Central Ring Puckering Enhances the Stokes Shift of Xanthene Dyes.

Small-molecule dyes are generally designed based on well-understood electronic effects. However, steric hindrance can promote excited-state geometric relaxation, increasing the difference between the positions of absorption and emission bands (the Stokes shift). Accordingly, we hypothesized that sterically induced central ring puckering in xanthene dyes could be used to systematically increase their Stokes shift. Through a combined experimental/quantum-chemical approach, we screened a group of (9-acylimino)-pyronin dyes with a perturbed central ring geometry. Our results showed that an atom with sp3 hybridization in position 10 of (9-acylimino)-pyronins induces central ring puckering and facilitates excited-state geometric relaxation, thereby markedly enhancing their Stokes shifts (by up to ~2000 cm-1). Thus, we prepared fluorescent (9-acylimino)-pyronin pH sensors, which showed a Stokes shift disparity between acid and base forms of up to ~8700 cm-1. Moreover, the concept of ring puckering-enhanced Stokes shift can be applied to a wide range of xanthene analogues found in the literature. Therefore, central ring puckering may be reliably used as a strategy for enhancing Stokes shifts in the rational design of dyes.

Excited-State (Anti)Aromaticity Explains Why Azulene Disobeys Kasha's Rule.

Fluorescence exclusively occurs from the lowest excited state of a given multiplicity according to Kasha's rule. However, this rule is not obeyed by a handful of anti-Kasha fluorophores whose underlying mechanism is still understood merely on a phenomenological basis. This lack of understanding prevents the rational design and property-tuning of anti-Kasha fluorophores. Here, we propose a model explaining the photophysical properties of an archetypal anti-Kasha fluorophore, azulene, based on its ground- and excited-state (anti)aromaticity. We derived our model from a detailed analysis of the electronic structure of the ground singlet, first excited triplet, and quintet states and of the first and second excited singlet states using the perturbational molecular orbital theory and quantum-chemical aromaticity indices. Our model reveals that the anti-Kasha properties of azulene and its derivatives result from (i) the contrasting (anti)aromaticity of its first and second singlet excited states (S1 and S2, respectively) and (ii) an easily accessible antiaromaticity relief pathway of the S1 state. This explanation of the fundamental cause of anti-Kasha behavior may pave the way for new classes of anti-Kasha fluorophores and materials with long-lived, high-energy excited states.

Luminescent Cationic Group 4 Metallocene Complexes Stabilized by Pendant N-Donor Groups.

Cationic group 4 metallocene complexes with pendant imine and pyridine donor groups were prepared as stable crystalline [B(C6F5)4]- salts either by protonation of the intramolecularly bound ketimide moiety in neutral complexes [(η5-C5Me5){η5-C5H4CMe2CMe2C(R)═N-κN}MCl] (M = Ti, Zr, Hf; R = t-Bu, Ph) by PhNMe2H+[B(C6F5)4]- to give [(η5-C5Me5){η5-C5H4CMe2CMe2C(R)═NH-κN}MCl]+[B(C6F5)4]- or by chloride ligand abstraction from the complexes [(η5-C5Me5)(η5-C5H4CMe2CH2C5H4N)MCl2] (M = Ti, Zr) by Li[B(C6F5)4]·2.5Et2O to give [(η5-C5Me5)(η5-C5H4CMe2CH2C5H4N-κN)MCl]+[B(C6F5)4]-. Solid state structures of the new compounds were established by X-ray diffraction analysis, and their electrochemical behavior was studied by cyclic voltammetry. The cationic complexes of Zr and Hf, compared to the corresponding neutral species, exhibited significantly enhanced luminescence predominantly from triplet ligand-to-metal (3LMCT) excited states with lifetimes up to 62 µs and quantum yields up to 58% in the solid state. DFT calculations were performed to explain the structural features and optical and electrochemical properties of the complexes.

No Threshold Exists for Recommending Revision Surgery in Metal-on-Metal Hip Arthroplasty Patients With Adverse Reactions to Metal Debris: A Retrospective Cohort Study of 346 Revisions.

