The effect of AZD9567 vs. prednisolone on glycaemic control in patients with type 2 diabetes mellitus: Results from a phase 2a clinical trial.

AIMS: Corticosteroids are the treatment of choice for many inflammatory diseases but often lead to adverse effects, including hyperglycaemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, an oral nonsteroidal selective glucocorticoid receptor modulator vs. prednisolone in 46 patients with type 2 diabetes mellitus. METHODS: In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (cohort 2); or placebo and prednisolone 5 mg daily (cohort 3). Treatment duration was 3 days with a 3-week washout between treatment periods. Glycaemic control was assessed after a standardized meal and with continuous glucose monitoring. RESULTS: A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions postmeal in cohort 1 (glucose area under the curve from 0 to 4 h -4.54%; 95% confidence interval [CI]: -8.88, -0.01; P = .049), but not in cohort 2 (-5.77%; 95% CI: -20.92, 12.29; P = .435). In cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to day 4 in insulin and glucagon secretion postmeal (P < .001 and P = .005, respectively) and change from baseline to Day 4 in GLP-1 response (P = .022). Significant differences between AZD9567 and prednisolone for 24-h glucose control were observed for both cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; P < .001) and cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; P < .001). CONCLUSION: AZD9567 significantly reduced treatment-induced hyperglycaemia compared with prednisolone.

Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease.

AIMS: This 3-part, randomised, phase 1 first-in-human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3-kinase (PI3K) γδ inhibitor developed as a novel inhaled anti-inflammatory treatment for respiratory disease. METHODS: Healthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1-7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once-daily doses on Days 4-12. RESULTS: In total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A population PK model, using nonlinear mixed-effect modelling, was developed to describe the PK of AZD8154. The terminal mean half-life of AZD8154 was 18.0-32.0 hours. The geometric mean of the absolute pulmonary bioavailability of AZD8154 via the inhaled route was 94.1%. CONCLUSION: AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug-associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing.

Focused Information Criterion for Restricted Mean Survival Times: Non-Parametric or Parametric Estimators.

Restricted Mean Survival Time (RMST), the average time without an event of interest until a specific time point, is a model-free, easy to interpret statistic. The heavy reliance on non-parametric or semi-parametric methods in the survival analysis has drawn criticism, due to the loss of efficacy compared to parametric methods. This assumes that the parametric family used is the true one, otherwise the gain in efficacy might be lost to interpretability problems due to bias. The Focused Information Criterion (FIC) considers the trade-off between bias and variance and offers an objective framework for the selection of the optimal non-parametric or parametric estimator for scalar statistics. Herein, we present the FIC framework for the selection of the RMST estimator with the best bias-variance trade-off. The aim is not to identify the true underling distribution that generated the data, but to identify families of distributions that best approximate this process. Through simulation studies and theoretical reasoning, we highlight the effect of censoring on the performance of FIC. Applicability is illustrated with a real life example. Censoring has a non-linear effect on FICs performance that can be traced back to the asymptotic relative efficiency of the estimators. FICs performance is sample size dependent; however, with censoring percentages common in practical applications FIC selects the true model at a nominal probability (0.843) even with small or moderate sample sizes.

A 17-marker panel for global genomic instability in breast cancer.

Genomic instability is a hallmark of cancer that plays a pivotal role in breast cancer development and evolution. A number of existing prognostic gene expression signatures for breast cancer are based on proliferation-related genes. Here, we identified a 17-marker panel associated with genome stability. A total of 136 primary breast carcinomas were stratified by genome stability. Matched gene expression profiles showed an innate segregation based on genome stability. We identified a 17-marker panel stratifying the training and validation cohorts into high- and low-risk patients. The 17 genes associated with genomic instability strongly impacted clinical outcome in breast cancer. Pathway analyses determined chromosome organisation, cell cycle regulation, and RNA processing as the underlying biological processes, thereby offering options for drug development and treatment tailoring. Our work supports the applicability of the 17-marker panel to improve clinical outcome prediction for breast cancer patients based on a signature accounting for genomic instability.

A comparison between young and old patients with triple-negative breast cancer: biology, survival and metastatic patterns.

