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Primary headaches, including migraine and tension-type headaches, are widespread and have a social, physical, mental, and economic impact. Among the key components of treatment are behavior interventions such as lifestyle modification. Scalable conversational agents (CAs) have the potential to deliver behavior interventions at a low threshold. To our knowledge, there is no evidence of behavioral interventions delivered by CAs for the treatment of headaches. This study has 2 aims. The first aim was to develop and test a smartphone-based coaching intervention (BalanceUP) for people experiencing frequent headaches, delivered by a CA and designed to improve mental well-being using various behavior change techniques. The second aim was to evaluate the effectiveness of BalanceUP by comparing the intervention and waitlist control groups and assess the engagement and acceptance of participants using BalanceUP. In an unblinded randomized controlled trial, adults with frequent headaches were recruited on the web and in collaboration with experts and allocated to either a CA intervention (BalanceUP) or a control condition. The effects of the treatment on changes in the primary outcome of the study, that is, mental well-being (as measured by the Patient Health Questionnaire Anxiety and Depression Scale), and secondary outcomes (eg, psychosomatic symptoms, stress, headache-related self-efficacy, intention to change behavior, presenteeism and absenteeism, and pain coping) were analyzed using linear mixed models and Cohen d. Primary and secondary outcomes were self-assessed before and after the intervention, and acceptance was assessed after the intervention. Engagement was measured during the intervention using self-reports and usage data. A total of 198 participants (mean age 38.7, SD 12.14 y; n=172, 86.9% women) participated in the study (intervention group: n=110; waitlist control group: n=88). After the intervention, the intention-to-treat analysis revealed evidence for improved well-being (treatment: β estimate=-3.28, 95% CI -5.07 to -1.48) with moderate between-group effects (Cohen d=-0.66, 95% CI -0.99 to -0.33) in favor of the intervention group. We also found evidence of reduced somatic symptoms, perceived stress, and absenteeism and presenteeism, as well as improved headache management self-efficacy, application of behavior change techniques, and pain coping skills, with effects ranging from medium to large (Cohen d=0.43-1.05). Overall, 64.8% (118/182) of the participants used coaching as intended by engaging throughout the coaching and completing the outro. BalanceUP was well accepted, and the results suggest that coaching delivered by a CA can be effective in reducing the burden of people who experience headaches by improving their well-being. German Clinical Trials Register DRKS00017422; https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00017422.

Globally, students face increasing mental health challenges, including elevated stress levels and declining well-being, leading to academic performance issues and mental health disorders. However, due to stigma and symptom underestimation, students rarely seek effective stress management solutions. Conversational agents in the health sector have shown promise in reducing stress, depression, and anxiety. Nevertheless, research on their effectiveness for students with stress remains limited. This study aims to develop a conversational agent-delivered stress management coaching intervention for students called MISHA and to evaluate its effectiveness, engagement, and acceptance. In an unblinded randomized controlled trial, Swiss students experiencing stress were recruited on the web. Using a 1:1 randomization ratio, participants (N=140) were allocated to either the intervention or waitlist control group. Treatment effectiveness on changes in the primary outcome, that is, perceived stress, and secondary outcomes, including depression, anxiety, psychosomatic symptoms, and active coping, were self-assessed and evaluated using ANOVA for repeated measure and general estimating equations. The per-protocol analysis revealed evidence for improvement of stress, depression, and somatic symptoms with medium effect sizes (Cohen d=-0.36 to Cohen d=-0.60), while anxiety and active coping did not change (Cohen d=-0.29 and Cohen d=0.13). In the intention-to-treat analysis, similar results were found, indicating reduced stress (β estimate=-0.13, 95% CI -0.20 to -0.05; P<.001), depressive symptoms (β estimate=-0.23, 95% CI -0.38 to -0.08; P=.003), and psychosomatic symptoms (β estimate=-0.16, 95% CI -0.27 to -0.06; P=.003), while anxiety and active coping did not change. Overall, 60% (42/70) of the participants in the intervention group completed the coaching by completing the postintervention survey. They particularly appreciated the quality, quantity, credibility, and visual representation of information. While individual customization was rated the lowest, the target group fitting was perceived as high. Findings indicate that MISHA is feasible, acceptable, and effective in reducing perceived stress among students in Switzerland. Future research is needed with different populations, for example, in students with high stress levels or compared to active controls. German Clinical Trials Register DRKS 00030004; https://drks.de/search/en/trial/DRKS00030004.

