Outcomes associated with matching patients' treatment preferences to physicians' recommendations: study methodology

Background  

Patients often express strong preferences for the forms of treatment available for their disease. Incorporating these preferences into the process of treatment decision-making might improve patients' adherence to treatment, contributing to better outcomes. We describe the methodology used in a study aiming to assess treatment outcomes when patients' preferences for treatment are closely matched to recommended treatments.     

Vaccine-elicited Human T Cells Recognizing Conserved Protein Regions Inhibit HIV-1

Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4⁺ cells and inhibited HIV-1 replication by up to 5.79 log₁₀. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8⁺ T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro.     

Optimization of Improved Motion-sensitized Driven-equilibrium (iMSDE) blood suppression for carotid artery wall imaging

Background

Improved motion-sensitized driven-equilibrium (iMSDE) preparations have been successfully used in carotid artery wall imaging to achieve blood suppression, but it causes notable signal loss, mostly due to inherent T₂ decay, eddy current effects and B₁⁺ inhomogeneity. In this study, we investigate the signal to noise ratio (SNR) and blood suppression performance of iMSDE using composite RF pulses and sinusoidal gradients. Optimized first moment (m₁) values for iMSDE prepared T₁- and T₂- weighted (T₁- and T₂-w) imaging are presented.

Methods

Twelve healthy volunteers and six patients with carotid artery disease underwent iMSDE and double inversion recovery (DIR) prepared T₁- and T₂-w fast spin echo (FSE) MRI of the carotid arteries. Modified iMSDE module using composite RF pulses and sinusoidal gradients were evaluated with a range of m₁. SNR of adjacent muscle, vessel wall and the lumen were reported. The optimized iMSDE module was also tested in a 3D variable flip angle FSE (CUBE) acquisition.

Results

The SNR of muscle was highest using sinusoidal gradients, and the relative improvement over the trapezoidal gradient increased with higher m₁ (p<0.001). Optimal SNR was observed using an iMSDE preparation scheme containing two 180° composite pulses and standard 90° and -90° pulses (p=0.151). iMSDE produced better blood suppression relative to DIR preparations even with a small m₁ of 487 mT*ms²/m (p<0.001). In T₁-w iMSDE, there was a SNR decrease and an increased T₂ weighting with increasing m_1. In T₂-w iMSDE, by matching the effective echo time (TE), the SNR was equivalent when m₁ was <= 1518 mT*ms²/m, however, higher m₁ values (2278 – 3108 mT*ms²/m) reduced the SNR. In the patient study, iMSDE improved blood suppression but reduced vessel wall CNR efficiency in both T₁-w and T₂-w imaging. iMSDE also effectively suppressed residual flow artifacts in the CUBE acquisition.

Conclusions

iMSDE preparation achieved better blood suppression than DIR preparation with reduced vessel wall CNR efficiency in T_1-w and T₂-w images. The optimized m₁s are 487 mT*ms²/m for T₁-w imaging and 1518 mT*ms²/m for T₂-w imaging. Composite 180° refocusing pulses and sinusoidal gradients improve SNR performance. iMSDE further improves the inherent blood suppression of CUBE.     

In vivo imaging of protease activity in arthritis: a novel approach for monitoring treatment response

OBJECTIVE: Sensitive noninvasive strategies for monitoring treatment response in rheumatoid arthritis (RA) would be valuable for facilitating appropriate therapy and dosing, evaluating clinical outcome, and developing more effective drugs. Because different proteases are highly up-regulated in RA and contribute significantly to joint destruction, in the present study we investigated whether such enzymes are suitable in vivo imaging biomarkers for early evaluation of treatment response in a murine model of RA. METHODS: Using a protease-activated near-infrared fluorescence (NIRF) imaging "smart" probe, we examined the presence and distribution of fluorescence in arthritic joints of mice with collagen-induced arthritis by both noninvasive fluorescence imaging and histology. Proteases that target the Lys-Lys cleavage site, including cathepsin B, activate probe fluorescence. Treatment monitoring data were obtained following methotrexate (MTX) therapy. RESULTS: Twenty-four hours after intravenous injection of the protease sensor, affected toes and paws of arthritic mice showed significantly higher fluorescence intensity than did toes and paws of healthy mice. Fluorescence from the protease probe and cathepsin B antibody histologic staining were localized in the vast majority of cells in the inflamed synovium. In arthritic animals treated with MTX (35 mg of MTX/kg 48 hours prior to probe injection), a significantly lower fluorescent signal (inflamed paws 50%, inflamed toes 70%) was observed as compared with untreated arthritic animals. CONCLUSION: Protease-activated NIRF probes are sensitive means of imaging the presence of target enzymes in arthritic joints and can be used for early monitoring of treatment response to antirheumatic drugs such as MTX.     

