Citations

Abstract Background Long-term mortality after primary THA is lower than in the general population, but it is unknown whether this is also true after revision THA. Questions/Purposes We examined (1) long-term mortality according to reasons for revision after revision THA, and (2) relative mortality trends by age at surgery, years since surgery, and calendar year of surgery. Methods This retrospective study included 5417 revision THAs performed in 4532 patients at a tertiary center between 1969 and 2011. Revision THAs were grouped by surgical indication in three categories: periprosthetic joint infections (938; 17%); fractures (646; 12%); and loosening, bearing wear, or dislocation (3833; 71%). Patients were followed up until death or December 31, 2016. The observed number of deaths in the revision THA cohort was compared with the expected number of deaths using standardized mortality ratios (SMRs) and Poisson regression models. The expected number of deaths was calculated assuming that the study cohort had the same calendar year, age, and sex-specific mortality rates as the United States general population. Results The overall age- and sex-adjusted mortality was slightly higher than the general population mortality (SMR, 1.09; 95% CI, 1.05-1.13; p < 0.001). There were significant differences across the three surgical indication subgroups. Compared with the general population mortality, patients who underwent revision THA for infection (SMR, 1.35; 95% CI, 1.24-1.48; p < 0.001) and fractures (SMR, 1.23; 95% CI, 1.11-1.37; p < 0.001) had significantly increased risk of death. Patients who underwent revision THA for aseptic loosening, wear, or dislocation had a mortality risk similar to that of the general population (SMR, 1.01; 95% CI, 0.96-1.06; p = 0.647). The relative mortality risk was highest in younger patients and declined with increasing age at surgery. Although the relative mortality risk among patients with aseptic indications was lower than that of the general population during the first year of surgery, the risk increased with time and got worse than that of the general population after approximately 8 to 10 years after surgery. Relative mortality risk improved with time after revision THA for aseptic loosening, wear, or dislocation. Conclusions Shifting mortality patterns several years after surgery and the excess mortality after revision THA for periprosthetic joint infections and fractures reinforce the need for long-term followup, not only for implant survival but overall health of patients having THA. Level of Evidence Level III, therapeutic study

Abstract Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, TC and AC, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B, and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death, apoptosis, and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1, and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-κB and MAPK/ERK pathways. The mutation signature was predominantly C&gt;T and T&gt;C transitions with a minor contribution of T&gt;G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors. Clin Cancer Res; 24(7); 1691–704. ©2018 AACR.

Abstract Motivation Recent studies have revealed a complex interplay between environment, the human microbiome and health and disease. Mediation analysis of the human microbiome in these complex relationships could potentially provide insights into the role of the microbiome in the etiology of disease and, more importantly, lead to novel clinical interventions by modulating the microbiome. However, due to the high dimensionality, sparsity, non-normality and phylogenetic structure of microbiome data, none of the existing methods are suitable for testing such clinically important mediation effect. Results We propose a distance-based approach for testing the mediation effect of the human microbiome. In the framework, the nonlinear relationship between the human microbiome and independent/dependent variables is captured implicitly through the use of sample-wise ecological distances, and the phylogenetic tree information is conveniently incorporated by using phylogeny-based distance metrics. Multiple distance metrics are utilized to maximize the power to detect various types of mediation effect. Simulation studies demonstrate that our method has correct Type I error control, and is robust and powerful under various mediation models. Application to a real gut microbiome dataset revealed that the association between the dietary fiber intake and body mass index was mediated by the gut microbiome. Availability and implementation An R package ‘MedTest’ is freely available at https://github.com/jchen1981/MedTest. Supplementary information Supplementary data are available at Bioinformatics online.

Abstract Aims The incidence of and factors associated with sudden cardiac death (SCD) early after an acute heart failure (HF) hospital admission have not been well defined. Methods and results We assessed SCD and ventricular arrhythmias in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, which included patients with acute HF with reduced or preserved ejection fraction. SCD, resuscitated SCD (RSCD), and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) were adjudicated from randomization through 30 days and were combined into a composite endpoint. Baseline characteristics associated with this composite were determined by logistic regression. RSCD and VT/VF were included as time-dependent variables in a Cox model evaluating the association of these variables with 180-day all-cause mortality. Among 7011 patients, the 30-day all-cause mortality rate was 3.8%; SCD accounted for 17% of these deaths. The 30-day composite event rate was 1.8% (n = 121). Ten patients had more than one event with 30-day Kaplan–Meier event rates of 0.6% for SCD [95% confidence interval (CI) 0.5%–0.9%, n = 43], 0.4% for RSCD (95% CI 0.2%–0.5%, n = 24), and 0.9% for VT/VF (95% CI 0.7%–1.2%, n = 64). In the multivariable model, chronic obstructive pulmonary disease, history of VT, male sex, and longer QRS duration were associated with SCD, RSCD, or VT/VF. A RSCD or VT/VF event was associated with higher 180-day mortality (adjusted hazard ratio 6.6, 95% CI 4.8–9.1, P &lt; 0.0001). Conclusions Approximately 2% of patients admitted for acute HF experienced SCD, RSCD, or VT/VF within 30 days of admission, and SCD accounted for 17% of all deaths within 30 days.

