BACKGROUND & AIMS: :Impaired everyday function is a diagnostic criterion for dementia, and a determinant of healthcare utilization and caregiver burden. Although many previous studies have demonstrated a cross-sectional relationship between cognition (particularly executive functions and memory) and everyday function in older adults, very little is known about longitudinal relationships between these domains. This study examined the association between longitudinal change in episodic memory (MEM) and executive functioning (EXEC) and change in everyday function. Participants were a cognitively heterogeneous group of 100 elderly persons including those with normal cognition, as well as those with mild cognitive impairment and dementia. They were followed for an average of 5 years. Random effects modeling showed that change in both MEM and EXEC were independently associated with rate of change in informant-rated instrumental activities of daily living (IADLs), even after controlling for age, education, and gender. Findings indicate that declines in MEM and EXEC over time make unique and independent contributions to declines in older adults' ability to function in daily life.

背景与目标： ：日常功能受损是痴呆症的诊断标准，并且是医疗保健利用率和护理人员负担的决定因素。尽管许多先前的研究已经证明了老年人的认知（特别是执行功能和记忆）与日常功能之间的横断面关系，但对这些领域之间的纵向关系知之甚少。这项研究检查了情节性记忆（MEM）和执行功能（EXEC）的纵向变化与日常功能变化之间的关联。参与者是一个认知异质性的群体，由100名老年人组成，包括那些具有正常认知能力的人，以及那些患有轻度认知障碍和痴呆症的人。他们平均随访了5年。随机效应模型表明，即使在控制了年龄，教育程度和性别之后，MEM和EXEC的变化也与知情者评定的日常工具活动（IADLs）的变化率独立相关。研究结果表明，MEM和EXEC随时间的下降对老年人日常生活功能的下降做出了独特而独立的贡献。

BACKGROUND & AIMS: BACKGROUND:The Daily Mile is designed to increase physical activity levels with children running or walking around school grounds for 15-min daily. It has been adopted by schools worldwide and endorsed as a solution to tackle obesity, despite no robust evidence of its benefits. We conducted a cluster randomised controlled trial to determine its clinical and cost-effectiveness. METHODS:Forty schools were randomly assigned (1:1) to either the Daily Mile intervention or control group in which only the usual school health and wellbeing activities were implemented. The primary outcome was BMI z-score (BMIz) at 12 months follow-up from baseline, with planned subgroup analysis to examine differential effects. Primary economic analysis outcome was incremental cost per Quality-Adjusted-Life-Year (QALY) gained. RESULTS:Using a constrained randomisation approach, balanced on school size, baseline BMIz and proportion of pupils eligible for free school meals, 20 schools were allocated to intervention (n = 1,153 participants) and 20 to control (n = 1,127); 3 schools withdrew (2 intervention, 1 control). At 12 months, BMIz data were available for 18 intervention schools (n = 850) and 19 control schools (n = 820 participants). Using intention-to-treat analysis the adjusted mean difference (MD) in BMIz (intervention - control) was -0.036 (95% CI: -0.085 to 0.013, p = 0.146). Pre-specified subgroup analysis showed a significant interaction with sex (p = 0.001) suggesting a moderate size benefit of The Daily Mile in girls (MD -0.097, 95% CI -0.156 to -0.037). This was consistent with the exploratory economic results that showed The Daily Mile to be highly cost-effective in girls (£2,492 per QALY), but not in boys, and overall to have a 76% chance of cost-effectiveness for the whole sample, at the commonly applied UK threshold of £20,000 per QALY. CONCLUSIONS:Overall the Daily Mile had a small but non-significant effect on BMIz, however, it had a greater effect in girls suggesting that it might be considered as a cost-effective component of a system-wide approach to childhood obesity prevention.

背景与目标： 背景：“每日里程”旨在提高孩子们每天在校园内奔跑或行走15分钟的体育活动水平。尽管没有确凿的证据证明它是肥胖的益处，但它已被全世界的学校所采用，并被认为是解决肥胖的一种解决方案。我们进行了一项集群随机对照试验，以确定其临床和成本效益。
方法：将40所学校随机（1：1）分配给Daily Mile干预组或对照组，其中仅实施常规的学校健康和福祉活动。主要结果是从基线开始的12个月随访中的BMI z评分（BMIz），并计划进行亚组分析以检查差异影响。主要的经济分析结果是每获得的质量调整生命年（QALY）产生的增量成本。
结果：采用约束随机化方法，在学校规模，基线BMIz和有资格获得免费校餐的学生比例之间取得平衡，分配了20所学校进行干预（n intervention = 1,153参与者）和20所学校进行控制（n = 1,127）； 3所学校退出了（2干预，1对照）。在12个月时，可获得18所干预学校（n = 850）和19所对照学校（n = 820参与者）的BMIz数据。使用意向治疗分析，BMIz（干预-对照）的调整后平均差（MD）为-0.036（95％CI：-0.085至0.013，p = 0.146）。预先指定的亚组分析显示与性别之间存在显着相互作用（p = 0.001），表明女孩的“每日里程”有中等大小的益处（MD -0.097，95％CI -0.156至-0.037）。这与探索性的经济结果相吻合，该研究结果显示“每日里程”在女孩中具有很高的成本效益（每QALY为2,492英镑），而在男孩中则不然，总体而言，整个样本具有76％的成本效益机会，在英国，通常每QALY需支付20,000英镑。
结论：总体而言，“每日英里”对BMIz的影响很小，但没有显着影响，但对女孩的BMIz影响更大，表明它可能被认为是全系统预防儿童肥胖症的一种经济有效的方法。

