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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.

Background\ud 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.\ud \ud Methods\ud 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.\ud \ud Results\ud 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.\ud \ud Conclusion\ud 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.

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.

To compare phakic and pseudophakic primary rhegmatogenous retinal detachments (RD) and, within phakic RD, eyes with and without cataract.Retrospective comparative clinical study.Setting: Online database of prospectively collected data. StudyPopulation: Patients aged ≥50 years who had undergone RD repair.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.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.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.

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 (INRday 1–INRday 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

To evaluate the influence of age on the clinical characteristics of primary rhegmatogenous retinal detachments (RRD).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.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 aged50 years. The presence of posterior vitreous detachment increased up to 50 years, then remained95%. 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 those30, with a minimum in the 70-79 age-range. The incidence of fellow-eye RRD decreased linearly with age.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 patients40 years and the significant phenotypical differences in the under 40 and over 50 age-groups highlight that there are several discrete forms of RRD.

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 R2 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.

Summary We consider a control theory approach to adaptive dose allocation of anticoagulants, based on an analysis of records of 152 patients on long-term warfarin treatment. We consider a selection of statistical models for the relationship between the dose of drug and subsequent blood clotting speed, measured through the international normalized ratio. Our main focus is on subsequent use of the model in guiding the choice of the next dose adaptively as patient-specific information accrues. We compare a naive long-term approach with a proportional-integral-plus method, with parameters estimated by either linear quadratic optimization or by stochastic resource allocation. We demonstrate advantages of the control approaches in comparison with a naive approach in simulations and through calculation of robust stability margins for the observed data.

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.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.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).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.

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.

Essentials The once-daily dosing of tinzaparin provides an advantage over other low molecular weight heparins. The recommended age-dependent doses of tinzaparin in children have not previously been validated. Once-daily administration of tinzaparin is a safe and effective treatment of childhood thrombosis. Recommended doses are appropriate but monitoring may be required due to inter-individual variation. SummaryBackground The recommended starting doses of tinzaparin for the treatment of thrombosis in children have not previously been validated. There are few data to support the efficacy and safety of once-daily tinzaparin dosing in children with thrombosis. Objectives To investigate the use of tinzaparin for the treatment of childhood thrombosis, and to evaluate the age-dependent dosing recommendations and define outcomes in terms of efficacy and safety. Methods This was a retrospective cohort study of children aged 0 to

We evaluated the contribution of patient-specific clinical and genetic factors to statin-related muscle toxicity (SRM) without a significant creatine kinase elevation (125 cases related to simvastatin or atorvastatin and 481 controls). The association between 12 single nucleotide polymorphisms (SNPs) in nine candidate genes and clinical factors with SRM was evaluated. Of the 12 SNPs genotyped, only rs4149056 in SLCO1B1 was associated with SRM in univariate analysis (with any statin, odd ratio (OR) = 1.73, 95% confidence interval (CI) = 1.14-2.62, P = 0.010) and this association was influenced by sex (P = 0.006) and BMI (P = 0.02). In multivariate and binary logistic regression analyses, SLCO1B1 rs4149056 genotype (OR = 1.66, 95% CI: 1.08-2.54, P = 0.014) and sex (OR = 1.72, 95% CI = 1.15-2.59, P = 0.006) were independently associated with muscle toxicity related to statin treatment. Patient-specific genetic and clinical factors associated with increased systemic exposure to statins are implicated in the full spectrum of SRM, including myalgia in addition to severe myopathy.

Summary 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

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.