PurposeCurrently, in clinical practice of intensity‐modulated proton therapy (IMPT), the influence of the minimum monitor unit (MU) constraint is taken into account through postprocessing after the optimization is completed. This may degrade the plan quality and plan robustness. This study aims to mitigate the impact of the minimum MU constraint directly during the plan robust optimization.Methods and materialsCao et al. have demonstrated a two‐stage method to account for the minimum MU constraint using linear programming without the impact of uncertainties considered. In this study, we took the minimum MU constraint into consideration using quadratic optimization and simultaneously had the impact of uncertainties considered using robust optimization. We evaluated our method using seven cancer patients with different machine settings.ResultThe new method achieved better plan quality than the conventional method. The D95% of the clinical target volume (CTV) normalized to the prescription dose was (mean [min–max]): (99.4% [99.2%–99.6%]) vs. (99.2% [98.6%–99.6%]). Plan robustness derived from these two methods was comparable. For all seven patients, the CTV dose–volume histogram band gap (narrower band gap means more robust plans) at D95% normalized to the prescription dose was (mean [min–max]): (1.5% [0.5%–4.3%]) vs. (1.2% [0.6%–3.8%]).ConclusionOur new method of incorporating the minimum MU constraint directly into the plan robust optimization can produce machine‐deliverable plans with better tumor coverage while maintaining high‐plan robustness.

The MRI community is using quantitative mapping techniques to complement qualitative imaging. For quantitative imaging to reach its full potential, it is necessary to analyze measurements across systems and longitudinally. Clinical use of quantitative imaging can be facilitated through adoption and use of a standard system phantom, a calibration/standard reference object, to assess the performance of an MRI machine. The International Society of Magnetic Resonance in Medicine AdHoc Committee on Standards for Quantitative Magnetic Resonance was established in February 2007 to facilitate the expansion of MRI as a mainstream modality for multi‐institutional measurements, including, among other things, multicenter trials. The goal of the Standards for Quantitative Magnetic Resonance committee was to provide a framework to ensure that quantitative measures derived from MR data are comparable over time, between subjects, between sites, and between vendors. This paper, written by members of the Standards for Quantitative Magnetic Resonance committee, reviews standardization attempts and then details the need, requirements, and implementation plan for a standard system phantom for quantitative MRI. In addition, application‐specific phantoms and implementation of quantitative MRI are reviewed. Magn Reson Med 79:48–61, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose We propose a robust treatment planning model that simultaneously considers proton range and patient setup uncertainties and reduces high linear energy transfer (LET) exposure in organs at risk (OARs) to minimize the relative biological effectiveness (RBE) dose in OARs for intensity‐modulated proton therapy (IMPT). Our method could potentially reduce the unwanted damage to OARs. Methods We retrospectively generated plans for 10 patients including two prostate, four head and neck, and four lung cancer patients. The “worst‐case robust optimization” model was applied. One additional term as a “biological surrogate (BS)” of OARs due to the high LET‐related biological effects was added in the objective function. The biological surrogate was defined as the sum of the physical dose and extra biological effects caused by the dose‐averaged LET. We generated nine uncertainty scenarios that considered proton range and patient setup uncertainty. Corresponding to each uncertainty scenario, LET was obtained by a fast LET calculation method developed in‐house and based on Monte Carlo simulations. In each optimization iteration, the model used the worst‐case BS among all scenarios and then penalized overly high BS to organs. The model was solved by an efficient algorithm (limited‐memory Broyden–Fletcher–Goldfarb–Shanno) in a parallel computing environment. Our new model was benchmarked with the conventional robust planning model without considering BS. Dose–volume histograms (DVHs) of the dose assuming a fixed RBE of 1.1 and BS for tumor and organs under nominal and uncertainty scenarios were compared to assess the plan quality between the two methods. Results For the 10 cases, our model outperformed the conventional robust model in avoidance of high LET in OARs. At the same time, our method could achieve dose distributions and plan robustness of tumors assuming a fixed RBE of 1.1 almost the same as those of the conventional robust model. Conclusions Explicitly considering LET in IMPT robust treatment planning can reduce the high LET to OARs and minimize the possible toxicity of high RBE dose to OARs without sacrificing plan quality. We believe this will allow one to design and deliver safer proton therapy.