BACKGROUND & AIMS: :We studied daily rhythmicity of body temperature (T(b)) before and during hibernation in Anatolian ground squirrels (Spermophilus xanthoprymnus) under natural and laboratory conditions using surgically implanted temperature loggers. Under both conditions, robust daily T(b) rhythmicity with parameters comparable to those of other ground squirrel species was observed before but not during hibernation. Euthermic animals had robust daily T(b) rhythms with a mean of 37.0 degrees C and a range of excursion of approximately 4 degrees C. No T(b) rhythm was detected during torpor bouts, either because T(b) rhythmicity was absent or because the daily range of excursion was smaller than 0.2 degrees C. The general patterns of hibernation that we observed in Anatolian ground squirrels were similar to those previously observed by other investigators in other species of ground squirrels.

背景与目标： ：我们在自然和实验室条件下，使用外科植入式温度记录仪研究了安纳托利亚松鼠（Spermophilus xanthoprymnus）冬眠前和休眠期间的每日体温节律（T（b））。在这两种情况下，冬眠前（而非冬眠期间）均观察到了具有与其他地松鼠种类相当的参数的稳定的每日T（b）节律。体温正常的动物每天平均有37.0摄氏度的T（b）节律，且偏移范围约为4摄氏度。在打架期间没有检测到T（b）节律，这是因为没有T（b）节律或因为每天的偏移范围小于0.2摄氏度。我们在安纳托利亚地松鼠中观察到的一般冬眠模式与之前在其他种类的地松鼠中的其他研究人员所观察到的冬眠模式相似。

BACKGROUND & AIMS: :Musculoskeletal disorders such as knee osteoarthritis (OA) are the primary cause of chronic pain in older adults. Recommended self-management strategies for knee OA include staying physically active in the face of pain, but many patients avoid activities they are capable of doing. The overall purpose of this study was to examine the extent to which daily pain catastrophizing, a maladaptive coping strategy, could influence OA patients' physical activity and sedentary behavior. The current study used data from 143 older knee OA patients who completed electronic daily diaries for 22 days and wore an accelerometer to capture physical activity and sedentary behavior. At the beginning of each day, patients reported their pain catastrophizing regarding the day ahead. Results from multilevel models demonstrated that on mornings when patients catastrophized more than usual about their pain in the day ahead, they spent more time in sedentary behavior and engaged in fewer minutes of moderate to vigorous physical activity that day. Cross-day lagged analyses further showed that the effect of morning pain catastrophizing on subsequent sedentary behavior extended to the next day. More time spent in sedentary behavior, in turn, contributed to greater pain catastrophizing the next morning. These findings support the mechanistic role of daily pain catastrophizing in the avoidance of physical activity for older OA patients, and suggest that effective interventions for pain catastrophizing may also reduce sedentary behavior and enhance physical activity, with longer-term benefits for pain management, physical function, and overall health.

背景与目标： ：肌肉骨骼疾病，例如膝骨关节炎（OA）是老年人慢性疼痛的主要原因。推荐的膝盖OA自我管理策略包括在面对疼痛时保持身体活动，但许多患者会避免进行自己能做的活动。这项研究的总体目的是研究灾难性的每日疼痛（一种适应不良的应对策略）在多大程度上影响OA患者的身体活动和久坐行为。当前的研究使用了143名年龄较大的膝盖OA患者的数据，这些患者完成了22天的每日电子日记，并佩戴了加速度计来捕捉身体活动和久坐的行为。在每天的开始，患者报告前一天的疼痛是灾难性的。多级模型的结果表明，早晨患者在前一天遭受的痛苦比平常多得多，他们在久坐行为上花费的时间更多，并且当天参加中度到剧烈运动的时间更少。跨日滞后分析进一步表明，早晨疼痛的灾难性后果对随后的久坐行为的影响延续到第二天。反过来，花在久坐行为上的时间更多，则导致第二天早上更大的痛苦成为灾难。这些发现支持了每日疼痛剧烈化在避免老年OA患者身体活动中的机械作用，并表明有效的疼痛剧烈化干预措施还可以减少久坐的行为并增强身体活动，对疼痛管理，身体机能具有长期益处，以及整体健康状况。