The main aim of this study was to screen various genetic and nongenetic factors that are known to alter warfarin response and to generate a model to predict stable warfarin maintenance dose for Indian patients. The study comprised of 300 warfarin-treated patients. Followed by extensive literature review, 10 single-nucleotide polymorphisms, that is, VKORC1-1639 G>A (rs9923231), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), FVII R353Q (rs6046), GGCX 12970 C>G (rs11676382), CALU c.*4A>G (rs1043550), EPHX1 c.337T>C (rs1051740), GGCX: c.214+597G>A (rs12714145), GGCX: 8016G>A (rs699664), and CYP4F2 V433M (rs2108622), and 5 nongenetic factors, that is, age, gender, smoking, alcoholism, and diet, were selected to find their association with warfarin response. The univariate analysis was carried out for 15 variables (10 genetic and 5 nongenetic). Five variables, that is, VKORC1-1639 G>A, CYP2C9*2, CYP2C9*3, age, and diet, were found to be significantly associated with warfarin response in univariate analysis. These 5 variables were entered in stepwise and multiple regression analysis to generate a prediction model for stable warfarin maintenance dose. The generated model scored R (2) of .67, which indicates that this model can explain 67% of warfarin dose variability. The generated model will help in prescribing more accurate warfarin maintenance dosing in Indian patients and will also help in minimizing warfarin-induced adverse drug reactions and a better quality of life in these patients.

Purpose: A variety of retinal topographical changes occur after internal limiting membrane (ILM) peeling for macular holes including a movement of the fovea toward the optic nerve. This study was carried out to assess the effect of the extent of ILM-peeled area on these changes and postoperative visual acuity. Methods: Prospective single-center study of a consecutive series of patients undergoing macular hole surgery. Preoperative and postoperative optical coherence tomography images were used to assess a variety of measures of retinal morphology. Transmission electron microscopy of the peeled ILM was used to assess residual retinal and vitreous side debris. The area of the ILM peeled was calculated from intraoperative images. Results: Fifty-six eyes of 56 patients were included. The mean area of ILM peeled was 9.5 mm2 (2.4-28.3 mm2). The mean disc-to-fovea distance (DFD) preoperatively was 3703 μm with a mean reduction of 52 μm postoperatively, representing a change of −1.29% with a wide range of −7.04% to 1.36%. Using stepwise linear regression, ILM-peeled area was significantly associated with a change in DFD ( P < .001), extent of a dissociated optic nerve fiber layer appearance ( P < .001), and postoperative visual acuity ( P = .025). Nasotemporal retinal thickness asymmetry was associated with the minimum linear diameter ( P < .001). Conclusion: The ILM-peeled area has a significant effect on changes in retinal topography and postoperative visual acuity separate from macular hole size. Further study is needed to assess the effect of ILM peeled size on visual function and to guide clinical practice.

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., Graphical abstract Image 1, Highlights • Inulin as 10g day-1 for 5 weeks significantly increased stool frequency in 16 older volunteers compared with maltodextrin.. • This increase was found in volunteers with low stool frequency (2 days or more per week without bowel movements). • Directions of changes in secondary outcomes were generally consistent with expectations for prebiotic effects of inulin. • Secondary outcomes included quality of life symptoms, stool consistency and composition of the faecal microbiota. • Among secondary outcomes, only softening of stool consistency reached significance within the present study.

Purpose A dissociated optic nerve fibre layer (DONFL) is a characteristic change noted in inner retinal morphology after internal limiting membrane (ILM) peeling. It is thought to be due to trauma to Muller cells as the ILM is peeled from their attached end plates. In this study, we aimed to determine the extent and size of Muller cell debris on the retinal side of excised ILM and assess whether this correlated with the extent of DONFL observed postoperatively. Method Prospective single centre study of a consecutive series of patients undergoing macular hole surgery. Transmission electron microscopy of the ILM was used to assess Muller cell debris and postoperative spectral domain optical coherence tomography (SD-OCT) to assess the extent of DONFL. A variety of other pre- and postoperative features was also included. Results Thirty-nine patients were analysed. There were retinal dimples characteristic of DONFL detected on SD-OCT in all 39 eyes. The portion of the retinal side of the ILM specimen covered by cellular debris ranged from 12% to 49%, with a median of 28%. Using linear regression, the percentage of retinal debris, the size of the debris and the postoperative visual acuity were significantly positively associated with the DONFL score. The total R squared for the model was 63.9%. Conclusion The extent of DONFL observed postoperatively can be partly explained by the amount of retinal side cellular debris on the retinal side of the peeled ILM. Surgical strategies which minimize this material could reduce the extent of DONFL.

