Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Objective: Report efficacy findings from three clinical trials (one phase 2 and two phase 3 [OPUS-1, OPUS-2]) of lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease (DED).

Research design and methods: Three 84-day, randomized, double-masked, placebo-controlled trials. Adults (≥18 years) with DED were randomized (1:1) to lifitegrast 5.0% or matching placebo. Changes from baseline to day 84 in signs and symptoms of DED were analyzed.

Main outcome measures: Phase 2, pre-specified endpoint: inferior corneal staining score (ICSS; 0–4); OPUS-1, coprimary endpoints: ICSS and visual-related function subscale (0–4 scale); OPUS-2, coprimary endpoints: ICSS and eye dryness score (EDS, VAS; 0–100).

Results: Fifty-eight participants were randomized to lifitegrast 5.0% and 58 to placebo in the phase 2 trial; 293 to lifitegrast and 295 to placebo in OPUS-1; 358 to lifitegrast and 360 to placebo in OPUS-2. In participants with mild-to-moderate baseline DED symptomatology, lifitegrast improved ICSS versus placebo in the phase 2 study (treatment effect, 0.35; 95% CI, 0.05–0.65; p?=?0.0209) and OPUS-1 (effect, 0.24; 95% CI, 0.10–0.38; p?=?0.0007). Among more symptomatic participants (baseline EDS ≥40, recent artificial tear use), lifitegrast improved EDS versus placebo in a post hoc analysis of OPUS-1 (effect, 13.34; 95% CI, 2.35–24.33; nominal p?=?0.0178) and in OPUS-2 (effect, 12.61; 95% CI, 8.51–16.70; p?<?0.0001).

Limitations: Trials were conducted over 12 weeks; efficacy beyond this period was not assessed.

Conclusions: Across three trials, lifitegrast improved ICSS in participants with mild-to-moderate baseline symptomatology in two studies, and EDS in participants with moderate-to-severe baseline symptomatology in two studies. Based on the overall findings from these trials, lifitegrast shows promise as a new treatment option for signs and symptoms of DED.     

腰硬联合镇痛及患者自控镇痛对产程及分娩结局的影响

目的 探讨腰硬联合(CSEA)及患者自控镇痛(PCEA)对产程及分娩结局的影响。方法 随机选取2014年1~12月足月待产、无妊娠合并症和并发症初产妇996例,其中503例产妇于活跃期实施CSEA+PCEA镇痛(分娩镇痛组),493例未行分娩镇痛(对照组),分别记录并比较两组产妇各产程时间、子宫收缩、镇痛效果、运动神经阻滞程度、产程中缩宫素的使用率、产后出血率、羊水Ⅲ度污染率、新生儿Apgar评分、产钳助产和剖宫产率。结果 分娩镇痛组第一产程、第二产程较对照组有所延长,差异有统计学意义(P<0.05);第三产程无明显改变;子宫收缩力减弱;分娩镇痛组较对照组镇痛效果显著,差异有统计学意义(P<0.05);运动阻滞程度低;缩宫素使用率、产后出血率、羊水Ⅲ度污染率、及新生儿Apgar评分及产钳助产和剖宫产率两组比较,差异均无统计学意义(P>0.05)。结论 腰硬联合分娩镇痛可能会使第一产程、第二产程延长,对子宫收缩力有一定的影响,但并未增加缩宫素的使用率及产钳助产和剖宫产率,其镇痛效果显著,运动阻滞程度低,对分娩结局无不良影响。     

Thermodynamic stability of wild-type and mutant p53 core domain

Some 50% of human cancers are associated with mutations in the core domain of the tumor suppressor p53. Many mutations are thought just to destabilize the protein. To assess this and the possibility of rescue, we have set up a system to analyze the stability of the core domain and its mutants. The use of differential scanning calorimetry or spectroscopy to measure its melting temperature leads to irreversible denaturation and aggregation and so is useful as only a qualitative guide to stability. There are excellent two-state denaturation curves on the addition of urea that may be analyzed quantitatively. One Zn²⁺ ion remains tightly bound in the holo-form of p53 throughout the denaturation curve. The stability of wild type is 6.0 kcal (1 kcal = 4.18 kJ)/mol at 25°C and 9.8 kcal/mol at 10°C. The oncogenic mutants R175H, C242S, R248Q, R249S, and R273H are destabilized by 3.0, 2.9, 1.9, 1.9, and 0.4 kcal/mol, respectively. Under certain denaturing conditions, the wild-type domain forms an aggregate that is relatively highly fluorescent at 340 nm on excitation at 280 nm. The destabilized mutants give this fluorescence under milder denaturation conditions.     

