Direct Comparison Studies Research Articles

Comparison of Angiogenic Activities of Three Neuropeptides, Substance P, Secretoneurin, and Neuropeptide Y Using Myocardial Infarction.

The interplay between neurogenesis and angiogenesis is crucial during the development mediated by neuro-angiogenic morphogens. In particular, the angiogenic activity of neuropeptides and their role in tissue regeneration have long been investigated for better understanding of their biological mechanisms and further applications. However, there have been few studies for direct comparison of angiogenic activities of neuropeptides for in vitro and in vivo models. In this study, we report that direct comparison of the angiogenic activities of neuropeptide Y, secretoneurin, and substance P (SP) immobilized on hydrogels in in vitro and in vivo experiments. A hyaluronic acid-based hydrogel is prepared by utilizing acrylated hyaluronic acid and thiolated peptides as a crosslinker and angiogenic factors, respectively. Angiogenic activities of three neuropeptides are evaluated not only by in vitro angiogenic and gene expression assays, but also by an in vivo chronic myocardial infarction model. The comparison of in vitro angiogenic activities of three peptides demonstrates that the SP-immobilized hydrogel shows a higher degree of cell network formation and angiogenic-specific genes than those of the other peptides and the control case. In addition, a three-dimensional angiogenic assay illustrates that more sprouting is observable in the SP group. Evaluation of regenerative activity in the chronic myocardial infarction model reveals that all three peptide-immobilized hydrogels induce increased cardiac function as well as structural regeneration. Among all the cases, the SP group provided the highest regenerative activity both in vitro and in vivo. In our comparison study, the SP-immobilized hydrogel shows the highest angiogenic activity and tissue regeneration among the test groups. This result suggests that nerve regeneration factors help angiogenesis in damaged tissues, which also highlights the importance of the neuro-angiogenic peptides as an element of tissue regeneration.

Balancing and cyclically sequencing synchronous, asynchronous, and hybrid unpaced assembly lines

Mixed-model assembly lines are product-oriented production layouts often employed for large scale manufacturing of similar products. The unpaced variant of these lines employs a conveyor to discretely move pieces between stations either synchronously or asynchronously. Workload balancing and product sequencing are common optimization problems associated with these lines. While many works detail balancing and sequencing separately, few explicitly combine these degrees of freedom. Furthermore, hybrid (i.e. partly synchronous and partly asynchronous) lines are not explicitly described by previous optimization models. This paper presents a mixed-integer linear programming model capable of representing such unpaced lines and explicitly combine balancing, sequencing and cyclical scheduling. The application of the proposed method to a new dataset demonstrates the advantages of simultaneously balancing and sequencing lines, generating more efficient solutions than previously described models for 238 out of 240 instances. These results implied, however, in greater computational costs required to combine the degrees of freedom. Furthermore, a direct performance comparison study between synchronous, asynchronous, and hybrid lines is conducted. This allows line designers and managers to explicitly evaluate economical trade-offs between these line types.

High discharged energy density of polymer nanocomposites containing paraelectric SrTiO3 nanowires for flexible energy storage device

Nanocomposites combining high permittivity ferroelectric nanofillers and high breakdown strength polymer have shown tremendous potential for pulsed power applications. Nevertheless, the discharged energy density and efficiency of these nanocomposites filled with ferroelectric fillers are limited due to the large remanent polarization of ferroelectric fillers employed. Here, uniform elongated morphology paraelectric SrTiO3 nanowires fillers were synthesized via a special stirring hydrothermal method. The fabricated P(VDF-CTFE)-based nanocomposites containing 3 vol% paraelectric SrTiO3 nanowires exhibit an enhanced discharged energy density of 8.8 J/cm3 at 3381 kV/cm, which exceeds most of the current reports at the same electric field. By direct comparison study with ferroelectric BaTiO3 nanowires fillers, the results show paraelectric SrTiO3 nanowires can simultaneously improve the discharged energy density and efficiency more effectively. Such enhancement in energy storage performance can be attributed to the following reasons: (I) The enhanced breakdown strength, which resulted from the reduced inhomogeneous electric fields via adopting the SrTiO3 nanowires with lower permittivity. (II) The paraelectric phase SrTiO3 nanowires show little hysteresis behavior compared to ferroelectric phase BaTiO3 nanowires. This work is of critical significance in making advanced dielectric nanocomposites that are viable for energy storage devices in current electronic and electrical applications.

