Benzo[a]pyrene-induced multigenerational changes in gene expression, behavior, and DNA methylation are primarily influenced by paternal exposure.

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is implicated in many developmental and behavioral adverse outcomes in offspring of exposed parents. The objective of this study was to investigate sex-dependent multigenerational effects of preconceptional effects of BaP exposure. Adult wild-type (5D) zebrafish were fed 708 µg BaP/g diet (measured) at a rate of 1% body weight twice/day (14 µg BaP/g fish/day) for 21 days. Fish were spawned using a crossover design, and parental (F0) behavior and reproductive indexes were measured. In offspring, behavioral effects were measured at 96 h post fertilization (hpf) in F1 & F2 larvae, and again when F1s were adults. Compared to controls, there was no significant effect on F0 adult behavior immediately following exposure, but locomotor activity was significantly increased in F1 adults of both sexes. Larval behavior (96 hpf, photomotor response assay) was significantly altered in both the F1 and F2 generations. To assess molecular changes associated with BaP exposure, we conducted transcriptome and DNA methylation profiling in F0 gametes (sperm and eggs) and F1 embryos (10 hpf) from all four crosses. Embryos resulting from the BaP male and control female cross had the most differentially expressed genes (DEGs) and differentially methylated regions (DMRs). Some DMRs were associated with genes encoding chromatin modifying enzymes suggesting regulation of chromatin conformation by DNA methylation. Overall, these results suggest that parental dietary BaP exposure significantly contributes to the multigenerational adverse outcomes.

Pay for performance and hip fracture outcomes: an interrupted time series and difference-in-differences analysis in England and Scotland.

AIMS: Hip fractures are associated with high morbidity, mortality, and costs. One strategy for improving outcomes is to incentivize hospitals to provide better quality of care. We aimed to determine whether a pay-for-performance initiative affected hip fracture outcomes in England by using Scotland, which did not participate in the scheme, as a control. MATERIALS AND METHODS: We undertook an interrupted time series study with data from all patients aged more than 60 years with a hip fracture in England (2000 to 2018) using the Hospital Episode Statistics Admitted Patient Care (HES APC) data set linked to national death registrations. Difference-in-differences (DID) analysis incorporating equivalent data from the Scottish Morbidity Record was used to control for secular trends. The outcomes were 30-day and 365-day mortality, 30-day re-admission, time to operation, and acute length of stay. RESULTS: There were 1 037 860 patients with a hip fracture in England and 116 594 in Scotland. Both 30-day (DID -1.7%; 95% confidence interval (CI) -2.0 to -1.2) and 365-day (-1.9%; 95% CI -2.5 to -1.3) mortality fell in England post-intervention when compared with outcomes in Scotland. There were 7600 fewer deaths between 2010 and 2016 that could be attributed to interventions driven by pay-for-performance. A pre-existing annual trend towards increased 30-day re-admissions in England was halted post-intervention. Significant reductions were observed in the time to operation and length of stay. CONCLUSION: This study provides evidence that a pay-for-performance programme improved the outcomes after a hip fracture in England. Cite this article: Bone Joint J 2019;101-B:1015-1023.

A qualitative study of patient experience of an open fracture of the lower limb during acute care.

Aims: The aim of this study was to explore the patients' experience of recovery from open fracture of the lower limb in acute care. Patients and Methods: A purposeful sample of 20 participants with a mean age of 40 years (20 to 82) (16 males, four females) were interviewed a mean of 12 days (five to 35) after their first surgical intervention took place between July 2012 and July 2013 in two National Health Service (NHS) trusts in England, United Kingdom. The qualitative interviews drew on phenomenology and analysis identified codes, which were drawn together into categories and themes. Results: The findings identify the vulnerability of the patients expressed through three themes; being emotionally fragile, being injured and living with injury. The participants felt a closeness to death and continued uncertainty regarding loss of their limb. They experienced strong emotions while also trying to contain their emotions for the benefit of others. Their sense of self changed as they became a person with visible wounds, needed intimate help, and endured pain. When ready, they imagined what it would be like to live with injury. Conclusion: Recovery activities require an increased focus on emotional wellbeing. Surgeons are aware of the need for clinical expertise and for adequate pain relief but may not be as aware that their patients require support regarding their body image and help to imagine their future life. Cite this article: Bone Joint J 2018;100-B:522-6.

