Relative Efficacies Research Articles

Comparison of Free Radical Scavenging Abilities of Various Chalcone Antioxidants

Free radicals are highly reactive chemical species found in cells; various reactive oxygen species (ROS) are produced as a result of normal cell metabolism, air pollution, smoking, UV radiation, and inflammation. Oxidative stress may be the cause of many neurodegenerative and cardiovascular diseases, and continued oxidative stress in cells leads to loss of cell membrane integrity, DNA damage, and apoptosis. Chalcone antioxidants, found in plants and foods, stabilize ROS. Chalcones have antifungal, anti‐inflammatory, antimalarial, antitumor, and antiviral activities. The present study concerns relative efficacies of various hydroxylated chalcones in comparison with one another and with synthetic antioxidants. Free radical scavenging abilities of seven hydroxylated chalcones were analyzed using 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) assays. Triplicate results confirmed previous results by our group that chalcones with 5′‐hydroxyl groups performed significantly better. Synthetic chalcones performed with less efficacy than natural chalcones. Butylated hydroxytoluene (BHT), a synthetic antioxidant found in processed foods, was used as a standard and had the least efficacy. In addition, the analysis of single crystal X‐ray studies on these chalcones solidifies the role of intermolecular interactions of hydroxyl groups in antioxidant activity. Supported by HHMI 52006322 and VC URSI 2012.

How Birth Interval and Antenatal Care Affects Postpartum Haemorrhage Prevention in Maiduguri, Nigeria

The following work studied how birth interval and antenatal care contribute to occurence of postpartum haemorrhage and how these factors modulates the preventive efficacies of oxytocin injection and misoprostol tablets in postpartum haemorrhage. A total of 1140 pregnant women who have received either oxytocin injection or oral misoprostol in third stage of labour as a prophylaxis of postpartum haemorrhage, were enrolled within three health care facilities in Maiduguri, Nigeria. Each patient was observed at parturition and for 24 h after during which blood lost was estimated to the nearest ml. Maternal characteristics were recorded in a structured proforma. The relationship of the occurrence of PPH (blood loss > 500 ml) and mean blood loss was studied with respect to the prophylactic medication used and some obstetric factors. The occurrence of PPH in subjects that had ‘inadequate’ resting period (29.3 %) was higher than that of the ‘adequate’ resting period group (2 %). Misoprostol exhibited greater PPH prevention in the “inadequate” resting period category (83.9 versus 38.8%). The enrolees that had inadequate antenatal care exhibited higher occurrence of PPH than the adequate group (21.6 versus 16.6%). In the misoprostol medication sub-group, there was significantly (p < 0.001) higher occurrence of PPH in the “adequate ANC” category (37.6%) than in the “inadequate ANC” category (7.1%). Inadequate birth interval and inadequate antenatal care are risk factors for PPH. The relative efficacies of oral misoprostol and parenteral oxytocin significantly vary with varying level of antenatal care and birth interval.

Relative efficacies of insulin and poly (lactic-co-glycolic) acid encapsulated nano-insulin in modulating certain significant biomarkers in arsenic intoxicated L6 cells

The present study evaluates relative efficacies of insulin and PLGA-loaded-nano-insulin (NIn) in combating arsenic-induced impairment of glucose uptake, insulin resistance and mitochondrial dysfunction in L6 skeletal muscle cells. L6 cells were treated with 0.5mM sodium arsenite for 30min and then the cells were further treated with either 100nM insulin (standardized dose) or either of the two doses, 50nM and 100nM of nano-insulin. Various biomarkers like pyruvate-kinase and glucokinase, ATP/ADP ratio, mitochondrial membrane potential, cytosolic release of mitochondrial cytochrome c, cell membrane potential and calcium-ion level were studied and analyzed to ascertain the status of mitochondrial functioning in all experimental and control sets of L6 cells. The size, morphology and zeta potential of formulated NIn were determined by using dynamic light scattering, scanning electronic and atomic-force microscopies. Expression of signalling cascades like GLUT4, IRS1, IRS2, UCP2, PI3, and p38 was critically analyzed. Overall results suggested that both insulin and NIn improved mitochondrial functioning in arsenite-intoxicated L6 cells, NIn showing better effects at a much lower dose (at nearly 10-fold decreased dose) than that produced by insulin. Nano-insulin being non-toxic and effective at a much lesser dose, therefore, has potential for therapeutic use in the management of arsenic induced diabetes.

