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Introduction: Unicompartmental knee replacement (UKR) is an effective surgical strategy in patients with isolated medial or lateral compartment osteoarthritis. Study aims were to (1) describe the epidemiology of patients undergoing revision of UKR to a hinge knee replacement (HKR); (2) identify factors influencing time to revision; (3) evaluate HKR survival., Materials and Methods: An analysis of National Joint Registry data was undertaken, exploring revision of UKR to HKR between 2007 and April 2021. Descriptive analysis of eligible patients and Cox Regression to identify key determinants of time to revision were performed. Failure of HKR post-revision was assessed using survival analysis., Results: 111 patients underwent revision of UKR to HKR. Median age at revision was 70 years and most common indications were instability (n = 42) and infection (n = 22). The most common implant was a rotating HKR. Significant independent factors associated with earlier revision were periprosthetic fracture (p = 0.03) and malalignment (p = 0.03). Progressive osteoarthritis (p = 0.01) and higher ASA grades (3: p = 0.01, 4: p < 0.01) delayed time to revision; patient sex and age were not significant factors. Ten patients required subsequent re-revision; median age at re-revision was 61 years. HKR revised from UKR had an 89.3% revision-free risk at 5 years. Male sex (p < 0.01) and younger age (p < 0.01) were associated with re-revision., Conclusions: Factors associated with time to revision may be used to counsel patients prior to UKR. The survivorship of the HKR of 89.3% at 5 years is concerning and careful consideration should be given when using this level of constraint when revising UKR in younger or male patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To assess the effect of sex and laterality on clinical features of primary rhegmatogenous retinal detachment (RRD)., Method: This study is a retrospective analysis of data prospectively collected. We extracted data from two online datasets over a 7-year period of patients older than 16 years who had undergone surgery for primary RRD. Data on baseline characteristics were analyzed to compare males versus females, and right versus left eyes., Results: Of 8133 eyes analyzed, 4342 (53.4%) were right. The overall male predominance (63.7%) was more marked in the age range 50-69 years. Men were more commonly pseudophakic and presented more frequently with baseline posterior vitreous detachment (PVD). Female sex was significantly associated with baseline myopia, retinal holes as causative retinal break, and isolated inferior RD. Men had more frequent foveal involvement, greater RRD extent, greater numbers and larger sized retinal tears including dialysis and giant retinal tears. Regarding laterality, foveal involvement, larger retinal breaks, isolated temporal RD and temporal retinal breaks were more common in right eyes, whereas left eyes were more myopic at baseline and presented more frequently with isolated nasal RD and nasal retinal breaks., Conclusions: This study confirmed the predominance of male sex and right laterality in RRD. Sex and laterality were associated with multiple presenting features of RRD including extent, break distribution, number, size and type, as well as RD distribution., (© 2023. The Author(s).)

Background: To evaluate the influence of age on the clinical characteristics of primary rhegmatogenous retinal detachments (RRD)., Methods: We conducted a retrospective review of a prospectively collected dataset. Data regarding adult patients (aged 16-100 years) who had undergone primary RRD repair, were extracted from two online databases. Baseline demographics, preoperative clinical characteristics and surgical management details were collected. Age-based groups (16-30, 30-39, 40-49, 50-59, 60-69, 70-79, ≥80) were compared using univariate analysis, with multivariate testing for interaction of age with sex, laterality and pseudophakia., Results: In total, 8,133 eyes were analysed, of which the majority (59%) were in the 50-69 age-range peaking at 60, with a male predominance (64%). Myopia was significantly more frequent in patients aged <50 years. The presence of posterior vitreous detachment increased up to 50 years, then remained >95%. Foveal involvement, grade C proliferative vitreoretinopathy, total RD and greater RD extent were more common and progressively increased after 60 years, with worsening visual acuity. Isolated superior RRDs became more prevalent with age reaching a plateau in the age-range 50-69, before reducing again; conversely, isolated inferior RRDs were commoner in those <30, with a minimum in the 70-79 age-range. The incidence of fellow-eye RRD decreased linearly with age., Conclusions: Age appeared a key variable in RRD phenotype influencing a wide range of RRD characteristics. The higher incidence of myopia, PVD absent and bilateral RRD in patients <40 years and the significant phenotypical differences in the under 40 and over 50 age-groups highlight that there are several discrete forms of RRD., (© 2022. Crown.)

