The Efficacy of Sequential Biologic Agents in Refractory Rheumatoid Arthritis after Failure of Initial DMARD and anti-Tumor Necrosis Factor Therapy

Introduction/Objective: The efficacy of biologic therapy in the treatment of rheumatoid arthritis (RA) has been well-established but, in practice, a quarter of patients will either not respond to the first biologic agent or will suffer an adverse event requiring a switch to a different drug. While clinical guidelines exist to help guide therapy and previous studies have examined sequential use of anti-TNF agents, there is little data to inform a multiple switch strategy. Our aim was to measure the efficacy of multiple switches of biologic in severe refractory RA. Methods: We enrolled 111 patients whose therapy with one anti-TNF agent had failed in this open-label observational study. These patients were all treated with a second biologic agent and 27 ultimately required treatment with a third. The response to the therapy and disease activity were assessed at 6 and 12 months after each switch. Results: The remission rates at 6 months were lower than previously reported and the initiation of a second biologic agent resulted in significant improvement at 12 months, including DAS remission in 36% of patients. The response in those receiving a third biologic was less pronounced, as might be expected in this relatively treatment-refractory population. In this group, only patients treated with tocilizumab had maintained remission at one year. Conclusion: Patients who do not respond to an anti-TNF agent often benefit from being switched to a second, or even third, biologic. Importantly, it may take longer than expected to fully assess the effectiveness of a second or third agent in patients with refractory disease.

Moving motives: How past and present strategy influence the market

We investigate the market’s reactions to serial acquirers that switch strategy. We collect data on 204 serial acquirers in four high tech industries, and use March’s explore-exploit framework, to classify these firms’ 1,415 acquisitions. We then distinguish, for example, exploration-based acquisitions, conducted after a series of exploitation-based acquisitions. Our results suggest that the market takes a portfolio perspective when reacting to an acquisition. In support of the ambidexterity literature, we show that the market responds positively to a switch from one type of strategy to another. Zooming in on the direction of the shift, we find that the market responds more positively to a switch towards exploration after exploitation, compared with the alternative. In so doing, we contribute to the literature on acquisition motives, by showing that prior announcements matter in explaining market reactions, and we contribute to the literature on ambidexterity, by showing that the market favours firms that oscillate between exploration and exploitation.

Age-related differences in how speakers relay news in face-threatening contexts

Following recent work on pragmatics and ageing, this study investigates how adults of different ages relay bad news in face-threatening situations. Three factors were manipulated between subjects: the recipient (whether or not they were affected by the news), the severity of the news, and whether or not the news was health-related. Participants (N=280; ages 18-89) delivered bad news both through open-ended responses and by selecting probability terms from multiple choice. Responses were coded for indirectness, uncertainty and emotion, and supported our initial predictions: younger adults were more sensitive to the recipient manipulation than older adults, while both age groups adjusted their speech similarly depending on the severity of the news. Older adults engaged in more face saving when the number of health scenarios increased, although they did not switch strategy across scenarios. Our results are consistent with previous evidence that younger adults are better at audience design than older adults. However, we also found that these skills are partially context-dependent, and could vary due to life circumstances and different communicative strategies at different ages.

Path Planning for Mobile Robot Based on Improved Bat Algorithm

Bat algorithm has disadvantages of slow convergence rate, low convergence precision and weak stability. In this paper, we designed an improved bat algorithm with a logarithmic decreasing strategy and Cauchy disturbance. In order to meet the requirements of global optimal and dynamic obstacle avoidance in path planning for a mobile robot, we combined bat algorithm (BA) and dynamic window approach (DWA). An undirected weighted graph is constructed by setting virtual points, which provide path switch strategies for the robot. The simulation results show that the improved bat algorithm is better than the particle swarm optimization algorithm (PSO) and basic bat algorithm in terms of the optimal solution. Hybrid path planning methods can significantly reduce the path length compared with the dynamic window approach. Path switch strategy is proved effective in our simulations.

Thromboembolism (TE) and adjuvant endocrine therapy (AET) in hormone receptor positive (HR+) early breast cancer (EBC): Did the evolution of treatment change the incidence of the adverse event? A metanalysis.

