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In the Dial-a-Ride problem (DARP), customers request transportation from an operator. A request consists of a specified pickup location and destination location along with a desired departure or arrival time and capacity demand. The aim of DARP is to minimize transportation cost while satisfying customer service level constraints (Quality of Service). In this paper, we present a genetic algorithm (GA) for solving the DARP. The algorithm is based on the classical cluster-first, route-second approach, where it alternates between assigning customers to vehicles using a GA and solving independent routing problems for the vehicles using a routing heuristic. The algorithm is implemented in Java and tested on publicly available data sets. The new solution method has achieved solutions comparable with the current state-of-the-art methods. [ABSTRACT FROM AUTHOR]

Competing Interests: Disclosures Dr McNally is or was a consultant for Amgen, AstraZeneca, Avidity, Cytokinetics, Pfizer, PepGen, Stealth Biopharma, Tenaya, and Invitae. She is the founder of Ikaika Therapeutics, Inc. These relationships are unrelated to this article.

Purpose: High-dose insulin/euglycemia (HDIE) is targeted therapy for β-blocker and calcium channel blocker overdose. A guideline using concentrated insulin infusions (20 units/mL), aggressive monitoring, and supportive recommendations was implemented. We sought to evaluate safety before and after HDIE guideline implementation and describe the patient population, insulin doses, supplemental dextrose, vasopressor use, hospital and intensive care unit (ICU) lengths of stay, and mortality., Methods: Retrospective review was performed of patients receiving HDIE before and after guideline implementation at an academic medical center and community hospital from March 2011 through December 2019. Information on patient and overdose demographics, ingestion data, vital signs, interventions, adverse events, and disposition was collected. Data are presented descriptively with comparisons using Mann-Whitney U analysis and Fisher's exact tests., Results: During the study period, 27 patients were treated with HDIE, 10 before guideline implementation (37%; mean [SD] initial insulin dose, 0.49 [0.35] units/kg/h; mean [SD] maximum insulin dose, 2.25 [3.29] units/kg/h; median [interquartile range] duration, 10 [5.5-18.75] hours) and 17 after guideline implementation (63%; mean [SD] initial insulin dose, 1.01 [0.34] units/kg/h; mean [SD] maximum insulin dose, 2.99 [5.05] unit/kg/h; median [interquartile range] duration, 16 [11.5-37] hours). Hypoglycemia, hypokalemia, and volume overload occurred in 80% vs 29% (P = 0.018), 40% vs 53% (P = 0.69), and 50% vs 65% (P = 0.69) of patients in the preguideline vs postguideline group, respectively. Most patients received an initial insulin bolus (85%; mean [SD], 70.3 [21.8] units, 0.9 [0.26] units/kg) and vasopressor infusion (85%). More postguideline patients received a dextrose infusion with a concentration of 20% or higher (93% vs 50%, P = 0.015). There were no differences in cardiac arrest, in-hospital mortality, or hospital or ICU length of stay between the groups., Conclusion: Hypoglycemia was reduced using an HDIE guideline and concentrated insulin., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The need for long-axis support is widespread among non-aquatic vertebrates and may be particularly acute for arboreal snakes when many vertebrae span sizable gaps between branches with diverse orientations. Hence, we used brown tree snakes ( Boiga irregularis ) bridging gaps to test how three-dimensional trajectories affected muscle activity and whether these motor patterns differed from those for the locomotion of terrestrial snakes and movements of other vertebrates. We used five trajectories: pitch angles of 90, 0 and -90 deg (downward) when yaw=0 deg, and 90 deg yaw angles to the left and right when pitch=0 deg. We recorded movement and electromyograms from the three largest epaxial muscles, which from dorsal to ventral are the semispinalis-spinalis (SSP), longissimus dorsi (LD) and iliocostalis (IL). Overall, the SSP had extensive bilateral activity, which resembled the motor pattern during the dorsiflexion of sidewinding snakes. Unlike any previously described terrestrial snake locomotion, bilateral activity of the LD and IL was also common during gap bridging. The largest amounts of muscle activity usually occurred for horizontal gaps, and muscle activity decreased markedly as soon as the snake's head touched the far edge of the gap. Snakes had the least amount of muscle activity for pitch=-90 deg. While turning sideways, muscles on the convex side had less activity when turning compared with the concave side. Hence, the orientation relative to gravity profoundly affected muscle activity during gap bridging, and these complex three-dimensional movements involved several previously undescribed variants of axial motor pattern., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

We have used combinatorial chemistry with amino acid mixtures (X) at positions 6 to 23 in vasoactive intestinal peptide (VIP) to optimize binding affinity and selectivity to the rat VPAC(1) receptor. The most efficient amino acid replacement was a substitution of alanine at position 18 to diphenylalanine (Dip), increasing the displacement efficiency of (125)I-VIP by 370-fold. The [Dip(18)]VIP(6-23) was subsequently used to find a second replacement, employing the same approach. Tyrosine at position 9 was selected and the resulting [Tyr(9),Dip(18)]VIP(6-23) analog has a K(i) value of 90 nM. This analog was unable to stimulate cAMP production at 10(-6) M but was able to inhibit VIP-induced cAMP stimulation (K(b) = 79 nM). The K(i) values of [Tyr(9),Dip(18)]VIP(6-23) using the rat VPAC(2) and PAC(1) receptors were 3,000 nM and >10,000 nM, respectively. Thus, [Tyr(9),Dip(18)]VIP(6-23) is a selective VPAC(1) receptor antagonist. The C-terminally extended form, [Tyr(9),Dip(18)]VIP(6-28), displays improved antagonistic properties having a K(i) and K(b) values of 18 nM and 16 nM, respectively. On the contrary, the fully extended form, [Tyr(9),Dip(18)]VIP(1-28), was a potent agonist with improved binding affinity (K(i) = 0.11 nM) and ability to stimulate cAMP (EC(50) = 0.23 nM) compared with VIP (K(i) = 1.7 nM, EC(50) = 1.12 nM). Furthermore, the specificity of this agonist to the VPAC(1) receptor was high, the K(i) values for the VPAC(2) and PAC(1) receptors were 53 nM and 3,100 nM, respectively. Seven other analogs with the [Tyr(9),Dip(18)] replacement combined with previously published VIP modifications have been synthesized and described in this work.