PSA-stratified detection rates for [68Ga]THP-PSMA, a novel probe for rapid kit-based 68Ga-labeling and PET imaging, in patients with biochemical recurrence after primary therapy for prostate cancer.

[68Ga]Tris(hydroxypyridinone)(THP)-PSMA is a novel radiopharmaceutical for one-step kit-based radiolabelling, based on direct chelation of 68Ga3+ at low concentration, room temperature and over a wide pH range, using direct elution from a 68Ge/68Ga-generator. We evaluated the clinical detection rates of [68Ga]THP-PSMA PET/CT in patients with biochemically recurrent prostate cancer after prostatectomy. Consecutive patients (n=99) referred for evaluation of biochemical relapse of prostate cancer by [68Ga]THP-PSMA PET/CT were analyzed retrospectively. Patients underwent a standard whole-body PET/CT (1 h p.i.), followed by delayed (3 h p.i.) imaging of the abdomen. PSA-stratified cohorts of positive PET/CT results, standardized uptake values (SUVs) and target-to-background ratios (TBRs) were analyzed, and compared between standard and delayed imaging. At least one lesion suggestive of recurrent or metastatic prostate cancer was identified on PET images in 52 patients (52.5%). Detection rates of [68Ga]THP-PSMA PET/CT increased with increasing PSA level: 94.1% for a PSA value of ≥10 ng/mL, 77.3% for a PSA value of 2 to <10 ng/mL, 54.5% for a PSA value of 1 to <2 ng/mL, 14.3% for a PSA value of 0.5 to <1 ng/mL, 20.0% for a PSA value of >0.2 to <0.5, and 22.2% for a PSA value of 0.01 to 0.2 ng/mL. [68Ga]THP-PSMA uptake (SUVs) in metastases decreased over time, whereas TBRs improved. Delayed imaging at 3 h p.i. exclusively identified pathologic findings in 2% of [68Ga]THP-PSMA PET/CT scans. Detection rate was higher in patients with a Gleason score ≥8 (P=0.02) and in patients receiving androgen deprivation therapy (P=0.003). In this study, [68Ga]THP-PSMA PET/CT showed suitable detection rates in patients with biochemical recurrence of prostate cancer and PSA levels ≥ 2 ng /mL. Detections rates were lower than in previous studies evaluating other PSMA ligands, though prospective direct radiotracer comparison studies are mandatory particularly in patients with low PSA levels to evaluate the relative performance of different PSMA ligands.

Do male athletes with already high initial haemoglobin mass benefit from 'live high-train low' altitude training?

What is the central question of this study? It has been assumed that athletes embarking on an 'live high-train low' (LHTL) camp with already high initial haemoglobin mass (Hbmass ) have a limited ability to increase their Hbmass further post-intervention. Therefore, the relationship between initial Hbmass and post-intervention increase was tested with duplicate Hbmass measures and comparable hypoxic doses in male athletes. What is the main finding and its importance? There were trivial to moderate inverse relationships between initial Hbmass and percentage Hbmass increase in endurance and team-sport athletes after the LHTL camp, indicating that even athletes with higher initial Hbmass can reasonably expect Hbmass gains post-LHTL. It has been proposed that athletes with high initial values of haemoglobin mass (Hbmass ) will have a smaller Hbmass increase in response to 'live high-train low' (LHTL) altitude training. To verify this assumption, the relationship between initial absolute and relative Hbmass values and their respective Hbmass increase following LHTL in male endurance and team-sport athletes was investigated. Overall, 58 male athletes (35 well-trained endurance athletes and 23 elite male field hockey players) undertook an LHTL training camp with similar hypoxic doses (200-230h). The Hbmass was measured in duplicate pre- and post-LHTL by the carbon monoxide rebreathing method. Although there was no relationship (r=0.02, P=0.91) between initial absolute Hbmass (in grams) and the percentage increase in absolute Hbmass , a moderate relationship (r=-0.31, P=0.02) between initial relative Hbmass (in grams per kilogram) and the percentage increase in relative Hbmass was detected. Mean absolute and relative Hbmass increased to a similar extent (P≥0.81) in endurance (from 916±88 to 951±96g, +3.8%, P<0.001 and from 13.1±1.2 to 13.6±1.1gkg-1 , +4.1%, P<0.001, respectively) and team-sport athletes (from 920±120 to 957±127g, +4.0%, P<0.001 and from 11.9±0.9 to 12.3±0.9gkg-1 , +4.0%, P<0.001, respectively) after LHTL. The direct comparison study using individual data of male endurance and team-sport athletes and strict methodological control (duplicate Hbmass measures and matched hypoxic dose) indicated that even athletes with higher initial Hbmass can reasonably expect Hbmass gain post-LHTL.

