Impact of sampling time deviations on the prediction of the area under the curve using regression limited sampling strategies

The regression limited sampling strategy approach (R‐LSS), which is based on a small number of blood samples drawn at selected time points, has been used as an alternative method for the estimation of the area under the concentration–time curve (AUC). However, deviations from planned sampling times may affect the performance of R‐LSS, influencing related therapeutic decisions and outcomes. The aim of this study was to investigate the impact of different sampling time deviation (STD) scenarios on the estimation of AUC by the R‐LSS using a simulation approach. Three types of scenarios were considered going from the simplest case of fixed deviations, to random deviations and then to a more realistic case where deviations of mixed nature can occur. In addition, the sensitivity of the R‐LSS to STD in each involved sampling point was evaluated. A significant impact of STD on the performance of R‐LSS was demonstrated. The tolerance of R‐LSS to STD was found to depend not only on the number of sampling points but more importantly on the duration of the sampling process. Sensitivity analysis showed that sampling points at which rapid concentration changes occur were relatively more critical for AUC prediction by R‐LSS. As a practical approach, nomograms were proposed, where the expected predictive performance of R‐LSS was provided as a function of STD information. The investigation of STD impact on the predictive performance of R‐LSS is a critical element and should be routinely performed to guide R‐LSS selection and use. Copyright © 2015 John Wiley & Sons, Ltd.     

Ablation of porcine ligamentum flavum with Ho:YAG,q‐switched Ho:YAG,and quadrupled Nd:YAG lasers

Background and Objectives

Ligamentum flavum (LF) is a tough, rubbery connective tissue providing a portion of the ligamentous stability to the spinal column, and in its hypertrophied state forms a significant compressive pathology in degenerative spinal stenosis. The interaction of lasers and this biological tissue have not been thoroughly studied. Technological advances improving endoscopic surgical access to the spinal canal makes selective removal of LF using small, flexible tools such as laser‐coupled fiber optics increasingly attractive for treatment of debilitating spinal stenosis. Testing was performed to assess the effect of Ho:YAG, Q‐switched Ho:YAG, and frequency quadrupled Nd:YAG lasers on samples of porcine LF. The objective was to evaluate the suitability of these lasers for surgical removal of LF.

Study Design/Materials and Methods

LF was resected from porcine spine within 2 hours of sacrifice and stored in saline until immediately prior to laser irradiation, which occurred within an additional 2 hours. The optical absorbance of a sample was measured over the spectral band from 190 to 2,360 nm both before and after dehydration. For the experiments using the Ho:YAG (λ = 2,080 nm, t_p = 140 µs, FWHM) and Q‐Switched Ho:YAG (λ = 2,080 nm, t_p = 260 ns, FWHM) lasers, energy was delivered to the LF through a laser‐fiber optic with 600 µm core and NA = 0.39. For the experiment using the frequency quadrupled Nd:YAG laser (λ = 266 nm, t_p = 5 ns FWHM), rather than applying the laser energy through a laser‐fiber, the energy was focused through an aperture and lens directly onto the LF. Five experiments were conducted to evaluate the effect of the given lasers on LF. First, using the Ho:YAG laser, the single‐pulse laser‐hole depth versus laser fluence was measured with the laser‐fiber in direct contact with the LF (1 g force) and with a standoff distance of 1 mm between the laser‐fiber face and the LF. Second, with the LF remaining in situ and the spine bisected along the coronal plane, the surface temperature of the LF was measured with an IR camera during irradiation with the Ho:YAG laser, with and without constant saline flush. Third, the mass loss was measured over the course of 450 Ho:YAG pulses. Fourth, hole depth and temperature were measured over 30 pulses of fixed fluence from the Ho:YAG and Q‐Switched Ho:YAG lasers. Fifth, the ablation rate and surface temperature were measured as a function of fluence from the Nd:YAG laser. Several LF staining and hole‐depth measurement techniques were also explored.