We consider a project scheduling environment in which the activities are partitioned among a set of agents. The owner of each activity can decide its length, which is linearly related to its cost within a minimum (crash) and a maximum (normal) length. For each day the project makespan is reduced with respect to its normal value, a reward is offered to the agents, and each agent receives a given ratio of the reward. As in classical game theory, we assume that the agents’ parameters are common knowledge. We study the Nash equilibria of the corresponding non-cooperative game as a desired state where no agent is motivated to change his/her decision. Regarding project makespan as an overall measure of efficiency, here we consider the worst and the best Nash equilibria (i.e., for which makespan is maximum and, respectively, minimum among Nash equilibria). We show that the problem of finding the worst Nash equilibrium is NP-hard (finding the best Nash equilibrium is already known to be strongly NP-hard), and propose an ILP formulation for its computation. We then investigate the values of the price of anarchy and the price of stability in a large sample of realistic size problems and get useful insights for the project owner.

Ongoing pain is one of the most common diseases and has major physical, psychological, social, and economic impacts. A mobile health intervention utilizing a fully automated text-based health care chatbot (TBHC) may offer an innovative way not only to deliver coping strategies and psychoeducation for pain management but also to build a working alliance between a participant and the TBHC. The objectives of this study are twofold: (1) to describe the design and implementation to promote the chatbot painSELfMAnagement (SELMA), a 2-month smartphone-based cognitive behavior therapy (CBT) TBHC intervention for pain self-management in patients with ongoing or cyclic pain, and (2) to present findings from a pilot randomized controlled trial, in which effectiveness, influence of intention to change behavior, pain duration, working alliance, acceptance, and adherence were evaluated. Participants were recruited online and in collaboration with pain experts, and were randomized to interact with SELMA for 8 weeks either every day or every other day concerning CBT-based pain management (n=59), or weekly concerning content not related to pain management (n=43). Pain-related impairment (primary outcome), general well-being, pain intensity, and the bond scale of working alliance were measured at baseline and postintervention. Intention to change behavior and pain duration were measured at baseline only, and acceptance postintervention was assessed via self-reporting instruments. Adherence was assessed via usage data. From May 2018 to August 2018, 311 adults downloaded the SELMA app, 102 of whom consented to participate and met the inclusion criteria. The average age of the women (88/102, 86.4%) and men (14/102, 13.6%) participating was 43.7 (SD 12.7) years. Baseline group comparison did not differ with respect to any demographic or clinical variable. The intervention group reported no significant change in pain-related impairment (P=.68) compared to the control group postintervention. The intention to change behavior was positively related to pain-related impairment (P=.01) and pain intensity (P=.01). Working alliance with the TBHC SELMA was comparable to that obtained in guided internet therapies with human coaches. Participants enjoyed using the app, perceiving it as useful and easy to use. Participants of the intervention group replied with an average answer ratio of 0.71 (SD 0.20) to 200 (SD 58.45) conversations initiated by SELMA. Participants' comments revealed an appreciation of the empathic and responsible interaction with the TBHC SELMA. A main criticism was that there was no option to enter free text for the patients' own comments. SELMA is feasible, as revealed mainly by positive feedback and valuable suggestions for future revisions. For example, the participants' intention to change behavior or a more homogenous sample (eg, with a specific type of chronic pain) should be considered in further tailoring of SELMA. German Clinical Trials Register DRKS00017147; https://tinyurl.com/vx6n6sx, Swiss National Clinical Trial Portal: SNCTP000002712; https://www.kofam.ch/de/studienportal/suche/70582/studie/46326.

This paper introduces the multi-vehicle cumulative covering tour problem whose motivation arises from humanitarian logistics. The objective is to determine a set of tours that must be followed by a fleet of vehicles in order to minimize the sum of arrival times (latency) at each visited location. There are three types of locations: mandatory, optional, and unreachable. Each mandatory location must be visited, and optional locations are visited in order to cover the unreachable locations. To guarantee the vehicle autonomy, the duration of each tour should not exceed a given time limit. A mixed integer linear formulation and a greedy randomized adaptive search procedure are proposed for this problem. The performance of the algorithm is assessed over a large set of instances adapted from the literature. Computational results confirm the efficiency of the proposed algorithm.

