Dynamic path analysis – a useful tool to investigate mediation processes in clinical survival trials

When it comes to clinical survival trials, regulatory restrictions usually require the application of methods that solely utilize baseline covariates and the intention‐to‐treat principle. Thereby, much potentially useful information is lost, as collection of time‐to‐event data often goes hand in hand with collection of information on biomarkers and other internal time‐dependent covariates. However, there are tools to incorporate information from repeated measurements in a useful manner that can help to shed more light on the underlying treatment mechanisms. We consider dynamic path analysis, a model for mediation analysis in the presence of a time‐to‐event outcome and time‐dependent covariates to investigate direct and indirect effects in a study of different lipid‐lowering treatments in patients with previous myocardial infarctions. Further, we address the question whether survival in itself may produce associations between the treatment and the mediator in dynamic path analysis and give an argument that because of linearity of the assumed additive hazard model, this is not the case. We further elaborate on our view that, when studying mediation, we are actually dealing with underlying processes rather than single variables measured only once during the study period. This becomes apparent in results from various models applied to the study of lipid‐lowering treatments as well as our additionally conducted simulation study, where we clearly observe that discarding information on repeated measurements can lead to potentially erroneous conclusions. Copyright © 2015 John Wiley & Sons, Ltd.     

3.0T MR IDEAL序列成像应用于腰骶神经根受压的初步临床研究

目的探讨IDEAL技术在腰椎间盘突出症中显示腰骶神经受压的临床应用价值。方法将明显腰腿痛并腰椎间盘突出的患者40例作为观察组,正常志愿者10例作为对照组,行腰骶神经根IDEAL序列冠状位薄层扫描和常规扫描,所有图像均经最大信号强度投影(MIP)和曲面重建(CPR)后处理,观察腰骶神经根的受压特点及其与突出椎间盘与邻近组织的关系。结果观察组40例中有92组腰椎间盘不同程度的疝出,而由此引起的神经根受压共81组,其中神经根侧隐窝段受压的概率显著大于椎管内段,但是任何部位的神经根受压好发生于同侧还是双侧受压并没有统计学意义(P=0.338)。另有4组神经根受压由增厚的黄韧带或骨质增生引起;有6组由神经根鞘囊肿引起。受压神经根的影像学表现为:(1)神经根局部缺损样压迹;(2)走行的改变;(3)形态的改变,包括局部肿胀,甚至截断样改变;(4)与邻近组织局部粘连,边界不清,边缘模糊;(5)局部脑脊髓间隙变窄或消失。结论 IDEAL序列能直观显示腰骶神经根与邻近结构的关系及受压特点,能够对神经根受压作出准确的定位和受压程度评估,对判断腰骶神经受压、损伤等具有一定的临床诊断价值,也能为临床早期选择正确的治疗方案及疗效观察提供可靠的参考依据。     

Robotic Kidney Transplantation with Regional Hypothermia: A Step-by-step Description of the Vattikuti Urology Institute–Medanta Technique (IDEAL Phase 2a)

Background

We recently reported on preclinical and feasibility studies (Innovation, Development, Exploration, Assessment, Long-term study [IDEAL] phase 0–1) of the development of robotic kidney transplantation (RKT) with regional hypothermia. This paper presents the IDEAL phase 2a studies of technique development.

Objectives

To describe the technique of RKT with regional hypothermia developed at two tertiary care institutions (Vattikuti Urology Institute and Medanta Hospital). We report on the safety profile and early graft function in these patients.

Design, setting, and participants

This is a prospective study of 50 consecutive patients who underwent live-donor RKT at Medanta Hospital following a 3-yr planning/simulation phase at the Vattikuti Urology Institute. Demographic details, and perioperative and postoperative outcomes are reported for the initial 25 recipients who have completed a minimum 6-mo follow-up.

Surgical procedure

Positioning and port placement were similar to that used for robotic radical prostatectomy. Allograft cooling was achieved by ice slush delivered through a GelPOINT device. The accompanying video details the operative technique.

Outcome measurements and statistical analysis

The primary outcome was posttransplant graft function. Secondary outcomes included technical success or failure and complication rates.