PURPOSE: To determine the biology, recurrence rate, metastatic patterns and survival times in primary triple-negative breast cancer (TNBC) with focus on the comparison between younger and elderly patients. METHODS: Patients with primary TNBC stage I-IV diagnosed from 2007 to 2015 were identified and information on tumor biology, stage, treatment, recurrences and death recorded. RESULTS: A total of 524 patients, median age 60 years (range 24-94) with a median follow-up of 55 months (range 0-129) were identified. Stage was similar in younger (< 40 years) (n = 58) and older (> 74 years) (n = 96) patients (p = 0.37). A statistically significant difference was found concerning histopathologic grade (p = 0.006) and Ki67 (median 80% versus 70%; p = 0.002) but not for LVI (p = 0.9) with more aggressive tumors among younger patients. Adjuvant/neoadjuvant chemotherapy was more frequently given to younger compared with older patients (96% versus 12%; p = 0.0005). Only brain (p = 0.016) and liver (p = 0.047) metastases were more often registered among younger patients while other locations were similar. Shorter survival times, recurrence-free survival (RFS), distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS) were found in the older group, although not after adjusting for adjuvant/neoadjuvant chemotherapy. Most deaths (68%) in the older group were caused by TNBC. When comparing patients > 75 years (n = 92) with ≤ 75 years (n = 432), a worse outcome among older was also observed: RFS (p = 0.00012), DDFS (p = 0.00041), BCSS (p < 0.0001) and survival following distant metastasis (p = 0.0064) CONCLUSIONS: Primary TNBC in younger patients is more often of poor differentiation grade and highly proliferative compared with older patients. The majority of older patients still have grade III tumors with a Ki67 > 60% and outcome is poor. Few older patients in our study were treated with chemotherapy both in adjuvant and palliative setting, underlining the need for more prospective trials and treatment options suitable for this patient population.

Are the First or the Second Hips of Staged Bilateral THAs More Similar to Unilateral Procedures? A Study from the Swedish Hip Arthroplasty Register.

BACKGROUND: Bilateral THAs performed in the same patient should not be considered independent observations, neither biologically nor statistically. As a result, when surgical results are reviewed, it is common to analyze only the first of the two hips, assuming that the first, and not the second hip of a staged bilateral THA, better resembles unilateral THAs. This assumption has not been empirically justified.Question/purposes (1) In patients with staged bilateral THA, is the first or second hip more similar to a unilateral THA in terms of age at surgery, presence of any preoperative Charlson comorbidity, and risk of postoperative reoperation? (2) Should the date of a first or second hip surgery of a staged bilateral THA be used as a starting point for patient survival to better resemble patients with unilateral THA? METHODS: We identified 68,357 THAs due to osteoarthritis in 63,613 patients from the Swedish Hip Arthroplasty Register (SHAR) in 1999-2015. Of those THAs, 14,780 concerned the first hip of a staged bilateral procedure performed between 1999 and 2004; 28,542 were unilaterals from 2004 to 2008, and 25,035 concerned the second hip of a staged bilateral procedure performed 2008 to 2015. We excluded patients who underwent one-stage bilateral THAs. We used different inclusion periods to distinguish unilateral procedures from the first and second hips from staged bilateral procedures because sufficiently long set-up and follow-up periods were needed before and after each period to identify possible contralateral THAs. This introduced potential period confounding, meaning that possible group differences might not be distinguished from unrelated outcome differences over time. We investigated if such time trends existed. It did not for age and reoperation rates, but it did for comorbidity and patient survival. Our primary study endpoint was whether patients with unilateral THAs were more similar to patients with a first hip of a staged bilateral THA, or to patients with their second hip operated. We used Student's t-test to compare mean age at surgery. The proportion of patients with at least one presurgery Charlson comorbidity were compared by 95% bootstrap confidence intervals, after subtracting the yearly time-trend to avoid period confounding. Postoperative risks of reoperation were compared by log-rank tests of Kaplan-Meier curves and by comparing 5-year reoperation rates by pair-wise 95% CIs. Our secondary study endpoint was to compare patient survival for patients with a unilateral THA, a first hip of a staged bilateral THA, or a second hip of a staged bilateral THA. We evaluated this by relative 5-year survival, comparing patients of each group with the general Swedish population of the same age, sex, and year of birth. This way, possible survival differences would be less likely explained by period confounding. RESULTS: Patients undergoing unilateral THA were older than those undergoing a first hip of a staged bilateral THA (70 ± 10 versus 66 ± 9 years, mean difference of 4; p < .001), but they were not different from patients undergoing the second hip of a staged bilateral THA (70 ± 9 years, mean difference of 0; p = 0.74). The period-adjusted proportion of patients with unilateral THA and presurgery comorbidity (Charlson index > 0) was 20% (95% CI: 19.8-20.7). This was no different from patients with a second hip from a staged bilateral THA (20%; 19.7-20.6), but higher compared to patients with a first hip of a staged bilateral THA (15%; 14.5-15.4). For reoperation rates, the log-rank tests showed no difference between unilateral THAs and the second hips of staged bilateral THAs ((Equation is included in full-text article.)). Such difference was found for unilaterals compared with the first hips of staged bilateral THAs ((Equation is included in full-text article.)). The Kaplan-Meier estimate of reoperation rates at 5 years after surgery were also no different for the unilateral THAs compared with the second hips of staged bilateral THAs (3% [95% CI 2.8 to 3.2] for both groups). It was lower (2% [95% CI 1.8 to 2.3]) for a first hip of a staged bilateral THA. For the secondary outcome, the relative 5-year survival differed for all groups. It was 105% (95% CI 104.9 to 105.9) for patients with unilateral THA, 107% (95% CI 106.3 to 107.4) for patients with a second hip from a staged bilateral THA and 109% (95% CI 108.8 to 109.5) for patients with a first hip of a staged bilateral THA. Patients with only a first hip of a planned staged bilateral THA who did not survive long enough to undergo their second THA were classified as unilaterals. The rank-order of survival curves are therefore by design ("immortal time bias"). We conclude, however, that survival for patients with unilateral THA more closely resembles the survival of patients with a second hip of a staged bilateral THA, compared with the first. CONCLUSIONS: Our findings, which are based on observational register data, challenge the common practice in epidemiologic studies of analyzing only the first hip of a staged bilateral THA. We recommend analyzing the second THA in a patient who has undergone staged bilateral THA rather than the first because the second procedure better resembles unilateral THA. LEVEL OF EVIDENCE: Level III, therapeutic study.