Structural modeling and simulation studies of human cyclooxygenase (COX) isozymes with selected terpenes: Implications in drug designing and development

In view of recently implicated role of COX-1 in human health and diseases, including cancer, development of safe and selective drugs, as COX-1 inhibitor is desirable. Human COX-1 and COX-2 isozymes have been modeled using in silico tools and relative efficacies of terpenoids as their inhibitors have been investigated by docking. The docking analyses of 10 selected terpenoids along with drugs revealed that all of the terpenoids were more potent inhibitors of COX-1 rather than COX-2 with the oleanolic acid as the most potent inhibitor of COX in general (binding energy [−18.68Kcal/mol and −18.25Kcal/mol] and estimated Ki [5.57×10−8µM and 11.4×10−8µM] for COX-1 and COX-2, respectively) and β-carotene as most selective inhibitor of COX-1. Furthermore, ibuprofen and aspirin were found to be preferential inhibitor of COX-1 and COX-2, respectively.

Pharmacodynamic Evaluation of the Intracellular Activity of Antibiotics towards Pseudomonas aeruginosa PAO1 in a Model of THP-1 Human Monocytes

Pseudomonas aeruginosa invades epithelial and phagocytic cells, which may play an important role in the persistence of infection. We have developed a 24-h model of THP-1 monocyte infection with P. aeruginosa PAO1 in which bacteria are seen multiplying in vacuoles by electron microscopy. The model has been used to quantitatively assess antibiotic activity against intracellular and extracellular bacteria by using a pharmacodynamic approach (concentration-dependent experiments over a wide range of extracellular concentrations to calculate bacteriostatic concentrations [Cs] and maximal relative efficacies [Emax]; Hill-Langmuir equation). Using 16 antipseudomonal antibiotics (three aminoglycosides, nine β-lactams, three fluoroquinolones, and colistin), dose-response curves were found to be undistinguishable for antibiotics of the same pharmacological class if data were expressed as a function of the corresponding MICs. Extracellularly, all of the antibiotics reached a bacteriostatic effect at their MIC, and their Emax exceeded the limit of detection (-4.5 log(10) CFU compared to the initial inoculum). Intracellularly, Cs values remained unchanged for β-lactams, fluoroquinolones, and colistin but were approximately 10 times higher for aminoglycosides, whereas Emax values were markedly reduced (less negative), reaching -3 log(10) CFU for fluoroquinolones and only -1 to -1.5 log(10) CFU for all other antibiotics. The decrease in intracellular aminoglycoside potency (higher Cs) can be ascribed to the acid pH to which bacteria are exposed in vacuoles. The decrease in the Emax may reflect a reversible alteration of bacterial responsiveness to antibiotics in the intracellular milieu. The model may prove useful for comparison of antipseudomonal antibiotics to reduce the risk of persistence or relapse of pseudomonal infections.