The administration of intermittent parathyroid hormone affects functional recovery from trochanteric fractured neck of femur: a randomised prospective mixed method pilot study.

AIMS: We wished to assess the feasibility of a future randomised controlled trial of parathyroid hormone (PTH) supplements to aid healing of trochanteric fractures of the hip, by an open label prospective feasibility and pilot study with a nested qualitative sub study. This aimed to inform the design of a future powered study comparing the functional recovery after trochanteric hip fracture in patients undergoing standard care, versus those who undergo administration of subcutaneous injection of PTH for six weeks. PATIENTS AND METHODS: We undertook a pilot study comparing the functional recovery after trochanteric hip fracture in patients 60 years or older, admitted with a trochanteric hip fracture, and potentially eligible to be randomised to either standard care or the administration of subcutaneous PTH for six weeks. Our desired outcomes were functional testing and measures to assess the feasibility and acceptability of the study. RESULTS: A total of 724 patients were screened, of whom 143 (20%) were eligible for recruitment. Of these, 123 were approached and 29 (4%) elected to take part. However, seven patients did not complete the study. Compliance with the injections was 11 out of 15 (73%) showing the intervention to be acceptable and feasible in this patient population. TAKE HOME MESSAGE: Only 4% of patients who met the inclusion criteria were both eligible and willing to consent to a study involving injections of PTH, so delivering this study on a large scale would carry challenges in recruitment and retention. Methodological and sample size planning would have to take this into account. PTH administration to patients to enhance fracture healing should still be considered experimental. Cite this article: Bone Joint J 2016;98-B:840-5.

Management of hip fractures in older people in Beijing: a retrospective audit and comparison with evidence-based guidelines and practice in the UK.

UNLABELLED: Despite the high burden of hip fracture in China, there is limited information on its management. This study investigated the management of hip fractures in a Beijing tertiary hospital and compared practice with that in 180 hospitals in the UK. The findings show a significant gap exists between the countries. INTRODUCTION: The purpose of this study was to determine if the management of older people with hip fractures in a Beijing tertiary hospital is comparable with the UK best practice guidelines for hip fracture management and the UK National Hip Fracture Database 2012, obtained from 180 hospitals. METHODS: A retrospective audit was undertaken in a large tertiary care hospital in Beijing. Data were compared with the National Hip Fracture Database 2012 collected in 180 hospitals in the UK on the proportion of patients managed according to the UK Blue Book standards. RESULTS: Sixty-six percent of patients were admitted to an orthopaedic ward within 24 h of fracture, while 100 % of patients in the UK were admitted to an orthopaedic ward within 24 h of arrival to an accident and emergency department. Only 8 % of patients received surgery within 48 h of admission compared with 83 % in the UK; 10 % received no surgery compared with 2.5 % in the UK; and 27 % received orthogeriatrician assessment compared with 70 % in the UK. New pressure ulcers developed in 2 % of patients compared with 3.7 % of those in the UK; whereas, 0.3 % of patients were assessed for osteoporosis treatment and 3.8 % received falls assessment, and comparable figures for the UK were 94 and 92 %, respectively. CONCLUSIONS: Significant gaps exist in hip fracture management in the Beijing hospital compared with the best practice achieved in 180 UK hospitals, highlighting the need to implement and evaluate proactive strategies to increase the uptake of best practice hip fracture care in China.

What is the effect of the weather on trauma workload? A systematic review of the literature.