Radiation-induced genomic instability in breast carcinomas of the Swedish hemangioma cohort.

Radiation-induced genomic instability (GI) is hypothesized to persist after exposure and ultimately promote carcinogenesis. Based on the absorbed dose to the breast, an increased risk of developing breast cancer was shown in the Swedish hemangioma cohort that was treated with radium-226 for skin hemangioma as infants. Here, we screened 31 primary breast carcinomas for genetic alterations using the OncoScan CNV Plus Assay to assess GI and chromothripsis-like patterns associated with the absorbed dose to the breast. Higher absorbed doses were associated with increased numbers of copy number alterations in the tumor genome and thus a more unstable genome. Hence, the observed dose-dependent GI in the tumor genome is a measurable manifestation of the long-term effects of irradiation. We developed a highly predictive Cox regression model for overall survival based on the interaction between absorbed dose and GI. The Swedish hemangioma cohort is a valuable cohort to investigate the biological relationship between absorbed dose and GI in irradiated humans. This work gives a biological basis for improved risk assessment to minimize carcinogenesis as a secondary disease after radiation therapy.

How do EQ-5D-3L and EQ-5D-5L compare in a Swedish total hip replacement population?

Background and purpose - To better detect small changes in postoperative outcome following total hip replacement (THR), the Swedish Hip Arthroplasty Register (SHAR) has decided to change from the EQ-5D-3L (3L) to the EQ-5D-5L (5L). To enable comparison of results obtained with use of the 2 versions of EQ-5D, transferal of results between the questionnaires used is necessary. We assessed the measurement properties of the EQ-5D-5L compared with the EQ-5D-3L, preoperatively and 1-year postoperatively in a Swedish THR population.Patients and methods - Patients eligible for elective THR during 2015 in Western Sweden were invited to the study. With a 2-week separation, the 3L and 5L questionnaires were administered to patients before and 1 year after surgery. Comparing the 2 versions of the EQ-5D, we investigated redistribution of responses, ceiling and floor effects, EQ VAS correlations (Spearman's rank correlation coefficient, rs), and EQ VAS scores for different severity levels by dimension (univariable ordinary least square regression).Results - The additional severity levels of the 5L version were frequently used on both measurement occasions (preoperative mobility 5%, self-care 17%, usual activities 20%, pain 5% and anxiety 3%, postoperative mobility 6%, self-care 5%, usual activities 8%, pain 9%, and anxiety 5%). Ceiling effects of the 3L version diminished overall by 7% using the 5L version. The correlations between the 2 EQ VAS scores obtained with the 3L and 5L instruments were strong both pre- (rs = 0.71) and postoperatively (rs = 0.87). Estimated EQ VAS scores for different levels of severity were consistent for all dimensions except for the mobility dimension of the preoperative 5L version and the anxiety dimension in the postoperative 5L version.Interpretation - Our findings support that the 5L has a higher resolution than the 3L version regarding description of health-related quality of life in patients undergoing THR in Sweden. The EQ VAS scores for different levels of severity agree well between the EQ-5D versions. This could potentially be used to develop a crosswalk value set for transforming 3L to 5L responses in this patient group.

Changes in health-related quality of life are associated with patient satisfaction following total hip replacement: an analysis of 69,083 patients in the Swedish Hip Arthroplasty Register.