藏茴香水提物对高脂血症大鼠血脂及肝功能的影响

目的：研究藏茴香水提物对大鼠血脂调节及肝脏的保护作用。方法将10 w 龄雄性 SD 大鼠48只,除空白对照组8只大鼠以外其余各组大鼠均采用高脂饲料喂养8 w 后,断尾采血测血脂,确定造模成功后随机分为模型对照组、血脂康对照组、空白对照组及藏茴香水提物高、中、低剂量组（300、150、75 mg·kg^-1·d^-1）,连续灌胃给药6 w,1次/d,模型对照组与空白对照组灌胃给予等量的生理盐水。每2周测1次体质量;末次给药后腹主动脉采血,测血清中的高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、总胆固醇（TC）、甘油三酯（TG）等血脂水平,测定谷草转氨酶（AST）、谷丙转氨酶（ALT）等脂类酶的活性及谷胱甘肽过氧化酶（GSH-Px）、超氧化物歧化酶（SOD）、脂肪过氧化物丙二醛（MDA）等抗氧化能力的变化。结果与空白对照组比较,模型对照组 TG、TC、LDL-C 均有显著升高,HDL-C 显著降低,差异均有统计学意义（P ＜0．05）。藏茴香各剂量组 TC、TG、LDL-C 逐渐降低,HDL-C 逐渐升高（说明藏茴香干预能有效调节血脂水平）。与模型对照组比较,藏茴香各剂量组大鼠血清血脂水平差异均有统计学意义。与空白对照组比较,模型对照组血清 AST、ALT 明显升高,有统计学差异（P ＜0．05）,血脂康对照组及藏茴香水提物各剂量组血清 AST、ALT 均显著降低;与模型对照组比较,藏茴香水提物高、中剂量组有统计学差异（P ＜0．05～0．01）,与小剂量组比较无统计学差异（P ＞0．05）。与空白对照组比较,模型对照组 SOD、MDA 水平升高,差异有统计学意义（P ＜0．05）;与模型对照组比较,藏茴香水提物高剂量组SOD、MDA 水平和血脂康对照组 SOD 水平差异有统计学意义（P ＜0．05）,与藏茴香水取物中、低剂量组比较无统计学差异（P ＞0．05）。模型     

The degree of gallbladder wall thickness and its impact on outcomes after laparoscopic cholecystectomy

Background

Laparoscopic cholecystectomy is the gold-standard procedure for management of symptomatic gallstone disease. Increased rates of conversion to an open procedure, increased postoperative complications, and longer lengths of stay are seen in thick-walled gallbladders. Previous studies have only evaluated gallbladder walls as being thick or not thick, without looking at the degree of thickness. We hypothesized that, the more severe the wall thickening, the greater the chance of conversions and complications, and the longer the lengths of stay.

Methods

All attempted laparoscopic cholecystectomies in our institution between 2006 and 2009 were retrospectively reviewed. Patients undergoing cholecystectomy for reasons other than gallstones (e.g., polyps or cancer) and those without preoperative ultrasounds were excluded. Patients were divided into four groups based on the degree of gallbladder wall thickness: normal (1–2?mm), mildly thickened (3–4?mm), moderately thickened (5–6?mm), and severely thickened (7?mm and above). Outcomes were compared amongst the groups.

Results

874 patients were included in the study. There were 68 conversions (7.8?%) and 58 complications (6.6?%). The incidence of conversions was 3.1, 5.1, 14.9, and 16.8?% in the four groups, respectively (p?<?0.001, χ ²), and the incidence of complications was 1.8, 6.7, 9.1, and 13.1?%, respectively (p?=?0.001, χ ²). The mean (±?standard deviation, SD) length of stay in days was 1.09?±?1.42, 1.83?±?3.24, 2.54?±?3.40 and 3.54?±?4.61, respectively [p?<?0.001, analysis of variance (ANOVA)].

Conclusions

A greater degree of gallbladder wall thickness is associated with an increased risk of conversion, increased postoperative complications, and longer lengths of stay. Classifying patients according to degree of gallbladder wall thickness gives more accurate assessment of the risk of surgery, as well as potential outcomes.