Indirect comparison of clobazam and other therapies for Lennox-Gastaut syndrome

In the absence of head-to-head trials, it is not feasible to make direct comparisons of antiepileptic therapies for the treatment of Lennox-Gastaut syndrome (LGS). We conducted indirect comparisons of the relative efficacies of clobazam, felbamate, lamotrigine, topiramate, and rufinamide as adjunctive treatments for LGS. Clinical studies of LGS patients were identified in a 2009 Cochrane review and by electronic database search. Five randomized controlled trials were included in this systematic review, which reports findings from indirect comparisons between clobazam and other approved adjunctive LGS therapies (felbamate, lamotrigine, topiramate, rufinamide) in the United States and Europe. As outcomes were not uniformly reported across studies, the primary efficacy endpoint from each trial was transformed into Cohen's d effect size, to facilitate indirect comparisons. Typical interpretations of Cohen's d results are as follows: d < 0.2, change not detectable; 0.2 ≤ d < 0.5, small change; 0.5 ≤ d < 0.8, moderate change; and 0.8 ≤ d, large change. High-dosage clobazam (1.0 mg/kg/day) was found to have the strongest treatment effect vs placebo (effect size 0.80), with moderate effects (effect sizes >0.50) for medium-dosage clobazam (0.5 mg/kg/day) and rufinamide. Felbamate, lamotrigine, and topiramate had low effect sizes. Indirect comparisons of numbers of total seizures and tonic-atonic seizures ('drop attacks') demonstrated superiority of both clobazam dosages over all comparators. High- and medium-dosage clobazam was estimated to be more efficacious than other LGS treatments. Our analysis relied on published data and could not draw on direct head-to-head data of clobazam with alternatives. Further comparative research is ongoing to assess the usefulness of clobazam for LGS.

Antibodies to gp120 and PD-1 Expression on Virus-Specific CD8 + T Cells in Protection from Simian AIDS

We compared the relative efficacies against simian immunodeficiency virus (SIV) challenge of three vaccine regimens that elicited similar frequencies of SIV-specific CD4(+) and CD8(+) T-cell responses but differed in the level of antibody responses to the gp120 envelope protein. All macaques were primed with DNA plasmids expressing SIV gag, pol, env, and Retanef genes and were boosted with recombinant modified vaccinia Ankara virus (MVA) expressing the same genes, either once (1 × MVA) or twice (2 × MVA), or were boosted once with MVA followed by a single boost with replication-competent adenovirus (Ad) type 5 host range mutant (Ad5 h) expressing SIV gag and nef genes but not Retanef or env (1 × MVA/Ad5). While two of the vaccine regimens (1 × MVA and 1 × MVA/Ad5) protected from high levels of SIV replication only during the acute phase of infection, the 2 × MVA regimen, with the highest anti-SIV gp120 titers, protected during the acute phase and transiently during the chronic phase of infection. Mamu-A*01 macaques of this third group exhibited persistent Gag CD8(+)CM9(+) effector memory T cells with low expression of surface Programmed death-1 (PD-1) receptor and high levels of expression of genes associated with major histocompatibility complex class I (MHC-I) and MHC-II antigen. The fact that control of SIV replication was associated with both high titers of antibodies to the SIV envelope protein and durable effector SIV-specific CD8(+) T cells suggests the hypothesis that the presence of antibodies at the time of challenge may increase innate immune recruiting activity by enhancing antigen uptake and may result in improvement of the quality and potency of secondary SIV-specific CD8(+) T-cell responses.

How some demographic factors affects postpartum haemorrhage prevention in Maiduguri, Nigeria

Aim: The following work studied how tribal affiliation, educational level and occupation of some women that had PPH in Maiduguri metropolis between September 2007 and March 2009 relate with PPH occurrence. The study was aimed at identifying possible risk factors and also to compare the relative prevention efficacies of oxytocin or misoprostol within the matrix of these factors. Method: A total of 1800 pregnant women who have received either oxytocin injection or oral misoprostol in third stage of labour as a prophylaxis of postpartum haemorrhage, were enrolled within three health care facilities in Maiduguri, Nigeria. Each patient was observed at parturition and for 24 h after, during which blood lost was estimated to the nearest millilitres. Demographic characteristics were recorded in a structured proforma. The relationship of the occurrence of PPH (occurrence of blood loss > 500 ml) and mean blood loss (MBL) was studied with respect to the prophylactic medication used and some demographic factors. Results: The incidence of PPH was higher in Igbo, and some “minority” tribes of Borno state (Babur, Bura, Mafa). The tribes that constituted the majority of the study population (Kanuri, and Hausa) exhibited low incidences of PPH. Significant relationships were demonstrated between PPH and educational levels and occupations of participants. Conclussions: It was concluded that PPH occurrence is related to tribal affiliation, educational level and occupation, and the relative efficacies of oxytocin and misoprostol varies between the tribal groups.