A Biomechanical Comparison of Proportional Electromyography Control to Biological Torque Control Using a Powered Hip Exoskeleton.

Despite a large increase in robotic exoskeleton research, there are few studies that have examined human performance with different control strategies on the same exoskeleton device. Direct comparison studies are needed to determine how users respond to different types of control. The purpose of this study was to compare user performance using a robotic hip exoskeleton with two different controllers: a controller that targeted a biological hip torque profile and a proportional myoelectric controller. We tested both control approaches on 10 able-bodied subjects using a pneumatically powered hip exoskeleton. The state machine controller targeted a biological hip torque profile. The myoelectric controller used electromyography (EMG) of lower limb muscles to produce a proportional control signal for the hip exoskeleton. Each subject performed two 30-min exoskeleton walking trials (1.0 m/s) using each controller and a 10-min trial with the exoskeleton unpowered. During each trial, we measured subjects' metabolic cost of walking, lower limb EMG profiles, and joint kinematics and kinetics (torques and powers) using a force treadmill and motion capture. Compared to unassisted walking in the exoskeleton, myoelectric control significantly reduced metabolic cost by 13% (p = 0.005) and biological hip torque control reduced metabolic cost by 7% (p = 0.261). Subjects reduced muscle activity relative to the unpowered condition for a greater number of lower limb muscles using myoelectric control compared to the biological hip torque control. More subjects subjectively preferred the myoelectric controller to the biological hip torque control. Myoelectric control had more advantages (metabolic cost and muscle activity reduction) compared to a controller that targeted a biological torque profile for walking with a robotic hip exoskeleton. However, these results were obtained with a single exoskeleton device with specific control configurations while level walking at a single speed. Further testing on different exoskeleton hardware and with more varied experimental protocols, such as testing over multiple types of terrain, is needed to fully elucidate the potential benefits of myoelectric control for exoskeleton technology.

Direct comparison study of DNA methylation markers in EpCAM-positive circulating tumour cells, corresponding circulating tumour DNA, and paired primary tumours in breast cancer.

Circulating Tumour Cells (CTCs) and circulating tumour DNA (ctDNA) represent a non-invasive liquid biopsy approach for the follow-up and therapy management of cancer patients. We evaluated whether DNA methylation status in CTCs and ctDNA is comparable and whether it reflects the status of primary tumours. We compared the methylation status of three genes, SOX17, CST6 and BRMS1 in primary tumours, corresponding CTCs and ctDNA in 153 breast cancer patients and healthy individuals, by using real time methylation specific PCR. We report a clear association between the EpCAM-positive CTC-fraction and ctDNA for SOX17 promoter methylation both for patients with early (P = 0.001) and metastatic breast cancer (P = 0.046) but not for CST6 and BRMS1. In early breast cancer, SOX17 promoter methylation in the EpCAM-positive CTC-fraction was associated with CK-19 mRNA expression (P = 0.006) and worse overall survival (OS) (P = 0.044). In the metastatic setting SOX17 promoter methylation in ctDNA was highly correlated with CK-19 (P = 0.04) and worse OS (Ρ = 0.016). SOX17 methylation status in CTCs and ctDNA was comparable and was associated with CK-19 expression but was not reflecting the status of primary tumours in breast cancer. DNA methylation analysis of SOX17 in CTCs and matched ctDNA provides significant prognostic value.

Evidence Is Enough?: A Systematic Review and Network Meta-Analysis of the Efficacy of Tamsulosin 0.2 mg and Tamsulosin 0.4 mg as an Initial Therapeutic Dose in Asian Benign Prostatic Hyperplasia Patients.

