Rigidly linking cyclometallated Ir(iii) and Pt(ii) centres: an efficient approach to strongly absorbing and highly phosphorescent red emitters

The synthesis and photophysical properties of an unprecedented tetranuclear complex are described, in which a fac-tris-cyclometallated Ir(III) centre is rigidly connected to three cyclometallated Pt(II) centres. The complex absorbs strongly up to ∼600 nm and emits red light with unusually high efficiency

Exploring power assumptions in the leadership and management debate

Purpose – The purpose of this paper is to take a fresh look at the leadership and management debate through exploring underlying power assumptions in the literature. Design/methodology/approach – The paper is a conceptual discussion that draws on the power-based literature to develop a framework to help conceptually understand leadership in relation to management.Findings – The paper highlights the historically clichéd nature of comments regarding conceptual similarities and differences between leadership and management. The paper draws attention to a problem within this debate – a confusion regarding assumptions of power. As a result the paper brings to the forefront perspectives of management that are of an emergent and non-work perspective which enables the development of a framework of the literature that includes managers “doing” leadership, managers “becoming” leaders, “being” leaders and managers, and leaders “doing” management. The paper goes on to explore the meaning and potential behind each part of the framework and suggests a need to develop an understanding of “doing” leadership and management and “being” managers and leaders through an exploration of “becoming” in organisations.Originality/value – This paper provides a new perspective on the leadership and management or leadership vs management question by introducing a non-work, emergent or personal perspective on management. Furthermore, this paper concludes that whether leadership and management are similar or different is dependent upon which power construct underlies each phenomenon, a consideration that has been neglected in the leadership and management debate for some time

Risk factors for femoral stem fracture following total hip arthroplasty : a systematic review and meta analysis

Background Femoral stem fracture following total hip arthroplasty (THA) is an infrequent but nevertheless devastating complication, with an increasing worldwide prevalence as demand for primary THA continues to increase. The aim of this study was to perform a systematic review and meta-analysis of risk factors for femoral stem fracture to help identify at risk patients. Methods A systematic search was conducted on EMBASE, MEDLINE and AMED to identify relevant studies. Data regard- ing study design, source, population, intervention, and outcomes was collated. Data extraction was performed on a custom form generated using Cochrane recommended methodology and analysis of risk factors performed including odds ratios (ORs) with 95% confidence intervals (CIs). Results A total of 15 studies reporting a total of 402 stem fractures in 49 723 THAs were identified. The median time from index procedure to stem fracture was 68 months (IQR 42.5–118) whilst mean age at index surgery was 61.8 years (SD 6.9). Male gender (OR = 3.27, 95% CI = 2.59–4.13, p < 0.001), patient weight above 80 kg (OR = 3.55, 95% CI = 2.88–4.37, p < 0.001), age under 63 years (OR = 1.22, 95% CI = 1.01–1.49, p < 0.001), varus stem alignment (OR = 5.77, 95% CI = 3.83– 8.7, p < 0.001), use of modular implants (OR = 1.95, 95% CI = 1.56–2.44, p < 0.01) and undergoing revision arthroplasty (OR = 3.33, 95% CI = 2.70–4.1, p < 0.001) were significant risk factors for prosthetic stem fracture. A risk window of 15 years post-surgery was identified. Conclusions This review concludes that patient weight, younger age, male sex, varus stem alignment, revision arthroplasty and use of modular stems are significant risk factors for femoral stem fracture. Modifying these risk factors where possible may help reduce incidence of femoral stem fracture in at risk patients.Peer reviewe

Experience of an anatomic femoral stem in a UK orthopaedic centre beyond 20 years of follow-up

