On SOCP-based disjunctive cuts for solving a class of integer bilevel nonlinear programs.

We study a class of integer bilevel programs with second-order cone constraints at the upper-level and a convex-quadratic objective function and linear constraints at the lower-level. We develop disjunctive cuts (DCs) to separate bilevel-infeasible solutions using a second-order-cone-based cut-generating procedure. We propose DC separation strategies and consider several approaches for removing redundant disjunctions and normalization. Using these DCs, we propose a branch-and-cut algorithm for the problem class we study, and a cutting-plane method for the problem variant with only binary variables. We present an extensive computational study on a diverse set of instances, including instances with binary and with integer variables, and instances with a single and with multiple linking constraints. Our computational study demonstrates that the proposed enhancements of our solution approaches are effective for improving the performance. Moreover, both of our approaches outperform a state-of-the-art generic solver for mixed-integer bilevel linear programs that is able to solve a linearized version of our binary instances. Supplementary Information: The online version contains supplementary material available at 10.1007/s10107-023-01965-1.

Fidelity of Motivational Interviewing in School-Based Intervention and Research.

Educational researchers and school-based practitioners are increasingly infusing motivational interviewing (MI) into new and existing intervention protocols to provide support to students, parents, teachers, and school administrators. To date, however, the majority of the research in this area has focused on feasibility of implementation rather than fidelity of implementation. In this manuscript, we will present MI fidelity data from 245 audio-recorded conversations with 113 unique caregivers and 20 coaches, who implemented a school-based, positive parenting intervention. The aggregate fidelity scores across coaches, parents, and sessions provide evidence the training and support procedures were effective in assisting school-based personnel to implement MI with reasonable levels of fidelity in practice settings. Further, results suggest that MI fidelity varied between sessions and coaches and that within-coach variation (e.g., session-level variation in the quality of MI delivered) greatly exceeded between-coach variation. Implications for practice and future research are discussed.

Mechanisms of Motivational Interviewing: a Conceptual Framework to Guide Practice and Research.

Reviews of the motivational interviewing (MI) training literature demonstrate MI is a nuanced skill set that takes carefully planned didactic training, application of skills in context-specific practice settings, and ongoing support to promote reflective practice and sustained proficiency. Despite the robust knowledge base related to training and how MI works to achieve favorable outcomes, these two literature bases are not well integrated. In an effort to inform and guide future research, we propose the mechanisms of motivational interviewing (MMI) conceptual framework, which expands upon previous work. Specifically, the framework adds training as an ongoing process consistent with Bennett-Levy's (Behav Cogn Psychother 34:57-78, 2006) model of skill development and acquisition to the existing two-path framework that helps us to understand how MI works to achieve its desired effects (Magill et al., J Consult Clin Psychol 82:973-983, 2014). Herein, we describe measures used to evaluate the mechanisms within the four MMI framework links: initial training to competency, competency to proficiency, proficiency to talk about change, and talk about change to behavior change. Next, we synthesize the literature associated with each of the mechanisms of the MMI. We conclude by discussing implications for practice and research. This framework offers a more complete path structure to understand the mechanisms of change associated with MI that could improve our understanding of inconsistent effect sizes observed across prior trials evaluating MI effectiveness.

A Motivational Interviewing Intervention for Adolescents in Accelerated High School Curricula: Applicability and Acceptability in a Second Sample.

The paper describes the applicability and acceptability of a selective intervention-Motivation, Assessment, and Planning (MAP)-for high school students that was developed based on the principles of motivational interviewing (MI) and tailored to the unique needs and strengths of students taking accelerated coursework, specifically Advanced Placement (AP) and International Baccalaureate (IB) classes. In addition to detailing the intervention in terms of MI spirit, processes, and relational and technical skills, we report applicability and acceptability data from a second iteration of MAP implementation in eight AP/IB programs in a Southeastern state during spring 2018. We analyzed quantitative and qualitative acceptability data from 121 high school freshmen (97 from AP and 24 from IB courses), as well as the seven MAP coaches who were trained using the Motivational Interview Training and Assessment System (Frey et al. 2017). To gain perspectives from the intended end users of the refined MAP, 12 school counselors and school psychologists who were not trained in MAP evaluated the intervention and provided qualitative and quantitative data on applicability and acceptability. All three stakeholder groups (students, coaches, and school mental health staff) rated and described the intervention as highly acceptable and appropriate for addressing the social-emotional needs of adolescents in AP/IB classes.