Background and purpose - Total hip replacement (THR) aims mainly to improve quality of life via restoration of hip function and provision of pain relief. This study sought to assess whether improvements in quality of life between the preoperative and 1-year postoperative period were associated with patient satisfactionPatients and methods - Data were extracted for 69,083 THR operations with complete data reported to the Swedish Hip Arthroplasty Register (SHAR) between 2008 and 2015. Health-related quality of life and patient satisfaction were captured using the Euro-Qol-5D (EQ-5D) and visual analogue scale (VAS), respectively. Multivariable analysis was performed to assess associations between the changes in pre- and postoperative EQ5D and patient satisfaction.Results - In patients reporting severe or moderate problems with mobility preoperatively, improvement to no problems was associated with numerically higher patient satisfaction (coefficient -18 [95% CI -22 to -14] and -18 [-18 to -17]). Improvement in the self-care dimension from severe or moderate problems to no problems was associated with numerically higher patient satisfaction (-15 [-16 to -14] and -13 [-15 to -11]). Improvement from severe problems with the ability to perform usual activities to no problems was associated with numerically higher patient satisfaction (-18 [-19 to -17]). This association was also found for improvement in pain/discomfort and anxiety/depression (-16 [-17 to -15] and -15 [-16 to -14]).Interpretation - Our results indicate that satisfaction with the operated hip is a valid patient-reported outcome reflecting the changes in different EQ-5D dimensions and should be included in the follow-up of patients after THR surgery.

Immunohistochemical validation of COL3A1, GPR158 and PITHD1 as prognostic biomarkers in early-stage ovarian carcinomas.

BACKGROUND: Ovarian cancer is the main cause of gynecological cancer-associated death. However, 5-year survival rates differ dramatically between the five main ovarian carcinoma histotypes. Therefore, we need to have a better understanding of the mechanisms that promote histotype-specific ovarian carcinogenesis and identify novel prognostic biomarkers. METHODS: Here, we evaluated the prognostic role of 29 genes for early-stage (I and II) ovarian carcinomas (n = 206) using immunohistochemistry (IHC). RESULTS: We provide evidence of aberrant protein expression patterns for Collagen type III alpha 1 chain (COL3A1), G protein-coupled receptor 158 (GPR158) and PITH domain containing 1 (PITHD1). Kaplan-Meier survival analysis revealed that COL3A1 expression was associated with shorter overall survival in the four major histotypes of epithelial ovarian carcinoma patients (P value = 0.026, HR = 2.99 (95% CI 1.089-8.19)). Furthermore, GPR158 and PITHD1 were shown to be histotype-specific prognostic biomarkers, with elevated GPR158 expression patterns in mucinous ovarian carcinoma patients with unfavorable overall survival (P value = 0.00043, HR = 6.13 (95% CI 1.98-18.98)), and an association with lower PITHD1 protein expression and unfavorable overall and disease-specific survival in clear-cell ovarian carcinoma patients (P value = 0.012, HR = 0.22 (95% CI 0.058-0.80); P value = 0.003, HR = 0.17 (95% CI 0.043-0.64)). CONCLUSIONS: The novel biomarkers identified here may improve prognostication at the time of diagnosis and may assist in the development of future individualized therapeutic strategies for ovarian carcinoma patients.

Choice of Prosthetic Implant Combinations in Total Hip Replacement: Cost-Effectiveness Analysis Using UK and Swedish Hip Joint Registries Data.

BACKGROUND: Prosthetic implants used in total hip replacements (THR) have a range of bearing surface combinations (metal-on-polyethylene, ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal), head sizes (small [<36 mm in diameter] and large [≥36 mm in diameter]), and fixation techniques (cemented, uncemented, hybrid, and reverse hybrid). These can influence prosthesis survival, patients' quality of life, and healthcare costs. OBJECTIVES: To compare the lifetime cost-effectiveness of implants for patients of different age and sex profiles. METHODS: We developed a Markov model to compare the cost-effectiveness of various implants against small-head cemented metal-on-polyethylene implants. The probability that patients required 1 or more revision surgeries was estimated from analyses of more than 1 million patients in the UK and Swedish hip joint registries, for men and women younger than 55, 55 to 64, 65 to 74, 75 to 84, and 85 years and older. Implant and healthcare costs were estimated from local procurement prices, national tariffs, and the literature. Quality-adjusted life-years were calculated using published utility estimates for patients undergoing THR in the United Kingdom. RESULTS: Small-head cemented metal-on-polyethylene implants were the most cost-effective for men and women older than 65 years. These findings were robust to sensitivity analyses. Small-head cemented ceramic-on-polyethylene implants were most cost-effective in men and women younger than 65 years, but these results were more uncertain. CONCLUSIONS: The older the patient group, the more likely that the cheapest implants, small-head cemented metal-on-polyethylene implants, were cost-effective. We found no evidence that uncemented, hybrid, or reverse hybrid implants were the most cost-effective option for any patient group. Our findings can influence clinical practice and procurement decisions for healthcare payers worldwide.

Geographical variations in patient-reported outcomes after total hip arthroplasty between 2008 - 2012.