BACKGROUND & AIMS: PURPOSE:The aim of this study was to evaluate the extent of the variation in the position of the prostate bed with respect to the bony anatomy. METHODS AND MATERIALS:Four patients were treated to 70 Gy in 35 fractions. Before each fraction, a megavoltage computed tomography (CT) of the prostate bed was obtained, resulting in a total of 140 CT studies. Retrospectively, each CT scan was aligned to the simulation kilovoltage scan based on bony anatomy and the prostate bed. The difference between the 2 alignments was calculated for each scan. RESULTS:The average differences (+/-1 SD) between the two alignments were 0.06+/-0.37, 0.10+/-0.86, and 0.39+/-1.27 mm in the lateral, longitudinal (SI), and vertical (AP) directions, respectively. Laterally, there was no difference>or=3 mm. The cumulative frequency of SI differences were as follows; >or=3 mm: 3%, >or=4 mm: 1%, and >or=5 mm: 1% (maximum: 5 mm). The cumulative frequency of AP differences were as follows; >or=3 mm: 7%, and >or=4 mm: 3% (maximum: 4 mm). CONCLUSION:In patients with prostate cancer receiving postoperative radiotherapy, the prostate bed motion relative to the pelvic bony anatomy is of a relatively small magnitude. Significant motion (>or=3 mm) is infrequent. However, small differences between the prostate bed and the bony anatomy still exist. This might have implications on treatment margins when daily alignment on bony anatomy is performed.

背景与目标： 目的：本研究的目的是评估相对于骨解剖结构的前列腺床位置变化的程度。
方法和材料：四例患者按35份分次接受70 Gy的治疗。在每个部分之前，先获得了前列腺床的兆伏计算机断层扫描（CT），总共进行了140次CT研究。回顾性地，将每个CT扫描与基于骨骼解剖结构和前列腺床的模拟千伏扫描对齐。每次扫描计算两次比对之间的差异。
结果：两次排列之间的横向，纵向（SI）和垂直（AP）方向的平均差异（/ -1 SD）分别为0.06 /-0.37、0.10 /-0.86和0.39 /-1.27 mm。横向上，没有差异>或= 3 mm。 SI差异的累积频率如下： ≥3mm：3％，≥4mm：1％，≥5mm：1％（最大：5mm）。 AP差异的累积频率如下： ≥3mm：7％，≥4mm：3％（最大：4mm）。
结论：在接受术后放疗的前列腺癌患者中，相对于骨盆骨解剖结构而言，前列腺床运动相对较小。很少有明显的运动（>或= 3 mm）。但是，前列腺床和骨解剖结构之间仍然存在微小差异。每天进行骨骼解剖对准时，这可能对治疗余量有影响。

BACKGROUND & AIMS: AIMS:To investigate the effect of adding the short-acting glucagon-like peptide 1 receptor agonist (GLP-1RA) exenatide to insulin treatment on markers of cardiovascular risk in type 1 diabetes. MATERIALS AND METHODS:In a randomized, double-blind, parallel-group trial, 108 individuals with type 1 diabetes aged ≥18 years on multiple daily injection therapy with a body mass index >22.0 kg/m2 and glycated haemoglobin concentration of 59 to 88 mmol/mol (7.5%-10.0%) were randomized (1:1) to preprandial subcutaneous injection of 10 μg exenatide (Byetta®) or placebo three times daily over 26 weeks as add-on treatment to existing insulin therapy. Reported markers of cardiovascular risk were secondary endpoints and were analyzed in a baseline-adjusted linear mixed model in the intention-to-treat population. The primary results of this study, the MAG1C (Meal-time Administration of exenatide for Glycaemic control in type 1 diabetes Cases) trial, were previously reported. RESULTS:Exenatide changed total fat mass by -2.6 kg (95% confidence interval [CI] -3.6; -1.6; P < 0.0001) and lean body mass by -1.1 kg (95% CI -1.9; -0.4; P = 0.01) compared with placebo, as assessed by dual-energy X-ray absorptiometry. Fat mass reductions were similar for central and peripheral fat mass. Exenatide did not change levels of interleukin-2 or -6; tumour necrosis factor-α; C-reactive protein; N-terminal prohormone of brain natriuretic peptide; or 8-oxo-7,8-dihydroguanosine (RNA oxidation marker) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (DNA oxidation marker). CONCLUSIONS:Exenatide added to insulin therapy in type 1 diabetes for 26 weeks resulted in body weight loss primarily from fat mass reduction, but had no effect on biomarkers of cardiovascular disease risk.