Simultaneous and Longitudinal Comparison of Interferon Gamma Release Assay Data from Health Care Workers in Japan

Background: Tuberculosis is one of the serious occupational diseases among health care workers, especially those who work with patients suffering from respiratory disorders. It is important to assess latent tuberculosis infection status in such workers using interferon- release assays, including QuantiFERON-TB Gold and its successor, the QuantiFERON-TB Gold in-Tube test. Although the relative efficacies of these two methods have been evaluated in patients with tuberculosis, data from health care workers in Japan have not been extensively examined. Purpose: In the present study, we examined the utilities of the QuantiFERON-TB Gold and QuantiFERON-TB Gold in-Tube tests to detect latent tuberculosis infections in staff working in a respiratory disease hospital in Japan. We also longitudinally compared data from these subjects obtained using the QuantiFERON-TB Gold assay. Methods: We collected blood samples from 120 staff members and performed both the QuantiFERON-TB Gold and QuantiFERON-TB Gold in-Tube assays. A total of 58 subjects had previously been tested 5 years prior using the QuantiFERON-TB Gold assay, and we compared these data with our more recent information. Results: The QuantiFERON-TB Gold in-Tube test tended to yield higher test values than did the QuantiFERONTB Gold test, suggesting that the former test may be more sensitive when used to detect latent tuberculosis infection. In both tests, the results differed in 32 instances (26.7%), associated with significant difference (p<0.001, =0.55). In 94 subjects with negative QuantiFERON-TB Gold test results, 16 (17.0%) were intermediate and 11 (11.7%) positive by QuantiFERON-TB Gold in-Tube test. The longitudinal comparison confirmed this suggestion. The number of subjects rated “intermediate” in terms of tuberculosis status differed, with statistical significance, when the two datasets were compared. Conclusion: Health care workers should be screened for possible tuberculosis infections using the QuantiFERON-TB Gold in-Tube test, which is more sensitive than the QuantiFERON-TB Gold test.

Laparoscopy versus open distal gastrectomy by expert surgeons for early gastric cancer in Japanese patients: short-term clinical outcomes of a randomized clinical trial

Short-term outcomes of laparoscopy-assisted distal gastrectomy (LADG) and open DG (ODG) have been investigated in previous clinical trials, but operative techniques and concomitant treatments have evolved, and up-to-date evidence produced by expert surgeons is required to provide an accurate image of the relative efficacies of the treatments. The purpose of this study was to compare laparoscopic versus ODG with respect to specific primary and secondary short-term outcomes. From October 2005 to February 2008, a total of 64 patients with early gastric cancer were randomly assigned to the LADG or the ODG group. One patient was excluded due to concurrent illness unrelated to the intervention, so the data from 63 patients were analyzed. The primary short-term outcome was the 4-day postoperative use of analgesics. Secondary short-term outcomes were postoperative residual pain, complications, days hospitalized, blood data, days with fever, and days to first flatus. There was a significant difference in favor of LADG for postoperative use of analgesics (P = 0.022). Unexpectedly, there was no significant difference in degree of pain in the immediate postoperative period, putatively due to the optimal use of analgesics. Of the secondary outcomes, residual pain at postoperative day 7 (P = 0.003) and days to first flatus (P = 0.001) were significantly better with LADG. Postoperative complications, number of days hospitalized, and number of days with fever were also better with LADG, but the differences were not significant. Blood data representing inflammation (WBC and CRP) showed marked differences, especially on postoperative day 7 (P = 0.0016 and P = 0.0061, respectively). LADG performed by expert surgeons results in less postoperative pain accompanied by decreased surgical invasiveness and is associated with fewer postoperative inconveniences. No preliminary suggestions of changes in long-term curability were observed. LADG for early gastric cancer is a feasible and safe procedure with short-term clinical results superior to those of ODG.