CD101 Topical Compared With Oral Fluconazole for Acute Vulvovaginal Candidiasis: A Randomized Controlled Trial.

OBJECTIVES: Vulvovaginal candidiasis (VVC) is an infection of the vagina's mucous membranes, caused by Candida albicans in more than 90% of acute VVC. Several topical and oral azole agents are available in a variety of formulations, and all seem to have similar effectiveness. Azoles are fungistatic, meaning that the fungi are inhibited from growth or replication but are not eradicated. Recurrent infection and developing azole resistance demonstrate a significant need for alternative treatments. MATERIALS AND METHODS: One hundred twenty-six women were randomized to 1 of the following 3 treatment cohorts: CD101 3% gel (n = 50) applied intravaginally on days 1 and 2, CD101 6% ointment (n = 50) applied intravaginally on day 1, or oral fluconazole 150 mg (n = 26) on day 1. Primary outcomes of clinical and mycological cure, as demonstrated by changes in the vaginal scores and mycological culture, were assessed on day 7 (±2 days), day 14 (±2 days), and day 28 (±7 days). Safety assessments included treatment-emergent adverse events. RESULTS: Ninety-nine women with positive Candida culture remained in the modified intent-to-treat population with 40 in each CD101 arm and 19 in the fluconazole arm. In the CD101 gel, CD101 ointment, and oral fluconazole groups, 35%, 30%, and 52.6% demonstrated clinical cure and 45%, 40%, and 57.9% had mycological cure at day 28, respectively. CONCLUSIONS: CD101 3% gel and CD101 6% ointment were well tolerated and produced similar rates of clinical and mycological cure in patients with an acute, moderate-to-severe episode of VVC. However, cure rates for these 2 formulations and regimens of CD101 were lower than those in patients treated with fluconazole.

Association of a genetic variant of BTN2A1 with metabolic syndrome in East Asian populations.

BACKGROUND: The authors previously showed that the C→T polymorphism (rs6929846) of butyrophilin, subfamily 2, member A1 gene (BTN2A1) was significantly associated with myocardial infarction in Japanese individuals. Given that metabolic syndrome (MetS) is an important risk factor for myocardial infarction, the association of the rs6929846 of BTN2A1 with myocardial infarction might be attributable, at least in part, to its effect on susceptibility to MetS. AIM: The aim of the present study was to examine the relation of the rs6929846 of BTN2A1 to MetS in East Asian populations. METHODS: The study population comprised 5210 Japanese or Korean individuals (3982 individuals with MetS, 1228 controls) from three independent subject panels. Japanese subject panels A and B comprised 1322 individuals with MetS and 654 controls, and 1909 individuals with MetS and 170 controls, respectively, whereas the Korean population samples comprised 751 individuals with MetS and 404 controls. RESULTS: Comparison of genotype distributions using the χ(2) test revealed that the genotype distributions and allele frequencies of rs6929846 were significantly (p<0.05) associated with MetS in Japanese subject panels A (T allele frequency: MetS, 0.091; controls, 0.054; p=6.1×10(-5)) and B (T allele frequency: MetS, 0.091; controls, 0.039; p=0013) but not in the Korean population samples (T allele frequency: MetS, 0.102; controls, 0.125; p=0.0997). Multivariable logistic regression analysis with adjustment for covariates revealed that the rs6929846 of BTN2A1 was significantly (p<0.017) associated with MetS in Japanese subject panel A (p=0.0055, OR 1.97) and in all individuals (p=0.0038, OR 1.38), with the T allele representing a risk factor for this condition. CONCLUSION: BTN2A1 may be a susceptible gene for MetS in Japanese individuals.