背景与目标： 目的：研究在胰岛素治疗中添加短效胰高血糖素样肽1受体激动剂（GLP-1RA）艾塞那肽对1型糖尿病心血管风险标志物的影响。
材料与方法：在一项随机，双盲，平行组试验中，对108名≥18岁的1型糖尿病患者进行了多次每日注射治疗，体重指数> 22.0 kg / m2，糖化血红蛋白浓度为59至88在26周内，每天3次在餐前皮下注射10μg艾塞那肽（Byetta®）或安慰剂，随机（1：1）将mmol / mol（7.5％-10.0％）作为现有胰岛素治疗的补充治疗。报告的心血管风险标志物是次要终点，并在经过意向治疗的人群中进行了基线调整的线性混合模型中进行了分析。该研究的主要结果是MAG1C（艾塞那肽的全日制口服以控制1型糖尿病患者的血糖）试验，此前已有报道。
结果：艾塞那肽使总脂肪量减少-2.6千克（95％置信区间[CI] -3.6; -1.6; P <0.0001），瘦体重减少-1.1千克（95％CI -1.9; -0.4; P = 0.01） ）与安慰剂比较（通过双能X射线吸收法评估）。中央和周围脂肪量的脂肪减少量相似。艾塞那肽未改变白介素2或-6的水平；肿瘤坏死因子-α； C反应蛋白脑利钠肽的N端激素原；或8-oxo-7,8-dihydroguanosine（RNA氧化标记）和8-oxo-7,8-dihydro-2'-deoxyguanosine（DNA氧化标记）。
结论：艾塞那肽在1型糖尿病的胰岛素治疗中使用了26周，导致体重减轻，主要原因是脂肪减少，但对心血管疾病风险的生物标志物没有影响。

BACKGROUND & AIMS: :Objectives: The work interval duration between the end of one workday and the start of the following workday is referred to as the daily rest period (DRP). The present study examined whether DRP - a proxy for sleep opportunity between work shifts - is associated with indicators of sleep debt and social jetlag among daytime workers. Methods: We used a web-based survey to gather data on demographics, average DRP in the previous month, time in bed (TIB), bedtime, wake-up time, and sleep timing on workdays and non-workdays. The Japanese daytime workers (n = 3,914) were divided into seven DRP groups (hours) as follows: <11, 11, 12, 13, 14, 15, and ≥16. Results: The two-way analyses of covariance (DRP group x day) for TIB, mid-sleep as sleep timing, bedtime, and wake-up time showed significant interactions (all p < .001). Specifically, TIB was significantly shorter, and mid-sleep and wake-up time were significantly earlier on workdays than on non-workdays, across all DRP groups (all p < .001). Additionally, the different values for TIB (sleep debt), sleep timing (social jetlag), bedtime, and wake-up time were calculated by subtracting workdays from non-workdays. The trend analysis showed that workers with longer DRP (sleep opportunity) had smaller differences in TIB, sleep timing, and wake-up time between workdays and non-workdays (all p < .001). Conclusions: Overall, daytime workers reported significant sleep debt and misalignment between work and free sleep-wake periods. However, workers with shorter DRPs (less sleep opportunity between shifts) reported significantly greater amounts of sleep debt and social jetlag than did workers with longer DRPs.

背景与目标： 目标：一个工作日结束至下一个工作日开始之间的工作间隔持续时间被称为每日休息时间（DRP）。本研究调查了DRP（工作轮班之间的睡眠机会的代表）是否与白天工作人员的睡眠债务和社会时差指标相关。方法：我们使用基于网络的调查来收集有关人口统计数据，上个月的平均DRP，上床时间（TIB），就寝时间，起床时间以及工作日和非工作日的睡眠时间的数据。日本的日间工作人员（n = 3,914）被分为七个DRP组（小时），分别为：<11、11、12、13、14、15和≥16。结果：对TIB，半睡，睡眠时间，就寝时间和苏醒时间进行协方差（DRP组x天）的双向分析显示出显着的交互作用（所有p <0.001）。具体而言，在所有DRP组中，TIB显着缩短，并且在工作日的半睡眠和唤醒时间比在非工作日显着更早（所有p <0.001）。此外，通过从非工作日中减去工作日来计算TIB（睡眠债务），睡眠时间（社会时差），就寝时间和起床时间的不同值。趋势分析表明，工作日与非工作日之间具有较长DRP（睡眠机会）的工人在TIB，睡眠时间和唤醒时间方面的差异较小（所有p <0.001）。结论：总体而言，日间工作人员报告了严重的睡眠负担，以及工作与自由睡眠-觉醒时间之间的错位。但是，与具有较长DRP的工人相比，具有较短DRP的工人（轮班之间较少的睡眠机会）报告了更多的睡眠债务和社会时差。

BACKGROUND & AIMS: :Many disorders can injure the spinal cord resulting in long-term chronic myelopathy. Spinal cord dysfunction influences the homeostasis of multiple organ systems ranging from the heart or lung to the integument, thus presenting a wide variety of challenges for medical management. Although most of our knowledge about the consequences of myelopathies derives from the study of traumatic spinal cord injuries, similar complications occur in myelopathies of all etiologies. The authors survey some of the important clinical issues that the general neurologist needs to consider in caring for patients with chronic spinal cord disease.

