Citations

ABSTRACT Objectives To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross‐regional practices across North America, Europe, and the Pacific. Methods Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta‐analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. Results The sample ( N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention‐deficit/hyperactivity disorder (ADHD), post‐traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first‐generation antipsychotic prescriptions varied, with higher rates observed in Europe. Conclusions Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context‐specific guidelines. Gaps in data on medication‐assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Abstract Migraine attacks can be provoked in people with underlying primary headache disorders by multiple peripheral mechanisms suggesting the possible convergence of trigeminal nociceptive inputs onto a common, unknown central circuit. As calcitonin gene-related peptide (CGRP) expressing cells in the parabrachial nucleus (PBN) have been implicated in nociplastic pains, we hypothesized that (a) PBN CGRP-expressing neurons and their projections to the central amygdala (CeA) may be an essential central relay of multiple peripheral inputs promoting injury-free migraine headache and (b) this pathway may prioritize threat from activation of cranial afferents over other nociceptive inputs. Periorbital cutaneous allodynia (CA) was determined following supradural application of a cocktail of inflammatory mediators (IM), CGRP or pituitary adenylate cyclase-activating polypeptide (PACAP), or systemic administration of nitroglycerin (NTG) in CalcaCre or wild-type mice. Decreased rearing and photophobia were respectively evaluated as measures of ongoing headache and light-evoked migraine-like pain. Phosphorylation of extracellular signal-regulated kinases (pERK) was evaluated to assess regional neuronal activation. Compared with vehicle, supradural IM increased pERK in the trigeminal nucleus caudalis and PBN, but not in the paraventricular thalamus. Chemogenetic activation (Gq-DREADD) of PBN CGRP neurons elicited CA and photophobia while decreasing rearing. Lesioning of PBN neurons with ibotenic acid suppressed CA produced by supradural IM. Chemogenetic silencing (Gi-DREADD) or expression of tetanus toxin (TeNT) in PBN Calca neurons to prevent neurotransmitter release also inhibited CA elicited by supradural IM, CGRP, PACAP or systemic NTG. CRISPR/Cas9 editing of CeA receptor-associated membrane protein-1 (Ramp1) prevented IM-induced migraine-like symptoms revealing CGRP/CGRP-receptor activation from PBN→CeA projections. In contrast, PBN lesions, chemogenetic manipulation, and TeNT expression in PBN Calca cells and CeA Ramp1 CRISPR/Cas9 editing did not affect acute pain responses induced by hind paw IM injection, intraperitoneal acetic acid, or acute nociceptive behaviors from IM stimulation of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve. These data reveal a central pathway composed of PBN Calca neurons and CeA CGRP receptor signaling that is both sufficient to elicit migraine-like pain in naive mice and necessary to promote migraine-like pain following activation of the ophthalmic (V1) branch of the trigeminal nerve. Importantly, this pathway is essential for acute pain arising from V1 trigeminal, but dispensable for acute stimuli from other nociceptive afferents. The prioritization of V1 acute nociception suggests evolutionary importance for detecting threats to the head to promote survival through advantageous behaviors such as defensive coping observed in migraine.

