FC Receptor-Mediated Activities of Env-Specific Monoclonal Antibodies Generated from Human Volunteers Receiving a DNA Prime-Protein Boost HIV Vaccine: A Dissertation

Human immunodeficiency type 1 (HIV-1) is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years’ infection and as a result, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that a moderate protection is possible, which may correlate with antibody dependent cellular cytotoxicity (ADCC) activity. Previous studies in the Lu lab demonstrated that in an HIV-1 vaccine phase I trial, DP6-001, a polyvalent Env DNA prime-protein boost formulation, could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities along with multiple Fc mediated effector functions. I developed a protocol for the production and analysis of HIV-1 Env-specific human monoclonal antibodies (mAbs) isolated from these DP6-001 vaccinees. By utilizing a labeled gp120 bait to isolate Env specific B cells, paired heavy and light chain immunoglobulin (Ig) genes were cloned and allowed for the production of monoclonal antibodies with specificity for gp120. By using this protocol, 13 isolated mAbs from four DP6-001 vaccinees showed broad binding activities to gp120 proteins of diverse subtypes, both autologous and heterologous to vaccine immunogens, with mostly conformational epitopes and a few V3 and C5 specific mAbs. Equally cross-reactive Fc-mediated functional activities, including ADCC and antibody dependent cellular phagocytosis (ADCP), were present with both immune sera and isolated mAbs, confirming the induction of non-neutralizing functional antibodies by the DNA prime- protein boost vaccination. Elicitation of broadly reactive mAbs by vaccination in healthy human volunteers confirms the value of the polyvalent formulation in this HIV-1 vaccine design

Outcome assessment after hip fracture : is EQ-5D the answer?

Objectives: To study the measurement properties of a joint specific patient reported outcome measure, a measure of capability and a general health-related quality of life (HRQOL) tool in a large cohort of patients with a hip fracture. Methods: Responsiveness and associations between the Oxford Hip Score (a hip specific measure: OHS), ICEpop CAPability (a measure of capability in older people: ICECAP-O) and EuroQol EQ-5D (general health-related quality of life measure: EQ-5D) were assessed using data available from two large prospective studies. The three outcome measures were assessed concurrently at a number of fixed follow-up time-points in a consecutive sequence of patients, allowing direct assessment of change from baseline, inter-measure associations and validity using a range of statistical methods. Results: ICECAP-O was not responsive to change. EQ-5D was responsive to change from baseline, with an estimated standardised effect size for the two datasets of 0.676 and 0.644 at six weeks and four weeks respectively; this was almost as responsive to change as OHS (1.14 at four weeks). EQ-5D correlated strongly with OHS; Pearson correlation coefficients were 0.74, 0.77 and 0.70 at baseline, four weeks and four months. EQ-5D is a moderately good predictor of death at 12 months following hip fracture. Furthermore, EQ-5D reported by proxies (relatives and carers) behaves similarly to self-reported scores. Conclusions: Our findings suggest that a general HRQOL tool such as EQ-5D could be used to measure outcome for patients recovering from hip fracture, including those with cognitive impairment

A randomised controlled trial of total hip arthroplasty versus resurfacing arthroplasty in the treatment of young patients with arthritis of the hip joint

Background: Hip replacement (arthroplasty) surgery is a highly successful treatment for patients with severe symptomatic arthritis of the hip joint. For older patients, several designs of Total Hip Arthroplasty have shown excellent results in terms of both function and value for money. However, in younger more active patients, there is approximately a 50% failure rate at 25 years for traditional implants. Hip resurfacing is a relatively new arthroplasty technique. In a recent review of the literature on resurfacing arthroplasty it was concluded that the short-term functional results appear promising but some potential early disadvantages were identified, including the risk of femoral neck fracture and collapse of the head of the femur. The aim of the current study is to assess whether there is a difference in functional hip scores at one year post-operation between Total Hip Arthroplasty and Resurfacing Arthroplasty. Secondary aims include assessment of complication rates for both procedures as well cost effectiveness. Methods/design: All patients medically fit for surgery and deemed suitable for a resurfacing arthroplasty are eligible to take part in this study. A randomisation sequence will be produced and administered independently. After consenting, all patients will be clinically reviewed and hip function, quality of life and physical activity level will be assessed through questionnaires. The allocated surgery will then be performed with the preferred technique of the surgeon. Six weeks post-operation hip function will be assessed and complications recorded. Three, six and 12 months post-operation hip function, quality of life and physical activity level will be assessed. Additional information about patients' out-of-pocket expenses will also be collected