BACKGROUND: Surgeons currently have difficulty when managing metal-on-metal hip arthroplasty (MoMHA) patients with adverse reactions to metal debris (ARMD). This stems from a lack of evidence, which is emphasized by the variability in the recommendations proposed by different worldwide regulatory authorities for considering MoMHA revision surgery. We investigated predictors of poor outcomes following MoMHA revision surgery performed for ARMD to help inform the revision threshold and type of reconstruction. METHODS: We retrospectively studied 346 MoMHA revisions for ARMD performed at 2 European centers. Preoperative (metal ions/imaging) and intraoperative (findings, components removed/implanted) factors were used to predict poor outcomes. Poor outcomes were postoperative complications (including re-revision), 90-day mortality, and poor Oxford Hip Score. RESULTS: Poor outcomes occurred in 38.5%. Shorter time (under 4 years) to revision surgery was the only preoperative predictor of poor outcomes (odds ratio [OR] = 2.12, confidence interval [CI] = 1.00-4.46). Prerevision metal ions and imaging did not influence outcomes. Single-component revisions (vs all-component revisions) increased the risk of poor outcomes (OR = 2.99, CI = 1.50-5.97). Intraoperative modifiable factors reducing the risk of poor outcomes included the posterior approach (OR = 0.22, CI = 0.10-0.49), revision head sizes ≥36 mm (vs <36 mm: OR = 0.37, CI = 0.18-0.77), ceramic-on-polyethylene revision bearings (OR vs ceramic-on-ceramic = 0.30, CI = 0.14-0.66), and metal-on-polyethylene revision bearings (OR vs ceramic-on-ceramic = 0.37, CI = 0.17-0.83). CONCLUSION: No threshold exists for recommending revision in MoMHA patients with ARMD. However postrevision outcomes were surgeon modifiable. Optimal outcomes may be achieved if surgeons use the posterior approach, revise all MoMHA components, and use ≥36 mm ceramic-on-polyethylene or metal-on-polyethylene articulations.

Has the threshold for revision surgery for adverse reactions to metal debris changed in metal-on-metal hip arthroplasty patients? A cohort study of 239 patients using an adapted risk-stratification algorithm.

Background and purpose - A risk-stratification algorithm for metal-on-metal hip arthroplasty (MoMHA) patients was devised by US experts to help clinicians make management decisions. However, the proposed algorithm did not cover all potential patient or surgical abnormalities. Therefore we adapted the US risk-stratification algorithm in MoMHA patients revised for adverse reactions to metal debris (ARMD) to determine the variability in the revision threshold, and also whether high-risk patients had inferior outcomes following revision.Patients and methods - We analysed 239 MoMHA revisions for ARMD between 2001 and 2016 from 2 centres with pre-revision blood metal ions and imaging. Patients were stratified (low risk, moderate risk, high risk) using pre-revision factors (implant, radiographic, blood metal ions, cross-sectional imaging) by adapting a published algorithm. The risk categories for each factor were assessed against revision year, revision centre, and post-revision outcomes (re-revision surgery, and any poor outcome).Results - Compared with hips revised before 2012, hips revised from 2012 onwards included more high-risk implants (44% vs. 17% pre-2012), high-risk radiographic features (85% vs. 69% pre-2012), and low-risk metal ions (41% vs. 19% pre-2012). 1 centre more frequently revised patients with high-risk implants (48% vs. 14%) and low-risk blood metal ions (45% vs. 15%) compared with the other. All these comparisons were statistically significant (p < 0.05). With the limited sample size available, implant, radiographic, blood metal ion, and cross-sectional imaging risk groups did not statistically significantly affect the rates of re-revision surgery or frequency of poor outcomes post-revision.Interpretation - When applying the adapted risk-stratification algorithm the threshold for ARMD revision changed over time, presumably due to increasing evidence, patient surveillance, and investigation since 2012. Lower blood metal ion thresholds were used from 2012 for ARMD revisions; however, there was evidence that centres attached different importance to metal ions when managing patients. High-risk patients did not have inferior outcomes following ARMD revision.

The effectiveness of blood metal ions in identifying bilateral metal-on-metal total hip arthroplasty patients at risk of adverse reactions to metal debris.