背景与目标： ：许多疾病可能会损伤脊髓，导致长期的慢性脊髓病。脊髓功能障碍会影响从心脏或肺部到皮被的多个器官系统的体内平衡，从而给医疗管理带来了各种各样的挑战。尽管我们对脊髓病的后果的大多数了解来自对脊髓损伤的研究，但在所有病因的脊髓病中都发生了类似的并发症。作者调查了一般神经科医生在照顾慢性脊髓疾病患者时需要考虑的一些重要临床问题。

BACKGROUND & AIMS: :A 33-year-old female is presented with the first case to our knowledge of new daily persistent headache (NDPH) with a large right benign non-toxic multinodular goiter causing carotid and vertebral compression with complete resolution of the headache immediately after thyroidectomy. Although this may be quite rare, hypothyroidism or hyperthyroidism causing NDPH, migraine, or an exacerbation of pre-existing migraine is not. Clinicians should consider routinely obtaining serum thyroid-stimulating hormone (TSH) and free T4 in patients with new onset frequent headaches or an exacerbation of prior primary headaches.

背景与目标： ：一名33岁的女性首次被告知我们新的每日持续性头痛（NDPH），伴有较大的右良性无毒多结节性甲状腺肿，引起颈动脉和椎骨受压，甲状腺切除术后立即完全缓解了头痛。尽管这种情况很少见，但引起NDPH，偏头痛或加重已有偏头痛的甲状腺功能减退或甲状腺功能亢进并不是这种情况。对于新出现的频繁头痛或先前原​​发性头痛加重的患者，临床医生应考虑常规获取血清甲状腺刺激激素（TSH）和游离T4。

BACKGROUND & AIMS: :The European Society of Cardiology (ESC) and the European Heart Rhythm Association (EHRA) published new guidelines for pacemaker and cardiac resynchronisation therapy in June 2013. The most important recommendations for daily clinical practice of pacemaker therapy firstly refer to the diagnosis of bradycardia and bradycardia-symptom-correlation. Bradycardia is classified into persistent and intermittent, the latter with and without documentation of spontaneous bradycardia. Evidence for pacemaker therapy depends on the quality of bradycardia-symptom-correlation. The indication for pacing in sick-sinus-syndrome and AV block is significantly simplified and the use of implantable loop-recording in syncope of unknown origin encouraged. If loop recorders document long asymptomatic pauses, the authors felt that an indication for pacing exists if pauses exceed 6 sec. Other newly defined pacing indications are syncope in bundle branch block and very long PR (> 300 ms), particularly in older patients and those with structural heart disease. New insights and recommendations are further provided for complications of pacemaker therapy, right ventricular pacing sites, perioperative anticoagulation, pacing and magnetic resonance imaging and remote monitoring. In conclusion, the new ESC guidelines elegantly summarize results of new trials and studies in bradycardia and pacemaker therapy and provide valuable recommendations for daily practice.

背景与目标： ：2013年6月，欧洲心脏病学会（ESC）和欧洲心律协会（EHRA）发布了有关起搏器和心脏再同步治疗的新指南。起搏器治疗的日常临床实践中最重要的建议首先涉及心动过缓的诊断和心动过缓症状相关。心动过缓分为持续性和间歇性，后者有或没有自发性心动过缓。起搏器治疗的证据取决于心动过缓-症状相关的质量。病窦综合征和房室传导阻滞起搏的指征明显简化，并鼓励在未知来源的晕厥中使用可植入的循环记录。如果循环记录器记录了很长的无症状停顿，则作者认为如果停顿超过6秒，则存在起搏迹象。其他新定义的起搏适应症是束支传导阻滞和很长的PR（> 300 ms）晕厥，尤其是在老年患者和患有结构性心脏病的患者中。对于起搏器治疗，右心室起搏部位，围手术期抗凝，起搏和磁共振成像以及远程监测的并发症，还提供了新的见识和建议。总之，新的ESC指南很好地总结了心动过缓和起搏器疗法的新试验和研究结果，并为日常实践提供了有价值的建议。