Warwick hip trauma study : a randomised clinical trial comparing interventions to improve outcomes in internally fixed intracapsular fractures of the proximal femur : protocol for The WHiT Study

Background Controversy exists regarding the optimal treatment for patients with displaced intracapsular fractures of the proximal femur. The recognised treatment alternatives are arthroplasty and internal fixation. The principal criticism of internal fixation is the high rate of non-union; up to 30% of patients will have a failure of the fixation leading to revision surgery. We believe that improved fracture healing may lead to a decreased rate of failure of fixation. We therefore propose to investigate strategies to both accelerate fracture healing and improve fixation that may significantly improve outcomes after internal fixation of intracapsular femoral fractures. We aim to test the clinical effectiveness of the osteoinductive agent platelet rich plasma and conduct a pilot study of a novel fixed-angle fixation system. Design We have planned a three arm, single centre, standard-of-care controlled, double blinded, pragmatic, randomised clinical trial. The trial will include a standard two-way comparison between platelet-rich plasma and standard-of-care fixation versus standard-of-care fixation alone. In addition there will be a subsidiary pilot arm testing a fixed-angle screw and plate fixation system

An evaluation of the quality of statistical design and analysis of published medical research : results from a systematic survey of general orthopaedic journals

Background: The application of statistics in reported research in trauma and orthopaedic surgery has become ever more important and complex. Despite the extensive use of statistical analysis, it is still a subject which is often not conceptually well understood, resulting in clear methodological flaws and inadequate reporting in many papers. Methods: A detailed statistical survey sampled 100 representative orthopaedic papers using a validated questionnaire that assessed the quality of the trial design and statistical analysis methods. Results: The survey found evidence of failings in study design, statistical methodology and presentation of the results. Overall, in 17% (95% confidence interval; 10–26%) of the studies investigated the conclusions were not clearly justified by the results, in 39% (30–49%) of studies a different analysis should have been undertaken and in 17% (10–26%) a different analysis could have made a difference to the overall conclusions. Conclusion: It is only by an improved dialogue between statistician, clinician, reviewer and journal editor that the failings in design methodology and analysis highlighted by this survey can be addressed

The Achilles tendon total rupture score : a study of responsiveness, internal consistency and convergent validity on patients with acute Achilles tendon ruptures

Background The Achilles tendon Total Rupture Score was developed by a research group in 2007 in response to the need for a patient reported outcome measure for this patient population. Beyond this original development paper, no further validation studies have been published. Consequently the purpose of this study was to evaluate internal consistency, convergent validity and responsiveness of this newly developed patient reported outcome measure within patients who have sustained an isolated acute Achilles tendon rupture. Methods Sixty-four eligible patients with an acute rupture of their Achilles tendon completed the Achilles tendon Total Rupture Score alongside two further patient reported outcome measures (Disability Rating Index and EQ 5D). These were completed at baseline, six weeks, three months, six months and nine months post injury. The Achilles tendon Total Rupture Score was evaluated for internal consistency, using Cronbach's alpha, convergent validity, through correlation analysis and responsiveness, by analysing floor and ceiling effects and calculating its relative efficiency in comparison to the Disability Rating Index and EQ 5D scores. Results The Achilles tendon Total Rupture Score demonstrated high internal consistency (Cronbachs alpha > 0.8) and correlated significantly (p < 0.001) with the Disability Rating Index at five time points (pre-injury, six weeks, three, six and nine months) with correlation coefficients between -0.5 and -0.9. However, the confidence intervals were wide. Furthermore, the ability of the new score to detect clinically important changes over time (responsiveness) was shown to be greater than the Disability Rating Index and EQ 5D. Conclusions A universally accepted outcome measure is imperative to allow comparisons to be made across practice. This is the first study to evaluate aspects of validity of this newly developed outcome measure, outside of the developing centre. The ATRS demonstrated high internal consistency and responsiveness, with limited convergent validity. This research provides further support for the use of this outcome measure, however further research is required to advocate its universal use in patients with acute Achilles tendon ruptures. Such areas include inter-rater reliability and research to determine the minimally clinically important difference between scores