Results and limitations

Fifty patients underwent RKT successfully, 7 in the phase 1 and 43 in the phase 2 stages of the study. For the initial 25 patients, mean console, warm ischemia, arterial, and venous anastomotic times were 135, 2.4, 12, and 13.4 min, respectively. All grafts were cooled to 18–20°C with no change in core body temperature. All grafts functioned immediately posttransplant and the mean serum creatinine level at discharge was 1.3 mg/dl (range: 0.8–3.1 mg/dl). No patient developed anastomotic leaks, wound complications, or wound infections. At 6-mo of follow-up, no patient had developed a lymphocele detected on CT scanning. Two patients underwent re-exploration, and one patient died of congestive heart failure (1.5 mo posttransplant).

Conclusions

RKT with regional hypothermia is safe and reproducible when performed by a team skilled in robotic surgery.

Patient summary

RKT is safe and effective when performed by surgeons experienced in robotic techniques.     

Whole-body 3D water/fat resolved continuously moving table imaging

PURPOSE: To study the feasibility of three-dimensional (3D) whole-body, head-to-toe, water/fat resolved MRI, using continuously moving table imaging technology. MATERIALS AND METHODS: Experiments were performed on nine healthy volunteers, acquiring 3D whole-body head-to-toe data under continuous motion of the patient table. Two different approaches for water/fat separation have been studied. Results of a three-point chemical shift encoding and a spectral presaturation technique were compared with respect to image quality and performance. Furthermore, fast, low-resolution, whole-body water/fat imaging was performed in two minutes total scan time to derive patient-specific parameters such as the total water/fat ratio, the intraperitoneal/extraperitoneal fat ratio, and the body mass index (BMI). RESULTS: Good water/fat separation with decent image quality was obtained in all cases. The three-point chemical shift encoding approach was found to be more efficient with respect to signal-to-noise ratio (SNR) and acquisition time. CONCLUSION: Whole-body water/fat sensitive MRI using continuous table motion is feasible and could be of interest for clinical practice. Some improvements of the method are desirable.     

Field map estimation with a region growing scheme for iterative 3-point water-fat decomposition.

Robust fat suppression techniques are required for many clinical applications. Multi-echo water-fat separation methods are relatively insensitive to B(0) field inhomogeneity compared to the fat saturation method. Estimation of this field inhomogeneity, or field map, is an essential and important step, which is well known to have ambiguity. For an iterative water-fat decomposition method recently proposed, ambiguities still exist, but are more complex in nature. They were studied by analytical expressions and simulations. To avoid convergence to incorrect field map solutions, an initial guess closer to the true field map is necessary. This can be achieved using a region growing process, which correlates the estimation among neighboring pixels. Further improvement in stability is achieved using a low-resolution reconstruction to guide the selection of the starting pixels for the region growing. The proposed method was implemented and shown to significantly improve the algorithm's immunity to field inhomogeneity.     

Validation of MRI biomarkers of hepatic steatosis in the presence of iron overload in the ob/ob mouse

Purpose:

To validate the utility and performance of a T correction method for hepatic fat quantification in an animal model of both steatosis and iron overload.

Materials and Methods:

Mice with low (n = 6), medium (n = 6), and high (n = 8) levels of steatosis were sedated and imaged using a chemical shift‐based fat‐water separation method to obtain magnetic resonance imaging (MRI) fat‐fraction measurements. Imaging was performed before and after each of two superparamagnetic iron oxide (SPIO) injections to create hepatic iron overload. Fat‐fraction maps were reconstructed with and without T correction. Fat‐fraction with and without T correction and T measurements were compared after each injection. Liver tissue was harvested and imaging results were compared to triglyceride extraction and histology grading.

Results:

Excellent correlation was seen between MRI fat‐fraction and tissue‐based fat quantification. Injections of SPIOs led to increases in R (=1/T). Measured fat‐fraction was unaffected by the presence of iron when T correction was used, whereas measured fat‐fraction dramatically increased without T correction.

Conclusion:

Hepatic fat‐fraction measured using a T‐corrected chemical shift‐based fat‐water separation method was validated in an animal model of steatosis and iron overload. T correction enables robust fat‐fraction estimation in both the presence and absence of iron, and is necessary for accurate hepatic fat quantification. J. Magn. Reson. Imaging 2012;35:844–851. © 2011 Wiley Periodicals, Inc.     