BACKGROUND: Hospital admission rates for a number of conditions have been linked to variations in the weather. It is well established that trauma workload displays significant seasonal variation. A reliable predictive model might enable targeting of high-risk groups for intervention and planning of hospital staff levels. To our knowledge there have been no systematic reviews of the literature on the relationship between weather and trauma workload, and predictive models have thus far been informed by the results of single studies. METHODS: We conducted a systematic review of bibliographic databases and reference lists up to June 2014 to identify primary research papers assessing the effect of specified weather conditions including temperature, rainfall, snow, fog, hail, humidity and wind speed on trauma workload, defined as admission to hospital, fracture or a Road Traffic Accident (RTA) resulting in a seriously injured casualty or fatality. RESULTS: 11,083 papers were found through electronic and reference search. 83 full papers were assessed for eligibility. 28 met inclusion criteria and were included in the final review; 6 of these related to the effect of the weather on trauma admissions, one to ambulance call out for trauma, 13 to fracture rate and 8 to RTAs. Increased temperature is positively correlated with trauma admissions. The rate of distal radius fractures is more sensitive to adverse weather than the rate of hip fractures. Paediatric trauma, both in respect of trauma admissions and fracture rate, is more sensitive to the weather than adult trauma. Adverse weather influences both RTA frequency and severity, but the nature of the relationship is dependent upon the timecourse of the weather event and the population studied. Important methodological differences between studies limit the value of the existing literature in building consensus for a generalisable predictive model. CONCLUSIONS: Weather conditions may have a substantial effect on trauma workload independent of the effects of seasonal variation; the population studied and timecourse of weather events appear critical in determining this relationship. Methodological differences between studies limit the validity of conclusions drawn from analysis of the literature, and we identify a number of areas that future research might address.

Differential targeting of feline photoreceptors by recombinant adeno-associated viral vectors: implications for preclinical gene therapy trials.

The cat is emerging as a promising large animal model for preclinical testing of retinal dystrophy therapies, for example, by gene therapy. However, there is a paucity of studies investigating viral vector gene transfer to the feline retina. We therefore sought to study the tropism of recombinant adeno-associated viral (rAAV) vectors for the feline outer retina. We delivered four rAAV serotypes: rAAV2/2, rAAV2/5, rAAV2/8 and rAAV2/9, each expressing green fluorescent protein (GFP) under the control of a cytomegalovirus promoter, to the subretinal space in cats and, for comparison, mice. Cats were monitored for gene expression by in vivo imaging and cellular tropism was determined using immunohistochemistry. In cats, rAAV2/2, rAAV2/8 and rAAV2/9 vectors induced faster and stronger GFP expression than rAAV2/5 and all vectors transduced the retinal pigment epithelium (RPE) and photoreceptors. Unlike in mice, cone photoreceptors in the cat retina were more efficiently transduced than rod photoreceptors. In mice, rAAV2/2 only transduced the RPE whereas the other vectors also transduced rods and cones. These results highlight species differences in cellular tropism of rAAV vectors in the outer retina. We conclude that rAAV serotypes are suitable for use for retinal gene therapy in feline models, particularly when cone photoreceptors are the target cell.

Effects on specific promoter DNA methylation in zebrafish embryos and larvae following benzo[a]pyrene exposure.

Benzo[a]pyrene (BaP) is an established carcinogen and reproductive and developmental toxicant. BaP exposure in humans and animals has been linked to infertility and multigenerational health consequences. DNA methylation is the most studied epigenetic mechanism that regulates gene expression, and mapping of methylation patterns has become an important tool for understanding pathologic gene expression events. The goal of this study was to investigate aberrant changes in promoter DNA methylation in zebrafish embryos and larvae following a parental and continued embryonic waterborne BaP exposure. A total of 21 genes known for their role in human diseases were selected to measure percent methylation by multiplex deep sequencing. At 96hpf (hours post fertilization) compared to 3.3hpf, dazl, nqo1, sox3, cyp1b1, and gstp1 had higher methylation percentages while c-fos and cdkn1a had decreased CG methylation. BaP exposure significantly reduced egg production and offspring survival. Moreover, BaP decreased global methylation and altered CG, CHH, and CHG methylation both at 3.3 and 96hpf. CG methylation changed by 10% or more due to BaP in six genes (c-fos, cdkn1a, dazl, nqo1, nrf2, and sox3) at 3.3hpf and in ten genes (c-fos, cyp1b1, dazl, gstp1, mlh1, nqo1, pten, p53, sox2, and sox3) at 96hpf. BaP also induced gene expression of cyp1b1 and gstp1 at 96hpf which were found to be hypermethylated. Further studies are needed to link aberrant CG, CHH, and CHG methylation to heritable epigenetic consequences associated with disease in later life.