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.

PurposeTo assess the changes in diabetic retinopathy (DR) in type 2 diabetes (T2DM) patients post bariatric surgery and report on the risk factors that may be associated with it.Patients and methodsRetrospective observational study of T2DM patients who underwent bariatric surgery in a UK specialist bariatric unit between 2009 and 2015. Preoperative and postoperative weight, HbA1c, and annual DR screening results were collected from medical records. Patients with preoperative retinal screening and at least one postoperative retinal screening were eligible for analysis. Multivariate analysis was used to explore significant clinical predictors on postoperative worsening in DR.ResultsA total of 102 patients were eligible for analysis and were followed up for 4 years. Preoperatively, 68% of patients had no DR compared to 30% with background retinopathy, 1% pre-proliferative retinopathy, and 1% proliferative retinopathy. In the first postoperative visit, 19% of patients developed new DR compared to 70% stable and 11% improved. These proportions remained similar for each postoperative visit over time. Young age, male gender, high preoperative HbA1c, and presence of preoperative retinopathy were the significant predictors of worsening postoperatively.ConclusionBariatric surgery does not prevent progression of DR. Young male patients with pre-existing DR and poor preoperative glycaemic control are most at risk of progression. All diabetic patients should attend regular DR screening post bariatric surgery to allow early detection of potentially sight-threatening changes, particularly among those with identifiable risk factors. Future prospective studies with prolonged follow-up are required to clarify the duration of risk.

In 2013, the National Health Service Commissioning board centralized the funding in England for up to three cycles of pre-implantation genetic diagnosis (PGD) for couples who have, or are carriers of, a specific genetic disorder. This study presents the historical data of PGD cycles and their clinical outcomes in UK as extrapolated from the national data registry. Retrospective analysis of outcome of cycles undergoing pre-implantation genetic diagnosis in the UK over the past 20 years was performed from the Human Fertilisation and Embryology Authority database (n = 2974). Binary logistic regression was used to determine trends over time and adjusted for maternal age. Briefly, the number of PGD cycles has risen 127-fold from 1991 to 2012 with 3.6-fold increase (360% rise) from 2004 to 2012. A total of one in four embryos following pre-implantation genetic diagnosis did not reach embryo transfer and 92% of these were due to a failure to survive. The live birth rate has risen over 20 years and there has been a steady decline in reported incidence of congenital abnormalities (p 0.07). PGD has thus emerged as a safe and effective alternative to prenatal diagnosis but with ever evolving technological advances, a robust system of data collection that incorporates techniques used and reporting of mutation-specific clinical outcomes is suggested.

During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Human life span is mainly dependent on environmental and genetic factors. Favourable modifications of lifestyle factors (e.g. physical activity, diet and not smoking) and healthcare (e.g. effective vascular disease prevention) have also increased human life span. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better health during their lifespan compared with contemporaries who died at a younger age?, 3) Do centenarians have protective modifications of body composition, fat distribution and energy expenditure, maintain high physical and cognitive function, and sustained engagement in social and productive activities?, 4) Do centenarians have genes which contribute to longevity?, 5) Do centenarians benefit from epigenetic phenomena?, 6). Is it possible to influence the transgenerational epigenetic inheritance (epigenetic memory) which leads to longevity?, 7) Is the influence of nutrigenomics important for longevity?, 8) Do centenarians benefit more from drug treatment, particularly in primary prevention?, and, 9) Are there any potential goals for drug research? Many definitions of successful ageing have been proposed, but at present there is no consensus definition. Such definitions may need to differentiate between "Longevity Syndrome" and "Exceptional Longevity"