FOCUS 2: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.

OBJECTIVES: Ceftaroline (active form of the prodrug ceftaroline fosamil) is a novel cephalosporin with activity against pathogens commonly associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and Gram-negative pathogens. This randomized, double-blind, Phase III study evaluated the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] of clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. METHODS: Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 2 registration number NCT00509106 (http://clinicaltrials.gov/ct2/show/NCT00509106). RESULTS: The study enrolled 627 patients, 315 of whom received ceftaroline fosamil and 307 of whom received ceftriaxone. Patients in both treatment groups had comparable baseline characteristics. Clinical cure rates were as follows: CE population, 82.1% (193/235) for ceftaroline fosamil and 77.2% (166/215) for ceftriaxone [difference (95% CI), 4.9% (-2.5, 12.5)]; and MITTE population, 81.3% (235/289) for ceftaroline fosamil and 75.5% (206/273) for ceftriaxone [difference (95% CI), 5.9% (-1.0, 12.7)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE (mMITTE) population were 83.3% (35/42) and 70.0% (28/40) for ceftaroline fosamil and ceftriaxone, respectively. Ceftaroline fosamil and ceftriaxone were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations due to an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, hypokalaemia, insomnia and phlebitis, and the most common AEs for ceftriaxone-treated patients were diarrhoea, insomnia, phlebitis and hypertension. CONCLUSIONS: Ceftaroline fosamil achieved high clinical cure and microbiological response rates in patients hospitalized with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile that is similar to that of ceftriaxone and other cephalosporins. Ceftaroline fosamil is a promising agent for the treatment of CAP.

FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.

OBJECTIVES: Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] in clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. METHODS: Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ct2/show/NCT00621504). RESULTS: Of 613 enrolled patients, 298 received ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (-0.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations because of an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, insomnia and nausea, and the most common AEs for ceftriaxone-treated patients were hypokalaemia, hypertension, nausea and diarrhoea. CONCLUSIONS: Ceftaroline fosamil demonstrated high clinical cure and microbiological response rates in hospitalized patients with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile similar to that of ceftriaxone and consistent with the cephalosporin class. In this study, ceftaroline fosamil was an effective and well-tolerated treatment option for CAP.

Applications of transcranial magnetic stimulation (TMS) in child and adolescent psychiatry.

Transcranial magnetic stimulation (TMS) is emerging as a new treatment and neurophysiological research tool for psychiatric disorders. Recent publications suggest that this modality will also serve as a treatment and research tool in child and adolescent psychiatry. Current reports on therapeutic trials of repetitive transcranial magnetic stimulation (rTMS) in adolescents have primarily focused on depression. However, other pilot work involves the treatment of attention-deficit/hyperactivity disorder (ADHD), autism and schizophrenia. Neurophysiological studies typically utilize single and paired-pulse TMS paradigms which index cortical excitability and inhibition. Initial studies have focused on ADHD, autism, and depression. General knowledge regarding TMS among child and adolescent psychiatrists is lacking. The aim of this review is to provide an overview of TMS in the context of child and adolescent psychiatry, discuss recent therapeutic and neurophysiological studies, and examine relevant ethical considerations.

Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia.