Aims: The aim of this study was to identify variables associated with time to revision, demographic details associated with revision indication, and type of prosthesis employed, and to describe the survival of hinge knee arthroplasty (HKA) when used for first-time knee revision surgery and factors that were associated with re-revision., Methods: Patient demographic details, BMI, American Society of Anesthesiologists (ASA) grade, indication for revision, surgical approach, surgeon grade, implant type (fixed and rotating), time of revision from primary implantation, and re-revision if undertaken were obtained from the National Joint Registry data for England, Wales, Northern Ireland, and the Isle of Man over an 18-year period (2003 to 2021)., Results: There were 3,855 patient episodes analyzed with a median age of 73 years (interquartile range (IQR) 66 to 80), and the majority were female (n = 2,480, 64.3%). The median time to revision from primary knee arthroplasty was 1,219 days (IQR 579 to 2,422). Younger age (p < 0.001), decreasing ASA grade (p < 0.001), and indications for revision of sepsis (p < 0.001), unexplained pain (p < 0.001), non-polyethylene wear (p < 0.001), and malalignment (p < 0.001) were all associated with an earlier time to revision from primary implantation. The median follow-up was 4.56 years (range 0.00 to 17.52), during which there were 410 re-revisions. The overall unadjusted probability of re-revision for all revision HKAs at one, five, and ten years after surgery were 2.7% (95% confidence interval (CI) 2.2 to 3.3), 10.7% (95% CI 9.6 to 11.9), and 16.2% (95% CI 14.5 to 17.9), respectively. Male sex (p < 0.001), younger age (p < 0.001), revision for septic indications (p < 0.001) or implant fracture (p = 0.010), a fixed hinge (p < 0.001), or surgery performed by a non-consultant grade (p = 0.023) were independently associated with an increased risk of re-revision., Conclusion: There were several factors associated with time to first revision. The re-revision rate was 16.2% at ten years; however, the risk factors associated with an increased risk of re-revision could be used to counsel patients regarding their outcome.Cite this article: Bone Joint J  2023;105-B(1):47-55.

Extracellular signalling proteins interact in networks rather than in isolation. In this context we investigated vitreous protein levels, including placental growth factor (PlGF), angiopoietin-2 (ANG2) and vascular endothelial growth factor (VEGF), in patients with proliferative diabetic retinopathy (PDR) with variable disease severities, and after anti-VEGF pre-treatment. Vitreous samples of 112 consecutive patients undergoing vitrectomy for PDR and of 52 non-diabetic patients with macular holes as controls were studied. A subset of the PDR patients were treated with either aflibercept (AFB, n = 25) or bevacizumab (BVZ)/ranibizumab (RZB) (n = 13), before surgery. Antibody-based analysis of 35 proteins (growth factors and cytokines) showed a significant increase in expression levels of 27 proteins in PDR patients as compared to controls. In network analysis of co-regulated proteins, a strong correlation in expression levels between VEGF, PlGF, MCP1 and ANG2 was found, mostly clustered around ANG2. In the AFB treatment group, concentrations of several proteins were decreased, including VEGFR1, whereas interleukin 6 and 8 were increased as compared to untreated PDR patients. The observed differences in vitreous protein levels between the different treatments and untreated PDR patients may underlie differences in clinical outcomes in patients with PDR., (© 2022. The Author(s).)

Background: The aim was to describe temporal changes and associated changes in patient demographics and surgical variables, revision rate and factors associated with revision of primary hinge knee arthroplasty (HKA) in the UK., Methods: National Joint Registry data for England, Wales, Northern Ireland and Isle of Mann was used to examine the temporal trends in patient demographics, surgical factors and indications for primary HKA usage over a 16-year (2003 to 2018) period and associated risk factors for revision., Results: There were 4921 patient episodes with a median follow up of 5.5 (range 0 to 16.3) years. The median age was 75years and the majority were female (72.9%). There was a tenfold increase in the use of HKA (p < 0.001), with an increased relative usage in female patients (p = 0.010), but no significant changes in age (p = 0.484) or BMI (p = 0.781). There were 227 revisions performed at a median of 695days. The overall unadjusted probabilities of revision at 1, 5 and 10 years were 1.5% (95% confidence intervals (CI) 1.1to1.8), 4.4% (95%CI 3.7 to 5.0) and 6.4% (95%CI 5.5 to 7.3), respectively. Cox proportional hazard analysis demonstrated younger age (p < 0.01), male sex (hazard ratio (HR) 1.43, p < 0.01), morbid obesity (HR 2.31, p = 0.022) or previous trauma as the indication (HR 1.48, p = 0.025) were associated with an increased risk of revision., Conclusion: There was an increase in the use of HKA with increased uptake among female patients. The revision rate was a 6.4% at 10 years, however, younger age, male sex, morbid obesity or previous trauma were associated with an increased risk of revision., Level of Evidence: III Retrospective study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

To investigate the relationship between vitreomacular traction (VMT) width, foveal floor width (FFW) and other anatomical characteristics between eyes of patients with VMT. Retrospective observational study of unilateral and bilateral VMT cases from two specialist ophthalmic centres in the United Kingdom (UK) between 2016 and 2018. For unilateral VMT cases: VMT width in the affected eye and FFW in the non-affected fellow eye were measured. In bilateral VMT cases: VMT width in both eyes was measured. In all cases, the presence of any associated inner or outer retinal, and vitreoretinal interface (VRI) changes, including epiretinal membrane, was also documented. 88 patients fulfilled the study criteria: 57 having unilateral and 31 bilateral VMT. For unilateral VMT cases, log (VMT) width was significantly correlated with FFW (r = 0.347, p = 0.008). Using stepwise linear regression, FFW (p = 0.004) and VRI changes (p = 0.03) were both significantly associated with VMT width with a R 2 of 0.21. In bilateral VMT cases, there was strong positive correlation between log (VMT) width (r = 0.88, p < 0.001), and the presence of any VRI (r = 0.90, p < 0.001) or outer retinal changes (r = 0.50, p < 0.001) between the two eyes. These findings suggest that individual variations in foveal morphology as measured by the FFW, along with the presence of vitreoretinal interface changes, are associated with the extent of VMT width. VMT width, VRI and outer retinal changes were also highly correlated between eyes in bilateral VMT, suggesting that individual patient factors, which may be genetic or acquired, determine their presence and extent., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