BACKGROUND & AIMS: BACKGROUND:Use/misuse of the opioid combination hydrocodone-acetaminophen has been associated with permanent hearing loss. Although reports have been rare, this potential effect can have significant detrimental effect on patients' overall quality of life. To date, the ototoxic effect of hydrocodone alone has not been systematically investigated. OBJECTIVE:In this report, we aimed to evaluate the potential ototoxicity of a novel, single-entity, once-daily, extended-release hydrocodone tablet (Hysingla® ER; HYD). STUDY DESIGN:Clinical study. SETTING:Audiology clinics in US. METHODS:Results from 1207 patients in two phase 3 clinical studies were evaluated: A placebo-controlled study with an enriched enrollment, randomized withdrawal design in patients with chronic low back pain, and an open-label, long-term, safety study in patients with chronic nonmalignant and non-neuropathic pain. Comprehensive audiologic assessments (comprising pure-tone air-conduction audiometry in the conventional [0.25-8 kHz] and ultra-high [10-16 kHz] frequencies, pure-tone bone-conduction audiometry, tympanometry, speech reception thresholds, and word recognition) were conducted at baseline and end-of-studies; air-conduction audiometry was conducted periodically during the studies. All audiologic assessments were performed in audiology clinics in the United States by licensed audiologists. The primary endpoint was changes from baseline in pure-tone air-conduction thresholds in the conventional frequencies during the studies. These trials are registered with ClinicalTrials.gov, identifiers NCT01400139 and NCT01452529. RESULTS:During the studies, mean changes from baseline in air-conduction thresholds were clinically unremarkable. Bidirectional variability across all test frequencies was observed; 82% of patients did not experience significant threshold changes during the studies, 7% had potential hearing decrement, and 10% experienced hearing sensitivity improvement. No notable differences were observed between patients receiving HYD and placebo or between different HYD doses. CONCLUSION:No ototoxic signal was observed for single-entity hydrocodone tablets at the dosages and treatment durations investigated. Key words: Audiologic monitoring, clinical trials, hydrocodone, opioids, ototoxicity monitoring, sensorineural hearing loss.

背景与目标： 背景：使用/滥用阿片类药物氢可酮-对乙酰氨基酚与永久性听力损失有关。尽管报道很少，但这种潜在影响可能会对患者的整体生活质量产生重大不利影响。迄今为止，尚未单独研究氢可酮的耳毒性作用。
目的：在本报告中，我们旨在评估新型，单实体，每日一次，延长释放的氢可酮片剂（Hysingla®ER; HYD）的潜在耳毒性。
研究设计：临床研究。
地点：美国的听力诊所。
方法：对两项3期临床研究中的1207例患者的结果进行了评估：一项安慰剂对照研究，包括一项丰富的研究，针对慢性下腰痛患者的随机停药设计以及一项针对患者的长期开放性安全性研究伴有慢性非恶性和非神经性疼痛。全面的听力学评估（包括常规[0.25-8 kHz]和超高[10-16 kHz]频率中的纯音气导测听，纯音骨导测听，鼓室测压，语音接收阈值和单词识别）在基线和研究结束时进行；在研究期间定期进行空气传导测听。所有听力学评估都是由持牌听力学家在美国的听诊诊所进行的。主要终点是研究期间常规频率中纯音空气传导阈值相对于基线的变化。这些试验已在ClinicalTrials.gov上注册，标识为NCT01400139和NCT01452529。
结果：在研究中，空气传导阈值相对于基线的平均变化在临床上无显着性。观察到在所有测试频率上的双向变化；在研究期间，有82％的患者没有出现明显的阈值变化，有7％的患者可能会听力下降，有10％的患者的听力敏感性得到了改善。在接受HYD和安慰剂的患者之间或不同HYD剂量之间未观察到显着差异。
结论：在所研究的剂量和治疗持续时间下，单实体氢可酮片未观察到耳毒性信号。关键词：听力学监测，临床试验，氢可酮，阿片类药物，耳毒性监测，感觉神经性听力损失。

BACKGROUND & AIMS: AIMS:This study seeks to examine whether contextual factors influence adolescents' daily smoking. A focus was placed on three modifiable policies operating at a national level, non-smoking policy at educational facilities, price and minimum age for buying tobacco. DESIGN:This study is based on a merged data set consisting of the 2001/02 Health Behavior in School-aged Children (HBSC) study and national-level data collected from the 2003 WHO European Tobacco Control Database and the World Development Indicators Database. HBSC is an international study including adolescents from 32 countries in Europe, Israel and North America. Data were analysed with multi-level hierarchical regression models. FINDINGS:The study found large differences in the prevalence of daily smoking among adolescents, and also large differences between boys and girls within some countries. The study found that smoking bans in schools were associated with lower odds ratios of daily smoking, which was the one positive association in the study. The study found no association between cigarette prices and adolescent daily smoking prevalence, and also the somewhat unexpected finding that having an age limit for allowing adolescents to purchase tobacco was associated with an increased risk of daily smoking. CONCLUSIONS:There was an association between mandatory national bans on smoking and lower smoking prevalence. This should be confirmed by studies that examine whether mandatory bans are more rigorously implemented than voluntary bans. If this association is causal, introducing mandatory bans may reduce adolescent smoking prevalence. The findings that price was unrelated to smoking prevalence undermine findings elsewhere that adolescent smokers are more price-sensitive than adult smokers, but longitudinal studies are needed.