Nitrites in Acute Myocardial Infarction Nishat Siddiqi1, Margaret Bruce1, Christopher J. Neil1, Graeme MacLennan2, Seonaidh Cotton2, Sofia A. Papadopoulou3, Baljit Jagpal1, Sue Brown3, Fatima Perez Gonzalez3, Satnam Singh1, Konstantin Schwarz1, Martin Feelisch4, Nicholas Bunce5, Pitt O Lim5, David Hildick-Smith6, John Horowitz7, Melanie Madhani8, Nicholas Boon9, Dana Dawson10, Juan-Carlos Kaski3, Michael P Frenneaux10. 1Dept of Cardiovascular Rsch, Univ of Aberdeen, Aberdeen, United Kingdom, 2Health Sciences Building (third floor), Centre for Healthcare Randomised Trials (CHaRT), Aberdeen, United Kingdom, 3Cardiovascular Sciences Rsch Centre, St George’s Univ of London, London, United Kingdom, 4Faculty of Medicine, Univ of Southampton, Southampton, 5Cardiology Dept, St George’s Healthcare NHS Trust, 6Cardiology Research Unit, Brighton and Sussex Univ Hospitals, Brighton, United Kingdom, 7Basil Hetzel Unit for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, 8Centre for Cardiovascular Sciences, Univ of Birmingham, Birmingham, United Kingdom, 9Centre for Cardiovascular Sciences, Univ of Edinburgh, Edinburgh, United Kingdom, 10School of Medicine and Dentistry, Univ of Aberdeen, Aberdeen Introduction :Despite reperfusion therapy for acute myocardial infarction (AMI), heart failure remains a major sequel. Reperfusion leads to further damage, described as ischemia-reperfusion-injury (IRI). This contributes up to 50% of the final infarct size. In pre-clinical models nitrite potently protects against IRI in the heart and other organs. Hypothesis :Intravenous (iv) sodium nitrite, administered immediately before opening of the infarct-related artery, results in significant reduction of IRI in patients with acute ST elevation MI (STEMI). Methods :In this phase II, randomised, placebo-controlled, double-blind, multicentre trial, 220 patients with first acute STEMI and TIMI 0 or 1 flow were randomised …

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 genotypeguided 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

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.

Background and Purpose— Studies in unrelated individuals have produced conflicting findings concerning the putative association between the interleukin-6 (IL-6) −174G/C polymorphism and carotid intimal-medial thickness (IMT). We have used a family-based genetic association design to assess the heritability of carotid IMT and to investigate the hypothesized association of carotid IMT with the IL-6 to −174G/C polymorphism. Methods— We studied 854 members of 224 white British families. The heritability of carotid IMT was determined using Multipoint Engine for Rapid Likelihood Inference. Genetic association analyses were carried out using ANOVA and family-based tests of association implemented in Quantitative Transmission Disequilibrium Test. A meta-analysis of previous studies of the association was conducted to place our result in context. Results— The heritability of carotid IMT was 24%. Under a recessive model (GG+GC versus CC), there was significant evidence of association between IL-6 to the −174G/C genotype and adjusted log e maximal carotid IMT ( F =5.469; P =0.02). Family-based analyses using Quantitative Transmission Disequilibrium Test showed no evidence of population stratification as a cause of the observed association (χ 2 1 =0.469; P =0.4934). The CC genotype was associated with a 4.8% increase in maximal carotid IMT and accounted for 0.6% of the observed variation in the trait, which is equivalent to 2.5% of the heritable component. A meta-analysis of the present and 2 previous large studies, which enrolled a total of 2930 subjects, confirmed the recessive effect of the C allele on carotid IMT ( P =0.0014). Conclusions— The genotype at the IL-6 to −174G/C polymorphism is associated with common carotid artery IMT, although the size of the genetic effect is small.