We investigated whether blood metal ions could effectively identify bilateral metal-on-metal total hip arthroplasty (THA) patients at risk of adverse reactions to metal debris (ARMD). Whole blood metal ions were sampled in 50 patients with bilateral 36mm Corail-Pinnacle THAs. Patients were divided into ARMD (n=10) and non-ARMD groups (n=40), with optimal ion thresholds for identifying ARMD determined using receiver operating characteristic analysis. Maximum cobalt or chromium produced the highest area under the curve (71.8%). The optimal ion threshold for distinguishing between patients with and without ARMD was 4.0µg/l (90.0%=sensitivity, 65.0%=specificity, 39.1%=positive predictive value, 96.3%=negative predictive value). Fixed regulatory authority thresholds missed more patients with ARMD (10%-12% missed) compared to our threshold (2% missed). Bilateral THA patients with blood metal ions below our threshold were at low-risk of ARMD. Compared to currently recommended fixed authority thresholds, our threshold appears preferable for managing patients with these particular implants.

Modulating NMDA Receptor Function with D-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model.

Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol(®)) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor NaB (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be determined, overall it supports continued glutamatergic drug development.

Influence of implant design on blood metal ion concentrations in metal-on-metal total hip replacement patients.

PURPOSE: Most factors considered to affect blood metal ions following metal-on-metal hip replacement are based on hip resurfacing patients. The study aims were to determine which factors affect blood metal ion concentrations following metal-on-metal total hip replacement (MoM THR). METHODS: All unilateral MoM THR patients at one centre with whole-blood cobalt (Co) and chromium (Cr) concentrations measured up to May 2013 were included. Blood sampling was at a mean of 4.5 years (range 1.1-11.8 years) postoperatively. RESULTS: Of 496 patients (mean age 59.1 years; 52.8% male), blood metal ions >7 µg/l were observed in 9.7% (n = 48). Large femoral head sizes (≥38 mm) had significantly higher (p < 0.0001) blood metal ions than smaller sizes (28/36 mm). Corail-Pinnacle implants produced significantly lower blood metal ions compared to other implant designs (p < 0.01 Co and Cr). Univariate linear regression demonstrated the only significant predictors of both blood Co and Cr concentrations were femoral head size (R(2) = 8.6% Co and R(2) = 3.3% Cr, both p < 0.0001) and implant design (R(2) = 8.8%, p = 0.005 Co and R(2) = 5.1%, p = 0.003 Cr). When the three THR implant design groups (Corail-Pinnacle, Synergy, Other) were analysed separately, femoral head size no longer significantly affected blood metal ions in any of the three implant design groups. CONCLUSIONS: Implant design was the most important factor affecting blood metal ion concentrations. We recommend the regularity of follow-up be tailored to survival rates of various MoM THR designs rather than according to femoral head size.

Long-term changes in blood metal ion levels in patients with hip resurfacing implants: implications for patient surveillance after 10 years follow-up.

BACKGROUND: Studies investigating changes in blood metal ion levels during the second decade of the implant lifetime in MoM hip resurfacing patients are scarce. METHODS: Patients implanted with either Birmingham Hip Resurfacing (BHR) or Articular Surface Replacement (ASR) hip resurfacings with >10 years follow-up and repeated blood metal ion measurements were identified at 2 large specialist European arthroplasty centres. After excluding patients with initial metal ion levels >7 ppb, the proportion of patients with an increase in blood metal ion levels above previously validated implant-specific thresholds (cobalt 2.15 ppb for unilateral implants, cobalt or chromium 5.5 ppb for bilateral) was assessed. RESULTS: We included 2743 blood metal ion measurements from 457 BHR patients (555 hips) and 216 ASR patients (263 hips). Of patients with initial metal ion levels below implant specific thresholds, increases in cobalt or chromium level, respectively, to above these thresholds during the second decade were seen as follows: unilateral BHR (cobalt = 15.6%), unilateral ASR (cobalt = 13.8%), bilateral BHR (cobalt = 8.2%, chromium = 11.8%), bilateral ASR (cobalt = 8.5%, chromium = 4.3%). Measurement-to-measurement changes exceeding +2.15 ppb or +5.5 ppb were, however, uncommon during the second decade. Subgroup results with small diameter (<50 mm) implants were similar. CONCLUSIONS: We recommend less frequent blood metal ion measurements are needed (every 3 to 5 years) for hip resurfacing patients if initial values were below 7ppb.

Budgeting based on need: a model to determine sub-national allocation of resources for health services in Indonesia.