PurposeWe compared the efficacy of tamsulosin between 0.2 mg and 0.4 mg in Asian prostatic hyperplasia (BPH) patients using network meta-analysis due to lack of studies with direct comparison.MethodsThe literature search was conducted using the MEDLINE, Embase, and Cochrane Library. Keywords used were “BPH,” “tamsulosin,” “placebo.” Experimental groups were defined as tamsulosin 0.2 mg (Tam 0.2) and 0.4 mg (Tam 0.4) and common control group was defined as placebo for indirect treatment comparison. Mixed treatment comparison was performed including one direct comparison study.ResultsSeven studies met the eligible criteria. Indirect treatment comparison revealed that total International Prostate Symptoms Score (IPSS) and quality of life score of IPSS were not significantly different in Tam 0.2 and Tam 0.4 (P>0.05). There was no significant difference of maximal flow rate and postvoid residual urine volume in Tam 0.2 and Tam 0.4 (P>0.05). Mixed treatment comparison including one direct comparison study showed inconsistency (P<0.001). Therefore, analysis using direct treatment comparison effect sizes of Tam 0.2 vs. placebo and Tam 0.4 vs. placebo was done and there was no significant difference.ConclusionsNetwork meta-analysis showed no difference of efficacy between tamsulosin 0.2 mg and 0.4 mg and the evidence of tamsulosin 0.4 mg as initial dose for Asian BPH patient seems to be insufficient. Therefore, initial dose of tamsulosin for Asian BPH patient should be 0.2 mg.

Invited commentary

The fact that the knowledge of human anatomy is essential to any clinician is self-evident. Even more detailed anatomic knowledge is needed for surgeons who operate on the knee or on the vasculature of the popliteal fossa; this includes anatomic variations of the popliteal artery. Modern imaging makes planning of surgical interventions much easier, yet in some cases the imaging either cannot be done or may not be sufficient for appropriate surgical planning. In these cases, being prepared to meet an unusual anatomy can save time and minimize surgical trauma. Despite this commonly shared understanding of the importance of an accurate anatomic knowledge, often we rely on old descriptions derived from a few cadaveric dissections. By combining available data from multiple sources, the manuscript published in this issue of the Journal provides contemporary information on the incidence of anatomic variants of the popliteal artery. It is reassuring to know that the prevalence of the most common variant (type I) is 96%, and each of those that are most challenging from the surgical point of view (II-A2 and II-C) have a prevalence of <0.5%. It is also useful to know that the prevalence of specific variants is different in populations of Asia, Europe, and North America, although no direct comparison studies have been done. Apart from the subject matter, this paper is an example of the utilization of contemporary research methodology, such as meta-analysis, in the fields of knowledge that traditionally rely on qualitative research. Hundreds of thousands of imaging studies are done in patients with different diseases and conditions as well as in healthy individuals. Many such studies use standard protocols. Despite the existence of such an enormous volume of anatomic information, few attempts have been made to mine these data and to produce generalizable knowledge. By demonstrating feasibility of such an approach, this paper serves as a catalyst for similar studies answering important anatomic questions, such as ethnic anatomic differences, differences between the cadaveric and imaging studies, and the clinical value of anatomic variants combined with pathologic changes. The evidence-based surgical anatomy of the popliteal artery and the variations in its branching patternsJournal of Vascular SurgeryVol. 65Issue 2PreviewThe goal of our study was to analyze the prevalence of branching pattern variations in the popliteal artery (PA) along with morphometrics of the PA to better address its importance in disease and vascular surgical procedures. Full-Text PDF Open Archive

Comparative efficacy and safety of infliximab biosimilar (BCD-055) and innovator infliximab in patients with ankylosing spondylitis (results of international, multiple-center, double-blind phase I and phase III clinical studies)