e12516 Background: The AET of HR+ EBC has been changing in the recent years. Aromatase inhibitors (AI) as upfront, or in a planned switch strategy after Tamoxifen (T), have been added to the choice of T alone. An increased risk of TE is well known in the T treated patients while AIs have showed a reduced rate of TE. Recently, adding the cyclin dependent kinase 4/6 inhibitors (CDK4/6) abemaciclib to AIs, has showed a positive impact in the high risk HR+ EBC subgroups, but we are seeing an increase of the TE rate. We conducted this meta-analysis to evaluate the impact of the new AETs on the incidence of TE if compared to the standard monotherapy. Methods: We performed a meta-analysis of the randomized phase III trials comparing the experimental AETs and the endocrine standard therapy. A random-effect model to find differences in the rate of TE events between the experimental treatments and the standard therapy has been used. Results: Twelve phase III trials were included. Five trials evaluated the upfront strategy, 6 studies the switch and one the combination with a CDK4/6inhibitor (i.e. abemaciclib). Overall, the new AETs did not significantly modify or affect the rate of TE events (OR 0.708, 0.444-1.130, p = 0.148) with high heterogeneity among studies (I2 87, p < 0.0001). Excluding the abemaciclib trial, the incidence of TE is reduced (OR 0.609, 0.462-0.802, p < 0.0001) with a moderate heterogeneity among the studies (I2 59, p < 0.006). Considering the upfront strategies with AIs, the TE events are reduced (OR 0.507, 0.394-0.651, p < 0.0001) but they are not if we consider the trials in which T is used upfront before AIs (OR 0.762, 0.546-1.065, p = 0.112). Conclusions: Overall, the new treatments (AIs alone or plus CDK4/6 inhibitors) did not affect the rate in TE events. AIs as upfront strategy is the safest AETs of HR+ EBC, being associated to the lowest incidence of TE. The switch strategy increases the TE rate whereas the addition of abemaciclib to the standard AET showed to significantly increase the TE events. The results of the currently ongoing trials with the CDK4/6 inhibitors will help to obtain additional data to evaluate any differences among the different CDK4/6 inhibitors and to clarify the weight of the TE adverse events in the balance of benefit/risk of this new adjuvant strategy.

Switch Strategy from Direct Aspiration First Pass Technique to Solumbra Improves Technical Outcome in Endovascularly Treated Stroke

Background: The major endovascular mechanic thrombectomy (MT) techniques are: Stent-Retriever (SR), aspiration first pass technique (ADAPT) and Solumbra (Aspiration + SR), which are interchangeable (defined as switching strategy (SS)). The purpose of this study is to report the added value of switching from ADAPT to Solumbra in unsuccessful revascularization stroke patients. Methods: This is a retrospective, single center, pragmatic, cohort study. From December 2017 to November 2019, 935 consecutive patients were admitted to the Stroke Unit and 176/935 (18.8%) were eligible for MT. In 135/176 (76.7%) patients, ADAPT was used as the first-line strategy. SS was defined as the difference between first technique adopted and the final technique. Revascularization was evaluated with modified Thrombolysis In Cerebral Infarction (TICI) with success defined as mTICI ≥ 2b. Procedural time (PT) and time to reperfusion (TTR) were recorded. Results: Stroke involved: Anterior circulation in 121/135 (89.6%) patients and posterior circulation in 14/135 (10.4%) patients. ADAPT was the most common first-line technique vs. both SR and Solumbra (135/176 (76.7%) vs. 10/176 (5.7%) vs. 31/176 (17.6%), respectively). In 28/135 (20.7%) patients, the mTICI was ≤ 2a requiring switch to Solumbra. The vessel’s diameter positively predicted SS result (odd ratio (OR) 1.12, confidence of interval (CI) 95% 1.03–1.22; p = 0.006). The mean number of passes before SS was 2.0 ± 1.2. ADAPT to Solumbra improved successful revascularization by 13.3% (107/135 (79.3%) vs. 125/135 (92.6%)). PT was superior for SS comparing with ADAPT (71.1 min (CI 95% 53.2–109.0) vs. 40.0 min (CI 95% 35.0–45.2); p = 0.0004), although, TTR was similar (324.1 min (CI 95% 311.4–387.0) vs. 311.4 min (CI 95% 285.5–338.7); p = 0.23). Conclusion: Successful revascularization was improved by 13.3% after switching form ADAPT to Solumbra (final mTICI ≥ 2b was 92.6%). Vessel’s diameter positively predicted recourse to SS.

Evaluation of the Efficacy and Tolerability of Dolutegravir Plus Lamivudine as a Switch Strategy in Treatment-experienced HIV-infected Patients

Background: Dual therapy containing dolutegravir (DTG) plus lamivudine (3TC) is a reasonable alternative antiretroviral therapy (ART) option in treatment-experienced patients, which could prevent long-term toxicity and reduce treatment cost. But so far, the effectiveness as safety data of this two-drug regimen is still limited. Methods: This observational study included treatment-experienced HIV-infected patients who switched to a dual regimen containing DTG (50mg/QD) plus 3TC (300mg/QD). Efficacy (HIV RNA <50 copies/mL), safety, and metabolic changes based on laboratory and clinical findings at 48 weeks were analyzed.Results: A total of 33 patients were included, who switched for the following reasons: treatment failure in 5 /33patients (15.2%), simplification in 10 patients (30.3%), and drug toxicity in 18 patients (54.5%). The patients were treated with ART for a median of 2.1 years (interquartile range = 1.0-4.2) before drug switching, and 28/33(84.8%) patients were virologically suppressed at baseline. After switching to DTG plus 3TC, all 33 patients (100%) showed HIV RNA <50 copies/mL after 48 weeks, and the CD4+ cell count was significantly increased (+82 cell/mm3, p=0.0071). We observed a significant increase in LDL-C (+0.77mg/dL, p<0.0001) after switch, however, triglycerides (-0.6mg/dL, p=0.0179) and cholesterol/HDL-C ratio (-0.327, p=0.0366) were found significantly decreased. A significant decrease in eGFR was also observed (-17.8 ml/min, p=0.0047). No patient discontinued due to adverse events.Conclusions: The use of dual therapy containing DTG and 3TC is effective and well-tolerated in treatment-experienced patients under any prior ART, without significant adverse drug reaction.