Proximal forearm fractures: epidemiology, functional results and predictors of outcome

Proximal forearm fractures account for over 10% of all upper limb fractures. There is limited epidemiological data available and much of the literature focuses on the more complex fracture patterns, with the role of non-operative management for the isolated proximal forearm fracture still to be defined. Prospective short and long-term patient reported outcome data for simple isolated fractures of the radial head and olecranon would help define the indications for the non-operative management of these injuries. This thesis aims to test the hypothesis that non-operative management provides a comparable outcome to operative intervention for defined fractures of the proximal forearm. A large prospective database of 6872 fractures collected over a one-year period was used to define the epidemiology of proximal forearm fractures. A separate large prospective study carried out over an eighteen-month period using a pre-defined management protocol for all isolated radial head and neck fractures was analysed to determine the short and long-term outcome. Additional retrospective databases were collected and analysed to determine the short and long-term outcome for the non-operative and operative management of olecranon fractures, as well as the operative management of complex radial head fractures. Finally, two prospective randomised controlled trials (PRCTs) of isolated displaced fractures of the olecranon were carried out to compare 1) tension band wire (TBW) versus plate fixation in younger patients (<75 years) and 2) operative versus non-operative management in elderly patients (≥75 years). The primary outcome measure for these studies was the upper limb specific patient reported Disabilities of the Arm, Shoulder and Hand (DASH) score. Secondary outcome measures included surgeon reported outcome scores, complication rates and cost. The incidence of proximal forearm fractures was 68 per 100,000. Radial head fractures fit a type D distribution curve (unimodal young man, bimodal woman) and radial neck type A (unimodal young man, unimodal older woman). Proximal ulna and olecranon fractures were both a type F (unimodal older man, unimodal older woman), with an increasing incidence after the 6th decade. Over 90% of proximal radial fractures were isolated stable fractures. Prospective analysis of 201 isolated proximal radius fractures found that the patient and surgeon reported outcome following primary non-operative management for Mason type 1 and type 2 (n=185) fractures was excellent in the short and long-term, with <2% of patients undergoing secondary surgical intervention. At a mean of 10 years post injury (n=100), the mean DASH score was 5.8 and 92% of patients were satisfied. Factors associated with a poorer short and long-term patient reported outcome included increasing fracture displacement (≥5mm) and socio-economic deprivation. Retrospective analysis of 105 acute unstable complex radial head fractures found that the mean short-term functional outcome was good (mean Broberg and Morrey Score 80) following radial head replacement. In the long-term (mean 7 years), 28% of patients required removal or revision of the prosthesis, with younger patients and silastic implants independent risk factors (both p<0.05). Retrospective analysis of 36 operatively managed isolated displaced olecranon fractures found satisfactory short and long-term outcomes, with the symptomatic metalwork removal rate 47% and the mean DASH 2.5 at a mean of seven years post injury. In the PRCT of plate (n=34) versus TBW (n=33) fixation, comparable functional and patient reported outcomes (DASH 8.5 vs 13.5; p=0.252) were found at one year following injury. Complication rates were significantly higher in the TBW group (63.3% vs 37.5%; p=0.042), predominantly due to a significantly higher rate of symptomatic metalwork removal (50.0% vs 21.9%; p=0.021), resulting in equivocal costs for both techniques (p=0.131). In older lower-demand patients, short and long-term retrospective analysis found very satisfactory outcomes following non-operative management of isolated displaced fractures of the olecranon, with patient satisfaction 91% and no patients requiring surgery for a symptomatic non-union. The preliminary results of the PRCT of non-operative (n=8) versus operative (n=11) management demonstrated comparable functional and patient reported outcomes at all points over the one-year following injury (all p≥0.05), with a higher rate of complications (81.8% vs 14.3%; p=0.013) and cost (p=0.01) following surgical intervention. The association found between fragility and the epidemiology of proximal forearm fractures highlighted the importance of considering non-operative management for these injuries. These findings support non-operative management for isolated stable radial head and neck fractures. For more complex injuries when radial head replacement is indicated, there is a high rate of removal or revision, with younger patients most at risk. In younger active patients with an isolated displaced fracture of the olecranon, TBW and plate fixation provide comparable short-term results, with TBW fixation as cost effective despite an increased rate of metalwork removal. In older lower demand patients, this data provides strong evidence for the non-operative management of isolated displaced olecranon fractures

Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome.

Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement. This latter finding makes Lck similar to ZAP70, another T-cell kinase whose aberrant expression in CLL cells also associates with BCR signalling capacity, but also different because ZAP70 is not easily pharmacologically targetable. Here we describe a robust method of measuring Lck expression in CLL cells using flow cytometry. However, unlike ZAP70 whose expression in CLL cells predicts prognosis, we find Lck expression and disease outcome in CLL are unrelated despite observations that its inhibition produces effects that biologically resemble the egress phenotype taken on by CLL cells treated with idelalisib. Taken together, our findings provide insight into the pathobiology of CLL to suggest a more complex relationship between expression of molecules within the BCR signalling pathway and disease outcome

Digital Signal Processing

Contains a research summary and reports on fifteen research projects.National Science Foundation FellowshipJoint Services Electronics Program (Contract DAAG29-78-C-0020)National Science Foundation (Grant ENG76-24117)U.S. Navy - Office of Naval Research (Contract N00014-75-C-0951)National Science Foundation (Grant ENG76-24117)Schlumberger-Doll Research Center FellowshipHertz Foundation FellowshipNational Aeronautics and Space Administration (Grant NSG-5157)U.S. Navy - Office of Naval Research (Contract N00014-77-C-0196

Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

Digital Signal Processing

Contains research objectives and reports on sixteen research projects.U.S. Navy - Office of Naval Research (Contract N00014-75-C-0852)National Science Foundation FellowshipNational Science Foundation (Grant ENG76-24117)U.S. Navy - Office of Naval Research (Contract N00014-77-C-0257)U.S. Air Force (Contract F19628-80-C-0002)U.S. Navy - Office of Naval Research (Contract N00014-75-C-0951)Schlumberger-Doll Research Center FellowshipHertz Foundation FellowshipGovernment of Pakistan ScholarshipU.S. Navy - Office of Naval Research (Contract N00014-77-C-0196

Genome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne

Digital Signal Processing

Contains summary of research and reports on sixteen research projects.U.S. Navy - Office of Naval Research (Contract N00014-75-C-0852)National Science Foundation FellowshipNATO FellowshipU.S. Navy - Office of Naval Research (Contract N00014-75-C-0951)National Science Foundation (Grant ECS79-15226)U.S. Navy - Office of Naval Research (Contract N00014-77-C-0257)Bell LaboratoriesNational Science Foundation (Grant ECS80-07102)Schlumberger-Doll Research Center FellowshipHertz Foundation FellowshipGovernment of Pakistan ScholarshipU.S. Navy - Office of Naval Research (Contract N00014-77-C-0196)U.S. Air Force (Contract F19628-81-C-0002)Hughes Aircraft Company Fellowshi