This article presents results from two clinical trials of infliximab biosimilar, BCD-055, including comparative data on the pharmacokinetics (PK), efficacy and safety of BCD-055 and innovator infliximab (IFX) in patients with ankylosing spondylitis (AS). Objective : The purpose of phase I clinical study ASART-1 was to evaluate the pharmacokinetic and safety profile of BCD-055 and to prove its equivalence with Remicade®, phase III study ASART-2 was conducted to evaluate the efficacy and tolerability of BCD-055 in comparison with Remicade® in patients with active AS. Patients and methods : Both studies were conducted as international multi-center randomized double-blind studies in direct comparison with innovator IFX. Inclusion and exclusion criteria, main examination methods, and drug regimens were the same in both trials. A total of 199 patients were enrolled in the studies. After the screening, the patients were stratified by CRP and BASDAI score, randomized (1:1 ratio in ASART-1; 2:1 ratio in ASART-2) into 2 arms and received BCD-055 or innovator IFX at a dose 5 mg/kg IV at 0, 2, 6 and then every 8 weeks (up to week 54). The primary endpoint for PK profile evaluation was the area under the concentration-time curve (AUC(0-tau)), maximum serum concentration of infliximab at steady state Cmax,ss. Efficacy was assessed by achieving ASAS20 at week 30, the endpoints for safety profile were the incidence of adverse events and serious adverse events during the maintenance-dosing phase and withdrawals from the study due to the safety reasons. Results : A total of 81 patients (ASART-1 study) were included in PK analysis, 199 patients were in efficacy and safety analysis. AUC(0-tau) value were 25,420,996.25±11,635,015.74 (ng/ml) Cmax,ss for BCD-055 and 26,114,705.71±12,102,376.9 (ng/ml)⋅h for INF innovator (p>0.05). Cmax,ss for BCD-055/Remicade® was 122,752 [99,401–151,553] ng/ml and 119,844 [98,120–132,772] ng/ml, respectively (p>0.05). ASAS20 was achieved at week 30 by 81.30% of the patients in the BCD-055 group, and 67.74% in the INF innovator group (p=0.061). The analysis of secondary endpoints (BASDAI, BASMI, BASFI, MASES, quality of life, chest excursion, and number of pathologically changed joints) showed no difference between the biosimilar and innovator groups. BCD-055 and innovator IFX showed highly similar safety profiles in both studies without cases of unexpected toxicity. The rates of AEs were equivalent for both drugs and were 48.48% and 58.21% of patients in the BCD-055 and Remicade®, respectively. Conclusion : BCD-055 is found to be equivalent in terms of PK, and showed the similarity in efficacy and safety profile compared with innovator IFX in patients with active AS.

Comparison of immunogenicity and safety of an influenza vaccine administered concomitantly with a 13-valent pneumococcal conjugate vaccine or 23-valent polysaccharide pneumococcal vaccine in the elderly.

PurposePrevious studies have demonstrated the immunogenicity and safety of the co-administration of the trivalent inactivated influenza vaccine (IIV3) with the polysaccharide pneumococcal vaccine (PPV) or pneumococcal conjugate vaccine (PCV). However, there is no direct comparison study that evaluates the immunogenicity and safety of IIV3 given concomitantly with PCV13 or PPV23 in the elderly.Materials and MethodsDuring the 2012-2013 influenza vaccination period, 224 healthy elderly volunteers aged 65 years and older randomly received IIV3 given concomitantly with either PCV13 (PCV13+IIV3) or PPV23 (PPV23+IIV3) in a 1:1 ratio. Serum hemagglutination-inhibiting antibodies for IIV3 were measured at the time of vaccination and 1 month after vaccination. Adverse events were recorded prospectively in a clinical diary during a 7-day period.ResultsA total of 220 participants blood samples for analysis of immunogenicity and kept a clinical diary for safety analysis (PCV13+IIV3, n=110; PPV23+IIV3, n=110). One month after vaccination, both groups satisfied the Committee for Medical Products for Human Use criteria for A/H1N1, A/H3N2 and B strains, showing comparable seroprotection rates, seroconversion rates and geometric mean titer fold. The assessments of immunogenicity were similar in both groups. The most common local and systemic reactions were pain at the injection site and generalized myalgia. They were generally mild or moderate in intensity. The adverse events were not statistically different between the two groups.ConclusionPCV13+IIV3 and PPV23+IIV3 demonstrated similar immunogenicity and safety in the elderly.

Influence of Macromolecular Crowding and Confinement on Enzyme Activity and Structure under Native and Denaturing Conditions

It is now well appreciated that both crowding and confinement influence enzyme structure and function due to excluded volume effects; however, the relative efficacies of these environments on protein fates remain unclear due to a lack of direct comparison studies. In this study, we explore the use of the biopolymer alginate to develop an in vitro platform to investigate the effects of both crowding and confinement on the behavior of two model enzymes - horseradish peroxidase and β-galactosidase. Alginate, in its solution phase, can be used as a crowding agent and, in its gel phase by crosslinking using divalent cations, to encapsulate and confine proteins, thereby allowing us to use the same system to directly compare the effects of crowding and confinement. Different degrees of crowding and confinement were achieved by varying the alginate concentration, and these studies demonstrated a clear dependence of enzyme activity on the degree of crowding and confinement. Moreover, our data also suggested that protein confinement in crosslinked alginate gels led to higher enhancements in enzyme activity under denaturing conditions relative to non-crosslinked crowded environments. Results from the kinetic analyses were corroborated using structural measurements of protein denaturation using the 8-anilinonaphthalene-1-sulfonic acid fluorescence assay.