Results

Aside from the expected absorbance peaks corresponding to the water in the LF, the most significant peaks in absorbance were located in the spectral band from 190 to 290 nm and persisted after the tissue was dehydrated. In the first experiment, using the Ho:YAG laser and with the laser‐fiber in direct contact with the LF, the lowest single‐pulse fluence for which LF was visibly removed was 35 J/cm². Testing was conducted at 6 fluences between 35 and 354 J/cm². Over this range the single‐pulse hole depth was shown to be near linear (R² = 0.9374, M = 1.6), ranging from 40 to 639 µm (N = 3). For the case where the laser‐fiber face was displaced 1 mm from the LF surface, the lowest single‐pulse fluence for which tissue was visibly removed was 72 J/cm². Testing was conducted at 4 energy densities between 72 and 180 J/cm². Over this range the single‐pulse hole depth was shown to be near linear (R² = 0.8951, M = 1.4), ranging from 31 to 220 µm (N = 3). In the second experiment, with LF in situ, constant flushing with room temperature saline was shown to drastically reduce surface temperature during exposure to Ho:YAG at 5 Hz with the laser‐fiber in direct contact with the LF. Without saline, over 1 minute of treatment with a per‐pulse fluence of 141 mJ/cm², the average maximum surface temperature measured 110°C. With 10 cc's of saline flushed over 1 minute and a per‐pulse laser fluence of 212 mJ/cm², the average maximum surface temperature was 35°C. In the third experiment, mass loss was shown to be linear over 450 pulses of 600 mJ from the Ho:YAG laser (212 J/cm², direct contact, N = 4; 108 J/cm², 1 mm standoff, N = 4). With the laser‐fiber in direct contact, an average of 53 mg was removed (R² = 0.996, M = 0.117) and with 1 mm laser‐fiber standoff, an average of 44 mg was removed (R² = 0.9988, M = 0.097). In the fourth experiment, 30 pulses of the Ho:YAG and Q‐Switched Ho:YAG lasers at 1 mm standoff, and 5 Hz produced similar hole depths for the tested fluences of 9 J/cm² (151 and 154 µm, respectively) and 18 J/cm² (470 and 442 µm, respectively), though the Ho:YAG laser produced significantly more carbonization around the rim of the laser‐hole. The increased carbonization was corroborated by higher measured LF temperature. In all tests with the Ho:YAG and Q‐Switched Ho:YAG, an audible photo‐acoustic affect coincided with the laser pulse. In the fifth experiment, with the frequency quadrupled Nd:YAG laser at 15 Hz for 450 pulses, ablation depth per pulse was shown to be linear for the fluence range of 0.18 – 0.73 J/cm² (R² = 0.989, M = 2.4). There was no noticeable photo‐acoustic effect nor charring around the rim of the laser‐hole.

Conclusion

The Ho:YAG, Q‐Switched Ho:YAG, and frequency quadrupled Nd:YAG lasers were shown to remove ligamentum flavum (LF). A single pulse of the Ho:YAG laser was shown to cause tearing of the tissue and a large zone of necrosis surrounding the laser‐hole. Multiple pulses of the Ho:YAG and Q‐Switched Ho:YAG lasers caused charring around the rim of the laser‐hole, though the extent of charring was more extensive with the Ho:YAG laser. Charring caused by the Ho:YAG laser was shown to be mitigated by continuously flushing the affected LF with saline during irradiation. The Nd:YAG laser was shown to ablate LF with no gross visible indication of thermal damage to surrounding LF. Lasers Surg. Med. 47:839–851, 2015. © 2015 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.     

Laminarthrectomy as a surgical approach for decompressing the spinal canal: assessment of preoperative versus postoperative dural sac cross-sectional areal (DSCSA)

Introduction

Surgery for lumbar spinal stenosis (LSS) is today the most frequently performed procedure in the adult lumbar spine. Long-term benefit of surgery for LSS is well documented both in randomized and in non-randomized trials. In this paper, we present the results from laminarthrectomy as an alternative surgical approach, which have theoretical advantages over other approaches. In this study, we wanted to study the clinical and radiological results of laminarthrectomy. Dural sac cross-sectional areal (DSCSA) is an objective method to quantify the degree of central stenosis in the spinal canal, and was used to measure whether we were able to achieve an adequate decompression of the spinal canal with laminarthrectomy as a surgical approach.