Introduction Increasing interest in the use of anatomical stems has developed as the prevalence of periprosthetic fractures (PPFs) continues to increase. The primary aim of this study was to determine the long-term survivorship and PPF rate of an anatomical femoral stem in a single UK centre. Patients and methods Between 2000 and 2002, 94 consecutive THAs were performed using the 170 mm Lubinus SP II anatomical femoral stem in our institution. Patient demographics, operative details and clinical outcomes were collected prospectively in an arthroplasty database. Patient records and national radiographic archives were reviewed finally at a mean of 21.5 years (SD 0.7) following surgery to identify occurrence of subsequent revision surgery, dislocation or periprosthetic fracture. Results Mean patient age at surgery was 65.8 years (SD 12.5, 34–88 years). There were 48 women (51%). Osteoarthritis was the operative indication in 88 patients (94%). Analysis of all-cause THA failure demonstrated a survivorship of 98.5% (95% confidence interval [CI], 98.0–99.3%) at 10 years and 96.7% (94.5–98.9%) at 21 years. The 20-year stem survival for aseptic loosening was 100% with no cases of significant lysis found (lucent line > 2 mm) and no stems required revision. Patient demographics did not appear to influence risk of revision (p > 0.05). There were 2 revisions in total (2 for acetabular loosening with original stems retained). There were no PPFs identified at mean 21.5 year follow-up and 5 dislocations (5%). Conclusions The Lubinus SP II 170 mm stem demonstrated excellent survivorship and negligible PPF rates over 20 years following primary THA.Peer reviewe

Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase

Cleavage of amyloid precursor protein (APP) by the Alzheimer's β-secretase (BACE1) is a key step in generating amyloid β-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with β-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates. Inhibitory activity is dependent on saccharide size and specific structural characteristics, and the mechanism of action involves blocking access of substrate to the active site. In cellular assays, HS specifically inhibits BACE1 cleavage of APP but not alternative cleavage by α-secretase. Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action. Furthermore, inhibition of cellular HS synthesis results in enhanced BACE1 activity. Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing

The Olympia anatomic polished cemented stem is associated with a high survivorship, excellent hip-specific functional outcome, and high satisfaction levels:follow-up of 239 consecutive patients beyond 15 years

Introduction: The Olympia femoral stem is a stainless steel, anatomically shaped, polished and three-dimensionally tapered implant designed for use in cemented total hip arthroplasty (THA). The primary aim of this study was to determine the long-term survivorship, radiographic outcome, and patient-reported outcome measures (PROMs) of the Olympia stem. Patients and methods: Between May 2003 and December 2005, 239 patients (264 THAs) underwent a THA with an Olympia stem in our institution. Patient-reported outcome measures were assessed using the Oxford Hip Score (OHS), EuroQol-5 dimensions (EQ-5D) score, and patient satisfaction at mean 10 years following THA. Patient records and radiographs were then reviewed at a mean of 16.5 years (SD 0.7, 15.3–17.8) following THA to identify occurrence of complications or revision surgery for any cause following surgery. Radiographs were assessed for lucent lines and lysis according to Gruen’s zones Results: Mean patient age at surgery was 68.0 years (SD 10.9, 31–93 years). There were 156 women (65%, 176 THAs). Osteoarthritis was the indication for THA in 204 patients (85%). All cause stem survivorship at 10 years was 99.2% (95% confidence interval [CI], 97.9%–100%) and at 15 years was 97.5% (94.6%–100%). The 15-year stem survival for aseptic loosening was 100%. Analysis of all-cause THA failure demonstrated a survivorship of 98.5% (96.3%–100%) at 10 years and 95.9% (92.4%–99.4%) at 15 years. There were 9 THAs with non-progressive lucent lines in a single Gruen zone and 3 had lines in two zones, and no patient demonstrated signs for lysis. At a mean of 10-year (SD 0.8, 8.7–11.3) follow-up, mean OHS was 39 (SD 10.3, range 7–48) and 94% of patients reported being very satisfied or satisfied with their THA. Conclusions: The Olympia stem demonstrated excellent 10-year PROMs and very high rates of stem survivorship at final follow-up beyond 15 years

Cost effectiveness of population based BRCA1 founder mutation testing in Sephardi Jewish women.