The treatment of stable paediatric forearm fractures using a cast that may be removed at home: comparison with traditional management in a randomised controlled trial.

We investigated whether, in the management of stable paediatric fractures of the forearm, flexible casts that can be removed at home are as clinically effective, cost-effective and acceptable to both patient and parent as management using a cast conventionally removed in hospital. A single-centre randomised controlled trial was performed on 317 children with a mean age of 9.3 years (2 to 16). No significant differences were seen in the change in Childhood Health Assessment Questionnaire index score (p = 0.10) or EuroQol 5-Dimensions domain scores between the two groups one week after removal of the cast or the absolute scores at six months. There was a significantly lower overall median treatment cost in the group whose casts were removed at home (£150.88 (sem 1.90) vs £251.62 (sem 2.68); p < 0.001). No difference was seen in satisfaction between the two groups (p = 0.48).

The role of platelet-rich plasma in tissue regeneration.

Platelet-rich plasma (PRP), an autologous derivative of whole blood that contains a supraphysiological concentration of platelets, has gained increasing attention in both the scientific literature and the wider media for its potential application in the treatment of traumatic musculoskeletal injury. The theoretical benefit of PRP in providing a local environment for tissue regeneration which is rich in growth factors and other cytokines has been supported by in vitro and animal studies which suggest a positive influence on the migration and proliferation of a number of cell types. However, the reported clinical use of PRP is largely confined to the last two decades and initially centred around its application in dental and maxillofacial surgery. More recently, developments in research of the regenerative effects of PRP in a range of tissue types including bone, cartilage, tendon and muscle, particularly in the context of traumatic injury, have attracted interest in fields such as orthopaedic and plastic surgery where effective union of sometimes poorly vascularised and damaged tissue is a critical determinant of successful clinical outcome. Despite the lack of high-quality trial data, results from clinical studies have been encouraging, and PRP administration remains an attractive strategy given its cost-effective and minimally invasive nature. In this review, we summarise the current literature on the use of PRP and highlight areas of controversy and emerging clinical applications.

Outcome measurements in major trauma--results of a consensus meeting.

BACKGROUND: The NHS Outcomes Framework for England has identified recovery from major injury as an important clinical area. At present, there are no established outcome indicators. As more patients survive major trauma, outcomes will need to be measured in terms of morbidity and not mortality alone. OBJECTIVE: To make recommendations for a selection of outcome measures that could be integrated into National Clinical Audit data collection and form part of clinical governance requirements for Regional Trauma Networks (RTNs) and measures by which RTNs are held to account by government. Specific focus was given to acute care and rehabilitation for both adults and children. METHOD: A Multiprofessional, multidisciplinary expert group reviewed the current evidence on outcome measures for major trauma in the adult and children's populations, informed by a systematic review carried out jointly by the Trauma Audit and Research Network (TARN) and the Cochrane Injuries Group. A structured discussion covered functional and quality of life outcome measures as well as patient experience and indicators such as return to work, education and social dependency. RESULTS: For the adult population the group agreed with the in-hospital performance and hospital discharge measures recommended in the TARN and Cochrane systematic review. Concerning longer-term outcome indicators, the group suggested the use of the Glasgow Outcome Scale - Extended (GOS-E) and European Quality of Life 5D (EQ-5D) with consideration to be given to the World Health Organisation Quality of Life survey (WHO-QoL). For patients who had ongoing inpatient rehabilitation needs the group thought the measurement of the Rehabilitation Complexity Scale (RCS) and Functional Independence Measure (FIM) were important in total brain injury and, the American Spinal Injury Association Impairment Scale (ASIA) and Spinal Cord Independence Measure (SCIM) in spinal cord injury. For children the group recommended the use of the King's Outcome Scale for Childhood Head Injury (KOSCHI) and Paediatric Quality of Life measure (Peds-QL) preferably at multiple intervals following injury to take into account effects on development. CONCLUSION: Specific recommendations were made for the use of outcome measures in adults and children with major trauma and those with complex rehabilitation needs following injury. More work on outcome measures in major trauma is needed especially for children. There are currently no robust measures of patient experience for use in major trauma. The importance of data linkage to allow measurement of non-clinical outcomes such as return to work, maintainence of education and societal dependency was emphasised by the group. A system for recording outcomes should be piloted post injury and at 6 and 12 months, with those still requiring inpatient rehabilitation after this time having longer follow up.

