A postal questionnaire was sent to 10,000 patients more than one year after their total knee replacement (TKR). They were assessed using the Oxford knee score and were asked whether they were satisfied, unsure or unsatisfied with their TKR. The response rate was 87.4% (8231 of 9417 eligible questionnaires) and a total of 81.8% (6625 of 8095) of patients were satisfied. Multivariable regression modelling showed that patients with higher scores relating to the pain and function elements of the Oxford knee score had a lower level of satisfaction (p < 0.001), and that ongoing pain was a stronger predictor of this. Female gender and a primary diagnosis of osteoarthritis were found to be predictors of lower levels of patient satisfaction. Differences in the rate of satisfaction were also observed in relation to age, the American Society of Anesthesiologists grade and the type of prosthesis. This study has provided data on the Oxford knee score and the expected levels of satisfaction at one year after TKR. The results should act as a benchmark of practice in the United Kingdom and provide a baseline for peer comparison between institutions.

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: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.

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.

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.

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. STUDY POPULATION: 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. MAIN OUTCOME MEASURES: 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. (C) 2021 Elsevier Inc. 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.

The purpose of this research was to determine which environmental factors within the pen space differ between the locations where pigs choose to lie and areas they avoid. Data on external weather conditions and the construction parameters for an existing commercial finishing pig building were input into a Dynamic Thermal (DT) model generating heat flow and surface temperature patterns in the structure and these were then input into a Computational Fluid Dynamics (CFD) model to generate data on the theoretical spatial patterns of temperature and air velocity within one room of this building on a specified day. The exact location of each pig in six selected pens within this room was taken from images from ceiling-mounted video cameras at four representative time points across the day. Using extracted air velocity and temperature data at the height of 0.64 m above the floor and a grid of approximately 600 mm to create a series of 'cells', the effective draught temperature (T-ED) was calculated from the models for each cell. Using a sequential regression model, the extent to which the actual lying locations of the pigs could be reliably predicted from the environmental conditions generated by model outputs and other pen factors was explored. The results showed that air velocity, T-ED and proximity to a solid pen partition (all significant at P < 0.05) had significant predictive value and collectively explained 15.55% of the total explained deviation of 17.13%. When the presence of an adjacent pig was considered, results showed that lying next to an adjacent pig, T-ED, air velocity and temperature accounted for 53.9%, 1.3%, 1.5% and 0.5% of the deviation in lying patterns, respectively (all P < 0.001). Thus, CFD model outputs could potentially provide the industry with a better understanding of which environmental drivers affect pigs' lying location choice, even before a building is built and stocked.

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.

SummaryWe 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.

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.

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.

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.

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.

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.

Vitamin K is essential, for the activation of clotting proteins, as well as the biosynthesis of osteocalcin in bones and the activation of matrix‐Gla protein needed in maintaining vasculature health. Cytochrome p450 4F2 (CYP4F2) enzyme is involved in vitamin K catabolism. Genetic polymorphism in CYP4F2 is thus likely to affect vitamin K systemic availability. We show that children on chronic warfarin therapy have low levels of vitamin K and vitamin K levels are linked to CYP4F2 genotype. Long‐term low levels of vitamin K, influenced by CYP4F2 genotype, might affect bone development and vascular health in children on chronic warfarin therapy.

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 mm 2 (2.4-28.3 mm 2 ). 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.

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.

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.