BACKGROUND: Health care on equal terms is a cornerstone of the Swedish health care system. Total hip arthroplasty (THA) is considered a success story in Sweden with low frequency of reoperations and restored health-related quality of life (HRQoL). Administratively, health care in Sweden is locally self-governed by 21 counties. In this longitudinal nation-wide observational study we assessed the possible geographical variations in 1-year follow-up patient-reported outcomes (PROs): EQ-5D index, EQ VAS, Pain VAS and Satisfaction VAS. METHODS: Study population consisted of 36,235 Swedish THA patients, operated during 2008 to 2012 due to hip osteoarthritis. Individual data came from Swedish Hip Arthroplasty Register, Statistics Sweden and National Board of Health and Welfare. We used descriptive statistics together with multivariable regression analysis to analyse the data. RESULTS: We observed county level differences in both preoperative and postoperative PROs. The results showed that the differences observed in preoperative PROs could not fully explain the differences observed in postoperative PROs, even after adjustment for patient demographics (age, sex, BMI, Elixhauser comorbidity index, marital status, educational level and disposable income). This indicates that other factors might influence the outcome after THA. CONCLUSION: Likely, structural and process differences such as indication for surgery have an influence on PROs after surgery. Standardization of care at hospital levels may decrease geographical variations in postoperative HRQoL. Remaining differences will then possibly be associated to patient demographics.

Is Parkinson's Disease Associated with Increased Mortality, Poorer Outcomes Scores, and Revision Risk After THA? Findings from the Swedish Hip Arthroplasty Register.

BACKGROUND: Neurological conditions such as Parkinson's disease are commonly accepted as a risk factor for an increased likelihood of undergoing revision surgery or death after THA. However, the available evidence for an association between Parkinson's disease and serious complications or poorer patient-reported outcomes after THA is limited and contradictory. QUESTIONS/PURPOSES: (1) Do patients with a preoperative diagnosis of Parkinson's disease have an increased risk of death after elective THA compared with a matched control group of patients? (2) After matching for patient- and surgery-related factors, do revision rates differ between the patients with Parkinson's disease and the matched control group? (3) Are there any differences in patient-reported outcome measures for patients with Parkinson's disease compared with the matched control group? METHODS: Data were derived from a merged database with information from the Swedish Hip Arthroplasty Register and administrative health databases. We identified all patients with Parkinson's disease who underwent THA for primary osteoarthritis between January 1, 1999 and December 31, 2012 (n = 490 after exclusion criteria applied). A control group was generated through exact one-to-one matching for age, sex, Charlson comorbidity index, surgical approach, and fixation method. Risk of death and revision were compared between the groups using Kaplan-Meier and log-rank testing. Patient-reported outcome measures (PROMs), routinely recorded as EQ-5D, EQ VAS, and pain VAS, were measured at the preoperative visit and at 1-year postoperatively; mean absolute values for PROM scores and change in scores over time were compared between the two groups. RESULTS: The risk of death did not differ at 90 days (control group risk = 0.61%; 95% CI = 0.00-1.3; Parkinson's disease group risk = 0.62%; 95% CI = 0.00-1.31; p = 0.998) or 1 year (control group = 2.11%; 95% CI = 0.81-3.39; Parkinson's disease group = 2.56%, 95% CI = 1.12-3.97; p = 0.670). At 9 years, the risk of death was increased for patients with Parkinson's disease (control group = 28.05%; 95% CI = 22.29-33.38; Parkinson's disease group = 54.35%; 95% CI = 46.72-60.88; p < 0.001). The risk of revision did not differ at 90 days (control group = 0.41%; 95% CI = 0.00-0.98; Parkinson's disease group = 1.03%; 95% CI = 0.13-1.92; p = 0.256). At 1 year, the risk of revision was higher for patients with Parkinson's disease (control group = 0.41%; 95% CI = 0.00-0.98; Parkinson's disease group = 2.10%; 95% CIs = 0.80-3.38; p = 0.021). This difference was more pronounced at 9 years (control group = 1.75%; 95% CI = 0.11-3.36; Parkinson's disease group = 5.44%; 95% CI = 2.89-7.91; p = 0.001) when using the Kaplan-Meier method. There was no difference between the control and Parkinson's disease groups for level of pain relief at 1 year postoperatively (mean reduction in pain VAS score for control group = 48.85, SD = 20.46; Parkinson's disease group = 47.18, SD = 23.96; p = 0.510). Mean change in scores for quality of life and overall health from preoperative measures to 1 year postoperatively were smaller for patients in the Parkinson's disease group compared with controls (mean change in EQ-5D scores for control group = 0.42, SD = 0.32; Parkinson's disease group = 0.30, SD = 0.37; p 0.003; mean change in EQ VAS scores for control group = 20.94, SD = 23.63; Parkinson's disease = 15.04, SD = 23.00; p = 0.027). CONCLUSIONS: Parkinson's disease is associated with an increased revision risk but not with short-term mortality rates relevant to assessing risk versus benefit before undergoing THR. The traditional reluctance to perform THR in patients with Parkinson's disease may be too conservative given that the higher long-term risk of death is more likely due to the progressive neurological disorder and not THR itself, and patients with Parkinson's disease report comparable outcomes to controls. Further research on outcomes in THR for patients with other neurological conditions is needed to better address the broader assumptions underlying this traditional teaching.Level of Evidence Level III, therapeutic study.