BACKGROUND: Allocating national resources to regions based on need is a key policy issue in most health systems. Many systems utilise proxy measures of need as the basis for allocation formulae. Increasingly these are underpinned by complex statistical methods to separate need from supplier induced utilisation. Assessment of need is then used to allocate existing global budgets to geographic areas. Many low and middle income countries are beginning to use formula methods for funding however these attempts are often hampered by a lack of information on utilisation, relative needs and whether the budgets allocated bear any relationship to cost. An alternative is to develop bottom-up estimates of the cost of providing for local need. This method is viable where public funding is focused on a relatively small number of targeted services. We describe a bottom-up approach to developing a formula for the allocation of resources. The method is illustrated in the context of the state minimum service package mandated to be provided by the Indonesian public health system. METHODS: A standardised costing methodology was developed that is sensitive to the main expected drivers of local cost variation including demographic structure, epidemiology and location. Essential package costing is often undertaken at a country level. It is less usual to utilise the methods across different parts of a country in a way that takes account of variation in population needs and location. Costing was based on best clinical practice in Indonesia and province specific data on distribution and costs of facilities. The resulting model was used to estimate essential package costs in a representative district in each province of the country. FINDINGS: Substantial differences in the costs of providing basic services ranging from USD 15 in urban Yogyakarta to USD 48 in sparsely populated North Maluku. These costs are driven largely by the structure of the population, particularly numbers of births, infants and children and also key diseases with high cost/prevalence and variation, most notably the level of malnutrition. The approach to resource allocation was implemented using existing data sources and permitted the rapid construction of a needs based formula that is highly specific to the package mandated across the country. Refinement could focus more on resources required to finance demand side costs and expansion of the service package to include priority non-communicable services.

How much does a Medical and Healthcare Products Regulatory Agency medical device alert for metal-on-metal hip arthroplasty patients really cost?

BACKGROUND: Many worldwide regulatory authorities recommend regular surveillance of metal-on-metal hip arthroplasty patients given high failure rates. However, concerns have been raised about whether such regular surveillance, which includes asymptomatic patients, is evidence-based and cost-effective. We determined: (1) the cost of implementing the 2015 MHRA surveillance in "at-risk" Birmingham Hip Resurfacing (BHR) patients; and (2) how many asymptomatic hips with adverse reactions to metal debris (ARMD) would have been missed without patient recall. METHODS: All BHR patients eligible for the 2015 MHRA recall (all females, and males with head sizes ⩽46 mm, regardless of symptoms) at one centre were invited for review (hips = 707; patients = 593). All patients were investigated (Oxford Hip Score, radiographs, blood metal ions, and targeted cross-sectional imaging) and managed accordingly. Surveillance costs were calculated using finance department data. RESULTS: The surveillance cost £105,921.79 (range £147.76-£257.50/patient). Radiographs (£39,598) and nurse practitioner time/assistance (£23,618) accounted for 60% of overall costs. 31 hips had ARMD on imaging (12 revised; 19 under surveillance). All revisions were symptomatic. 7 hips with ARMD under surveillance were asymptomatic and remain under regular review. The number needed to treat to avoid missing one asymptomatic ARMD case was 101 patients, representing a cost of £18,041 to avoid one asymptomatic case. CONCLUSIONS: Implementing MHRA surveillance for "at-risk" BHR patients was extremely costly. The risk of asymptomatic ARMD was low with the BHR (1%), suggesting recommended follow-up in asymptomatic patients is not cost efficient. This raises concerns about the increasingly intensive surveillance recommended in the 2017 MHRA guidance for metal-on-metal hip patients.

Pharmacokinetics of Intramuscularly Administered Thermoresponsive Polymers.

Aqueous solutions of some polymers exhibit a lower critical solution temperature (LCST); that is, they form phase-separated aggregates when heated above a threshold temperature. Such polymers found many promising (bio)medical applications, including in situ thermogelling with controlled drug release, polymer-supported radiotherapy (brachytherapy), immunotherapy, and wound dressing, among others. Yet, despite the extensive research on medicinal applications of thermoresponsive polymers, their biodistribution and fate after administration remained unknown. Thus, herein, they studied the pharmacokinetics of four different thermoresponsive polyacrylamides after intramuscular administration in mice. In vivo, these thermoresponsive polymers formed depots that subsequently dissolved with a two-phase kinetics (depot maturation, slow redissolution) with half-lives 2 weeks to 5 months, as depot vitrification prolonged their half-lives. Additionally, the decrease of TCP of a polymer solution increased the density of the intramuscular depot. Moreover, they detected secondary polymer depots in the kidneys and liver; these secondary depots also followed two-phase kinetics (depot maturation and slow dissolution), with half-lives 8 to 38 days (kidneys) and 15 to 22 days (liver). Overall, these findings may be used to tailor the properties of thermoresponsive polymers to meet the demands of their medicinal applications. Their methods may become a benchmark for future studies of polymer biodistribution.