According to both trial and clinical data on direct oral anticoagulants (DOACs) elderly patients are at greatest risk of bleeding. It is unclear whether age intrinsically affects anticoagulation response. To investigate the age-related sensitivity to DOACs, we compared the pharmacological activity of the direct factor Xa inhibitor, rivaroxaban, between young and elderly subjects ex-vivo. 36 fit elderly and 30 fit young subjects [median (IQR) age: 83(75-87) vs 30(26-38) years] provided a blood sample. Clotting parameters were measured in the resultant plasma samples incubated with rivaroxaban (100-500 ng/ml). Parametric, non-parametric tests and regression lines adjusted for rivaroxaban concentration and baseline values were used to compare data. Rivaroxaban produced a greater prolongation of both Prothrombin Time (PT) and modified Prothrombin Time (mPT) (both p < 0.001) in the elderly compared to young subjects (with difference in mean PT increasing from 1.6 to 6.1s and for mPT from 23.5 to 71.1s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentration, respectively). Factor X and factor II activity was significantly lower in the elderly in the presence of rivaroxaban (p < 0.001 for both). Rivaroxaban prolonged time-based parameters and suppressed the amount of thrombin generation to a significantly greater extent in the elderly compared to young subjects [%change from baseline for Endogenous Thrombin Potential (ETP): - 35.0 ± 4.4 vs - 29.8 ± 7.4 nM*min; p = 0.002]. The use of validated DOAC assays will be of considerable benefit for monitoring elderly patients who, because of their increased sensitivity to rivaroxaban, may require lower doses of the drug for therapeutic anticoagulation., (© 2020. The Author(s).)

Purpose: To compare phakic and pseudophakic primary rhegmatogenous retinal detachments (RD) and, within phakic RD, eyes with and without cataract., Design: Retrospective comparative clinical study., Methods: Setting: Online database of prospectively collected data. StudyPopulation: Patients aged ≥50 years who had undergone RD repair., Procedure: Data included baseline demographic and clinical features, surgical details, and anatomical and functional outcomes. Univariate analysis was performed to compare pseudophakic with phakic RD, and phakic RD with and without cataract. Age and sex dependency of variables was analyzed and the association of preoperative variables with final visual acuity was assessed using multivariate analysis. MainOutcomeMeasures: Preoperative features, intraoperative management, postoperative outcomes, association of preoperative features with postoperative outcomes., Results: Of 4,231 eyes, 1,212 were pseudophakic and 3,019 phakic, among which 310 had cataract. Pseudophakic RD showed significant differences compared with phakic RD, including older age, higher prevalence of male sex, foveal detachment, grade C proliferative vitreoretinopathy (PVR), inferior retinal breaks, inferior retinal involvement, and greater RD extent. Despite the more advanced features of pseudophakic RD, pseudophakia was a positive factor for visual outcome. Contralateral RD was more frequent in pseudophakic than phakic RD eyes (P < .0001). Within phakic RD, phakic RD with cataract exhibited several similarities with pseudophakic RD, including greater age, more frequent foveal detachment, PVR, and greater RD extent., Conclusions: The presenting features differed significantly between pseudophakic and phakic RD, with greater occurrence of inferior retinal breaks and inferior retinal involvement in particular. Phakic RD with cataract shared several features in common with pseudophakic RD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Patients on warfarin are required to withdraw from treatment for a fixed period (normally 5 days) prior to an invasive procedure. However, the anticoagulant effect of warfarin subsides at different rates among different patients, exposing some to increased risk of either thrombosis or bleeding. In a recent study in patients awaiting surgery, following warfarin cessation the INR declined slower over time in those with two CYP2C9 variant alleles, increasing age, weight and number of comorbidities and that INR decline was faster in those with higher maintenance INR value. Subsequently, we developed an algorithm which predicts INR decline in individual patients after 5 days of warfarin cessation. The current study validated the algorithm. An independent cohort of patients completing a short course of warfarin took part in the study. INR values for subsequent 9 days and CYP2C9 genotype were available. The predicted INR decline (INR day 1 -INR day 5 ) was compared to the observed one (where an INR check on day 5 was unavailable, INR was estimated using a linear approximation model). There was a strong correlation between the decline in INR by day 5 and that predicted from the algorithm for the 117 patients (r = 0.949, p < 0.001). The algorithm was precise, with low degree of bias and variance of the prediction error. The algorithm can accurately predict the INR decline following warfarin cessation in individual adult patients. The use of this easily adoptable algorithm can reduce cancellation or delays of planned surgical procedures.