BACKGROUND: Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin with bactericidal activity against pathogens causing community-acquired pneumonia (CAP), including Streptococcus pneumoniae. Ceftaroline was evaluated for the treatment of CAP in 2 randomized, double-blind, multicenter trials: Ceftaroline Community Acquired Pneumonia Trial versus Ceftriaxone in Hospitalized Patients (FOCUS) 1 and FOCUS 2. METHODS: Patients hospitalized (but not admitted to an intensive care unit) with Pneumonia Outcomes Research Team risk class III or IV CAP requiring intravenous therapy were randomized to ceftaroline 600 mg every 12 h or ceftriaxone 1 g every 24 h for 5-7 days. Patients in FOCUS 1 received 2 doses of oral clarithromycin 500 mg every 12 h on day 1. RESULTS: In the individual trials, clinical cure rates in the clinically evaluable (CE) population for ceftaroline versus ceftriaxone were as follows: FOCUS 1, 86.6% vs 78.2% (difference, 8.4%; 95% confidence interval [CI], 1.4%-15.4%); FOCUS 2, 82.1% vs 77.2% (difference, 4.9%; 95% CI, -2.5% to 12.5%). In the integrated analysis, 614 patients received ceftaroline and 614 received ceftriaxone. Of the CE patients treated with ceftaroline, 84.3% achieved clinical cure, compared with 77.7% of ceftriaxone-treated patients (difference, 6.7%; 95% CI, 1.6%-11.8%). Clinical cure rates in the modified intent-to-treat efficacy population were 82.6% versus 76.6% for ceftaroline and ceftriaxone (difference, 6.0%; 95% CI, 1.4%-10.7%). Ceftaroline and ceftriaxone were well tolerated; rates of adverse events, serious adverse events, deaths, and premature discontinuations caused by an adverse event were similar in both treatment arms. CONCLUSIONS: Ceftaroline was noninferior to ceftriaxone in the individual trials. In this integrated analysis, clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group. Ceftaroline was well tolerated, with a safety profile similar to that of ceftriaxone.

Retrospective population pharmacokinetic/pharmacodynamic analysis of pyridostigmine, a cholinesterase inhibitor, in Chinese males.

OBJECTIVES: We have characterised the population pharmacokinetics-pharmacodynamics of pyridostigmine given as pyridostigmine bromide. METHODS: Over three days 50 healthy Chinese male subjects each received seven doses of 30 mg pyridostigmine bromide orally (3 x 10 mg every 8 h). Plasma concentrations of pyridostigmine and red blood cell acetylcholinesterase (AChE) activity were determined at various times within the eight hours after the first and the seventh doses. The resulting pharmacokinetic data were fitted to a single compartment open model with first-order absorption and elimination. The pharmacodynamics were modelled using an inhibitory E(max) model. The potential influence of demographic and biological covariates on the model parameters was investigated. Nonlinear mixed effects modelling was performed using NONMEM. KEY FINDINGS: The apparent clearance and volume of distribution as well as absorption rate constant of plasma pyridostigmine were estimated to be 136 l/h, 130 l and 0.68 1/h, respectively. The maximum red blood cell AChE activity decrease (E(max)) and plasma pyridostigmine concentration producing 50% of this reduction (EC50) were estimated to be 9.32 AChE units per gram haemoglobin and 51.9 ng/ml, respectively. None of the tested covariates were found to be correlated with any of the model parameters. Dosing simulations suggested that 30 mg repeated every six hours might be needed to achieve steady-state trough percentage inhibition above the recommended 10% in healthy Chinese males. CONCLUSIONS: The pharmacokinetics and the effects of pyridostigmine on red blood cell AChE activity were described using a mixed effects model. For Chinese males, the dosing interval may have been shorter than that recommended for the Caucasian population. Additional studies are needed to confirm these findings.

Broadband IR supercontinuum generation using single crystal sapphire fibers.

In this paper, an investigation on broadband IR supercontinuum generation in single crystal sapphire fibers is presented. It is experimentally demonstrated that broadband IR supercontinuum spectrum (up to 3.2microm) can be achieved by launching ultra-short femtosecond laser pulses into single crystal sapphire fiber with a dimension 115microm in diameter and 5cm in length, which covers both the near IR spectral region and the lower end of the mid-IR spectral range. Furthermore, the mechanism of supercontinuum generation in single crystal sapphire fibers is briefly addressed. When the fiber length is shorter than the dispersion length, the self-phase modulation dominates the broadening effect. In this case, the broad supercontinuum spectrum with a smooth profile can be obtained. However, when the fiber length is longer than the dispersion length, the soliton-related dynamics accompanied by the self-phase modulation dominates the broadening effect. There are discrete spikes in the spectrum (corresponding to different order solitons). The above assumption of supercontinuum generation mechanism is quantitatively modeled by the computer simulation program and verified by the experimental results. Thus, one can adjust the spectral profile by properly choosing the length of the sapphire fibers. The broad IR spectral nature of this supercontinuum source can be very useful in a variety of applications such as broadband LADAR, remote sensing, and multi-spectrum free space communications.

