Stuart A. Aitken

Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation

Mammalian chromosomes fold into arrays of megabase‐sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal substructures that are often cell type specific, but their higher‐order organization remains elusive. Here, we investigate TAD higher‐order interactions with Hi‐C through neuronal differentiation and show that they form a hierarchy of domains‐within‐domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree‐like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency.

The Epidemiology of Radial Head and Neck Fractures

PURPOSE The aim of this study was to define the epidemiological characteristics of proximal radial fractures. METHODS Using a prospective trauma database of 6,872 patients, we identified all patients who sustained a fracture of the radial head or neck over a 1-year period. Age, sex, socioeconomic status, mechanism of injury, fracture classification, and associated injuries were recorded and analyzed. RESULTS We identified 285 radial head (n = 199) and neck (n = 86) fractures, with a patient median age of 43 years (range, 13-94 y). The mean age of male patients was younger when compared to female patients for radial head and neck fractures, with no gender predominance seen. Gender did influence the mechanism of injury, with female patients commonly sustaining their fracture following a low-energy fall. Radial head fractures were associated more commonly with complex injuries according to the Mason classification, while associated injuries were related to age, the mechanism of injury, and increasing fracture complexity. CONCLUSIONS Radial head and neck fractures have distinct epidemiological characteristics, and consideration for osteoporosis in a subset of patients is recommended. TYPE OF STUDY/LEVEL OF EVIDENCE Prognostic IV.

The epidemiology of fractures of the proximal ulna

INTRODUCTION The aim of our study was to report the epidemiological characteristics of fractures of the proximal ulna. METHODS From our prospective trauma database of 6872 fractures, we identified all acute fractures of the proximal ulna from a 1-year period between July 2007 and June 2008. Age, gender, mode of injury, fracture classifications, associated injuries and treatment were the factors documented and analysed. RESULTS There were 78 fractures of the proximal ulna with a mean age of 57 years (15-97). Males (n=35) sustained their fracture at a significantly younger age than females (p=0.041), with no gender predominance seen (p=0.365). The overall fracture distribution was a unimodal older male and unimodal older female type-F curve. The most common mode of injury was a simple fall from standing height (n=52, 67%), with younger patients more likely to sustain their injuries following a high-energy mechanism such as sports or a motor vehicle collision (p<0.001). Seventeen (22%) patients sustained associated injuries to the ipsilateral limb, with an associated proximal radial fracture most frequent (n=13, 17%). Open fractures were seen in five (6.4%) patients. A total of 64 patients had a fracture of the olecranon, with the Mayo 2A most frequently seen (n=47, 60%). CONCLUSIONS Fractures of the proximal ulna are fragility fractures that predominantly occur in elderly patients. Given the number of elderly patients sustaining these injuries, research is needed to determine the role of non-operative treatment for these fractures, particularly in patients with multiple co-morbidities and low functional demands.

Transcriptional dynamics reveal critical roles for non-coding RNAs in the immediate-early response

The immediate-early response mediates cell fate in response to a variety of extracellular stimuli and is dysregulated in many cancers. However, the specificity of the response across stimuli and cell types, and the roles of non-coding RNAs are not well understood. Using a large collection of densely-sampled time series expression data we have examined the induction of the immediate-early response in unparalleled detail, across cell types and stimuli. We exploit cap analysis of gene expression (CAGE) time series datasets to directly measure promoter activities over time. Using a novel analysis method for time series data we identify transcripts with expression patterns that closely resemble the dynamics of known immediate-early genes (IEGs) and this enables a comprehensive comparative study of these genes and their chromatin state. Surprisingly, these data suggest that the earliest transcriptional responses often involve promoters generating non-coding RNAs, many of which are produced in advance of canonical protein-coding IEGs. IEGs are known to be capable of induction without de novo protein synthesis. Consistent with this, we find that the response of both protein-coding and non-coding RNA IEGs can be explained by their transcriptionally poised, permissive chromatin state prior to stimulation. We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line. Our computational statistical method is well suited to meta-analyses as there is no requirement for transcripts to pass thresholds for significant differential expression between time points, and it is agnostic to the number of time points per dataset.

The epidemiology of acute sports-related fractures in adults

OBJECTIVE To determine the incidence and epidemiology of acute sports-related fractures in adults. DESIGN Retrospective analysis of a prospectively collected database containing all in-patient and out-patient fractures in a defined patient population in 2000. SETTING Orthopaedic Trauma Unit. RESULTS There were 5953 fractures in 2000 of which 761 (12.8%) were caused in sporting accidents. The overall incidence was 142/10(5) with 261/10(5) in males and 35/10(5) in females. The mean age was 25.6 years. 41 sports caused the fractures but 10 sports accounted for 86.8% of fractures. In 40 sports the highest prevalence of fractures were in the upper limb and the commonest fractures seen were in the distal radius, metacarpus and finger phalanges although the highest prevalence was in the clavicle. Sports fractures comprised 16.5% of upper limb fractures and 7.5% of lower limb fractures. Our results suggest that there are 80,000-85,000 sports fractures annually in the United Kingdom of which about 18,000 require operative treatment. CONCLUSIONS Sporting activities are the third most common cause of fractures. With increasing affluence it is likely that they will increase. Fractures of the wrist and hand are the most common but in some sports there are a number of higher energy fractures. Our results suggest that, even in sport, there are a number of osteoporotic fractures usually occurring in women.