AIMS: Genetic variation in the fatty acid translocase (CD36) gene has been shown in animal models to affect several risk factors for the development of left-ventricular hypertrophy, but this phenotype has not, thus far, been investigated in humans. We examined the relationship between common genetic polymorphisms in the CD36 gene and left-ventricular mass. METHODS AND RESULTS: We studied a cohort of 255 families comprising 1425 individuals ascertained via a hypertensive proband. Seven single-nucleotide polymorphisms which together tagged common genetic variation in the CD36 gene were genotyped using a SEQUENOM MALDI-TOF instrument. There was evidence of association between the rs1761663 polymorphism in intron 1 of the CD36 gene and left-ventricular mass determined either by echocardiography (P=0.003, N=780) or electrocardiography (P=0.001, N=814). There was also association between rs1761663 genotype and body mass index (P

Objectives To determine risk factors for revision in patients implanted with a commonly used metal on metal (MoM) hip replacement. Design Retrospective cohort study in combination with a prospective national retrieval study (Northern Retrieval Registry (NRR)). Setting Combined orthopaedic unit in combination with the NRR. Participants All patients implanted with a DePuy Pinnacle MoM hip prostheses by the 2 senior authors were invited to attend for a review which included clinical examination, blood metal ion measurements, radiographs and targeted imaging. Explanted components underwent wear analysis using validated methodology and these results were compared with those obtained from the NRR. Results 489 MoM Pinnacle hips were implanted into 434 patients (243 females and 191 males). Of these, 352 patients attended the MoM recall clinics. 64 patients had died during the study period. For the purposes of survival analysis, non-attendees were assumed to have well-functioning prostheses. The mean follow-up of the cohort as a whole was 89 months. 71 hips were revised. Prosthetic survival for the whole cohort was 83.6% (79.9–87.3) at 9 years. The majority of explanted devices exhibited signs of taper junction failure. Risk factors for revision were bilateral MoM prostheses, smaller Pinnacle liners, and implantation in 2006 and later years. A significant number of devices were found to be manufactured out of their specifications. This was confirmed with analysis of the wider data set from the NRR. Conclusions This device was found to have an unacceptably high revision rate. Bilateral prostheses, those implanted into female patients and devices implanted in later years were found to be at greater risk. A significant number of explanted components were found to be manufactured with bearing diameters outside of the manufacturer's stated tolerances. Our findings highlight the clinical importance of hitherto unrecognised variations in device production.

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.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).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.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.

Patient-reported outcome measures (PROMs) are increasingly being used to assess functional outcome and patient satisfaction. They provide a framework for comparisons between surgical units, and individual surgeons for benchmarking and financial remuneration. Better performance may bring the reward of more customers as patients and commissioners seek out high performers for their elective procedures. Using National Joint Registry (NJR) data linked to PROMs we identified 22 691 primary total knee replacements (TKRs) undertaken for osteoarthritis in England and Wales between August 2008 and February 2011, and identified the surgical factors that influenced the improvements in the Oxford knee score (OKS) and EuroQol-5D (EQ-5D) assessment using multiple regression analysis. After correction for patient factors the only surgical factors that influenced PROMs were implant brand and hospital type (both p < 0.001). However, the effects of surgical factors upon the PROMs were modest compared with patient factors. For both the OKS and the EQ-5D the most important factors influencing the improvement in PROMs were the corresponding pre-operative score and the patient’s general health status. Despite having only a small effect on PROMs, this study has shown that both implant brand and hospital type do influence reported subjective functional scores following TKR. In the current climate of financial austerity, proposed performance-based remuneration and wider patient choice, it would seem unwise to ignore these effects and the influence of a range of additional patient factors.