In hybrid electric vehicles, the electrical powertrain system has multiple energy sources that it can gather power from to satisfy the propulsion power requested by the vehicle at each instant. This paper focusses on the minimization of the fuel consumption of such a vehicle, taking advantage of the different energy sources. Based on global optimization approaches, the proposed heuristics find solutions that best split the power requested between the multi-electrical sources available. A lower bounding procedure is introduced to validate the quality of the solutions. Computational results show a significant improvement over previous results from the literature in both the computing time and the quality of the solutions.

The objective of this study was to investigate, whether the plant-derived isothiocyanate Sulforaphane (SFN) enhances the antitumor activities of the chemotherapeutic agent oxaliplatin (Ox) in a cell culture model of colorectal cancer. Caco-2 cells were cultured under standard conditions and treated with increasing concentrations of SFN [1–20 μM] and/or Ox [100 nM–10 μM]. For co-incubation, cells were pre-treated with SFN for 24 h. Cell growth was determined by BrdU incorporation. Drug interactions were assessed using the combination-index method (CI) (Cl < 1 indicates synergism). Apoptotic events were characterized by different ELISA techniques. Protein levels were examined by Western blot analysis. Annexin V- and propidium iodide (PI) staining followed by FACS analysis was used to differentiate between apoptotic and necrotic events. SFN and Ox alone inhibited cell growth of Caco-2 cells in a dose-dependent manner, an effect, which could be synergistically enhanced, when cells were incubated with the combination of both agents. Co-treated cells further displayed distinctive morphological changes that occurred during the apoptotic process, such as cell surface exposure of phosphatidylserine, membrane blebbing as well as the occurence of cytoplasmic histone-associated DNA fragments. Further observations thereby pointed toward simultaneous activation of both extrinsic and intrinsic apoptotic pathways. With increasing concentrations and treatment duration, a shift from apoptotic to necrotic cell death could be observed. In conclusion, the data suggest that the isothiocyanate SFN sensitizes colon cancer cells to Ox-induced cell growth inhibition via induction of different modes of cell death.

We propose a framework to compute approximate Nash equilibria in integer programming games with nonlinear payoffs, i.e., simultaneous and non-cooperative games where each player solves a parametrized mixed-integer nonlinear program. We prove that using absolute approximations of the players' objective functions and then computing its Nash equilibria is equivalent to computing approximate Nash equilibria where the approximation factor is doubled. In practice, we propose an algorithm to approximate the players' objective functions via piecewise linear approximations. Our numerical experiments on a cybersecurity investment game show the computational effectiveness of our approach.

This work considers nonconvex mixed integer nonlinear programming where nonlinearity comes from the presence of the two-dimensional euclidean norm in the objective or the constraints. We build from the euclidean norm piecewise linearization proposed by Camino et al. (Comput. Optim. Appl. https://doi.org/10.1007/s10589-019-00083-z, 2019) that allows to solve such nonconvex problems via mixed-integer linear programming with an arbitrary approximation guarantee. Theoretical results are established that prove that this linearization is able to satisfy any given approximation level with the minimum number of pieces. An extension of the piecewise linearization approach is proposed. It shares the same theoretical properties for elliptic constraints and/or objective. An application shows the practical appeal of the elliptic linearization on a nonconvex beam layout mixed optimization problem coming from an industrial application.

The objective of this study was to investigate, whether the naturally occurring polyphenol resveratrol (Res) enhances the anti-tumor activities of the chemotherapeutic agent oxaliplatin (Ox) in a cell culture model of colorectal cancer, also with regard to a possible inflammatory response and cytotoxic side-effects. Res and Ox in combination synergistically inhibit cell growth of Caco-2 cells, which seems to be due to the induction of different modes of cell death and further leads to an altered cytokine profile of cocultured macrophages. Moreover, combinatorial treatment does not affect non-transformed cells as severe cytotoxicity is not detected in human foreskin fibroblasts and platelets.