Materials and methods

All patients operated on with this approach consecutively in the period 1 January 2008 to 31 March 2009 were included in the study. All perioperative complications were noted. Clinical results were measured by means of a questionnaire. The patients that agreed to attend the study had an MRI taken of the operated level. DSCSA before and after surgery of the actual level were measured by three observers. We then performed a correlation test between increase of area and clinical results. We also tested for inter- and intra-observer reability.

Results

Fifty-six laminarthrectomy were performed. There were 17 % complications, none of them were life-threatening or disabling. 46 patients attended the study and answered the questionnaire. Thirty-four patients (83 %) reported clinical improvement, whereas six (13 %) patients reported no improvement, and two (4 %) patients reported that they were worse. Mean ODI was 23.0. Mean EQ-5D was 0.77. Mean VAS-score for back-pain was 3.1 and mean VAS-score for leg-pain was 2.8. Mean DSCSA were measured to 80 mm² before surgery and 161 mm² after surgery. That gave an increase of DSCSA of 81 mm² (101 %). We found a significant positive correlation between increase of area and clinical results. We also found consistent inter- and intra-observer reability.

Discussion

In this study, the clinical results of laminarthrectomy were good, and comparable with other reports for LSS. The rates of complications are also comparable with other reports in spinal surgery. A significant increase in the spinal canal diameter was achieved. Within the limitations a retrospective study gives, we conclude that laminarthrectomy seems to be a safe and effective surgical approach for significant decompressing the adult central spinal canal, and measurement of DSCSA, before and after surgery seems to be a good way to quantify the degree of decompression.     

Effectiveness of Physical Therapy Combined With Epidural Steroid Injection for Individuals With Lumbar Spinal Stenosis: A Randomized Parallel-Group Trial

Objective

To examine the effectiveness of epidural steroid injection (ESI) and back education with and without physical therapy (PT) in individuals with lumbar spinal stenosis (LSS).

早期心理干预对首发老年脑卒中后抑郁患者康复的影响

目的 探讨早期心理干预对首发老年脑卒中后抑郁患者康复的影响,为临床干预提供依据.方法 将100例首发老年脑卒中后抑郁患者随机分为康复组和对照组,每组50例.两组均根据病情给予神经内科常规治疗,康复组在此基础上于入院1周内开展心理干预.观察3个月.于治疗前及治疗1个月、2个月及3个月末采用汉密顿抑郁量表、改良Barthe...     

Effect of a prototype lumbar spinal stenosis belt versus a lumbar support on walking capacity in lumbar spinal stenosis: a randomized controlled trial

BACKGROUND CONTEXT

Lumbar spinal stenosis (LSS) can impair blood flow to the spinal nerves giving rise to neurogenic claudication and limited walking ability. Reducing lumbar lordosis can increases the volume of the spinal canal and reduce neuroischemia. We developed a prototype LSS belt aimed at reducing lumbar lordosis while walking.

有限取样法估算中国肾移植患者单个核细胞内 他克莫司的暴露量

目的:建立预测肾移植患者服用他克莫司后外周血单个核细胞(PBMC)内暴露量的有限取样法(LSS)模型.方法:23例接受包括他克莫司在内的三联免疫疗法的肾移植患者,收集给药后0、0.5、1、1.5、2、4、6、8、10、12 h全血标本提取PBMC,采用LC-MS/MS法测定PBMC中他克莫司浓度.以多元线性分析法,获得他克莫司AUC0～12h的LSS估算模型.用Bland-Altman评价模型的预测值和实际测量值的一致性.结果:建立了包含1～4个采样时间点的LSS模型(r2=0.570～0.989).预测他克莫司AUC0～12h的最佳模型为C2-C4-C6-C10(r2=0.989).C0.5-C6模型(r2=0.849)则适用于短期需要监测的门诊患者.结论:由2-4个时间点组成的LSS模型是评估中国肾移植患者他克莫司AUC0～12 h的有效方法,可为临床监测他克莫司细胞内暴露量提供参考.     