Activity of ceftaroline against extracellular (broth) and intracellular (THP-1 monocytes) forms of methicillin-resistant Staphylococcus aureus: comparison with vancomycin, linezolid and daptomycin

Ceftaroline fosamil is approved for treatment of acute bacterial skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We examined the activity of its active metabolite (ceftaroline) against intracellular forms of S. aureus in comparison with vancomycin, daptomycin and linezolid. Two methicillin-susceptible S. aureus (MSSA) and 11 MRSA strains with ceftaroline MICs from 0.125 to 2 mg/L [two strains vancomycin- and one strain linezolid-resistant (EUCAST interpretative criteria); VISA and cfr+] were investigated. The activity was measured in broth and after phagocytosis by THP-1 monocytes in concentration-dependent experiments (24 h of incubation) to determine: (i) relative potencies (EC(50)) and static concentrations (C(s)) (mg/L and × MIC); and (ii) relative activities at human C(max) (E(C)(max)) and maximal relative efficacies (E(max)) (change in log(10) cfu compared with initial inoculum). Ceftaroline stability and cellular accumulation (at 24 h) were measured by mass spectrometry. Ceftaroline showed similar activities in broth and in monocytes compared with vancomycin, daptomycin and linezolid, with no impact of resistance mechanisms to vancomycin or linezolid. For all four antibiotics, intracellular E(C)(max) and E(max) were considerably lower than in broth (∼0.5 log(10) versus 4-5 log(10) cfu decrease), but the EC(50) and C(s) showed comparatively little change (all values between ∼0.3 and ∼6× MIC). The mean cellular to extracellular ceftaroline concentration ratios (20 mg/L; 24 h) were 0.66 ± 0.05 and 0.90 ± 0.36 in uninfected and infected cells, respectively. In vitro, ceftaroline controls the growth of intracellular MRSA to an extent similar to that of vancomycin, linezolid and daptomycin for strains with a ceftaroline MIC ≤ 2 mg/L.

A network meta‐analysis to compare glycaemic control in patients with type 2 diabetes treated with exenatide once weekly or liraglutide once daily in comparison with insulin glargine, exenatide twice daily or placebo

The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exenatide once weekly (ExQW) and liraglutide once daily (QD) are indicated to improve glycaemic control in patients with type 2 diabetes. Although glycaemic control with ExQW versus liraglutide QD 1.8 mg has been directly compared, no studies have compared ExQW with liraglutide QD 1.2 mg or determined the probable relative efficacies of various injectable therapies for glycaemic control; therefore, a network meta-analysis was performed to address these questions. A systematic review identified randomized controlled trials of ≥24 weeks that compared ExQW, liraglutide QD (1.2 mg, 1.8 mg), insulin glargine, exenatide twice daily (ExBID), or placebo. Twenty-two studies evaluating 11 049 patients were included in the network meta-analysis. Mean differences in HbA1c relative to placebo or each other and probability rankings were estimated. Estimated mean differences in HbA1c versus placebo were -1.15% (95% CrI: -1.31 to -1.00) for ExQW, -1.01% (95% CrI: -1.18 to -0.85) for liraglutide 1.2 mg, and -1.18% (95% CrI: -1.32 to -1.04) for liraglutide 1.8 mg. HbA1c differences for ExQW versus liraglutide 1.2 mg and 1.8 mg were -0.14% (95% CrI: -0.34 to 0.06) and 0.03% (95% CrI: -0.14 to 0.18), respectively. The estimated mean difference in HbA1c between liraglutide 1.2 mg and 1.8 mg was 0.17% (95% CrI: 0.02-0.30). Results were consistent when adjusted for background antihyperglycaemic medications and diabetes duration. This network meta-analysis did not identify meaningful differences in HbA1c lowering between ExQW and both liraglutide doses, suggesting that these GLP-1 RAs have similar glycaemic effects.

