries, some of which are serious and may cause significant morbidity and possible mortality. These injuries could have significant resource implications, especially for smaller rural hospitals.

Intra-Articular Synovial Haemangioma of the Elbow in an Adolescent Male.

Intra-articular haemangiomas are rare phenomena and are difficult to diagnose and manage. We describe a case in which a haemangioma was found at the time of elbow arthroscopy in an adolescent male. The case highlights the advantage of early arthroscopic assessment and also that synovial haemangiomas must be considered as a rare differential diagnosis in unexplained elbow and joint pain.