Morbidity and mortality in patients undergoing lower limb arthroplasty surgery during the initial surge of the COVID-19 pandemic in the UK at a single-speciality orthopaedic hospital.

AIMS: The COVID-19 pandemic posed significant challenges to healthcare systems across the globe in 2020. There were concerns surrounding early reports of increased mortality among patients undergoing emergency or non-urgent surgery. We report the morbidity and mortality in patients who underwent arthroplasty procedures during the UK first stage of the pandemic. METHODS: Institutional review board approval was obtained for a review of prospectively collected data on consecutive patients who underwent arthroplasty procedures between March and May 2020 at a specialist orthopaedic centre in the UK. Data included diagnoses, comorbidities, BMI, American Society of Anesthesiologists grade, length of stay, and complications. The primary outcome was 30-day mortality and secondary outcomes were prevalence of SARS-CoV-2 infection, medical and surgical complications, and readmission within 30 days of discharge. The data collated were compared with series from the preceding three months. RESULTS: There were 167 elective procedures performed in the first three weeks of the study period, prior to the first national lockdown, and 57 emergency procedures thereafter. Three patients (1.3%) were readmitted within 30 days of discharge. There was one death (0.45%) due to SARS-CoV-2 infection after an emergency procedure. None of the patients developed complications of SARS-CoV-2 infection after elective arthroplasty. There was no observed spike in complications during in-hospital stay or in the early postoperative period. There was no statistically significant difference in survival between pre-COVID-19 and peri-COVID-19 groups (p = 0.624). We observed a higher number of emergency procedures performed during the pandemic within our institute. CONCLUSION: An international cohort has reported 30-day mortality as 28.8% following orthopaedic procedures during the pandemic. There are currently no reports on clinical outcomes of patients treated with lower limb reconstructive surgery during the same period. While an effective vaccine is developed and widely accepted, it is very likely that SARS-CoV2 infection remains endemic. We believe that this report will help guide future restoration planning here in the UK and abroad. Cite this article: Bone Jt Open 2021;2(5):323-329.

Neurofilaments form a highly stable stationary cytoskeleton after reaching a critical level in axons.

The ultrastructural view of the axonal cytoskeleton as an extensively cross-linked network of neurofilaments (NFs) and other cytoskeletal polymers contrasts with the dynamic view suggested by axonal transport studies on cytoskeletal elements. Here we reconcile these perspectives by showing that neurons form a large NF network along axons which is unequivocally stationary, metabolically stable, and maintained by NFs and nonfilamentous subunit assemblies undergoing slow transport by intermittent rapid movements and pauses. In mouse primary cortical neurons transfected with EGFP-NFL, formation of this stationary NF network requires a critical level of NFs, which explains its absence in NF-poor developing neurons studied previously. Most NFs at proximal axon regions were in a stationary structure coexisting with a smaller pool of moving EGFP-NFL assemblies that were mainly nonfilamentous. Distally along the same axon, EGFP-labeled NFL was much less abundant, and we detected only short filaments moving bidirectionally by slow transport (rapid movements and pauses) as previously described. In living mice, >25% of radiolabeled newly synthesized NFs remained in optic axons after slowly transported NFs had exited. Retained NF remained fixed over several months in a nonuniform distribution and exhibited exceptionally slow turnover (t(1/2) >2.5 months), implying that, at steady state, >90% of NFs in mature optic axons comprise the stationary cytoskeleton and <10% are undergoing slow transport. These findings reconcile in vitro and in vivo axonal transport observations, showing that slowly transported NFs or subunit oligomers are precursors to a highly stable stationary cytoskeletal network that supports mature axons.

Hydrodehalogenation of organohalides by Et3SiH catalysed by group 4 metal complexes and B(C6F5)3.