Postoperative Thromboprophylaxis With New Oral Anticoagulants is Superior to LMWH in Hip Arthroplasty Surgery: Findings from the Swedish Registry.

BACKGROUND: Although the use of thromboprophylaxis is well established, there is no consensus on the preferred thromboprophylaxis regimen after THA; large, population-based studies offer an opportunity to examine this problem in a robust way that can complement results from randomized trials. QUESTIONS/PURPOSES: Using data from a large national registry, we asked: (1) Is there any difference between low-molecular weight heparin (LMWH) and new oral anticoagulants in preventing symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), after THA? (2) Are there any differences in safety parameters, such as bleeding, reoperations and mortality, between LMWH and new oral anticoagulants? METHODS: Between 2008 and 2012, 78,066 THAs were performed in Sweden. This study evaluated 32,663 (42%) of them, selected through the merger of several national registries. These patients underwent unilateral THA due to primary osteoarthritis. They had not experienced any venous thromboembolic events 5 years before the index operation and were not prescribed potent antithrombotic agents, of any type, in the 6 months before the index operation. Additionally, their postoperative thromboprophylaxis was confirmed in a national registry by purchase of prescribed medications. We divided the cohort into two groups: those patients who received new oral anticoagulants (5752, 18%) and those who received LMWH (26,881, 82%) as postoperative thromboprophylaxis. Our primary endpoints were the frequencies of symptomatic DVT and symptomatic PE within 3 months of surgery. Our secondary comparison was a between-group comparison of bleeding (by way of diagnostic coding), reoperation, and mortality within 3 months of surgery. Odds ratios (OR) are presented with 95% confidence intervals (CIs) as pooled results for the two groups after adjustment for duration of thromboprophylaxis (short or extended for at least 28 days), year of the index operation, Elixhauser comorbidity index, sex, age and previous treatment with platelet aggregation inhibitors. RESULTS: The risk of symptomatic DVT was lower in the group that received new oral anticoagulants than the group that received LMWH (0.3% versus 0.6%, OR, 0.47; 95% CI, 0.27-0.76; p = 0.026). The risk of symptomatic PE was lower in the group that received new oral anticoagulants than the group that received LMWH (0.1% versus 0.4%, OR, 0.36; 95% CI, 0.16-0.69; p = 0.005). There was no difference in the risk of bleeding (by way of diagnostic coding) (OR, 1.03; 95% CI, 0.82-1.28; p = 0.688), reoperation (OR, 1.02; 95% CI, 0.71-1.44; p = 0.860) or mortality (OR, 0.83; 95% CI, 0.31-1.88; p = 0.883) between groups. CONCLUSIONS: New oral anticoagulants were associated with a lower risk of symptomatic DVT and symptomatic PE in this large, registry study, and we observed no differences in the risk of bleeding, reoperation, or death between the groups. Although we were able to control for a number of potential confounding variables, we cannot ascertain the indications that drove the prescription decisions in this setting, and there were important between-group differences in terms of duration of thromboprophylaxis (new oral anticoagulants generally were used for a longer period of time after surgery). Future studies, preferably large randomized trials with pragmatic inclusion criteria, to analyze symptomatic DVT, symptomatic PE and death are needed to confirm or refute our findings. LEVEL OF EVIDENCE: Level III, therapeutic study.

Patient-reported outcomes in hip resurfacing versus conventional total hip arthroplasty: a register-based matched cohort study of 726 patients.

Background and purpose - The theoretical mechanical advantages of metal-on-metal hip resurfacing (MoM-HR) compared with conventional total hip arthroplasty (THA) have been questioned. Studies including measures of patient-reported function, physical activity, or health-related quality of life have been sparse. We compared patient-reported outcomes in MoM-HR patients with a matched group of patients with conventional THA at 7 years post-surgery. Patients and methods - Patients and patient data were retrieved from the Swedish Hip Arthroplasty Register. The case group, consisting of 363 patients with MoM-HR, was matched 1:1 with a control group, consisting of patients with a conventional THA. Patients were sent a postal patient-reported outcome measures (PROM) questionnaire including the Hip Disability and Osteoarthritis Outcome Score (HOOS), EQ-5D, and VAS pain. We used multivariable linear regression analyses to investigate the influence of prosthesis type. Results - 569 patients (78%) returned the questionnaire with complete responses (299 MoM-HRs and 270 conventional THAs). MoM-HR was associated with better scores in HOOS function of daily living (4 percentage units) and HOOS function in sport and recreation (8 percentage units) subscales. Type of prosthesis did not influence HOOS quality of life, HOOS pain, HOOS symptoms, EQ-5D index, hip pain, or satisfaction as measured with visual analog scales. Interpretation - At mean 7 years post-surgery, patients with hip resurfacing had somewhat better self-reported hip function than patients with conventional THA. The largest difference between groups was seen in the presumed most demanding subscale, i.e., function in sport and recreation.