The MRI finding of the nerve root sedimentation sign: Its clinical validity and operative relativity for patients with lumbar spinal stenosis

Background

Lumbar spinal stenosis (LSS) is increasingly being recognised as a cause of disabling low back and lower extremities pain in adult population. Advanced spinal imaging thought as confirmation tool for the diagnosis and as preoperative tool to delineate the extent and precise location of the pathology. Nerve roots normally sediment, due to gravity, to the dorsal part of the dural sac, which was known as negative sedimentation sign. If there is MRI finding of nerve roots in the ventral part of the dural sac the sedimentation sign is positive.

Objectives

To evaluate the presence of the MRI finding of positive sedimentation sign in patients clinically suspected to have lumbar spinal stenosis and to follow up operated cases to identify the absence of the radiological signs in the operated cases.

Material and methods

70 patients clinically suspected to have lumbar spinal stenosis evaluated by MRI lumbosacral spine in supine position. A panel of two radiologists reviewed radiological data. MRI features were agreed by both radiologists in 48 patients. Out of these 48 patients; 25 were operated upon for central decompressive laminectomy, partial medial facetectomy and foraminotomy with instrumented fusion and fixation if indicated. Visual analogue score (VAS) collectively preoperative and postoperative was compared and the walking distance postoperative was reported and follow up MRI studies were done one year after the operation.

Results

Operated patients’ mean age was 58.2 years; nineteen patients were operated upon for simple decompressive laminectomy for the affected levels. Walking distance preoperative range 100–700 metres, improved postoperative to be 1474.0 ± 601.1. VAS for pain preoperative was 9.28 ± 0.84, improved at 12 month follow up to be 0.84 ± 0.62. Postoperative MRI done to evaluate the cross sectional area (CSA) became more than 80 mm² in the absence of the sedimentation sign and was negative in 22 cases.

Conclusion

The MRI finding of positive sedimentation sign is a good positive sign to rule in lumbar spinal stenosis with high specificity and sensitivity; negative sedimentation sign can be used in postoperative follow up of decompression patients.     

Four-dimensional elastic light-scattering fingerprints as preneoplastic markers in the rat model of colon carcinogenesis

BACKGROUND & AIMS: Identification of preneoplastic changes in histologically normal epithelium (the "field effect") could provide a powerful screening tool for colorectal cancer. However, to date, reliable detection has not been possible. We have recently developed a new generation of optical technology, 4-dimensional elastic light-scattering fingerprinting (4D-ELF), which enables us to probe the nanoscale/microscale architecture of living cells. We therefore investigated whether 4D-ELF would be able to identify preneoplastic changes in the colonocytes of the azoxymethane (AOM)-treated rat model of colon carcinogenesis. METHODS: Forty-eight Fisher 344 rats were randomized to either 2 weekly injections of AOM or saline. Animals were killed 2-20 weeks after the second injection of AOM. Colons were removed and subjected to 4D-ELF analysis, with a subset undergoing assessment of aberrant crypt foci (ACF). All AOM-treated animals were compared with age-matched saline-treated controls. RESULTS: AOM-induced ACF became apparent at approximately 4-6 weeks and continued to increase over time. ACF were predominantly located in the distal colon. At 2 weeks (before development of ACF), there were marked changes in a number of 4D-ELF signatures. The relevance to carcinogenesis of these 4D-ELF-detected microarchitectural abnormalities is supported by their spatial and temporal correlation with subsequent development of ACF. All changes reported were highly statistically significant. CONCLUSIONS: We show that probing the nanoscale cellular architecture with 4D-ELF provided an unprecedented tool for detecting the earliest stages of colon carcinogenesis. Future studies are necessary to explore the clinical applicability of this technology and elucidate the biological determinants of these microarchitectural changes.