Removal of surface bacteria by irrigation

We examined the efficacy of various irrigation solutions delivered through a power irrigator to remove bacteria from three different surfaces. Titanium, stainless-steel, and cortical bone surfaces were coated with three different bacterial species: Staphylococcus aureus, Pseudomonas aeruginosa, and Staphylococcus epidermidis. They were then irrigated with 1 L of fluid delivered by jet lavage. The fluids tested were normal saline and solutions of bacitracin, neomycin, and soap. One set of specimens was not irrigated, as a control. After irrigation, the specimens were sonicated to remove residual bacteria, and the sonicate was quantitatively cultured to allow evaluation of the amount of residual bacteria on the surface. The results showed that removal of bacteria reflects an interaction between bacterial species, surface characteristics, and irrigation solution. Fewer bacteria were present in all the irrigation groups than in the control. Soap solution was as good as or better than any other solution at removing all three types of bacteria from all three surfaces, although not all of the pairwise comparisons were statistically significant. There was a significant advantage to soap solution over antibiotic irrigant or saline alone in removing Staphylococcus epidermidis from metallic surfaces. The use of a soap solution for irrigation seems to improve the removal of some bacteria from some surfaces in this experimental model and may represent a better type of irrigation additive.     

Alpha-adrenoreceptor reagents. 4. Resolution of some potent selective prejunctional alpha 2-adrenoreceptor antagonists

The resolution of three 2-substituted derivatives of idazoxan is described. The enantiomers show large separations in activity in a variety of in vitro and in vivo tests, and the active isomers are all potent and selective antagonists at the alpha 2-adrenoreceptor. The significance of these results in relation to those published on the enantiomers of idazoxan and to those on optically active alpha 2-adrenoreceptor agonists is discussed.     

5339例创伤患者创伤及死亡特点分析

目的　探讨创伤患者创伤及死亡特点。方法　回顾性分析 1996年 1月至 2 0 0 0年 12月我院收治 5 3 3 9例创伤患者的临床资料。结果　 5 3 3 9例创伤患者中男性 3 910例 ,女性 14 2 9例 ,平均受伤年龄 (3 5 3± 3 3 7)岁 ,2 0～ 2 9岁占 64 19%。治愈好转5 168例 ,死亡 47例 ,3 1例死于重型、特重型颅脑损伤。结论　创伤的高危人群为青壮年 ,且男性多于女性 ,交通事故是本组创伤的第一位原因。把创伤的预防与控制作为一项政府工程 ,加强宣传和教育 ,改善交通状况等均对创伤的预防与控制有重要意义     

Endoscopic pterygopalatine space surgery

Although lesions of the pterygopalatine space are uncommon, there are instances in which this relatively inaccessible region must be entered for biopsy or excision of masses. Traditional open approaches to the pterygopalatine space, involving external or intraoral incisions, provide limited visualization and carry associated morbidities. The evolution and advancement of endoscopic sinus surgical technique in recent years has led to its application to anatomic areas outside the strict limits of the sinonasal cavities. Such minimally invasive approaches are safe, effective, and spare unnecessary discomfort to the patient. This article describes the authors' method for performing an endoscopic approach to the pterygopalatine space.     

Release of cortical catecholamines by visual stimulation requires activity in thalamocortical afferents of monkey and cat

Catecholamine (CA) release was measured in vivo in the monkey and cat visual cortices electrochemically. Stereate-modified, graphite-paste electrodes were used to monitor changes in norepinephrine and dopamine release. Micromolar changes in CA concentration were obtained by stimulation of the eye with nonspecific (strobe) or specific (oriented bars, radial gratings) stimuli. CA release depended on which eye was illuminated. Electrodes passed tangentially through the striate area recorded release following visual stimulation of one eye or the other in succession, and the shift in eye dominance occurred at about 500 microns intervals. The magnitude of CA release was highly correlated with the ocular dominance of neuronal activity measured with tungsten microelectrodes. Light-stimulated release was not recorded in monkey area V2, V4, or somatosensory area 1, but was recorded in cat V2, suggesting that the presence of LGN afferents is associated with CA release. Results are discussed in terms of the role of geniculate activity and the specific role of CAs in cortical information processing.     

Renal function and the disposition of antidepressants and their metabolites.

Reports of plasma concentrations of antidepressants and their metabolites in patients with reduced renal function have been reviewed. The consequences of alteration of various pharmacokinetic factors on drug and metabolite concentrations have been compared with the observed data. Concentrations of drugs that are more than 95 percent metabolized are not altered by decreased renal function. Concentrations of drugs that are mostly excreted unchanged in urine are greatly increased in patients with reduced renal function. Concentrations of metabolites that account for 10 percent or more of the dose of a parent drug in urine are usually increased. In general, the observations can be explained without hypothesizing an effect of reduced renal function on clearance by metabolism.