Following arthroplasty of the knee, the patient’s perception of improvement in symptoms is fundamental to the assessment of outcome. Better clinical outcome may offset the inferior survival observed for some types of implant. By examining linked National Joint Registry (NJR) and patient-reported outcome measures (PROMs) data, we aimed to compare PROMs collected at a minimum of six months post-operatively for total (TKR: n = 23 393) and unicondylar knee replacements (UKR: n = 505). Improvements in knee-specific (Oxford knee score, OKS) and generic (EuroQol, EQ-5D) scores were compared and adjusted for case-mix differences using multiple regression. Whereas the improvements in the OKS and EQ-5D were significantly greater for TKR than for UKR, once adjustments were made for case-mix differences and pre-operative score, the improvements in the two scores were not significantly different. The adjusted mean differences in the improvement of OKS and EQ-5D were 0.0 (95% confidence interval (CI) -0.9 to 0.9; p = 0.96) and 0.009 (95% CI -0.034 to 0.015; p = 0.37), respectively. We found no difference in the improvement of either knee-specific or general health outcomes between TKR and UKR in a large cohort of registry patients. With concerns about significantly higher revision rates for UKR observed in worldwide registries, we question the widespread use of an arthroplasty that does not confer a significant benefit in clinical outcome.

This study addresses the epidemiology of knee injuries in adolescent males. Data were collected prospectively from 41 Premiership soccer academies over a 5 year period from July 2000 to June 2005. A total of 12,306 player seasons were registered in the U9 to the U16 age categories with a total of 1750 recordable injuries specific to the knee joint. There was a mean incidence of 0.71 (95% confidence interval ± 0.05) knee injuries per player per year, and a median of 17 (inter-quartile range 9-38) training days and 2 (inter-quartile range 1-4) matches missed per knee injury. Knee injuries were found to be most common in the 14-16 year age group. Six hundred and nine (35% of total) injuries were classed as severe resulting in more than 28 days' absence. Injuries were more likely to be sustained in a competitive or match-play environment (862 or 52%) than in training (796 or 48%), and a non-contact mechanism was implicated in 823 (55%) of recorded cases. Peaks in injury numbers were seen in early season and subsequent to the winter break. Sprain was the most common diagnosis recorded, with the medial collateral ligament affected in 23% of all knee injuries. Knee injuries are common in elite youth footballers. In this uninsured age group, it could be argued that earlier medical intervention may reduce long-term damage to the immature skeleton.

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

Diabet. Med. 27, 1450–1453 (2010) Abstract Aims Obesity and insulin resistance have been linked to rising incidence and earlier onset of Type 1 diabetes. Inherited differences in insulin action might also influence the evolution of Type 1 diabetes. Our aim was to determine whether parental BMI and insulin resistance influences age of onset of Type 1 diabetes in their offspring. Methods BMI standard deviation score and age at diagnosis of Type 1 diabetes was examined in 227 children, and in 206 of these was compared with local matched control subjects. Non-diabetic parents of a subgroup of 80 children with Type 1 diabetes were recruited. Parental BMI was compared with local adult control subjects. The relationship between parental BMI, waist–hip ratio, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels and age at diagnosis of Type 1 diabetes in offspring was examined. Results We found no relationship between age at diagnosis of Type 1 diabetes in children and BMI standard deviation score (P = 0.5). Children with Type 1 diabetes and their parents were heavier than matched control subjects (mean BMI standard deviation score ± sd in children = 0.66 ± 1.06 vs. 0.32 ± 1.16 in control subjects, P = 0.002; mean parental BMI ± sd 27.7 ± 0.4 vs. 25.5 ± 0.4 kg/m2 in control subjects; P

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

This paper describes an intergenerational project developed in partnership between a social work degree program and an Older People's Theatre group. Bringing together a small group of students, older actors, and film makers, methods from drama and the arts were utilised to explore the topic of intimacy and sexuality in later life. The project produced digital stimulus learning materials. Formal evaluation identified beneficial outcomes for participants highlighting the advantages of older people's leadership in social work education and the transformative potential of the dramatic learning methods used. Such pedagogical approaches are essential to achieve genuine quality personalized outcomes for older people in contact with care services.