Efficacy and safety of different doses of evolocumab in reducing low-density lipoprotein cholesterol levels: A meta-analysis.

Evolocumab has been considered as an efficacious, safe and promising therapeutic modality for hypercholesterolemia and is associated with cardiovascular diseases. The efficacy and safety of two different doses of evolocumab were evaluated and the safety of evolocumab was compared with that of a placebo and ezetimibe. PubMed and EMBASE databases were searched and randomized controlled trials that examined the effect and safety of evolomucab compared with a placebo and ezetimibe were retrieved. Two authors independently performed article reviews and study quality evaluations. Odds ratios (ORs) were calculated using a fixed or random-effects model [95% confidence intervals (CIs)]. In the direct comparison, a significant reduction was observed in the muscle-associated events compared with ezetimibe [OR=0.54 (95% CI, 0.31–0.93); P (Z)=0.03, P (Q)=0.43, I2=0%]. In the adjusted indirect comparison of evolocumab 140 mg Q2W vs. evolocumab 420 mg Q4W, no significant differences in efficacy [OR=1.04 (95% CI, 0.55–1.99); P (Z)=0.90] or adverse events [OR=1.08 (95% CI, 0.66–1.74); P (Z)=0.76] were identified. The funnel plots of these direct comparison studies indicated that there was no publication bias. The results of this meta-analysis demonstrate that evolocumab significantly reduced low-density lipoprotein cholesterol levels, and no difference was noted between evolocumab 140 mg Q2W and evolocumab 420 mg Q4W. Furthermore, evolocumab had fewer muscle-associated events than ezetimibe.

Roles of particle size, shape and surface chemistry of mesoporous silica nanomaterials on biological systems

The successful application of mesoporous silica nanomaterials (MSNs) in biomedical fields requires careful consideration of their spatial dimensions, biofunctionality, specific cellular uptake efficiency, biocompatibility and targeting delivery efficacy. A deep understanding of the interactions between MSNs and biological systems is thus of significant importance. To this end, over the past few decades, studies aimed at synthesis of MSNs with controlled size, shape and surface chemistry properties and exploring the roles of these properties on in vitro and in vivo biological performance have been conducted. These studies provide new and foundational information for engineering the next generation of mesoporous silica-based nanoscale devices. This review highlights the current progress on the controlled synthesis of size, shape and surface chemistry tuneable MSNs, emphasises the roles of size, shape and surface chemistry on biological systems with a special focus on the direct comparison studies, and discusses the emerging design paradigm for building mesoporous silica-based particulate systems.

Application of Indirect Comparison to theDrug Development Process: Forecasting Direct Comparison Study Results.

Application of Indirect Comparison to theDrug Development Process: Forecasting Direct Comparison Study Results.

Can Automated Imaging for Optic Disc and Retinal Nerve Fiber Layer Analysis Aid Glaucoma Detection?

PurposeTo compare the diagnostic performance of automated imaging for glaucoma.DesignProspective, direct comparison study.ParticipantsAdults with suspected glaucoma or ocular hypertension referred to hospital eye services in the United Kingdom.MethodsWe evaluated 4 automated imaging test algorithms: the Heidelberg Retinal Tomography (HRT; Heidelberg Engineering, Heidelberg, Germany) glaucoma probability score (GPS), the HRT Moorfields regression analysis (MRA), scanning laser polarimetry (GDx enhanced corneal compensation; Glaucoma Diagnostics (GDx), Carl Zeiss Meditec, Dublin, CA) nerve fiber indicator (NFI), and Spectralis optical coherence tomography (OCT; Heidelberg Engineering) retinal nerve fiber layer (RNFL) classification. We defined abnormal tests as an automated classification of outside normal limits for HRT and OCT or NFI ≥ 56 (GDx). We conducted a sensitivity analysis, using borderline abnormal image classifications. The reference standard was clinical diagnosis by a masked glaucoma expert including standardized clinical assessment and automated perimetry. We analyzed 1 eye per patient (the one with more advanced disease). We also evaluated the performance according to severity and using a combination of 2 technologies.Main Outcome MeasuresSensitivity and specificity, likelihood ratios, diagnostic, odds ratio, and proportion of indeterminate tests.ResultsWe recruited 955 participants, and 943 were included in the analysis. The average age was 60.5 years (standard deviation, 13.8 years); 51.1% were women. Glaucoma was diagnosed in at least 1 eye in 16.8%; 32% of participants had no glaucoma-related findings. The HRT MRA had the highest sensitivity (87.0%; 95% confidence interval [CI], 80.2%–92.1%), but lowest specificity (63.9%; 95% CI, 60.2%–67.4%); GDx had the lowest sensitivity (35.1%; 95% CI, 27.0%–43.8%), but the highest specificity (97.2%; 95% CI, 95.6%–98.3%). The HRT GPS sensitivity was 81.5% (95% CI, 73.9%–87.6%), and specificity was 67.7% (95% CI, 64.2%–71.2%); OCT sensitivity was 76.9% (95% CI, 69.2%–83.4%), and specificity was 78.5% (95% CI, 75.4%–81.4%). Including only eyes with severe glaucoma, sensitivity increased: HRT MRA, HRT GPS, and OCT would miss 5% of eyes, and GDx would miss 21% of eyes. A combination of 2 different tests did not improve the accuracy substantially.ConclusionsAutomated imaging technologies can aid clinicians in diagnosing glaucoma, but may not replace current strategies because they can miss some cases of severe glaucoma.