A comparative evaluation of NB30, NB54 and PTC124 in translational read‐through efficacy for treatment of an USH1C nonsense mutation

Translational read-through-inducing drugs (TRIDs) promote read-through of nonsense mutations, placing them in the spotlight of current gene-based therapeutic research. Here, we compare for the first time the relative efficacies of new-generation aminoglycosides NB30, NB54 and the chemical compound PTC124 on retinal toxicity and read-through efficacy of a nonsense mutation in the USH1C gene, which encodes the scaffold protein harmonin. This mutation causes the human Usher syndrome, the most common form of inherited deaf-blindness. We quantify read-through efficacy of the TRIDs in cell culture and show the restoration of harmonin function. We do not observe significant differences in the read-through efficacy of the TRIDs in retinal cultures; however, we show an excellent biocompatibility in retinal cultures with read-through versus toxicity evidently superior for NB54 and PTC124. In addition, in vivo administration of NB54 and PTC124 induced recovery of the full-length harmonin a1 with the same efficacy. The high biocompatibilities combined with the sustained read-through efficacies of these drugs emphasize the potential of NB54 and PTC124 in treating nonsense mutation-based retinal disorders.

Contractile Efficacy of Various Prostaglandins in Pregnant Rat Myometrium Pretreated With Oxytocin

Oxytocin pretreatment of pregnant rat myometrium has been shown to reduce the contractions produced by further administration of oxytocin, as a function of the desensitization phenomenon. It is unclear whether this phenomenon affects the contractions produced by various prostaglandins that are used in the management of postpartum hemorrhage. The objective of this study was to investigate the contractile effects of various prostaglandins after oxytocin pretreatment and to compare their relative efficacies in vitro on pregnant rat myometrial strips. Myometrial samples from 29 pregnant Wistar rats at term were isolated and pretreated with oxytocin (10(-8) mol/L, experimental group) or physiological salt solution (control group) for 1 hour. They were then subjected to dose-response testing with oxytocin (n = 32), PGF2α (n = 16), dinoprostone (n = 14), alprostadil (n = 14), or misoprostol (n = 15) with cumulative increases in the organ bath concentrations from 10(-10) to 10(-5) mol/L. The contractile efficacies of various prostaglandins and oxytocin during the dose response were analyzed using mixed linear modeling and compared between the groups. There was no significant difference in the amplitude, frequency, motility index (amplitude × frequency), or area under the curve of all prostaglandins between the groups pretreated with oxytocin and the control group. However, there was a significant decrease in the frequency (P = .02) and motility index (P = .05) in the dose-response curves of oxytocin in the groups pretreated with oxytocin compared with the control groups. Overall, oxytocin produced superior contractions compared with all other prostaglandins, while dinoprostone and misoprostol produced the weakest contractions. The uterotonic effects of various prostaglandins are not affected by oxytocin desensitization; and despite desensitization, oxytocin provides superior contractions compared with the prostaglandins.

Incidence of C-shaped root canal systems in mandibular second molars in the native Chinese population by analysis of clinical methods

The aims of the study were to investigate the incidence of C-shaped root canal systems in mandibular second molars in a native Chinese population using radiography and clinical examination under microscope and to compare the relative efficacies of these methods. For the recognition of C-shaped root canal system, 1 146 mandibular second molars were selected and examined. Teeth with C-shaped canal systems were categorized by using the radiographic classification criteria and the modified Melton's method. C-shaped canals were identified in 397 (34.64%) mandibular second molars by radiography (type I, 31.23% type II, 38.29% type III, 30.48%). Clinical examination showed that 449 (39.18%) cases exhibited C-shaped canal systems (C1, 22.94% C2, 48.11% C3a, 15.59% C3b, 13.36%). As for the result of the radiographic and clinical combined examination, C-shaped root canals were found in 473 (41.27%) mandibular second molars (C1, 21.78% C2, 45.67% C3a, 16.70% C3b, 15.86%). The incidence of C-shaped root canal diagnosed by radiographic method was statistically different from that by clinical examination and the combined examination (P<0.05). The study indicated a high incidence of C-shaped canal system in a Chinese population. The combination of microscopic and radiographic examination is an effective method in identifying the C-shaped root canal system.