Inulin is a soluble dietary fibre, also classified as a prebiotic, extracted from chicory roots. The present study aimed to determine the effect of consumption of native chicory inulin on the stool frequency of middle-aged to older adults (40-75 years old) with uncomfortably but not clinically relevant low stool frequency, specified as two to four days without bowel movements per week. Two randomised, double blind, placebo-controlled crossover trials were conducted using similar protocols in differing populations. Trial A was conducted in Amsterdam, The Netherlands and subsequently Trial B was conducted in Newcastle, United Kingdom. Both trials involved supplementation for 5 weeks with 10 g per day of inulin or placebo, a washout period of 2 weeks, and then crossed over to receive the other treatment. In Trial B, faecal gut microbiota composition was assessed using 16S rRNA gene sequencing. In Trial A, which 10 volunteers completed, the stool frequency was significantly increased to an average 4.9 ± 0.23 (SEM) times per week during inulin periods versus 3.6 ± 0.25 in the periods with placebo ( p  = 0.01). In contrast, in Trial B which 20 volunteers completed, there was no significant effect of the inulin on stool frequency (7.5 ± 2.1 times per week with inulin, 8.1 ± 3.0 with placebo, p  = 0.35). However, many subjects in Trial B had a stool frequency >5 per week also for the placebo period, in breach of the inclusion criteria. Combining the data of 16 low stool frequency subjects from Trials A and B showed a significant effect of inulin to increase stool frequency from 4.1 to 5.0 per week ( p  = 0.032). Regarding secondary outcomes, stool consistency was significantly softer with inulin treatment compared to placebo periods, it increased 0.29 on the Bristol stool scale ( p  = 0.008) when data from all subjects of Trials A and B were combined. No other differences in bowel habit parameters due to inulin consumption were significant. None of the differences in specific bacterial abundance, alpha or beta diversity were significant, however the trends were in directions consistent with published studies on other types of inulin. We conclude that 10 g per day of native chicory inulin can increase stool frequency in subjects with low stool frequency., (© 2019 The Authors.)

Introduction: Warfarin therapy is stopped for a fixed period prior to surgery to minimise risk of perioperative bleeding. However, anticoagulation subsides at varying rates among different patients. We evaluated the influence of genetic (CYP2C9 and VKORC1), patient and clinical factors on warfarin clearance and the decline in INR following warfarin withdrawal., Materials and Methods: 131 patients completing a course of warfarin provided blood samples over 9 days for initial genotyping, and measurement of INR and plasma warfarin enantiomer concentrations., Results: S-warfarin clearance was significantly lower in patients with either CYP2C9 single (*2 or *3) or double (*2*2 or *2*3) variant alleles compared to those with wild-type genotype (P < 0.001). Regression analysis revealed that patient age (P = 0.037) and CYP2C9 *2*2 & *2*3 genotype (P = 0.005), but not VKORC1 genotype, significantly affected the time taken for the resumption of normal coagulation (INR value declining to ≤1.5)., Conclusions: The inter-individual variability in the time needed for normal coagulation to resume following warfarin withdrawal is influenced, in the main, by variance in S-warfarin clearance, which in turn is affected by CYP2C9 polymorphism and age. Cost-effectiveness of pharmacogenetics-based algorithms incorporating CYP2C9 genotype and patient age could be increased if used not only to guide dosing decisions but also estimation of the correct length of time needed for individual patients to stop taking warfarin prior to surgery., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: Time within therapeutic INR range (TTR) predicts benefits/risk of warfarin therapy. Identification of individual- and centre-related factors that influence TTR, and addressing them to improve anticoagulation control, are important. This study examined the impact of individual and centre-related factors upon long-term anticoagulation control in atrial fibrillation patients in seven UK-based monitoring services., Methods: Data between 2000 and 2014 on 25 270 patients (equating to 203 220 patient years) [18 120 (71.7%) in general practice, 2348 (9.3%) in hospital-based clinics and 4802 (19.0%) in domiciliary service] were analysed., Results: TTR increased with increasing age, peaking around 77% at 70-75 years, and then declined, was lower in females than males, and in dependent home-monitored patients than those attending clinic (P < 0.0001). TTR, number of dose changes and INR monitoring events and the probability of TTR ≤ 65%, differed across the centres (P < 0.0001)., Conclusions: Although all the participating centres ostensively followed a standard dosing algorithm, our results indicate that variations in practice do occur between different monitoring sites. We suggest feedback on TTR for individual monitoring sites gauged against the average values reported by others would empower the individual centres to improve quality outcomes of anticoagulation therapy by identifying and adjusting contributory factors within their management system., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients., (© 2017 John Wiley & Sons Ltd.)