Effect size comparison of ketorolac nasal spray and commonly prescribed oral combination opioids for pain relief after third molar extraction surgery

Objective: Opioids are frequently used for treatment of moderate to severe short-term pain, but concerns exist about this treatment approach. Ketorolac tromethamine nasal spray, a nonsteroidal anti-inflammatory, is indicated for the short-term management of moderate to moderately severe pain requiring analgesia at the opioid level. However, there are no direct comparison studies between ketorolac nasal spray and opioids. The objective of this study was to use an effect size analysis to compare the effectiveness of ketorolac nasal spray with oral combination opioid formulations in treating moderate to severe short-term pain.Methods: An effect size analysis of three randomized, double-blind, placebo-controlled studies of third molar extraction surgery compared pain relief with ketorolac nasal spray and commonly prescribed combination opioids including hydrocodone/acetaminophen (APAP), oxycodone/APAP, oxycodone/ibuprofen and tramadol HCl/APAP. Effect size comparisons were made using total pain relief scores (TOTPAR6 or TOTPAR8; the weighted sum of pain relief scores through 6 or 8 h). Pain relief was measured using a five-point categorical rating scale (0 = none; 4 = complete). The effect size equivalent correlation, r, was determined using an online effect size calculator. The treatment effect size r compared with placebo was classified using established criteria (small = 0.20–0.49, moderate = 0.50–0.79 and large = ≥ 0.80).Results: TOTPAR6 data indicated a moderate effect size for ketorolac nasal spray 31.5 mg (0.51) and oxycodone/ibuprofen 5/400 mg (0.64) and a small effect size for hydrocodone/APAP 7.5/500 mg (0.24) and oxycodone/APAP 5/325 mg (0.32). TOTPAR8 data indicated small effect sizes for ketorolac nasal spray (0.48), hydrocodone/APAP 10/650 mg (0.43), tramadol HCl/APAP 75/650 mg (0.35) and tramadol HCl/APAP 37.5/325 mg (0.17).Conclusion: The treatment effect sizes of ketorolac nasal spray were similar to or higher than the opioid comparators after third molar surgery, a well-accepted pain model. These results support ketorolac nasal spray as an effective treatment for moderate to moderately severe short-term pain.

Droxidopa for neurogenic orthostatic hypotension

Introduction: Neurogenic orthostatic hypotension is a disabling manifestation of autonomic failure seen in disorders such as multiple system atrophy, pure autonomic failure, Lewy body disease, Parkinson’s disease, autonomic neuropathies and dopamine β-hydroxylase deficiency.Areas covered: Droxidopa is an orally administered norepinephrine prodrug that was approved in the US in the year 2014 for the treatment of neurogenic orthostatic hypotension. This review examines the published pharmacodynamic, pharmacokinetic, safety and efficacy data including the results of phase II and phase III studies of droxidopa.Expert opinion: Droxidopa has been shown to have measurable clinical benefit in reducing the symptoms of neurogenic orthostatic hypotension, in particular postural lightheadedness despite its modest pressor effect, and it has been well-tolerated. As studies to date have demonstrated only short-term efficacy and safety, longer-term studies are needed to establish the durability of efficacy. An important safety concern is droxidopa’s potential to exacerbate supine hypertension, which commonly occurs in neurogenic orthostatic hypotension. Direct comparison studies are needed with other treatment approaches for neurogenic orthostatic hypotension.