Catalytic hydrodehalogenation (HDH) of aliphatic organohalides such as trifluorotoluenes by Et3SiH proceeds in the presence of readily available group 4 metal compounds: Cp'2MX2 (Cp' = η5-C5H5 or η5-C5Me5; X = F, Cl, or Me; M = Ti, Zr, or Hf), CpTiCl3 and TiCl4 with a catalytic amount of B(C6F5)3. The use of metallocenes in combination with the borane activator leads to a better selectivity of the reaction, i.e., suppression of Friedel-Crafts alkylations of arenes.

Chelating Polymers for Hereditary Hemochromatosis Treatment.

Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron-chelating moieties (benzene-1,2-diol, benzene-1,2,3-triol, and 1,10-phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125 I-labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next-generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.

Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial.

BACKGROUND: Platinum-based combination chemotherapy is standard treatment for the majority of patients with advanced non-small-cell lung cancer (NSCLC). The trial investigates the importance of the choice of platinum agent and dose of cisplatin in relation to patient outcomes. METHODS: The three-arm randomised phase III trial assigned patients with chemo-naïve stage IIIB/IV NSCLC in a 1:1:1 ratio to receive gemcitabine 1250 mg/m2 on days 1 and 8 of a 3-week cycle with cisplatin 80 mg/m2 (GC80) or cisplatin 50 mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Primary outcome measure was survival time, aiming to test for a difference between treatment arms and also assess non-inferiority with pre-defined margin selected as hazard ratio (HR) of 1.2. Secondary outcome measures included response rate, adverse events and quality of life (QoL). FINDINGS: The trial recruited 1363 patients. Survival time differed significantly across the three treatment arms (p = 0.046) with GC50 worst with median 8.2 months compared to 9.5 for GC80 and 10.0 for GCb6. HRs (adjusted) for GC50 compared to GC80 was 1.13 (95% confidence interval [CI] 0.99-1.29) and for GC50 compared to GCb6 was 1.23 (95% CI: 1.08-1.41). GCb6 was significantly non-inferior to GC80 (HR = 0.93, upper limit of one-sided 95% CI 1.04). Adjusting for QoL did not change the findings. Best objective response rates were 29% (GC80), 20% (GC50) and 27% (GCb6), p < 0.007. There were more dose reductions and treatment delays in the GCb6 arm and more adverse events (60% with at least one grade 3-4 compared to 43% GC80 and 30% GC50). INTERPRETATION: In combination with gemcitabine, carboplatin at AUC6 is not inferior to cisplatin at 80 mg/m2 in terms of survival. Carboplatin was associated with more adverse events and not with better quality of life. Cisplatin at the lower dose of 50 mg/m2 has worse survival which is not compensated by better quality of life. CLINICALTRIALS. GOV IDENTIFIER: NCT00112710. EUDRACT NUMBER: 2004-003868-30. CANCER RESEARCH UK TRIAL IDENTIFIER: CRUK/04/009.

Metal-on-Metal Total Hip Arthroplasty Associated with Adverse Local Tissue Reaction and Pseudoaneurysm of the Superior Gluteal Artery: A Case Report and Literature Review.

Adverse local tissue reaction (ALTR) and pseudoaneurysm formation are rare but known complications following metal-on-metal hip total hip arthroplasty (THA). We report the first known case in the English literature of a concurrent unilateral ALTR and pseudoaneurysm of the superior gluteal artery in the same patient. Following minimal rise in serum metal ions, an ultrasound of the right hip demonstrated an avascular solid/cystic lesion anterolaterally in keeping with an ALTR. More posterolaterally, a second discrete thick-walled cystic lesion was identified. Doppler interrogation demonstrated a "yin yang" pattern suggestive of a pseudoaneurysm. Magnetic resonance imaging confirmed the presence of an anterolateral periarticular lesion with a second discrete lesion within the gluteus medius. Subsequent computed tomography angiography confirmed the presence of arterial contrast blush within the posterior gluteal lesion adjacent to the superior gluteal artery. The patient remains asymptomatic and is being managed conservatively. We review the imaging characteristics of ALTR and pseudoaneurysm occurring post-THA. When a complex solid/cystic lesion is encountered in a patient with a THA, radiologists must ensure that the lesion is interrogated with color Doppler to confidently distinguish a pseudotumor from a pseudoaneurysm. This information is vital to the surgeon to avoid unexpected hemorrhage if revision joint replacement surgery is being contemplated.