Background: Large-diameter (≥36-mm) metal-on-metal (MoM) total hip replacements have been shown to fail at an unacceptably high rate. Globally, the DePuy Pinnacle prosthesis was the most widely used device of this type. There is evidence to suggest that one of the main reasons for the poor clinical performance of large-diameter MoM prostheses is the metal debris released from the head-stem taper junction-i.e., taper junction failure. The aim of this study was to investigate variation in the as-manufactured finish of the female taper surface and to determine its influence on material loss. We hypothesized that rougher surfaces with higher relative material peaks would be significantly associated with greater taper wear rates., Methods: We analyzed 93 Articul/eze femoral head tapers with a 36-mm bearing diameter that had been used in combination with a Corail titanium uncemented stem. The influence of the surface topography of the as-manufactured female taper surface on taper wear was examined by means of a multiple regression model, taking into account other known variables., Results: We identified great variation in the as-manufactured surface finish of the female taper surface, with a range of measured Ra values from 0.14 to 4.20 μm. The roughness of the female taper surface appeared to be the most important variable associated with taper wear (p < 0.001). The best-fitting regression model, including duration in vivo, head offset, reduced peak height (Rpk) value, stem shaft angle, and bearing surface wear rate, explained approximately 44% of the variation in taper wear rates., Conclusions: We concluded that the roughness of the female taper surface appears to be a significant factor in metal debris release from head-stem taper junctions., Clinical Relevance: This study shows evidence that previously unappreciated variations in manufacturing processes may have a major impact on the clinical outcomes of patients.

Aims: Stabilization of anticoagulation control is seminal to reducing the risk of adverse effects of vitamin K antagonists. Reliable information on how ageing influences this is lacking. We set out to assess the true age-related changes in anticoagulation control, how gender and patient setting influence this, and the possible implications of these for patient outcomes and management., Methods: In atrial fibrillation (AF) patients of a unified anticoagulant service monitoring patients in general practice or hospital-based clinics and housebound patients at home, international normalized ratio (INR) and warfarin dose data between 2000 and 2013 were extracted via the DAWN dosing program. Anticoagulation control was assessed by calculating percentage time spent within target INR (TTR)., Results: A total of 2094 AF patients [938 (44.8%) in general practice (GP) and 531 (25.4%) in hospital (H)-based clinics and 625 (29.8%) through the domiciliary service (D)] were evaluated. The frequency of warfarin dose changes and INR monitoring events declined until about age 67, then increased as patients got older. The TTR according to age was significantly lower and the probability of having a TTR ≤65% according to age was higher for D than for H and GP, and females had a greater probability of having a TTR ≤65% than age-matched males., Conclusion: Identification of factors underlying poorer anticoagulation control in older housebound patients and the introduction of effective modifications to improve the clinical effectiveness of anticoagulation in such patients is needed., (© 2016 The British Pharmacological Society.)

Background: novel oral anticoagulants may be particularly cost-effective when INR control (TTR) with warfarin is poor or monitoring difficult., Setting: the Newcastle upon Tyne monitoring service, set in hospital or general practice and a domiciliary-based service for housebound patients., Objectives: to examine anticoagulation stability and costs of monitoring., Subjects: three hundred and twenty-six atrial fibrillation patients, 75 years and over, with target INR of two to three, accessing hospital (n = 100), general practice (n = 122) and domiciliary (n = 104) service., Methods: age, co-morbidities, length of warfarin treatment, medications, INR values and dose changes from January to December 2011 were recorded, and costs analysed., Results: home-monitored patients had taken warfarin for longer, mean 5.2 years, than hospital (3.7) or general practice (3.1) patients. Age and total number of drugs prescribed chronically were negatively related to TTR. INR measurements and dose changes were negatively associated with the duration of treatment, positively correlated with co-morbidities. The mean TTR was 78% in hospital, 71% in general practice and 68% in domiciliary monitored patients. INR was monitored more often in hospital and domiciliary groups than in general practice and more dose changes occurred in the domiciliary group than in others. Costs of warfarin and monitoring were £128 per patient per year for hospital, £126 for general practice and £222 for domiciliary patients., Conclusions: further exploration of the clinical effectiveness of novel anticoagulants in dependent patients is warranted to determine to what extent trial outcomes so far achieved in a fitter elderly population are influenced by the chronic co-morbidities of old age., (© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: To compare quantitative point of care (POC) with laboratory d-dimer testing in patients with suspected venous thromboembolism (VTE) presenting to the emergency department., Methods: A prospective single centre diagnostic study in adults presenting with suspected VTE (pleuritic chest pain or leg swelling), Results: Main outcome measures were the statistical correlation of the two methods. Secondary outcome measures were: test turnaround times, correlation between D-dimer levels, Wells score and final diagnosis. The results showed that there was strong evidence of POC D-dimer being sufficiently accurate to be used as a screening device. The correlation between the two logged assay scores was good. Both logged scores correlated similarly with the Wells score. Once an equivalent cut-off value for POC D-dimer (412 ng/mL) was established, there were only 4 of 100 cases all of which were extremely close to the cut-off. D-dimer turnaround time decreased by 83%. A further recent analysis of laboratory times done in 2013 demonstrates that POC D-dimer results remain 62% quicker. Based on the D-dimer results 27 patients were scanned. The median Wells score in this group was 3.0 (range 2-10) median POC D-dimer levels of 2590 (412-5000) and median lab D-dimer levels of 864 (230-13 000) showing good correlation between D-dimer positive patients and the Wells score. Seven patients had positive scans. There was a significant difference in both logged D-dimer scores between the negative and positive groups indicating that raised D-dimer levels correlate well with final diagnosis., Conclusions: The POC device was comparable with the laboratory device and was sufficiently accurate to be used as a screening tool in the emergency department setting.