Water-silicone separated volumetric MR acquisition for rapid assessment of breast implants

Purpose:

To develop a robust T₂‐weighted volumetric imaging technique with uniform water‐silicone separation and simultaneous fat suppression for rapid assessment of breast implants in a single acquisition.

Materials and Methods:

A three‐dimensional (3D) fast spin echo sequence that uses variable refocusing flip angles was combined with a three‐point chemical‐shift technique (IDEAL) and short tau inversion recovery (STIR). Phase shifts of ?π/6, +π/2, and +7π/6 between water and silicone were used for IDEAL processing. For comparison, two‐dimensional images using 2D‐FSE‐IDEAL with STIR were also acquired in axial, coronal, and sagittal orientations.

Results:

Near‐isotropic (true spatial resolution—0.9 × 1.3 × 2.0 mm³) volumetric breast images with uniform water‐silicone separation and simultaneous fat suppression were acquired successfully in clinically feasible scan times (7:00–10:00 min). The 2D images were acquired with the same in‐plane resolution (0.9 × 1.3 mm²), but the slice thickness was increased to 6 mm with a slice gap of 1 mm for complete coverage of the implants in a reasonable scan time, which varied between 18:00 and 22:30 min.

Conclusion:

The single volumetric acquisition with uniform water and silicone separation enables images to be reformatted into any orientation. This allows comprehensive assessment of breast implant integrity in less than 10 min of total examination time. J. Magn. Reson. Imaging 2012;35:1216‐1221. © 2012 Wiley Periodicals, Inc.

     

A Summary and Critical Assessment of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Filling the Gaps

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines has recently released the new cholesterol treatment guideline. This update was based on a systematic review of the evidence and replaces the previous guidelines from 2002 that were widely accepted and implemented in clinical practice. The new cholesterol treatment guideline emphasizes matching the intensity of statin treatment to the level of atherosclerotic cardiovascular disease (ASCVD) risk and replaces the old paradigm of pursuing low-density lipoprotein cholesterol targets. The new guideline also emphasizes the primacy of the evidence base for statin therapy for ASCVD risk reduction and lists several patient groups that will not benefit from statin treatment despite their high cardiovascular risk, such as those with heart failure (New York Heart Association class II-IV) and patients undergoing hemodialysis. The guideline has been received with mixed reviews and significant controversy. Because of the evidence-based nature of the guideline, there is room for several questions and uncertainties on when and how to use lipid-lowering therapy in clinical practice. The goal of the Mayo Clinic Task Force in the assessment, interpretation, and expansion of the ACC/AHA cholesterol treatment guideline is to address gaps in information and some of the controversial aspects of the newly released cholesterol management guideline using additional sources of evidence and expert opinion as needed to guide clinicians on key aspects of ASCVD risk reduction.     

Evaluation of adipose tissue volume quantification with IDEAL fat-water separation

Purpose:

To validate i terative d ecomposition of water and fat with e cho a symmetry and l east‐squares estimation (IDEAL) for adipose tissue volume quantification. IDEAL allows MRI images to be produced only from adipose‐containing tissues; hence, quantifying adipose tissue should be simpler and more accurate than with current methods.

Materials and Methods:

Ten healthy controls were imaged with 1.5 Tesla (T) Spin Echo (SE), 3.0T T1‐weighted spoiled gradient echo (SPGR), and 3.0T IDEAL‐SPGR. Images were acquired from the abdomen, pelvis, mid‐thigh, and mid‐calf. Mean subcutaneous and visceral adipose tissue volumes were compared between the three acquisitions for each subject.

Results:

There were no significant differences (P > 0.05) between the three acquisitions for subcutaneous adipose tissue volumes. However, there was a significant difference (P = 0.0002) for visceral adipose tissue volumes in the abdomen. Post hoc analysis showed significantly lower visceral adipose tissue volumes measured by IDEAL versus 1.5T (P < 0.0001) and 3.0T SPGR (P < 0.002). The lower volumes given by IDEAL are due to its ability to differentiate true visceral adipose tissue from other bright structures like blood vessels and bowel content that are mistaken for adipose tissue in non‐fat suppressed images.

Conclusion:

IDEAL measurements of adipose tissue are equivalent to established 1.5T measurement techniques for subcutaneous depots and have improved accuracy for visceral depots, which are more metabolically relevant. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.