Association between patient survival following reoperation after total hip replacement and the reason for reoperation: an analysis of 9,926 patients in the Swedish Hip Arthroplasty Register.

Background and purpose - The association between long-term patient survival and elective primary total hip replacement (THR) has been described extensively. The long-term survival following reoperation of THR is less well understood. We investigated the relative survival of patients undergoing reoperation following elective THR and explored an association between the indication for the reoperation and relative survival. Patients and methods - In this observational cohort study we selected the patients who received an elective primary THR and subsequent reoperations during 1999-2017 as recorded in the Swedish Hip Arthroplasty Register. The selected cohort was followed until the end of the study period, censoring or death. The indications for 1st- and eventual 2nd-time reoperations were analyzed and the relative survival ratio of the observed survival and the expected survival was determined. Results - There were 9,926 1st-time reoperations and of these 2,558 underwent further reoperations. At 5 years after the latest reoperation, relative survival following 1st-time reoperations was 0.94% (95% CI 0.93-0.96) and 0.90% (CI 0.87-0.92) following 2nd-time reoperations. At 5 years patients with a 1st-time reoperation for aseptic loosening had higher survival than expected; however, reoperations performed for periprosthetic fracture, dislocation, and infection had lower survival. Interpretation - The relative survival following 1st- and 2nd-time reoperations in elective THR patients differs by reason for reoperation. The impact of reoperation on life expectancy is more obvious for infection/dislocation and periprosthetic fracture.

Contemporary posterior surgical approach in total hip replacement: still more reoperations due to dislocation compared with direct lateral approach? An observational study of the Swedish Hip Arthroplasty Register including 156,979 hips.

Background and purpose - The direct lateral approach (DLA) and the posterior approach (PA) are the most common surgical approaches in total hip replacement (THR) in Sweden. We investigated how the relationship between surgical approach and risk of reoperation due to dislocation has evolved over time. Patients and methods - Data were extracted from the Swedish Hip Arthroplasty Register from 1999 to 2014. We selected all THRs due to osteoarthritis with head sizes 28, 32, and 36 mm that were performed with either the DLA or the PA. Resurfacing prostheses were excluded. Kaplan-Meier curves for risk of reoperation due to dislocation and all-cause for the 2 surgical approaches were compared for 2 periods (1999-2006 and 2007-2014) up to 2 years postoperatively. We used Cox regression for sex, age, type of fixation, and head size to determine hazard ratios (HR) with DLA set as reference. Results - 156,979 THRs met the selection criteria. In 1999-2006, the PA was associated with increased risk of reoperation due to dislocation (HR 2.3, 95% CI 1.7-3.0) but there was no difference in the risk of all-cause reoperation (HR 1.1, CI 0.9-1.2). In 2007-2014 there was no statistically significant difference in the risk of reoperation due to dislocation (HR 1.2, CI 0.9-1.6) but the risk of all-cause reoperation was lower (HR 0.8, CI 0.7-0.9) for the PA. Interpretation - This study confirms historic reports on the increased risk of early reoperations due to dislocations using the PA compared with the DLA. However, in contemporary practice, the higher risk of reoperation due to dislocation associated with PA has declined, now being similar to that after DLA. We believe improved surgical technique for the PA may explain the results. Surprisingly, the PA was associated with lower risk of all-cause reoperation in 2007-2014. This finding warrants further investigation.

An international comparison of THA patients, implants, techniques, and survivorship in Sweden, Australia, and the United States.

Background and purpose - International comparisons of total hip arthroplasty (THA) practices and outcomes provide an opportunity to enhance the quality of care worldwide. We compared THA patients, implants, techniques, and survivorship in Sweden, Australia, and the United States. Patients and methods - Primary THAs due to osteoarthritis were identified using Swedish (n = 159,695), Australian (n = 279,693), and US registries (n = 69,641) (2003-2015). We compared patients, practices, and implant usage across the countries using descriptive statistics. We evaluated time to all-cause revision using Kaplan-Meier survival curves. We assessed differences in countries' THA survival using chi-square tests of survival probabilities. Results - Sweden had fewer comorbidities than the United States and Australia. Cement fixation was used predominantly in Sweden and cementless in the United States and Australia. The direct anterior approach was used more frequently in the United States and Australia. Smaller head sizes (≤ 32 mm vs. ≥ 36 mm) were used more often in Sweden than the United States and Australia. Metal-on-highly cross-linked polyethylene was used more frequently in the United States and Australia than in Sweden. Sweden's 5- (97.8%) and 10-year THA survival (95.8%) was higher than the United States' (5-year: 97.0%; 10-year: 95.2%) and Australia (5-year: 96.3%; 10-year: 93.5%). Interpretation - Patient characteristics, surgical techniques, and implants differed across the 3 countries, emphasizing the need to adjust for demographics, surgical techniques, and implants and the need for global standardized definitions to compare THA survivorship internationally.