Abstract Mild traumatic brain injury (mTBI) commonly induces transient acute (APTH) or persistent (PPTH) post-traumatic headache (PTH) that often resembles migraine. As orexin B sensitizes male but not female murine, nonhuman primate, and human dorsal root ganglion neurons and supradural orexin B/orexin receptor 2 (OX2R) signaling elicits migraine-like pain in naïve male, but not female, mice we explored possible sexually dimorphic contributions of orexin B/OX2R to PTH. In mice of both sexes, mTBI-induced transient cephalic allodynia, a surrogate measure of APTH. After APTH resolution, allodynia was reinstated by exposure to normally innocuous stress or by inhalational delivery of a subthreshold concentration of umbellulone, a TRPA1 agonist, suggesting the expression of PPTH. In contrast to these nonselective stimuli, subthreshold supradural orexin B induced PPTH only in male mTBI mice. Intranasal delivery of a CRISPR/Cas9 plasmid to edit trigeminal OX2R expression prevented APTH and development of PPTH selectively in male mTBI mice. Daily oral suvorexant, a dual orexin receptor antagonist (DORA), beginning immediately after mTBI, prevented APTH as well as PPTH. Critically, starting suvorexant treatment after resolution of APTH also prevented stress- or umbellulone-induced PPTH. EEG/EMG-defined sleep architecture or immobility-defined sleep was not disrupted in this mTBI model suggesting that suvorexant benefits are unlikely related to sleep modulation. Our findings reveal a male-specific mechanism of PTH maintained by orexin B/OX2R signaling and suggest that approved DORAs may be beneficial in treating APTH and preventing transition to PPTH in men. Importantly, DORAs may also be effective in men with established PPTH.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Background: Secondary mitral regurgitation (SMR) is characterized by a pathological process impacting the left ventricle (LV) as opposed to the mitral valve (MV). In the absence of structural alterations to the MV, the expansion of the LV or impairment of the papillary muscles (PMs) may ensue. A number of technical procedures are accessible for the purpose of determining the optimal resolution for MR. Nevertheless, there is a dearth of rigorous data to facilitate a comparative analysis of MV replacement, MV repair (including subvalvular repair), and transcatheter mitral valve interventions (TMV-Is). The objective of this investigation is to evaluate and compare the efficacy and clinical outcomes of transcatheter mitral valve repair (TMV-r) utilizing the edge-to-edge mitral valve repair (TEER) procedure in comparison to conventional surgical mitral valve interventions (S-SMVis) in patients with secondary mitral regurgitation. Methods and analysis: A consortium of five cardiac surgery institutions from four European states and Japan have joined forces to establish a multicenter observational registry, designated TEERMISO. Patients who underwent technical procedures for SMR between January 2007 and December 2023 will be enrolled consecutively into the TEERMISO registry. The investigation team evaluated the comparative efficacy of replacement and repair techniques, utilizing both the standard surgical methodology and the transcatheter intervention. The primary clinical outcome will be the degree of left ventricular remodeling, as assessed by the left ventricular end-diastolic volume index, at 10 years. The forthcoming research will assess a variety of secondary endpoints, among which all-cause mortality will be the primary endpoint. Subsequent assessments will be made in the following order: functional status, hospitalization, neurocognition, physiological measures (echocardiographic assessment), occurrence of adverse clinical incidents, and reoperation. Ethics and dissemination: The multicenter design of the database is anticipated to reduce the potential for bias associated with institutional caseload and surgical experience. All participating centers possess an established mitral valve protocol that facilitates comprehensive follow-up and management of any delayed mitral complications following replacement surgery or surgical repair of the secondary mitral regurgitation. The data collected will provide insights into the impact of diverse surgical approaches on standard mitral valve surgery and TEER. This will facilitate the evaluation of LV remodeling over the course of long-term post-procedural follow-up. Trial Registration: ClinicalTrials.gov ID: NCT05090540; IRB ID: 202201143

Background We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine. Methods Male and female C57BL6J mice received either supradural orexin B and an inflammatory mediator cocktail (IM) with migraine-like pain behaviors and photophobia recorded. Expression of orexin 2 receptor (OX2R) in trigeminal ganglion (TG) and phosphorylated extracellular signal-regulated kinases (ERK) levels in trigeminal nucleus caudalis (TNC) were evaluated. Orexin B-induced excitability of TG cells was assessed with patch-clamp electrophysiology. Intranasal delivery of CRISPR/Cas9 plasmids was used to edit the expression of OX2R in the TG. Results Supradural orexin B induced migraine-like pain behaviors, photophobia and increased TNC ERK phosphorylation exclusively in males. Blockade of orexin signaling with supradural suvorexant, a dual orexin receptor antagonist, prevented, but did not reverse, migraine-like pain in males induced by supradural IM cocktail. OX2R expression was higher in male TG and orexin B increased TG neuron excitability in males. Intranasal OX2R CRISPR/Cas9 reduced TG receptor expression and orexin B-induced TNC ERK phosphorylation and prevented migraine-like pain induced by supradural orexin B in males. Conclusions Our studies reveal a male-specific mechanism of TG nociceptor sensitization and migraine-like pain behavior mediated by orexin B/OX2R signaling. Sexually dimorphic mechanisms of trigeminal nociceptor sensitization and activation offer opportunities to improve patient outcomes by considering patient sex and may influence clinical trial design and interpretation.