Treatment of post-operative infections following proximal femoral fractures: our institutional experience.

Proximal femoral fractures (PFFs) are a major health concern in the elderly population. Improvements made in implants and surgical techniques resulted in faster rehabilitation and shorter length of hospital stay. Despite this, the reduced physiological reserve, associated co-morbidities and polypharmacy intake of the elderly population put them at high risk of postoperative complications particularly of infectious origin. Out of 10061 patients with proximal femoral fractures 105 (1.05%) developed surgical site infection; 76 (72%) infections occurred in patients who had sustained intracapsular (IC) fractures with the remaining 29 (28%) infections occurring in patients with extracapsular (EC) neck of femur fractures. The median number of additional surgical debridements was 2 (range 1-7). MRSA was isolated in 49 (47%) of the cases; 38 patients (36%) ultimately underwent a Girdlestone's excisional arthroplasty. Mortality at 30 days and 3 months was 10% and 31%, respectively. It was noted that post-operative hip infection predisposed to a prolonged length of stay in the acute unit and subsequently to a more dependent destination after discharge.

The cost and consequences of proximal femoral fractures which require further surgery following initial fixation.

We evaluated the cost and consequences of proximal femoral fractures requiring further surgery because of complications. The data were collected prospectively in a standard manner from all patients with a proximal femoral fracture presenting to the trauma unit at the John Radcliffe Hospital over a five-year period. The total cost of treatment for each patient was calculated by separating it into its various components. The risk factors for the complications that arose, the location of their discharge and the mortality rates for these patients were compared to those of a matched control group. There were 2360 proximal femoral fractures in 2257 patients, of which 144 (6.1%) required further surgery. The mean cost of treatment in patients with complications was £18,709 (£2606.30 to £60,827.10), compared with £8610 (£918.54 to £45,601.30) for uncomplicated cases (p < 0.01), with a mean length of stay of 62.8 (44.5 to 79.3) and 32.7 (23.8 to 35.0) days, respectively. The probability of mortality after one month in these cases was significantly higher than in the control group, with a mean survival of 209 days, compared with 496 days for the controls. Patients with complications were statistically less likely to return to their own home (p < 0.01). Greater awareness and understanding are required to minimise the complications of proximal femoral fractures and consequently their cost.

Orthopaedic trauma research priority-setting exercise and development of a research network.

INTRODUCTION: Clinical practice should be informed by high quality evidence, of which randomised controlled trials (RCTs) are considered the gold standard. Surgical trials are inherently difficult with potential problems around clinical equipoise and participant acceptability. This is often most true with trial designs comparing operative and non-operative treatments. It is hoped that research activity can be maximised by collaborating in (a) the identification of research questions and (b) involvement in clinical trials. Development of the national research networks can be utilised to provide support for research endeavours within the orthopaedic trauma community. AIMS: To identify and prioritise the research questions felt to be of most importance by the orthopaedic trauma community. Research studies will be considered for questions given the highest priority. METHODS: A Delphi approach was used to determine consensus between the faculty members of the AOUK. A two round process was used to elicit the research questions and then to rank them in order of priority. RESULTS: 217 members of the AOUK Long Bone Faculty were asked to submit research questions, predominantly consultant orthopaedic surgeons. A 22% response rate generated 147 questions. These were collated and the most frequent 24 sent back out for ranking by mean scores. A 55% response to this second round identified 10 top questions. Literature searches for these 10 looked at current knowledge of the subject, completed and ongoing research projects. We also looked at the advantages and disadvantages of undertaking a study and the most appropriate methodology. CONCLUSION: The response rates demonstrated a clear interest in developing a collaborative research strategy. This can be enhanced by utilising the support of the National Institute of Health Research Clinical Research Networks (NIHR CRN).

Computer-aided quantification of retinal neovascularization.

