A New Arthritis Therapy with Oxidative Burst Inducers

BACKGROUND: Despite recent successes with biological agents as therapy for autoimmune inflammatory diseases such as rheumatoid arthritis (RA), many patients fail to respond adequately to these treatments, making a continued search for new therapies extremely important. Recently, the prevailing hypothesis that reactive oxygen species (ROS) promote inflammation was challenged when polymorphisms in Ncf1, that decrease oxidative burst, were shown to increase disease severity in mouse and rat arthritis models. Based on these findings we developed a new therapy for arthritis using oxidative burst-inducing substances. METHODS AND FINDINGS: Treatment of rats with phytol (3,7,11,15-tetramethyl-2-hexadecene-1-ol) increased oxidative burst in vivo and thereby corrected the effect of the genetic polymorphism in arthritis-prone Ncf1 (DA) rats. Importantly, phytol treatment also decreased the autoimmune response and ameliorated both the acute and chronic phases of arthritis. When compared to standard therapies for RA, anti-tumour necrosis factor-α and methotrexate, phytol showed equally good or better therapeutic properties. Finally, phytol mediated its effect within hours of administration and involved modulation of T cell activation, as injection prevented adoptive transfer of disease with arthritogenic T cells. CONCLUSIONS: Treatment of arthritis with ROS-promoting substances such as phytol targets a newly discovered pathway leading to autoimmune inflammatory disease and introduces a novel class of therapeutics for treatment of RA and possibly other chronic inflammatory diseases

Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer:A Randomized Clinical Trial

PURPOSE:Resectable non-small-cell lung cancer (NSCLC) with a high probability of mediastinal nodal involvement requires mediastinal staging by endosonography and, in the absence of nodal metastases, confirmatory mediastinoscopy according to current guidelines. However, randomized data regarding immediate lung tumor resection after systematic endosonography versus additional confirmatory mediastinoscopy before resection are lacking.METHODS:Patients with (suspected) resectable NSCLC and an indication for mediastinal staging after negative systematic endosonography were randomly assigned to immediate lung tumor resection or confirmatory mediastinoscopy followed by tumor resection. The primary outcome in this noninferiority trial (noninferiority margin of 8% that previously showed to not compromise survival, Pnoninferior &lt;.0250) was the presence of unforeseen N2 disease after tumor resection with lymph node dissection. Secondary outcomes were 30-day major morbidity and mortality.RESULTS:Between July 17, 2017, and October 5, 2020, 360 patients were randomly assigned, 178 to immediate lung tumor resection (seven dropouts) and 182 to confirmatory mediastinoscopy first (seven dropouts before and six after mediastinoscopy). Mediastinoscopy detected metastases in 8.0% (14/175; 95% CI, 4.8 to 13.0) of patients. Unforeseen N2 rate after immediate resection (8.8%) was noninferior compared with mediastinoscopy first (7.7%) in both intention-to-treat (Δ, 1.03%; UL 95% CIΔ, 7.2%; Pnoninferior =.0144) and per-protocol analyses (Δ, 0.83%; UL 95% CIΔ, 7.3%; Pnoninferior =.0157). Major morbidity and 30-day mortality was 12.9% after immediate resection versus 15.4% after mediastinoscopy first (P =.4940).CONCLUSION:On the basis of our chosen noninferiority margin in the rate of unforeseen N2, confirmatory mediastinoscopy after negative systematic endosonography can be omitted in patients with resectable NSCLC and an indication for mediastinal staging.</p

PUNCHING SHEAR IN PRESTRESSED CONCRETE DECK SLABS: A COMPREHENSIVE STUDY

A large number of bridges in the Netherlands have transversely post tensioned deck slabs cast in-situ between flanges of precast girders and were found to be critical in shear when evaluated by Eurocode 2. To investigate the bearing (punching shear) capacity of such bridges, a 1:2 scale bridge model was constructed in the laboratory and static tests were performed by varying the transverse prestressing level (TPL). A 3D solid, 1:2 scale model of the real bridge, similar to the experimental model, was developed in the finite element software DIANA and several nonlinear analyses were carried out. It was observed that the experimental and numerical ultimate load carrying capacity was much higher than predicted by the governing codes due to lack of consideration of compressive membrane action (CMA). In order to incorporate CMA in the Model Code 2010 (fib 2012) punching shear provisions for prestressed slabs, numerical and theoretical approaches were combined. As a result, sufficient factor of safety was observed when the real bridge design capacity was compared with the design wheel load of Eurocode 1. It was concluded that the existing bridges still had sufficient residual bearing capacity with no problems of serviceability and structural safety

Stop Criteria for Flexure for Proof Load Testing of Reinforced Concrete Structures

Existing bridges with large uncertainties can be assessed with a proof load test. In a proof load test, a load representative of the factored live load is applied to the bridge at the critical position. If the bridge can carry this load without distress, the proof load test shows experimentally that the bridge fulfills the requirements of the code. Because large loads are applied during proof load tests, the structure or element that is tested needs to be carefully monitored during the test. The monitored structural responses are interpreted in terms of stop criteria. Existing stop criteria for flexure in reinforced concrete can be extended with theoretical considerations. These proposed stop criteria are then verified with experimental results: reinforced concrete beams failing in flexure and tested in the laboratory, a collapse test on an existing reinforced concrete slab bridge that reached flexural distress, and the pilot proof load tests that were carried out in the Netherlands and in which no distress was observed. The tests in which failure was obtained are used to evaluate the margin of safety provided by the proposed stop criteria. The available pilot proof load tests are analyzed to see if the proposed stop criteria are not overly conservative. The result of this comparison is that the stop criteria are never exceeded. Therefore, the proposed stop criteria can be used for proof load tests for the failure mode of bending moment in reinforced concrete structures.Concrete Structure

Perspectives of couples with high risk of transmitting genetic disorders

Objective: To investigate the preference for preimplantation genetic diagnosis (PGD) as an alternative to prenatal diagnosis (PND) in a large group of couples representing a wide array of genetic disorders. We also investigated the couple's familiarity with PGD and presented time trade-off scenarios for PGD versus PND, as PGD treatment is regularly accompanied by waiting lists. Design: Questionnaire study. Setting: Patient organizations representing genetic disorders. Patient(s): A total of 210 couples carrying genetic disorders. Main Outcome Measure(s): Preference for PGD or PND and familiarity with PGD in carrier couples. Result(s): Fifteen organizations representing 38 genetic disorders agreed to participate. Nine hundred eighty-three couples responded. In total 210 couples were in their reproductive years (women 18-40 years) and had a desire to conceive. Ninety couples (42%) had never heard of PGD. After they were informed, 127 couples (60%) wanted to have diagnostic testing (PND or PGD) performed. Ninety-four (74%) of these couples preferred testing with PGD. When no waiting list was used 102 couples (80%) preferred PGD. With a 2-year waiting list for PGD, 58 couples (46%) would opt for PGD. Conclusion(s): Many carrier couples are unaware of the existence of PGD. When informed, most couples prefer PGD more than PND. The preference for PGD decreases with longer waiting lists. (Fertil Steril (R) 2010;94:1239-43. (C) 2010 by American Society for Reproductive Medicine.