Background: Severe adolescent idiopathic scoliosis (AIS) can be treated with instrumented fusion, but the number of anchors needed for optimal correction is controversial. Methods: We conducted a multicenter, randomized study that included patients undergoing spinal fusion for single thoracic curves between 45° and 65°, the most common form of operatively treated AIS. Of the 211 patients randomized, 108 were assigned to a high-density screw pattern and 103, to a low-density screw pattern. Surgeons were instructed to use ≥1.8 implants per spinal level fused for patients in the high-implant-density group or ≤1.4 implants per spinal level fused for patients in the low-implant-density group. The primary outcome measure was the percent correction of the coronal curve at the 2-year follow-up. The power analysis for this trial required 174 patients to show equivalence, defined as a 95% confidence interval (CI) within a ±10% correction margin with a probability of 90%. Results: In the intention-to-treat analysis, the mean percent correction of the coronal curve was equivalent between the high-density and low-density groups at the 2-year follow-up (67.6% versus 65.7%; difference, −1.9% [95% CI: −6.1%, 2.2%]). In the per-protocol cohorts, the mean percent correction of the coronal curve was also equivalent between the 2 groups at the 2-year follow-up (65.0% versus 66.1%; difference, 1.1% [95% CI: −3.0%, 5.2%]). A total of 6 patients in the low-density group and 5 patients in the high-density group required reoperation (p = 1.0). Conclusions: In the setting of spinal fusion for primary thoracic AIS curves between 45° and 65°, the percent coronal curve correction obtained with use of a low-implant-density construct and that obtained with use of a high-implant-density construct were equivalent. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Abstract Purpose: Pharmacologic ascorbate (P-AscH−) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH− with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH− in humans. Patients and Methods: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan–Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. Results: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7–26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. Conclusions: P-AscH− combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255

Abstract Repeated stress produces hyperalgesic priming in preclinical models, but underlying mechanisms remain uncertain. As stress engages kappa opioid receptors (KORs), we hypothesized that repeated administration of KOR agonists might mimic, in part, stress-induced hyperalgesic priming. The potential contribution of circulating prolactin (PRL) and dysregulation of the expression of PRL receptor (PRLR) isoforms in sensory neurons after KOR agonist administration was also investigated. Mice received 3 daily doses of U-69593 or nalfurafine as a “first-hit” stimulus followed by assessment of periorbital tactile allodynia. Sixteen days after the first KOR agonist administration, animals received a subthreshold dose of inhalational umbellulone, a TRPA1 agonist, as the second-hit stimulus and periorbital allodynia was assessed. Cabergoline, a dopamine D2 receptor agonist, was used to inhibit circulating PRL in additional cohorts. Prolactin receptor isoforms were quantified in the V1 region of the trigeminal ganglion after repeated doses of U-69593. In both sexes, KOR agonists increased circulating PRL and produced allodynia that resolved within 14 days. Hyperalgesic priming, revealed by umbellulone-induced allodynia in animals previously treated with the KOR agonists, also occurred in both sexes. However, repeated U-69593 downregulated the PRLR long isoform in trigeminal neurons only in female mice. Umbellulone-induced allodynia was prevented by cabergoline co-treatment during priming with KOR agonists in female, but not male, mice. Hyperalgesic priming therefore occurs in both sexes after either biased or nonbiased KOR agonists. However, a PRL/PRLR-dependence is observed only in female nociceptors possibly contributing to pain in stress-related pain disorders in females.