A network meta-analysis of the efficacy of inhaled antibiotics for chronic Pseudomonas infections in cystic fibrosis

BackgroundVarious inhaled antibiotics are currently used for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients, however their relative efficacies are unclear. We compared the efficacy of the inhaled antibiotics tobramycin (TIP, TIS-T, TIS-B), colistimethate sodium (colistin) and aztreonam lysine for inhalation (AZLI) based on data from randomised controlled trials. MethodsIn the base case, efficacies of antibiotics were compared using a network meta-analysis of seven trials including change from baseline in forced expiratory volume in 1second (FEV1) % predicted, P. aeruginosa sputum density and acute exacerbations. ResultsThe tobramycin preparations, AZLI and colistin, showed comparable improvements in efficacy in terms of FEV1% predicted at 4weeks; the difference in % change from baseline (95%CrI) for TIP was compared to TIS-T (-0.55, -3.5;2.4), TIS-B (-0.64, -7.1;5.7), AZLI (3.64, -1.0;8.3) and colistin (5.77, -1.2;12.8). ConclusionWe conclude that all studied antibiotics have comparable efficacies for the treatment of chronic P. aeruginosa lung infection in CF.

Anti-Vascular Endothelial Growth Factor Drug Treatment of Diabetic Macular Edema: The Evolution Continues

Diabetic mellitus is the leading cause of blindness in working aged patients in developing nations. Due to the buildup of abnormal metabolites from several overactive biochemical pathways, chronic hyperglycemia causes oxidative stress in the retina which upregulates vascular endothelial growth factor (VEGF). Together with other growth factors and metabolites, VEGF causes endothelial cell proliferation, vasodilation, recruitment of inflammatory cells, and increased vascular permeability, leading to breakdown of the blood-retinal barrier. This allows trans-cellular exudation into the interstitial space resulting in diabetic macular edema (DME). For over 3 decades the standard treatment for DME has been laser photocoagulation. Though laser reduces the incidence of vision loss by 50%, few eyes with diffuse edema experience improved vision. This has led physicians to use the VEGF-binding drugs pegaptanib, ranibizumab, and aflibercept, each of which has been approved for the treatment of exudative macular degeneration, and bevacizumab which is commonly used off-label for a variety of chorioretinal disorders. Intravitreal administration of each drug frequently causes rapid improvement of DME with sustained improvement in vision through 2 years. Though these drugs significantly outperform laser photocoagulation over treatment periods of 1 year of less, the advantages appear to lessen when trials approach 2 years. Further studies to better determine relative efficacies of anti-VEGF drugs and laser photocoagulation are continuing.

Indirect Comparison of Clobazam and Adjunctive Therapies for Lennox-Gastaut Syndrome: Results of an Effect-Size Analysis (P06.121)

Objective: We conducted indirect comparisons of the relative efficacies of clobazam, felbamate, lamotrigine, topiramate, and rufinamide as adjunctive treatments for patients with Lennox-Gastaut syndrome (LGS). Background It is not feasible to make direct comparisons of treatments for LGS without head-to-head studies. Design/Methods: We compared Phase III clobazam results in LGS 1 with RCT results of approved adjunctive LGS therapies from a 2009 Cochrane Review. 2 One of two lamotrigine studies in the Cochrane Review was not included, since randomization methodology for the published study was unclear. Since all 5 studies in our analysis, including the clobazam trial, employed these drugs with adjunctive therapy vs. placebo plus adjunctive therapy, we used traditional, pair-wise indirect comparisons to evaluate clobazam vs. the other drugs. As trial outcomes were not identical, we transformed primary endpoints into effect sizes (using Cohen9s d ). Typical interpretations of Cohen9s d results are: d d d d , large change. Results: High-dosage clobazam (1.0 mg/kg/day) had the greatest effect size, followed by medium-dosage clobazam (0.5 mg/kg/day), and rufinamide. According to Cohen9s d interpretation, effect size (0.80) for high-dosage clobazam was important. Medium-dosage clobazam and rufinamide had d -values >0.50, indicating a moderate clinical effect vs. placebo. Comparisons of numbers of total and drop or tonic-clonic seizures also supported the greater effect of high-dosage clobazam. Because of the few studies in the analysis, however, no results achieved statistical significance. Conclusions: High- and medium-dosage clobazam was estimated to be more efficacious than other LGS treatments. Our analysis relied on published data and could not draw on direct head-to-head data of clobazam with alternatives. Further comparative research is ongoing to assess the usefulness of clobazam for LGS. 1 Ng YT, et al. Neurology . 2011;77:1473–81. 2 Hancock EC, et al. Cochrane Database Syst Rev . 2009;8:CD003277. Supported by: Lundbeck SAS. Disclosure: Dr. Cramer has received personal compensation for activities with Bial, Eisai Inc., Sepracor, and UCB Pharma. Dr. Sabin has received personal compensation for activities with Lundbeck SAS as an employee. Dr. Gani has received personal compensation for activities with Lundbeck Research USA, Inc. an employee. Dr. Francois has received personal compensation for activities with Lundbeck Research USA, Inc.