Patella resurfacing during primary total knee arthroplasty (TKA) remains controversial. Variation in published results for patella resurfacing may potentially be explained by differences in design between TKA brands. We interrogated NJR-PROMs data to ascertain whether there is an early functional benefit to resurfacing the patella, both overall and for each of the five most popular primary knee designs through use of the Oxford Knee Score. A total of 8103 resurfaced TKAs and 15,290 nonresurfaced TKAs were studied. There was a large variation in the proportion of knees undergoing patella resurfacing by brand (Nexgen=16% versus Triathlon=52%). Patellar resurfacing did not significantly influence the magnitude of improvement in overall knee function or anterior knee-specific function irrespective of TKA brand or for cruciate retaining versus sacrificing designs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy., Methods: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation., Results: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001)., Conclusions: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).

Congenital cardiovascular malformation (CVM) exhibits familial predisposition, but most of the specific genetic factors involved are unknown. Postulating that rare variants in genes in critical cardiac developmental pathways predispose to CVM, we systematically surveyed three genes of the bone morphogenetic protein (BMP) signaling pathway for novel variants. Exonic, splice site, and untranslated regions of BMPR1A, BMPR2, and SMAD6 genes were sequenced in 90 unrelated sporadic cases of CVM. One nonsynonymous variant (p.C484F) with predicted functional impact was found in the MAD homology 2 domain of SMAD6, an intracellular inhibitor of BMP signaling. Sequencing this domain in an additional 346 cases of CVM yielded two further nonsynonymous variants (p.P415L and p.A325T). Functional effects of all three SMAD6 mutations were investigated using BMP signaling assays in vitro. Two SMAD6 variants (p.C484F and p.P415L) had significantly (P < 0.05) lower activity than wild-type SMAD6 in inhibiting BMP signaling in a transcriptional reporter assay. In addition, the p.C484F variant had a significantly (P < 0.05) lower capacity to inhibit an osteogenic response to BMP signaling. We conclude that low-frequency deleterious variants in SMAD6 predispose to CVM. This is the first report of a human disease phenotype related to genetic variation in SMAD6., (© 2012 Wiley Periodicals, Inc.)

Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (-1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.

Background: Children with malignant disease are at increased risk of bone disorders and cardiovascular disease. Vitamin D status may influence this risk and so we assessed vitamin D levels in children with malignant disease undergoing active treatment or surveillance post-therapy., Procedure: This was an outpatient-based cross-sectional study of 61 children with a history of malignancy (median age 11.1 years; range 1.5-24.4 years) and 60 control subjects (median age 8.4 years; range 0.2-18.0 years) attending hospital for the management of non-malignant disorders. Serum vitamin D (25-OH-D), parathormone levels and bone biochemistry were determined. Vitamin D status and its relationship to age, sex, ethnicity, time of sampling and presence of malignant disease was determined., Results: Vitamin D status was suboptimal in 62% of cases (25-OH-D < 50 nmol/L [20 ng/ml]). Vitamin D deficiency (25-OH-D < 25 nmol/L [10 ng/ml]) was more common in children with malignant disease than controls (21.3% vs. 3.3%; P = 0.013). Month of sampling (P < 0.001), ethnicity (P < 0.001), older age (P = 0.011), and history of malignancy (P = 0.012) were associated with a poorer vitamin D status., Conclusions: Vitamin D levels [25-OH-D] are lower in survivors of childhood cancer in comparison to control children with the majority either insufficient or deficient. Assessment and adequate replacement of vitamin D status may be of particular value in this group of children., (Copyright © 2011 Wiley-Liss, Inc.)

Juvenile idiopathic arthritis (JIA) is a disabling and destructive condition that commonly affects the knee during childhood. Our study aimed to look at the outcome of knee replacement in this uncommon group, set a benchmark for survival and determine predictors of functional results. Patients were identified from a regional specialist rheumatology clinic set up for the care of adult patients with JIA. Outcome was assessed using Stanford HAQ 20-item disability scale, patient administered WOMAC questionnaire and Knee society score. This retrospective cohort includes 34 knee replacements in 20 patients with JIA performed at a median age of 35 years with median follow up of 16 years. Median WOMAC and Knee society score at last follow up were 61.7 and 60.8 respectively. The pain component of the scores was significantly (p<0.001) better than functional component. Strong negative correlation (R=-0.79, p<0.001) was noted between Knee society function score and HAQ score. Moderate negative correlation (R=-0.42; p=0.02) was noted between Knee society function score and age at onset of the disease. Multiple stepwise regression analysis to estimate the predictors of functional results showed that the only significant (p<0.001) predictor for functional outcome was disease activity, as predicted by the HAQ score. Kaplan Meier survival analysis revealed an estimated survival of 58.5% at 20 years. Knee replacement is a satisfactory pain relieving procedure in JIA patients, although survival may be poor. Disease activity as determined by HAQ score, may predict functional results., (Copyright 2009 Elsevier B.V. All rights reserved.)