Rodent models of retinal angiogenesis play a pivotal role in angiogenesis research. These models are a window to developmental angiogenesis, to pathological retinopathy, and are also in vivo tools for anti-angiogenic drug screening in cancer and ophthalmic research. The mouse model of oxygen-induced retinopathy (OIR) has emerged as one of the leading in vivo models for these purposes. Many of the animal studies that laid the foundation for the recent breakthrough of anti-angiogenic treatments into clinical practice were performed in the OIR model. However, readouts from the OIR model have been time-consuming and can vary depending on user experience. Here, we present a computer-aided quantification method that is characterized by (i) significantly improved efficiency, (ii) high correlation with the established hand-measurement protocols, and (iii) high intra- and inter-individual reproducibility of results. This method greatly facilitates quantification of retinal angiogenesis while at the same time increasing lab-to-lab reproducibility of one of the most widely used in vivo models in angiogenesis research.

The biology of platelet-rich plasma and its application in trauma and orthopaedic surgery: a review of the literature.

Although mechanical stabilisation has been a hallmark of orthopaedic surgical management, orthobiologics are now playing an increasing role. Platelet-rich plasma (PRP) is a volume of plasma fraction of autologous blood having platelet concentrations above baseline. The platelet alpha granules are rich in growth factors that play an essential role in tissue healing, such as transforming growth factor-beta, vascular endothelial growth factor, and platelet-derived growth factor. PRP is used in various surgical fields to enhance bone and soft-tissue healing by placing supraphysiological concentrations of autologous platelets at the site of tissue damage. The easily obtainable PRP and its possible beneficial outcome hold promise for new regenerative treatment approaches. The aim of this literature review was to describe the bioactivities of PRP, to elucidate the different techniques for PRP preparation, to review animal and human studies, to evaluate the evidence regarding the use of PRP in trauma and orthopaedic surgery, to clarify risks, and to provide guidance for future research.

Outcome of surgery for reconstruction of fractures of the acetabulum. The time dependent effect of delay.

This is a retrospective case review of 237 patients with displaced fractures of the acetabulum presenting over a ten-year period, with a minimum follow-up of two years, who were studied to test the hypothesis that the time to surgery was predictive of radiological and functional outcome and varied with the pattern of fracture. Patients were divided into two groups based on the fracture pattern: elementary or associated. The time to surgery was analysed as both a continuous and a categorical variable. The primary outcome measures were the quality of reduction and functional outcome. Logistic regression analysis was used to test our hypothesis, while controlling for potential confounding variables. For elementary fractures, an increase in the time to surgery of one day reduced the odds of an excellent/good functional result by 15% (p = 0.001) and of an anatomical reduction by 18% (p = 0.0001). For associated fractures, the odds of obtaining an excellent/good result were reduced by 19% (p = 0.0001) and an anatomical reduction by 18% (p = 0.0001) per day. When time was measured as a categorical variable, an anatomical reduction was more likely if surgery was performed within 15 days (elementary) and five days (associated). An excellent/good functional outcome was more likely when surgery was performed within 15 days (elementary) and ten days (associated). The time to surgery is a significant predictor of radiological and functional outcome for both elementary and associated displaced fractures of the acetabulum. The organisation of regional trauma services must be capable of satisfying these time-dependent requirements to achieve optimal patient outcomes.

Deep wound infection after proximal femoral fracture: consequences and costs.

The purpose of this study was to assess the impact of deep wound infection after surgery for proximal femoral fracture (PFF) on the patient in terms of mortality and social consequences, and on the National Health Service in terms of financial burden. Sixty-one cases of PFF over a six-year period were complicated with deep surgical wound infection. These cases were compared with a matched control group of 122 patients without infection. Infected cases had greatly increased hospital stay (P<0.001), were 4.5 times less likely to survive to discharge (P=0.002), and if they survived, were three times less likely to return to their original residence (P=0.05). The total cost of treatment per infected case was 24,410 pound sterling compared with 7210 pound sterling for controls (P<0.001). Meticillin-resistant Staphylococcus aureus (MRSA) infection increased admission length and cost compared with non-MRSA infection (P=0.02). Deep wound infection after PFF is a devastating and costly complication for both the patient and the healthcare services. The cost consequences should be considered when allocating resources to trauma services to ensure adequate provision to minimize infection risks and to accommodate treatment costs in this vulnerable group.