A risk assessment model for Escherichia coli O157:H7 in ground beef and beef cuts in Canada: Evaluating the effects of interventions

A stochastic, quantitative risk assessment model was developed to evaluate the public health risks associated with consumption of ground beef and beef cuts contaminated with Escherichia coli O157:H7 in Canada. The objectives of this work were to evaluate the relative effects of pre-harvest and processing interventions on public health risks using a novel approach, and compare the baseline risks from consumption of ground beef, non-intact beef cuts, and intact beef cuts. Rather than considering efficacy of all interventions at primary production and processing as default values, the model incorporated findings from critical systematic review and meta-analysis of published literature. Public health risks, expressed as average probability of illness per serving, were reduced by 30.9%–72.1%, 44.0%–96.5%, and 95.1%–99.9%, for single pre-harvest interventions, single processing interventions excluding water spray chilling, and combinations of interventions, respectively, relative to a worst-case scenario where no pre-harvest or processing interventions were applied. Combinations of interventions applied at pre-harvest and throughout processing resulted in the greatest relative risk reductions through their effects on both prevalence and concentration of the pathogen in cattle faeces and on cattle carcasses. The use of systematic review methodology to critically assess the results of scientific studies before use of the data in risk modelling enhances the confidence in risk predictions and provides a more evidenced-based model for public health analyses. Analysis of conditions reflective of current practices in Canada indicated that risks from consumption of ground beef were approximately two to three orders of magnitude greater than those for beef cuts, suggesting that risk management measures should focus on the former product to maximize benefits to public health. Risks from consumption of non-intact beef cuts, that is, steaks or roasts that are tenderized, were an order of magnitude greater than those for intact beef cuts. The model provides a useful tool to compare relative efficacies of different intervention strategies to determine their potential impact on public health risks. This tool can be used to evaluate an essentially limitless combination of intervention scenarios and can be adapted to include interventions applied at different points along the farm-to-fork continuum as critically-reviewed data become available.

The safety and efficacy of live attenuated influenza vaccine in young children with asthma or prior wheezing

In the European Union and Canada, an Ann Arbor strain live attenuated influenza vaccine (LAIV) is approved for use in children aged 2–17 years, including those with mild to moderate asthma or prior wheezing. The safety and efficacy of LAIV versus trivalent inactivated influenza vaccine (TIV) in children with asthma aged 6–17 years have been demonstrated. However, few data are available for children younger than 6 years of age with asthma or prior wheezing. Safety and efficacy data were collected for children aged 2–5 years with asthma or prior wheezing from two randomized, multinational trials of LAIV and TIV (N = 1,940). Wheezing, lower respiratory illness, and hospitalization were not significantly increased among children receiving LAIV compared with TIV. Increased upper respiratory symptoms and irritability were observed among LAIV recipients (p < 0.05). Relative efficacies were consistent with the results observed in the overall study populations, which demonstrated fewer cases of culture-confirmed influenza illness in LAIV compared with TIV recipients. Study results support the safety and efficacy of LAIV among children aged 2–17 years with mild to moderate asthma or a history of wheezing. Data regarding LAIV use are limited among individuals with severe asthma or active wheezing within the 7 days before vaccination.