There have been marked changes in the management of juvenile idiopathic arthritis (JIA) over recent decades, mainly with earlier use of methotrexate (MTX). Our aim was to describe orthopaedic interventions in a large group of adults with JIA followed up over several decades. This was a retrospective observational study of adult JIA patients attending a teaching hospital clinic, with information collated on JIA subtype, disease duration, orthopaedic interventions, and exposure to MTX. The study included 144 patients with median disease duration of 19 years. Survival analysis showed that joint surgery was observed in the majority (75%) of patients with disease duration over 40 years with a trend for less joint surgery in patients with oligoarticular JIA. In total, 41 patients (28.5%) had received joint surgery, and 17/41 (41%) have required multiple procedures. Of those who have required joint surgery, 20/41 (48%) had started MTX in their adult years, with only 5/41 (12%), starting MTX prior to first joint replacement and none within 5 years of disease onset. Of the patients who have not had joint surgery to date, most (46/103, 45%) were receiving MTX or another immunosuppressive agent; in the majority of cases, MTX was started within 2 years of disease onset. Many adults with JIA require joint replacement surgery and ongoing immunosuppressive treatments, emphasising that JIA is not a benign disease. Many patients who have had joint replacement surgery have had exposure to MTX albeit after many years after disease onset; it remains to be seen whether patients who have received MTX therapy early in their disease course will ultimately have less requirement for joint surgery.

Context: The aldosterone to renin ratio (ARR) is a marker of aldosterone excess, widely used to screen for primary aldosteronism (PA). The significance of a raised ARR in normotensive and hypertensive subjects and the phenotypic and familial factors affecting it are unclear., Objective: We estimated the distribution and heritability of the ARR and tested for associations between ARR and blood pressure (BP) with 11 polymorphisms at the CYP11B1/CYP11B2 locus., Design and Setting: A total of 1172 individuals from 248 Caucasian families ascertained via a hypertensive proband were evaluated., Main Outcome Measure: Plasma aldosterone was measured by RIA, and plasma renin concentration was measured by the LIAISON Direct Renin chemiluminescent immunoassay., Results: Unadjusted and adjusted ARR were continuously distributed in normotensives and hypertensives, with no evidence of a cutoff that would identify a separate population with PA. Median ARR was 4.19 ng/liter per mIU/liter (range, 0.04-253.16). ARR levels were higher in females and associated with age, body mass index, and potassium. Antihypertensive agents had significant predictable effects on the ARR. Renin was negatively associated, and ARR was positively associated with ambulatory BP readings (P < 0.001) in subjects not taking antihypertensives. The heritability of the ARR was 38.1% (P < 10(-8)). Plasma aldosterone, but not ARR, was influenced by the intron 2 conversion variation in the CYP11B2 gene (beta = -0.07; P = 0.04)., Conclusions: The ARR is continuously distributed, is influenced by genetic and environmental factors, and is not a marker of a distinct pathological abnormality but possibly reflects the long-term influence of aldosterone on cardiovascular homeostasis.

Plasma potassium is a moderately heritable phenotype, but no robust associations between common single nucleotide polymorphisms (SNPs) and plasma potassium have previously been described. Genetic influences on renal potassium handling could be important in the etiology of hypertension. We have tested whether common genetic variation in the gene encoding the beta-subunit of the epithelial sodium channel (SCNN1B) affects plasma potassium and blood pressure level in a study of 1,425 members of 248 families ascertained on a proband with hypertension. We characterized family members for blood pressure using ambulatory monitoring, measured plasma potassium in venous blood samples, and genotyped four SNPs that spanned the SCNN1B gene. We found highly significant association between genotype at the SCNN1B rs889299 SNP situated in intron 4 of the gene and plasma potassium. Homozygotes for the rarer T allele had on average a 0.15 mM lower plasma potassium than homozygotes for the common C allele, with an intermediate value for heterozygotes (trend, P = 0.0003). Genotype at rs889299 accounted for approximately 1% of the total variability in plasma potassium, or around 3% of the total heritable fraction. There was no association between genotype at any SCNN1B SNP and blood pressure considered as a quantitative trait, or with hypertension affection status. We have shown a modest sized but highly significant effect of common genetic variation in the SCNN1B gene on plasma potassium. Interaction between the rs889299 SNP and functional SNPs in other genes influencing aldosterone-responsive distal tubular electrolyte transport may be important in the etiology of essential hypertension.