The effect of surgical approach on the histology of the femoral head following resurfacing of the hip : analysis of retrieval specimens

Objectives: We aimed to determine the effect of surgical approach on the histology of the femoral head following resurfacing of the hip. Methods: We performed a histological assessment of the bone under the femoral component taken from retrieval specimens of patients having revision surgery following resurfacing of the hip. We compared the number of empty lacunae in specimens from patients who had originally had a posterior surgical approach with the number in patients having alternative surgical approaches. Results: We found a statistically significant increase in the percentage of empty lacunae in retrieval specimens from patients who had the posterior approach compared with other surgical approaches (p < 0.001). Conclusions: This indicates that the vascular compromise that occurs during the posterior surgical approach does have long-term effects on the bone of the femoral head, even if it does not cause overt avascular necrosis

All interventions differ, although some are more different than others

It is a well-known statement of statistical wisdom that all treatments differ. We could substitute the word ‘intervention’ or the phrase ‘surgical procedure’ for ‘treatment’ and qualify the word ‘differ’ by, for instance, saying “have different outcomes”. Yet, in doing so we challenge far more than semantics, questioning the relevance of much of the research reported in The Bone and Joint Journal, and the wider medical literature. For example, the DRAFFT study compared the clinical effectiveness of Kirschner wire fixation with locking plate fixation for patients with a dorsally displaced fracture of the distal radius. Selectively picking out the key result of the paper one would conclude that there was no difference in outcomes between the two groups; thus that there was no difference between the treatments. This result seems to contradict the first statement in this paragraph, which follows from the simple argument that by definition all treatments must be different because no two things can ever be exactly the same in every respect. This sounds like a matter of philosophical interest only, but understanding how we reconcile this apparent contradiction helps shed light on an issue that continues to be a cause of confusion for many authors submitting papers to our Journal

Comparison of hip function and quality of life of total hip arthroplasty and resurfacing arthroplasty in the treatment of young patients with arthritis of the hip joint at 5 years

ObjectiveTo compare the medium-term clinical effectiveness of total hip arthroplasty and resurfacing arthroplasty.DesignSingle centre, two-arm, parallel group, assessor blinded, randomised controlled trial with 1:1 treatment allocation.SettingA large teaching hospital in England.Participants122 patients older than 18 years with severe arthritis of the hip joint, suitable for resurfacing arthroplasty of the hip. Patients were excluded if they were considered to be unable to adhere to trial procedures or complete questionnaires.InterventionsTotal hip arthroplasty (replacement of entire femoral head and neck); hip resurfacing arthroplasty (replacement of the articular surface of femoral head only, femoral neck remains intact). Both procedures replaced the articular surface of the acetabulum.OutcomesThe outcome measures were hip function assessed using the Oxford Hip Score (OHS) and health-related quality of life assessed using the EuroQol (EQ-5D). Patients were followed up annually for a minimum of 5 years. Outcome data were modelled using the generalised estimating equation methodology to explore temporal variations during follow-up.Results60 patients were randomly assigned to hip resurfacing arthroplasty and 62 to total hip arthroplasty. 95 (78%) of the 122 original study participants provided data at 5 years. There was a small decrease in both hip functions and quality of life in both groups of patients each year during the 5-year follow-up period. However, there was no evidence of a significant difference between treatments group in the OHS (P=0.333) or the EQ-5D (P=0.501).ConclusionsWe previously reported no difference in outcome in the first year after surgery. The current medium-term results also show no evidence of a difference in hip function or health-related quality of life in the 5 years following a total hip arthroplasty versus resurfacing arthroplasty.Trial registration numberISRCTN33354155. UKCRN 4093