The epidemiology of sports-related fractures of the hand

OBJECTIVE To describe the incidence and epidemiology of acute sports-related hand fractures in the adult general population. DESIGN Retrospective analysis of a prospectively collected database recording all inpatient and outpatient fractures in a well-defined population during 2000. SETTING Department of Trauma and Orthopaedics, Royal Infirmary of Edinburgh, UK. RESULTS During 2000, 1430 hand fractures were recorded, 320 of which (22.4%) were sports injuries. Males were more commonly injured (86%). The overall incidence was 60/10(5)(104/10(5) among males and 17/10(5) among females). The average age was 24 years. There were 39 (12.2%) carpal, 108 (33.8%) metacarpal and 173 (54.1%) phalangeal fractures. Damage to the first and fifth rays was most common. Open fractures were uncommon (n=7; 2.2%). Eight sports were responsible for 87.8% of fractures, each sport displaying a characteristic pattern of injury within the hand. The majority of fractures (87.2%) were treated on an outpatient basis. CONCLUSIONS Sporting activity accounts for 22.4% of all hand fractures, with relatively few requiring operative intervention. Young males are most commonly affected. Certain sports are associated with distinct fracture patterns, allowing appropriate preventive measures to be taken.

Scaphoid Fracture Epidemiology

Background: The current available literature related to scaphoid fracture epidemiology is inconsistent. The aim of this study was to describe the epidemiology of true scaphoid fractures in a defined adult population. Methods: Using a prospective database, we identified all patients who sustained a radiographically confirmed acute fracture of the scaphoid over a 1-year period. Age, gender, mechanism of injury, the Herbert fracture classification, and associated injuries were recorded and analyzed. Results: There were 151 scaphoid fractures diagnosed giving an annual incidence of 29 per 100,000 (95% confidence interval, 25–34). The median age of males was significantly younger when compared with females (p = 0.002), with a male (n = 105) predominance seen (p < 0.001). Low-energy falls from a standing height were most common (40.4%), but with males being significantly more likely to sustain their fracture after a high-energy injury (p < 0.001). The most common fracture was Herbert classification B2 (n = 55, 36.4%), with unstable fractures more common in younger patients (p = 0.025) following a high-energy injury (p = 0.042). Conclusions: We have reported the epidemiology of true scaphoid fractures, with young males at risk of sustaining a fracture. Knowledge of the true incidence of scaphoid fractures and an understanding of the demographic risk factors are essential when assessing the suspected scaphoid fracture, particularly when considering further imaging modalities.

Recreational mountain biking injuries

Mountain biking is increasing in popularity worldwide. The injury patterns associated with elite level and competitive mountain biking are known. This study analysed the incidence, spectrum and risk factors for injuries sustained during recreational mountain biking. The injury rate was 1.54 injuries per 1000 biker exposures. Men were more commonly injured than women, with those aged 30–39 years at highest risk. The commonest types of injury were wounding, skeletal fracture and musculoskeletal soft tissue injury. Joint dislocations occurred more commonly in older mountain bikers. The limbs were more commonly injured than the axial skeleton. The highest hospital admission rates were observed with head, neck and torso injuries. Protective body armour, clip-in pedals and the use of a full-suspension bicycle may confer a protective effect.

The outcome of fractures in very elderly patients

We compared case-mix and outcome variables in 1310 patients who sustained an acute fracture at the age of 80 years or over. A group of 318 very elderly patients (≥ 90 years) was compared with a group of 992 elderly patients (80 to 89 years), all of whom presented to a single trauma unit between July 2007 and June 2008. The very elderly group represented only 0.6% of the overall population, but accounted for 4.1% of all fractures and 9.3% of all orthopaedic trauma admissions. Patients in this group were more likely to require hospital admission (odds ratio 1.4), less likely to return to independent living (odds ratio 3.1), and to have a significantly longer hospital stay (ten days, p = 0.01). The 30- and 120-day unadjusted mortality was greater in the very elderly group. The 120-day mortality associated with non-hip fractures of the lower limb was equal to that of proximal femoral fractures, and was significantly increased with a delay to surgery > 48 hours for both age groups (p = 0.04). This suggests that the principle of early surgery and mobilisation of elderly patients with hip fractures should be extended to include all those in this vulnerable age group.

Multiple fractures in the elderly

We present the prevalence of multiple fractures in the elderly in a single catchment population of 780,000 treated over a 12-month period and describe the mechanisms of injury, common patterns of occurrence, management, and the associated mortality rate. A total of 2335 patients, aged ≥ 65 years of age, were prospectively assessed and of these 119 patients (5.1%) presented with multiple fractures. Distal radial (odds ratio (OR) 5.1, p < 0.0001), proximal humeral (OR 2.2, p < 0.0001) and pelvic (OR 4.9, p < 0.0001) fractures were associated with an increased risk of sustaining associated fractures. Only 4.5% of patients sustained multiple fractures after a simple fall, but due to the frequency of falls in the elderly this mechanism resulted in 80.7% of all multiple fractures. Most patients required admission (> 80%), of whom 42% did not need an operation but more than half needed an increased level of care before discharge (54%). The standardised mortality rate at one year was significantly greater after sustaining multiple fractures that included fractures of the pelvis, proximal humerus or proximal femur (p < 0.001). This mortality risk increased further if patients were < 80 years of age, indicating that the existence of multiple fractures after low-energy trauma is a marker of mortality.