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Abstract Background Headache is a pain disorder present in populations world-wide with a higher incidence in females. Specifically, the incidences of medication overuse headache (MOH) have increased worldwide. Comorbidities of MOH include photosensitivity, anxiety, “brain fog”, and decreased physical activity. The FDA-approved long-lasting selective β2-adrenergic receptor agonist, formoterol, is currently approved for use in severe asthma and chronic obstructive pulmonary disease. Recently, interest in repurposing formoterol for use in other disorders including Alzheimer’s disease, and neuropathic pain after spinal cord injury and traumatic brain injury has gained traction. Thus, revisiting known side-effects of formoterol, like headache and anxiety, could inform treatment paradigms. The endocannabinoid (eCB) system is implicated in the etiology of preclinical headache, with observed decreases in the circulating levels of endogenous cannabinoids, referred to as Clinical Endocannabinoid Deficiency. As cross-talk between the eCB system and adrenergic receptors has been reported, this study investigated the role of the eCB system and ability of formoterol to induce headache-like periorbital allodynic behavior. Methods Female 8-week-old C57Bl/6J mice were treated daily with formoterol (0.3 mg/kg, i.p.) for up to 42-days, during which they were assessed for periorbital allodynia, open field/novel object recognition, and photosensitivity. At the end of the study, the periaqueductal grey (PAG), a brain region known to contribute to both headache induction and maintenance, was collected and subjected to LC-MS to quantify endocannabinoid levels. Results Mice exhibited periorbital allodynia at nearly all time points tested and photosensitivity from 28-days onward. Levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptor 1 (CB1R) expression were altered by both age and upon treatment with formoterol. Administration of FAAH/MAGL inhibitors, to target the eCB system, and a non-selective cannabinoid receptor agonist, WIN 55,212 reversed the formoterol-induced periorbital allodynia. Conclusions These results suggest that formoterol is dysregulates eCB tone to drive headache-like periorbital allodynic behaviors. These results could help inform preventative treatment options for individuals receiving formoterol, as well as provide information on the interaction between the eCB and adrenergic system. Graphical Abstract

Abstract Background Opioid use disorder (OUD) remains a significant public health issue as the number of opioid-related overdose deaths continues to reach new highs each year. Buprenorphine/Naloxone is a medication that has been shown to be highly effective for the treatment of OUD. However, the clinical management of patients on this medication is challenging as many patients discontinue treatment prematurely. We conducted a qualitative study focusing on experienced prescribers of buprenorphine to learn about what they believe are key challenges in prescribing this medication to patients with OUD and related strategies for improving treatment outcomes. Methods We conducted two rounds of interviews with 12 prescribers who were either trained as a primary care physician, nurse practitioner, or physician assistant. These prescribers were recruited from an academically-based treatment program, a community health center, and a commercial substance use disorder treatment facility. Interview data were coded and analyzed in accordance with a grounded theory approach. Results Key findings and related recommendations emerged for patient monitoring, integration of behavioral health with prescribing, patient volume requirements, and use of telehealth. Conclusion The interviews generated a number of recommendations for improving patient outcomes from buprenorphine treatment. Some of these recommendations can be implemented quite readily whereas others entail more substantial resources and time commitments.

The acceptability of school-based interventions has been regularly examined among teachers and parents; however, students are less frequently assessed despite being the recipients of most interventions. Although recent studies have begun exploring how different student characteristics (e.g., gender) and types of acceptability assessments (e.g., dynamic) impact students' ratings, no studies have examined the role of intervention dosage despite early conceptual models highlighting the linkage between intervention acceptability, dosage, adherence, and effectiveness. This study explored 255 third-grade students' intervention dosage and acceptability ratings within the context of a class-wide writing intervention administered over 7 weeks. Results indicated that most students received a high number of intervention sessions throughout the study and rated the intervention as moderately acceptable. There was a statistically significant gender difference in students' postintervention acceptability ratings, with female students rating the class-wide writing intervention higher than male students. In addition, intervention dosage was a statistically significant predictor of students' postintervention acceptability ratings, although gender did not moderate these findings.

Background Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and Results We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value

We have conducted 0D, 1D, 2D, and 3D simulations of an idealized coaxial impedance-matched Marx generator (IMG) [Phys. Rev. Accel. Beams 20, 040402 (2017)PRABCJ2469-988810.1103/PhysRevAccelBeams.20.040402]. The 0D calculations were conducted with a four-element circuit model; the 1D, 2D, and 3D calculations were conducted with highly resolved, fully electromagnetic representations. The IMG consists of 30 stages distributed axially and connected electrically in series. Each stage is powered by two bricks separated by 180° and connected electrically in parallel. Each brick comprises two opposite-polarity capacitors in series with a single switch. The bricks drive an internal impedance-matched coaxial transmission line terminated by a resistive load. The simulations neglect effects due to the switch-triggering circuit, the capacitor-charging circuit, external conducting boundaries, and reactive components of the load. We find dimensionality does not significantly affect the electrical power delivered by the IMG to its load: peak load powers estimated by the 0D, 1D, 2D, and 3D simulations agree to within 1%. The 3D calculations demonstrate that electromagnetic power radiated by the bricks, and axial gaps between stages, reduces the peak load power by less than ∼1%. Each simulation assumes the load impedance is 34% above that at which the load power is maximized. Operating an IMG with such an overmatched load offers several advantages while decreasing the peak load power by only 2%. The 0D, 1D, 2D, and 3D models outlined herein could be adapted to assess computationally competing IMG designs, and conduct a variety of numerical IMG experiments, before an IMG is constructed.

Introduction: The effectiveness of post-surgical rehabilitation following lumbar disc herniation (LDH) surgery is unclear. Research question: To investigate the effectiveness and safety of rehabilitation interventions initiated within three months post-surgery for adults treated surgically for LDH. Material and methods: This systematic review searched seven databases from inception to November 2023. Independent reviewers screened studies, assessed and extracted data, and rated the certainty of the evidence using the GRADE approach. Results: This systematic review retrieved 20,531 citations and included 25 randomized controlled trials. The high certainty evidence suggests that adding Pilates exercise to routine care and cognitive behavioral therapy may improve function immediately post-intervention (1 RCT), and that adding whole-body magnetic therapy to exercise, pharmacological and aquatic therapy may reduce low back pain intensity (1 RCT) immediately post-intervention. Compared to placebo, pregabalin did not reduce low back pain or leg pain intensity (1 RCT) (moderate to high certainty evidence). We found no differences between: 1) behavioral graded activity vs. physiotherapy (1 RCT); 2) exercise and education vs. neck massage or watchful waiting (1 RCT); 3) exercise, education, and in-hospital usual care vs. in-hospital usual care (1 RCT); 4) functional or staged exercise vs. usual post-surgical care including exercise (2 RCTs); and 5) supervised exercise with education vs. education (1 RCT). No studies assessed adverse events. Discussion and conclusion: Evidence on effective and safe post-surgical rehabilitation interventions is sparse. This review identified two interventions with potential short-term benefits (Pilates exercises, whole-body magnetic therapy) but safety is unclear, and one with an iatrogenic effect (pregabalin).