Injection therapies for Achilles tendinopathy

Background: Achilles tendinopathy is a common condition, often with significant functional consequences. As a wide range of injection treatments are available, a review of randomised trials evaluating injection therapies to help inform treatment decisions is warranted. Objectives: To assess the effects (benefits and harms) of injection therapies for people with Achilles tendinopathy. Search methods: We searched the following databases up to 20 April 2015: the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, CINAHL and SPORTDiscus. We also searched trial registers (29 May 2014) and reference lists of articles to identify additional studies. Selection criteria: We included randomised and quasi-randomised controlled trials evaluating injection therapies in adults with an investigator-reported diagnosis of Achilles tendinopathy. We accepted comparison arms of placebo (sham) or no injection control, or other active treatment (such as physiotherapy, pharmaceuticals or surgery). Our primary outcomes were function, using measures such as the VISA-A (Victorian Institute of Sport Assessment-Achilles questionnaire), and adverse events. Data collection and analysis: Two review authors independently extracted data from the included studies. We assessed treatment effects using mean differences (MDs) and 95% confidence intervals (CIs) for continuous variables and risk ratios (RRs) and 95% CIs for dichotomous variables. For follow-up data, we defined short-term as up to six weeks, medium-term as up to three months and longer-term as data beyond three months. We performed meta-analysis where appropriate. Main results: We included 18 studies (732 participants). Seven trials exclusively studied athletic populations. The mean ages of the participants in the individual trials ranged from 20 years to 50 years. Fifteen trials compared an injection therapy with a placebo injection or no injection control, four trials compared an injection therapy with active treatment, and one compared two different concentrations of the same injection. Thus no trials compared different injection therapies. Two studies had three trial arms and we included them twice in two different categories. Within these categories, we further subdivided injection therapies by mode of action (injury-causing versus direct repair agents). The risk of bias was unclear (due to poor reporting) or high in six trials published between 1987 and 1994. Improved methodology and reporting for the subsequent trials published between 2004 and 2013 meant that these were at less risk of bias. Given the very low quality evidence available from each of four small trials comparing different combinations of injection therapy versus active treatment and the single trial comparing two doses of one injection therapy, only the results of the first comparison (injection therapy versus control) are presented. There is low quality evidence of a lack of significant or clinically important differences in VISA-A scores (0 to 100: best function) between injection therapy and control groups at six weeks (MD 0.79, 95% CI -4.56 to 6.14; 200 participants, five trials), three months (MD -0.94, 95% CI -6.34 to 4.46; 189 participants, five trials) or between six and 12 months (MD 0.14, 95% CI -6.54 to 6.82; 132 participants, three trials). Very low quality evidence from 13 trials showed little difference between the two groups in adverse events (14/243 versus 12/206; RR 0.97, 95% CI 0.50 to 1.89), most of which were minor and short-lasting. The only major adverse event in the injection therapy group was an Achilles tendon rupture, which happened in a trial testing corticosteroid injections. There was very low quality evidence in favour of the injection therapy group in short-term (under three months) pain (219 participants, seven trials) and in the return to sports (335 participants, seven trials). There was very low quality evidence indicating little difference between groups in patient satisfaction with treatment (152 participants, four trials). There was insufficient evidence to conclude on subgroup differences based on mode of action given that only two trials tested injury-causing agents and the clear heterogeneity of the other 13 trials, which tested seven different therapies that act directly on the repair pathway. Authors' conclusions: There is insufficient evidence from randomised controlled trials to draw conclusions on the use, or to support the routine use, of injection therapies for treating Achilles tendinopathy. This review has highlighted a need for definitive research in the area of injection therapies for Achilles tendinopathy, including in older non-athletic populations. This review has shown that there is a consensus in the literature that placebo-controlled trials are considered the most appropriate trial design