Broadband supercontinuum generation covering UV to mid-IR region by using three pumping sources in single crystal sapphire fiber.

In this paper, we demonstrate that the the bandwidth of the supercontinuum spectrum generated in a large mode area sapphire fiber can be enhanced by employing triple pumping sources. Three pumping sources with wavelengths of 784 nm, 1290 nm, and 2000 nm are launched into a single crystal sapphire fiber that is 5 cm in length and has a core diameter of 115 microm. The nonlinear interactions due to self-phase modulation and four-wave mixing form a broadband supercontinuum that covers the UV, visible, near-IR and lower mid-IR regions. Furthermore, we explore the possibility of generating a broadband supercontinuum expanding from the UV to far-IR region by increasing the number of pumping sources with wavelengths in the mid- and far-IR.

Bend-insensitive ultra short long-period gratings by the electric arc method and their applications to harsh environment sensing and communication.

Ultra short long-period gratings (LPGs) fabricated using the electric arc discharge method are demonstrated with regular single-mode fibers. The gratings were as short as two periods, which were the shortest LPGs ever reported. The evolution of this short gratings and their characteristics are investigated in this paper. The excellent bending insensitivity and high temperature robustness demonstrated by this unique LPG make it particularly suitable for harsh environment sensing and communication.

Guillain-Barré syndrome following bee venom acupuncture.

Bee venom acupuncture has been widely used in Oriental medicine with limited evidence of effectiveness. Most of the complications due to bee venom acupuncture are local or systemic allergic reactions. However, serious medical and neurological complications have also been reported. We herein describe the treatment of a 68-year-old woman who developed progressive quadriplegia 10 days after receiving multiple honeybee venom sting acupuncture treatments. The electrophysiological findings were consistent with Guillain-Barré syndrome (GBS). The temporal relationship between the development of GBS and honeybee venom sting acupuncture is suggestive of a cause-and-effect relationship, although the precise pathophysiology and causative components in honeybee venom need to be verified.

Reversible C-C bond formation: solid state structure of the aldol-like addition product of adamantanone to a 1,5-diazapentadienyllithium, and its solution state retro-aldol dissociation.

Analysis of crystals of the lithium complex of the tripodal ligand formed upon addition of adamantanone to a 1,5 diazapentadienyllithium complex reveals a long C-C bond which ruptures upon dissolution in non-co-ordinating solvents.

Topology of trajectories of the 2D Navier-Stokes equations.

In spectral form the 2D incompressible Navier-Stokes equations in a square periodic region will be represented by 430 complex Fourier amplitudes which correspond to isotropic truncation of the upper wave number 16. For small viscosity, we have found five equilibrium states I-V in the entire range of forcing; I-fixed point, II-circle, III-closed orbit, IV-torus, and V-chaos. The fixed-point equilibrium state is the laminar flow. As the forcing passes through a critical value, the fixed point evolves directly to equilibrium state III under a typical multimode forcing. The chaotic transition takes place on a 2-torus-like manifold (equilibrium state IV) which is the product space of a circle and the closed orbit of equilibrium state III, similar to the quasiperiodic 2-torus of Ruelle and Takens. For sufficiently large forcing, the evolution of equilibrium state V is nothing but a simulation of quasistationary 2D turbulence. From the Lyapunov exponents of turbulent flows, we have evaluated the constants in the theoretical results of Foias and his colleagues, which relate the determining mode and fractal dimension with the enstrophy dissipation wave number of 2D turbulence.