Clonal relatedness in tumour pairs of breast cancer patients.

BACKGROUND: Molecular classification of tumour clonality is currently not evaluated in multiple invasive breast carcinomas, despite evidence suggesting common clonal origins. There is no consensus about which type of data (e.g. copy number, mutation, histology) and especially which statistical method is most suitable to distinguish clonal recurrences from independent primary tumours. METHODS: Thirty-seven invasive breast tumour pairs were stratified according to laterality and time interval between the diagnoses of the two tumours. In a multi-omics approach, tumour clonality was analysed by integrating clinical characteristics (n = 37), DNA copy number (n = 37), DNA methylation (n = 8), gene expression microarray (n = 7), RNA sequencing (n = 3), and SNP genotyping data (n = 3). Different statistical methods, e.g. the diagnostic similarity index (SI), were used to classify the tumours as clonally related recurrences or independent primary tumours. RESULTS: The SI and hierarchical clustering showed similar tendencies and the highest concordance with the other methods. Concordant evidence for tumour clonality was found in 46% (17/37) of patients. Notably, no association was found between the current clinical guidelines and molecular tumour features. CONCLUSIONS: A more accurate classification of clonal relatedness between multiple breast tumours may help to mitigate treatment failure and relapse by integrating tumour-associated molecular features, clinical parameters, and statistical methods. Guidelines need to be defined with exact thresholds to standardise clonality testing in a routine diagnostic setting.

Do Patients Live Longer After THA and Is the Relative Survival Diagnosis-specific?

BACKGROUND: Hip replacements are successful in restoring mobility, reducing pain, and improving quality of life. However, the association between THA and the potential for increased life expectancy (as expressed by mortality rate) is less clear, and any such association could well be influenced by diagnosis and patient-related, socioeconomic, and surgical factors, which have not been well studied. QUESTIONS/PURPOSES: (1) After controlling for birth year and sex, are Swedish patients who underwent THA likely to survive longer than individuals in the general population? (2) After controlling for relevant patient-related, socioeconomic/demographic factors and surgical factors, does relative survival differ across the various diagnoses for which THAs were performed in Sweden? METHODS: Data from the Swedish Hip Arthroplasty Register, linked to administrative health databases, were used for this study. We identified 131,808 patients who underwent THA between January 1, 1999, and December 31, 2012. Of these, 21,755 had died by the end of followup. Patient- and surgery-specific data in combination with socioeconomic data were available for analysis. We compared patient survival (relative survival) with age- and sex-matched survival data in the entire Swedish population according to Statistics Sweden. We used multivariable modeling proceeded with a Cox proportional hazards model in transformed time. RESULTS: Patients undergoing elective THA had a slightly improved survival rate compared with the general population for approximately 10 years after surgery. At 1 year after surgery, the survival in patients undergoing THA was 1% better than the expected survival (r = 1.01; 95% confidence interval [CI], 1.01-1.02; p < 0.001); at 5 years, this increased to 3% (r = 1.03; 95% CI, 1.03-1.03; p < 0.001); at 10 years, the difference was 2% (r = 1.02; 95% CI, 1.02-1.03; p < 0.001); and by 12 years, there was no difference between patients undergoing THA and the general population (r = 1.01; 95% CI, 0.99-1.02; p = 0.13). Using the diagnosis of primary osteoarthritis as a reference, hip arthroplasties performed for sequelae of childhood hip diseases had a similar survival rate (hazard ratio [HR], 1.02; 95% CI, 0.88-1.18; p = 0.77). Patients undergoing surgery for osteonecrosis of the femoral head (HR, 1.69; 95% CI, 1.60-1.79; p < 0.001), inflammatory arthritis (HR, 1.49; 95% CI, 1.38-1.61; p < 0.001), and secondary osteoarthritis (HR, 2.46; 95% CI, 2.03-2.99; p < 0.001) all had poorer relative survival. Comorbidities and the Elixhauser comorbidity index had a negative association with relative survival. Level of achieved education (middle level of education: HR, 0.90, 95% CI, 0.87-0.93, p < 0.001; high level: 0.76, 95% CI, 0.73-0.80, p < 0.001) and marital status (single status: HR, 1.33; 95% CI, 1.28-1.38; p < 0.001) were also negatively associated with survival. CONCLUSIONS: Whereas it has been known that in most patients, THA improves quality of life, this study demonstrates that it also is associated with a slightly increased life expectancy that lasts for approximately 10 years after surgery, especially among patients whose diagnosis was primary osteoarthritis. This adds further proof of a health-economic value for this surgical intervention. The reasons for the increase in relative survival are unknown but are probably multifactorial. LEVEL OF EVIDENCE: Level III, therapeutic study.