BACKGROUND: Population-based BRCA1/BRCA2 founder-mutation testing has been demonstrated as cost effective compared with family history based testing in Ashkenazi Jewish women. However, only 1 of the 3 Ashkenazi Jewish BRCA1/BRCA2 founder mutations (185delAG[c.68_69delAG]), 5382insC[c.5266dupC]), and 6174delT[c.5946delT]) is found in the Sephardi Jewish population (185delAG[c.68_69delAG]), and the overall prevalence of BRCA mutations in the Sephardi Jewish population is accordingly lower (0.7% compared with 2.5% in the Ashkenazi Jewish population). Cost-effectiveness analyses of BRCA testing have not previously been performed at these lower BRCA prevalence levels seen in the Sephardi Jewish population. Here we present a cost-effectiveness analysis for UK and US populations comparing population testing with clinical criteria/family history-based testing in Sephardi Jewish women. STUDY DESIGN: A Markov model was built comparing the lifetime costs and effects of population-based BRCA1 testing, with testing using family history-based clinical criteria in Sephardi Jewish women aged ≥30 years. BRCA1 carriers identified were offered magnetic resonance imaging/mammograms and risk-reducing surgery. Costs are reported at 2015 prices. Outcomes include breast cancer, ovarian cancer, and excess deaths from heart disease. All costs and outcomes are discounted at 3.5%. The time horizon is lifetime, and perspective is payer. The incremental cost-effectiveness ratio per quality-adjusted life-year was calculated. Parameter uncertainty was evaluated through 1-way and probabilistic sensitivity analysis. RESULTS: Population testing resulted in gain in life expectancy of 12 months (quality-adjusted life-year = 1.00). The baseline discounted incremental cost-effectiveness ratio for UK population-based testing was £67.04/quality-adjusted life-year and for US population was $308.42/quality-adjusted life-year. Results were robust in the 1-way sensitivity analysis. The probabilistic sensitivity analysis showed 100$100,000/quality-adjusted life-year US willingness-to-pay thresholds. Scenario analysis showed that population testing remains cost effective in UK and US populations, even if premenopausal oophorectomy does not reduce breast cancer risk or if hormone replacement therapy compliance is nil. CONCLUSION: Population-based BRCA1 testing is highly cost effective compared with clinical criteria-driven approach in Sephardi Jewish women. This supports changing the paradigm to population-based BRCA testing in the Jewish population, regardless of Ashkenazi/Sephardi ancestry

3D Bioprinting of Mature Bacterial Biofilms for Antimicrobial Resistance Drug Testing

The potential to bioprint and study 3D bacterial biofilm constructs could have great clinical significance at a time when antimicrobial resistance is rising to dangerously high levels worldwide. In this study, clinically relevant bacterial species including Escherichia coli, Staphylococcus aureus (MSSA), Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa were 3D bioprinted using a double-crosslinked alginate bioink to form mature bacteria biofilms, characterized by confocal laser scanning microscopy (CLSM) and fluorescent staining. Solid and porous bacteria-laden constructs were reproducibly bioprinted with thicknesses ranging from 0.25 to 4 mm. We demonstrated 3D bioprinting of thicker biofilms (>4 mm) than found in currently available in vitro models. Bacterial viability was excellent in the bioprinted constructs, with CLSM observation of bacterial biofilm production and maturation possible for at least 28 d in culture. Importantly, we observed the complete five-step biofilm life cycle in vitro following 3D bioprinting for the first time, suggesting the formation of mature 3D bioprinted biofilms. Bacterial growth was faster in thinner, more porous constructs whilst constructs crosslinked with BaCl 2 concentrations of above 10 mM had denser biofilm formation. 3D MRSA and MSSA biofilm constructs were found to show greater resistance to antimicrobials than corresponding two-dimensional (2D) cultures. Thicker 3D E. coli biofilms had greater resistance to tetracycline than thinner constructs over 7 d of treatment. Our methodology allowed for the precise 3D bioprinting of self-supporting 3D bacterial biofilm structures that developed biofilms during extended culture. 3D biofilm constructs containing bacterial biofilms produce a model with much greater clinical relevance compared to 2D culture models and we have demonstrated their use in antimicrobial testing

Cost-effectiveness of population based BRCA testing with varying Ashkenazi Jewish ancestry.