Aims: To localize chromosomal regions (or quantitative trait loci) that harbour genetic variants influencing the variability of electrocardiographic (ECG) and echocardiographic left ventricular hypertrophy (LVH)., Methods and Results: We evaluated genetic linkage to ECG Sokolow-Lyon voltage, ECG Cornell voltage product, ECG left ventricular (LV) mass, and to echocardiographic septal wall thickness, LV cavity size, and LV mass in 868 members of 224 white British families. A genome-wide scan was performed with microsatellite markers that covered the genome at 10-cM intervals and linkage was assessed by variance components analysis. We identified chromosomal regions suggestive of linkage for Sokolow-Lyon voltage on chromosome 10q23.1 [log(10) of the odds (LOD = 2.21, P = 0.0007)], for ECG Cornell voltage product on chromosome 17p13.3 (LOD = 2.67; P = 0.0002), and for ECG LV mass on chromosome 12q14.1 (LOD = 2.19; P = 0.0007). There was a single region of possible linkage for echocardiographic LV mass on chromosome 5p14.1 (LOD = 1.6; P = 0.003)., Conclusion: Stronger genetic signals for LVH were found using electrocardiographic than echocardiographic measurements, and the genetic determinants of each of these appear to be distinct. Chromosomes 10, 12, and 17 are likely to harbour genetic loci that exert a major influence on electrocardiographic LVH.

Aims: The ADIPOQ gene encodes the protein adiponectin, and decreased circulating adiponectin levels have been observed in cardiovascular disease. We investigated the role of the ADIPOQ gene single-nucleotide polymorphisms (SNPs) A-11426G, G-11391A, C-11377G, and T45G with plasma adiponectin levels and common carotid artery intima media thickness (IMT) in a cohort of healthy subjects participating in the RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) study., Methods and Results: Anthropometric and metabolic assessment and B-mode ultrasound of the carotid IMT were measured in 1306 subjects [589 men; 717 women, mean +/- SD age 43.8 +/- 8.3 years, BMI 25.5 +/- 4.0 kg/m(2)] recruited from 19 centres in 14 European countries. Carriers of the -11426G allele and homozygous carriers of the -11391G allele had significantly lower plasma adiponectin levels. These relationships remained significant after adjusting for age, sex, recruitment centre, and BMI. Carriers of SNP -11377G allele had significantly greater IMT values compared with C allele homozygotes [geometric mean (interquartile range) 601 (543-665) vs. 590 (537-647) mum, P = 0.021]. This relationship became stronger after correcting for key covariates, including plasma adiponectin levels (P = 0.011)., Conclusion: Variation within the ADIPOQ gene promoter is directly associated with carotid IMT in healthy subjects and is independent of circulating adiponectin levels.

Background: Many previous studies have investigated whether there is an association between genotypes at the angiotensinogen (AGT) gene and hypertensive status, but few have incorporated quantitative data. Although meta-analyses support a possible effect of AGT variants on blood pressure (BP), substantial unexplained between-study heterogeneity has been observed. We hypothesized that a primary effect of AGT variants on arterial stiffness (and thus pulse pressure) might explain such heterogeneity, and tested for such an effect in a family study., Methods: We studied 1425 individuals from 248 families ascertained through a proband with essential hypertension. BP was measured using 24 h ambulatory monitoring, and polymorphisms of the AGT gene that had been previously associated with hypertension and/or plasma angiotensinogen levels were typed. Pulse pressure was used as a measurement of arterial stiffness., Results: We observed a highly significant association between genotypes at the AGT C-532T polymorphism and pulse pressure (p = 0.00006). Each T allele was associated with a 5% lower pulse pressure (that is, an additive effect). This resulted from opposing genotypic effects to (slightly) lower systolic BP and (slightly) elevate DBP., Conclusions: These results suggest that genetic variation at the angiotensinogen locus may primarily affect arterial stiffness, and therefore pulse pressure. The heterogeneity between previous genetic studies of AGT and hypertension status could in part be explained by this finding, since case selection criteria based on systolic BP, diastolic BP, or both would result in different levels of selection for the -532T allele.

Patients receiving warfarin who have unstable control of anticoagulation have a significantly lower intake of dietary vitamin K compared with their stable counterparts. We hypothesized that supplementation with oral vitamin K would improve stability in patients with previously unstable control of anticoagulation. Seventy warfarin-treated patients with unstable anticoagulation control were randomly assigned in a double-blinded fashion to receive a daily amount of 150 mug oral vitamin K or placebo orally for 6 months. Measures of stability of anticoagulation control in the 6-month study period were compared with those in the 6 months immediately prior to it. Vitamin K supplementation resulted in a significantly greater decrease in standard deviation of international normalized ratio (INR) compared with placebo (-0.24 +/- 0.14 vs -0.11 +/- 0.18; P < .001) and a significantly greater increase in percentage time within target INR range (28% +/- 20% vs 15% +/- 20%; P < .01). Anticoagulation control improved in 33 of 35 patients receiving vitamin K supplementation; of these, 19 fulfilled our criteria for having stable control of anticoagulation. However, only 24 of 33 patients receiving placebo demonstrated some degree of improvement, with only 7 patients fulfilling the criteria for having stable control. Concomitant supplementation of vitamin K, perhaps through reducing the relative day-to-day variability in dietary vitamin K intake, can significantly improve anticoagulation control in patients with unexplained instability of response to warfarin.

Context: Variation in the region of chromosome 8 including the genes steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown., Objective: Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism., Design: We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus., Participants: Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband., Main Outcome Measures: We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype., Results: The heritability of THAldo excretion was 52% (P < 10(-6)). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P < 0.001)., Conclusions: Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.

Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.