The Kaposi's sarcoma-associated herpesvirus ORF57 protein and its multiple roles in mRNA biogenesis

Post-transcriptional events which regulate mRNA biogenesis are fundamental to the control of gene expression. A nascent mRNA is therefore steered through multimeric RNA–protein complexes that mediate its capping, splicing, polyadenylation, nuclear export, and ultimately its translation. Kaposi’s sarcoma-associated herpesvirus (KSHV) mRNA transport and accumulation protein, or ORF57, is a functionally conserved protein found in all herpesviruses which plays a pivotal role in enhancing viral gene expression at a post-transcriptional level. As such, ORF57 has been implicated in multiple steps of RNA biogenesis, including augmenting viral splicing, protecting viral RNAs from degradation to enhancing viral mRNA nuclear export and translation. In this review, we highlight the multiple roles of KSHV ORF57 in regulating the post-transcriptional events which are fundamental to the control of virus gene expression

Association between surgical volume and failure of primary total hip replacement in England and Wales: findings from a prospective national joint replacement register

Objective To investigate the association of volume of total hip arthroplasty (THA) between consultants and within the same consultant in the previous year and the hazard of revision using multilevel survival models. Design Prospective cohort study using data from a national joint replacement register. Setting Elective THA across all private and public centres in England and Wales between April 2003 and February 2017. Participants Patients aged 50 years or more undergoing THA for osteoarthritis. Intervention The volume of THA conducted in the preceding 365 days to the index procedure. Main outcome and measure Revision surgery (excision, addition or replacement) of a primary THA. Results Of the 579 858 patients undergoing primary THA (mean baseline age 69.8 years (SD 10.2)), 61.1% were women. Multilevel survival found differing results for between and within-consultant effects. There was a strong volume–revision association between consultants, with a near-linear 43.3% (95% CI 29.1% to 57.4%) reduction of the risk of revision comparing consultants with volumes between 1 and 200 procedures annually. Changes in individual surgeons (within-consultant) case volume showed no evidence of an association with revision. Conclusion Separation of between-consultant and within- consultant effects of surgical volume reveals how volume contributes to the risk of revision after THA. The lack of association within-consultants suggests that individual changes to consultant volume alone will have little effect on outcomes following THA. These novel findings provide strong evidence supporting the practice of specialisation of hip arthroplasty. It does not support the practice of low-volume consultants increasing their personal volume as it is unlikely their results would improve if this is the only change. Limiting the exposure of patients to consultants with low volumes of THA and greater utilisation of centres with higher volume surgeons with better outcomes may be beneficial to patients

The association of body mass index with risk of long-term revision and 90-day mortality following primary total hip replacement:Findings from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man

BACKGROUND: The influence of obesity on outcomes following total hip replacement is unclear. Restriction of total hip replacement on the basis of body mass index (BMI) has been suggested. The purpose of this study was to assess the influence of BMI on the risk of revision and 90-day mortality. METHODS: This was a population-based, longitudinal cohort study of the National Joint Registry (NJR) for England, Wales, Northern Ireland and the Isle of Man. Using data recorded from April 2003 to December 2015, linked to Office for National Statistics data, we ascertained revision and 90-day mortality rates following primary total hip replacement by BMI category. The probability of revision was estimated using Kaplan-Meier methods. Associations of BMI with revision and mortality were explored using adjusted Cox proportional hazards regression models. RESULTS: We investigated revision and 90-day mortality among 415,598 and 413,741 primary total hip replacements, respectively. Each data set accounts for approximately 52% of the total number of recorded operations in the NJR. Thirty-eight percent of the patients were classified as obese. At 10 years, class-III obese patients had the highest cumulative probability of revision (6.7% [95% confidence interval (CI), 5.5% to 8.2%]), twice that of the underweight group (3.3% [95% CI, 2.2% to 4.9%]). When the analysis was adjusted for age, sex, American Society of Anesthesiologists [ASA] grade, year of operation, indication, and fixation type, compared with patients with normal BMI, significantly elevated hazard ratios (HRs) for revision were observed for patients in the BMI categories of class-I obese (≥30 to <35 kg/m) (HR, 1.14 [95% CI, 1.07 to 1.22]), class-II obese (≥35 to <40 kg/m) (HR, 1.30 [95% CI, 1.19 to 1.40]), and class-III obese (≥40 to ≤60 kg/m) (HR, 1.43 [95% CI, 1.27 to 1.61]) (p < 0.0005 for all). Underweight patients had a substantially higher cumulative probability of 90-day mortality (1.17%; 95% CI, 0.86% to 1.58%) compared with patients with normal BMI (0.43%; 95% CI, 0.39% to 0.48%). The risk of 90-day mortality was significantly higher for the underweight group (HR, 2.09 [95% CI, 1.51 to 2.89]; p < 0.0005) and significantly lower for patients who were categorized as overweight (HR, 0.70; 95% CI, 0.61 to 0.81; p < 0.0005), class-I obese (HR, 0.69 [95% CI, 0.59 to 0.81]; p < 0.0005), and class-II obese (HR, 0.79 [95% CI, 0.63 to 0.98]; p = 0.049) compared with patients with normal BMI. CONCLUSIONS: Although long-term revision rates following total hip replacement were higher among obese patients, we believe that the rates remained acceptable by contemporary standards and were balanced by a lower risk of 90-day mortality. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence

Analysis of change in patient-reported outcome measures with floor and ceiling effects using the multilevel Tobit model:a simulation study and an example from a National Joint Register using body mass index and the Oxford Hip Score

OBJECTIVES: This study has three objectives. (1) Investigate the association between body mass index (BMI) and the efficacy of primary hip replacement using a patient-reported outcome measure (PROMs) with a measurement floor and ceiling, (2) Explore the performance of different estimation methods to estimate change in PROMs score following surgery using a simulation study and real word data where data has measurement floors and ceilings and (3) Lastly, develop guidance for practising researchers on the analysis of PROMs in the presence of floor and ceiling effects. DESIGN: Simulation study and prospective national medical device register. SETTING: National Register of Joint Replacement and Medical Devices. METHODS: Using a Monte Carlo simulation study and data from a national joint replacement register (162 513 patients with pre- and post-surgery PROMs), we investigate simple approaches for the analysis of outcomes with floor and ceiling effects that are measured at two occasions: linear and Tobit regression (baseline adjusted analysis of covariance, change-score analysis, post-score analysis) in addition to linear and multilevel Tobit models. PRIMARY OUTCOME: The primary outcome of interest is change in PROMs from pre-surgery to 6 months post-surgery. RESULTS: Analysis of data with floor and ceiling effects with models that fail to account for these features induce substantial bias. Single-level Tobit models only correct for floor or ceiling effects when the exposure of interest is not associated with the baseline score. In observational data scenarios, only multilevel Tobit models are capable of providing unbiased inferences. CONCLUSIONS: Inferences from pre- post-studies that fail to account for floor and ceiling effects may induce spurious associations with substantial risk of bias. Multilevel Tobit models indicate the efficacy of total hip replacement is independent of BMI. Restricting access to total hip replacement based on a patients BMI can not be supported by the data

Higher 30-day mortality associated with the use of intramedullary nails compared with sliding hip screws for the treatment of trochanteric hip fractures:a prospective national registry study

Aims The aim of this study was to investigate the association between the type of operation used to treat a trochanteric fracture of the hip and 30-day mortality. Patients and Methods Data on 82 990 patients from the National Hip Fracture Database were analyzed using generalized linear models with incremental case-mix adjustment for patient, non-surgical and surgical characteristics, and socioeconomic factors. Results The use of short and long intramedullary nails was associated with an increase in 30-day mortality (adjusted odds ratio (OR) 1.125, 95% confidence interval (CI) 1.040 to 1.218; p = 0.004) compared with the use of sliding hip screws (12.5% increase). If this were causative, it would represent 98 excess deaths over the four-year period of the study and one excess death would be caused by treating 112 patients with an intramedullary nail rather than a sliding hip screw. Conclusion There is a 12.5% increase in the risk of 30-day mortality associated with the use of an intramedullary nail compared with a sliding hip screw in the treatment of a trochanteric fractures of the hip.</p