BACKGROUND: Population-based BRCA1/BRCA2 testing has been found to be cost-effective compared with family history-based testing in Ashkenazi-Jewish women were >30 years old with 4 Ashkenazi-Jewish grandparents. However, individuals may have 1, 2, or 3 Ashkenazi-Jewish grandparents, and cost-effectiveness data are lacking at these lower BRCA prevalence estimates. We present an updated cost-effectiveness analysis of population BRCA1/BRCA2 testing for women with 1, 2, and 3 Ashkenazi-Jewish grandparents. STUDY DESIGN: Decision analysis model. METHODS: Lifetime costs and effects of population and family history-based testing were compared with the use of a decision analysis model. 56% BRCA carriers are missed by family history criteria alone. Analyses were conducted for United Kingdom and United States populations. Model parameters were obtained from the Genetic Cancer Prediction through Population Screening trial and published literature. Model parameters and BRCA population prevalence for individuals with 3, 2, or 1 Ashkenazi-Jewish grandparent were adjusted for the relative frequency of BRCA mutations in the Ashkenazi-Jewish and general populations. Incremental cost-effectiveness ratios were calculated for all Ashkenazi-Jewish grandparent scenarios. Costs, along with outcomes, were discounted at 3.5%. The time horizon of the analysis is "life-time," and perspective is "payer." Probabilistic sensitivity analysis evaluated model uncertainty. RESULTS: Population testing for BRCA mutations is cost-saving in Ashkenazi-Jewish women with 2, 3, or 4 grandparents (22-33 days life-gained) in the United Kingdom and 1, 2, 3, or 4 grandparents (12-26 days life-gained) in the United States populations, respectively. It is also extremely cost-effective in women in the United Kingdom with just 1 Ashkenazi-Jewish grandparent with an incremental cost-effectiveness ratio of £863 per quality-adjusted life-years and 15 days life gained. Results show that population-testing remains cost-effective at the £20,000-30000 per quality-adjusted life-years and $100,000 per quality-adjusted life-years willingness-to-pay thresholds for all 4 Ashkenazi-Jewish grandparent scenarios, with ≥95% simulations found to be cost-effective on probabilistic sensitivity analysis. Population-testing remains cost-effective in the absence of reduction in breast cancer risk from oophorectomy and at lower risk-reducing mastectomy (13%) or risk-reducing salpingo-oophorectomy (20%) rates. CONCLUSION: Population testing for BRCA mutations with varying levels of Ashkenazi-Jewish ancestry is cost-effective in the United Kingdom and the United States. These results support population testing in Ashkenazi-Jewish women with 1-4 Ashkenazi-Jewish grandparent ancestry

Therapeutic potential of somatic cell nuclear transfer for degenerative disease caused by mitochondrial DNA mutations

Induced pluripotent stem cells (iPSCs) hold much promise in the quest for personalised cell therapies. However, the persistence of founder cell mitochondrial DNA (mtDNA) mutations limits the potential of iPSCs in the development of treatments for mtDNA disease. This problem may be overcome by using oocytes containing healthy mtDNA, to induce somatic cell nuclear reprogramming. However, the extent to which somatic cell mtDNA persists following fusion with human oocytes is unknown. Here we show that human nuclear transfer (NT) embryos contain very low levels of somatic cell mtDNA. In light of a recent report that embryonic stem cells can be derived from human NT embryos, our results highlight the therapeutic potential of NT for mtDNA disease, and underscore the importance of using human oocytes to pursue this goal