Abstract 14909: Hydrogen Peroxide-Responsive Nanoparticles Reduce Myocardial Ischemia/Reperfusion Injury

During myocardial ischemia/reperfusion (I/R), a large amount of reactive oxygen species (ROS) is produced which causes oxidative stress and leads to severe cellular and tissue damage. In particular, overproduction of hydrogen peroxide (H2O2) is considered as a main cause of I/R-mediated tissue damage by inducing inflammation and apoptosis. Therefore, rapid elimination of H2O2 and suppression of oxidative stress are thought to be reasonable strategies to treat myocardial I/R injury. Recently, we generated novel H2O2-responsive antioxidant polymer nanoparticles (PVAX and HPOX) that are able to target the site of ROS overproduction and impede the progression of oxidative stress-associated diseases. In this study, PVAX nanoparticles were selected as therapeutic agents for myocardial I/R injury based on the results of direct comparison studies in vitro and in vivo. To explore therapeutic effect of PVAX on cardiac I/R injury, cardiac function 2 weeks after reperfusion was evaluated. A single dose of PVAX (3mg/kg) showed a significant improvement in both cardiac output (8.1± 0.7 vs. 3.4±0.3) and fraction shortening (43.8± 0.9 vs. 31.2±3.8) compared with poly (lactic-co-glycolic acid) (PLGA) particle, a lacking H2O2 responsible nanoparticle. Consistent with cardiac function evaluation, PVAX significantly reduced the myocardial infarction /area at risk compared with PLGA (48.7±4.2 vs.14.5±2.1). In addition, PVAX effectively reduced caspase-3 activation (2.6±0.1 vs.1.4±0.1) and TUNEL-positive cells (8.2±1.8 vs. 2.7±0.6) compared with PLGA. Furthermore, PVAX significantly decreased TNF-α (5.5±0.4 vs. 3.0±0.3) and MCP-1 (2.3±0.1 vs. 1.4±0.1) mRNA levels. To explore the antioxidant effect of PVAX by scavenging ROS, dihydroethidium (DHE) staining was used as an indicator of ROS generation. PVAX effectively suppressed the generation of ROS caused by I/R while a number of DHE-positive cells were observed in a group of PLGA I/R. In addition, PVAX significantly reduced the level of NADPH oxidase (NOX) 2 and 4 expression, which favors the reduction in ROS generation after I/R. Taken together, these results suggest that H2O2-responsive antioxidant PVAX has tremendous potential as a therapeutic agent for myocardial I/R injury.

Performance of 18F-FET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: systematic review and meta-analysis.

For the past decade (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET) have been used for the assessment of patients with brain tumor. However, direct comparison studies reported only limited numbers of patients. Our purpose was to compare the diagnostic performance of FET and FDG-PET. We examined studies published between January 1995 and January 2015 in the PubMed database. To be included the study should: (i) use FET and FDG-PET for the assessment of patients with isolated brain lesion and (ii) use histology as the gold standard. Analysis was performed on a per patient basis. Study quality was assessed with STARD and QUADAS criteria. Five studies (119 patients) were included. For the diagnosis of brain tumor, FET-PET demonstrated a pooled sensitivity of 0.94 (95% CI: 0.79-0.98) and pooled specificity of 0.88 (95% CI: 0.37-0.99), with an area under the curve of 0.96 (95% CI: 0.94-0.97), a positive likelihood ratio (LR+) of 8.1 (95% CI: 0.8-80.6), and a negative likelihood ratio (LR-) of 0.07 (95% CI: 0.02-0.30), while FDG-PET demonstrated a sensitivity of 0.38 (95% CI: 0.27-0.50) and specificity of 0.86 (95% CI: 0.31-0.99), with an area under the curve of 0.40 (95% CI: 0.36-0.44), an LR+ of 2.7 (95% CI: 0.3-27.8), and an LR- of 0.72 (95% CI: 0.47-1.11). Target-to-background ratios of either FDG or FET, however, allow distinction between low- and high-grade gliomas (P > .11). For brain tumor diagnosis, FET-PET performed much better than FDG and should be preferred when assessing a new isolated brain tumor. For glioma grading, however, both tracers showed similar performances.