背景与目标： 目的：本研究旨在研究背景因素是否影响青少年的日常吸烟。重点放在了在国家一级实施的三项可修改政策，教育设施中的禁烟政策，购买烟草的价格和最低年龄。
设计：本研究基于合并的数据集，该数据集包括2001/02学龄儿童健康行为（HBSC）研究以及从2003年世卫组织欧洲烟草控制数据库和世界发展指标数据库收集的国家级数据。 HBSC是一项国际研究，包括来自欧洲，以色列和北美的32个国家的青少年。使用多层次的层次回归模型分析数据。
结果：该研究发现青少年中每天吸烟的流行率存在很大差异，在某些国家中男孩和女孩之间也存在较大差异。该研究发现，学校禁止吸烟与每日吸烟几率较低相关，这是该研究的一项积极关联。该研究发现卷烟价格与青少年每日吸烟率之间没有关联，并且还有些出乎意料的发现，即允许青少年购买烟草的年龄限制与每日吸烟风险增加相关。
结论：国家强制性禁烟与降低吸烟率之间存在关联。这应该通过研究来验证，即研究强制性禁令是否比自愿性禁令更加严格地执行。如果这种关联是有因果关系的，则实施强制性的禁令可能会降低青少年吸烟率。价格与吸烟流行率无关的发现破坏了其他地方的发现，即青少年吸烟者比成人吸烟者对价格更敏感，但需要进行纵向研究。

BACKGROUND & AIMS: PURPOSE:Based on the observation that epileptic seizures can occur at specific times of the day, we looked for daily variation in an intracranial electrographic feature used by a responsive neurostimulator system to detect seizures. METHODS:A computationally efficient measure of intracranial EEG energy or complexity, the line length baseline, was calculated and reported by an external responsive neurostimulator during a clinical trial of device safety. Data were obtained from 24 consecutive patients with medically intractable epilepsy undergoing intracranial monitoring over 2 to 54 days to localize the seizure onset zone. Measurements from individual subjects made at different times of day over many days were displayed on a single 24-h cycle and fit with a cosine function to characterize the time of the maximum value. The timing of epileptic seizures was also noted. RESULTS:The time of the maximum line length baseline value had a bimodal distribution with relative peaks at 05:30 and 15:00 hours. The time of the maximum value did not associate with specific brain regions, except that a nocturnal peak was not measured from temporal neocortex. The temporal distribution of maximum values was similar to the timing of epileptic seizures. CONCLUSION:The line length baseline feature of the intracranial EEG shows daily variation with location specific characteristics within individual subjects.

背景与目标： 目的：基于观察到癫痫性癫痫发作可能在一天的特定时间发生，我们寻找了反应性神经刺激系统用来检测癫痫发作的颅内电描记图特征的每日变化。
方法：在设备安全性临床试验期间，由外部响应神经刺激器计算并报告了颅内脑电图能量或复杂度的有效计算方法，即线长基线。从连续2到54天内接受颅内监测以定位癫痫发作区的连续24例医学上难治的癫痫患者获得数据。在单个一天的24小时周期内显示在一天中的不同时间进行的对单个对象的测量，并具有余弦函数以表征最大值的时间。还注意到了癫痫发作的时间。
结果：最大线长基线值的时间呈双峰分布，相对峰出现在05:30和15:00小时。最大值的时间与特定的大脑区域无关，只是没有从颞新皮层测量到夜间的峰值。最大值的时间分布类似于癫痫发作的时间。
结论：颅内脑电图的线长基线特征显示个体受试者中具有特定位置特征的每日变化。

BACKGROUND & AIMS: PURPOSE:Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. METHODS AND MATERIALS:Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completion rate, and survival. RESULTS:A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. CONCLUSIONS:In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.

背景与目标： 目的：膀胱保存疗法是一种治疗肌肉浸润性尿路上皮癌（UC）的有效方法。在这项研究中，我们通过每日放疗和每周紫杉醇治疗7个月的非膀胱切除术候选人。肿瘤表现出her2 / neu过表达的患者，每周还接受曲妥珠单抗治疗。
方法和材料：六十八例可评估的患者接受了放射疗法和紫杉醇曲妥珠单抗治疗（第1组）或单独使用紫杉醇治疗（第2组）。根据her2 / neu免疫组织化学结果分配组。患者接受了1.8 Gy的分数，总剂量为64.8 Gy。该研究的主要终点是与治疗相关的毒性，次要终点包括完全缓解（CR）率，方案完成率和生存率。
结果：第1组共治疗了20例可评估患者，第2组共治疗了46例患者。第1组中有20例患者中有7例（35％）出现急性治疗相关不良事件（AEs），第46组中有14例患者中有14例观察到急性治疗相关不良事件（AEs） 2（30.4％）。 60％（第1组）和74％（第2组）的患者完成了方案治疗。大多数不完全归因于毒性，并且大多数AE是胃肠道的，包括1种5级AE（第1组）。另外两例死亡（均为第2组）均与方案治疗无关。没有观察到意外的心脏，血液或其他毒性。 1年组的CR率为72％，2组为68％。
结论：对于不适合进行膀胱切除术的肌肉浸润性UC患者，每日放疗联合紫杉醇是一种有效的治疗策略，具有较高的完成率和中度毒性。在一般认为其结果较差的her2 / neu阳性肿瘤患者中，加入曲妥珠单抗似乎可产生相当的疗效和毒性。为了进一步治疗这种具有挑战性的疾病，应该进行进一步的生物标记物驱动的试验。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:Aclidinium bromide is a long-acting muscarinic antagonist approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). This 12-week phase III study evaluated efficacy and tolerability of aclidinium 200 or 400 μg in patients with moderate-to-severe COPD. METHODS:In this double-blind study, 544 patients with COPD were randomized to placebo or twice-daily aclidinium 200 or 400 μg administered by Genuair(®)/Pressair(®). Lung function, health status [measured by the St. George's Respiratory Questionnaire (SGRQ)], dyspnea [measured using the Transition Dyspnea Index (TDI)], and safety were assessed throughout the study. RESULTS:Mean changes from baseline in morning trough forced expiratory volume in 1 s (FEV(1)) at week 12 (primary endpoint) were significantly higher for aclidinium than for placebo (200 μg, 51 mL; 400 μg, 72 mL; both p < 0.05). Aclidinium also significantly improved other lung function outcomes. At week 12, improvements from baseline were observed with aclidinium in SGRQ total score (200 μg, -6.0; 400 μg, -5.4) and TDI focal score (200 μg, 1.0; 400 μg, 1.3). Furthermore, clinically important improvements in SGRQ total and TDI focal scores were achieved by 45 and 51 % of patients, respectively, who received aclidinium 400 μg, with a significant difference versus placebo for TDI (p < 0.05). Anticholinergic-related adverse events (e.g., dry mouth) were infrequent, occurring <2 % for any event in any treatment group. Both aclidinium doses were well tolerated. CONCLUSION:This study demonstrates efficacy and safety of aclidinium in COPD patients. Unexpected baseline imbalances between treatment groups may have impacted the aclidinium treatment benefit in this study.

背景与目标： 背景与目的：溴氰菊酯是一种长效毒蕈碱拮抗剂，被批准用于与慢性阻塞性肺疾病（COPD）相关的支气管痉挛的长期维持治疗。这项为期12周的III期研究评估了200或400μg沙丁胺醇对中重度COPD患者的疗效和耐受性。
方法：在这项双盲研究中，将544名COPD患者随机分配给Genuair（R）/ Pressair（R）给予安慰剂或每日两次200或400μg的阿地丁。在整个研究过程中，评估了肺功能，健康状况（通过圣乔治呼吸问卷（SGRQ）测量），呼吸困难（使用过渡呼吸困难指数（TDI）测量）和安全性。
结果：第12周（主要终点）在1 s（FEV（1））的早晨谷中强迫呼气量相对于基线的平均变化显着高于安慰剂（200μg，51 mL; 400μg，72 mL;两者均） p ＜0.05）。 Aclidinium还可以显着改善其他肺功能的预后。在第12周时，沙丁草胺的SGRQ总得分（200μg，-6.0; 400μg，-5.4）和TDI焦点得分（200μg，1.0; 400μg，1.3）较基线有改善。此外，分别接受Aclidinium 400μg的45％和51％的患者分别实现了SGRQ总得分和TDI得分的临床重要改善，与安慰剂相比，TDI差异有统计学意义（p <0.05）。抗胆碱能相关的不良事件（例如口干）很少见，在任何治疗组中，任何事件的发生率均＜2％。两种阿地丁剂量均耐受良好。
结论：本研究证明了沙丁胺醇对COPD患者的疗效和安全性。治疗组之间基线的意外失衡可能影响了本研究中阿立丁铵治疗的益处。