Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide1. Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development2,3. For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase (Tert) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERThigh acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERThigh acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras-MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERThigh acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.

Neutrophil Heterogeneity Is Modified during Acute Lung Inflammation in Apoa1-/- Mice.

Neutrophils play important roles in inflammatory airway diseases. In this study, we assessed whether apolipoprotein A-I modifies neutrophil heterogeneity as part of the mechanism by which it attenuates acute airway inflammation. Neutrophilic airway inflammation was induced by daily intranasal administration of LPS plus house dust mite (LPS+HDM) to Apoa1-/- and Apoa1+/+ mice for 3 d. Single-cell RNA sequencing was performed on cells recovered from bronchoalveolar lavage fluid on day 4. Unsupervised profiling identified 10 clusters of neutrophils in bronchoalveolar lavage fluid from Apoa1-/- and Apoa1+/+ mice. LPS+HDM-challenged Apoa1-/- mice had an increased proportion of the Neu4 neutrophil cluster that expressed S100a8, S100a9, and Mmp8 and had high maturation, aggregation, and TLR4 binding scores. There was also an increase in the Neu6 cluster of immature neutrophils, whereas neutrophil clusters expressing IFN-stimulated genes were decreased. An unsupervised trajectory analysis showed that Neu4 represented a distinct lineage in Apoa1-/- mice. LPS+HDM-challenged Apoa1-/- mice also had an increased proportion of recruited airspace macrophages, which was associated with a reciprocal reduction in resident airspace macrophages. Increased expression of a common set of proinflammatory genes, S100a8, S100a9, and Lcn2, was present in all neutrophils and airspace macrophages from LPS+HDM-challenged Apoa1-/- mice. These findings show that Apoa1-/- mice have increases in specific neutrophil and macrophage clusters in the lung during acute inflammation mediated by LPS+HDM, as well as enhanced expression of a common set of proinflammatory genes. This suggests that modifications in neutrophil and macrophage heterogeneity contribute to the mechanism by which apolipoprotein A-I attenuates acute airway inflammation.

Asthmatic patients with high serum amyloid A have proinflammatory HDL: Implications for augmented systemic and airway inflammation.

RATIONALE: Serum amyloid A (SAA) is bound to high-density lipoproteins (HDL) in blood. Although SAA is increased in the blood of patients with asthma, it is not known whether this modifies asthma severity. OBJECTIVE: We sought to define the clinical characteristics of patients with asthma who have high SAA levels and assess whether HDL from SAA-high patients with asthma is proinflammatory. METHODS: SAA levels in serum from subjects with and without asthma were quantified by ELISA. HDLs isolated from subjects with asthma and high SAA levels were used to stimulate human monocytes and were intravenously administered to BALB/c mice. RESULTS: An SAA level greater than or equal to 108.8 µg/mL was defined as the threshold to identify 11% of an asthmatic cohort (n = 146) as being SAA-high. SAA-high patients with asthma were characterized by increased serum C-reactive protein, IL-6, and TNF-α; older age; and an increased prevalence of obesity and severe asthma. HDL isolated from SAA-high patients with asthma (SAA-high HDL) had an increased content of SAA as compared with HDL from SAA-low patients with asthma and induced the secretion of IL-6, IL-1ß, and TNF-α from human monocytes via a formyl peptide receptor 2/ATP/P2X purinoceptor 7 axis. Intravenous administration to mice of SAA-high HDL, but not normal HDL, induced systemic inflammation and amplified allergen-induced neutrophilic airway inflammation and goblet cell metaplasia. CONCLUSIONS: SAA-high patients with asthma are characterized by systemic inflammation, older age, and an increased prevalence of obesity and severe asthma. HDL from SAA-high patients with asthma is proinflammatory and, when intravenously administered to mice, induces systemic inflammation, and amplifies allergen-induced neutrophilic airway inflammation. This suggests that systemic inflammation induced by SAA-high HDL may augment disease severity in asthma.

Low-Level BCR::ABL1 Transcript at Diagnosis in Childhood Leukemia: A 10-Year Single Institution Study.

INTRODUCTION: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is a high risk form of ALL associated with dismal outcomes in the pre-tyrosine kinase inhibitor (TKI) era. Addition of a TKI to chemotherapy improves outcomes. Therefore, testing for the presence of the Philadelphia chromosome by at least two methods at the time of diagnosis is critical. Diagnostic testing may include karyotype, fluorescent in situ hybridisation (FISH), and RT-PCR for the BCR::ABL1 transcript. The significance of low-level BCR::ABL1 transcript by RT-PCR in the absence of the Philadelphia chromosome on karyotype or by FISH is unknown. METHODS: This is a retrospective review of children diagnosed with acute leukemia at our institution from 2010 to 2020. Those positive for the BCR::ABL1 transcript by qualitative RT-PCR, and negative for t(9;22) by karyotype or FISH were analyzed for demographics, cytogenetic and molecular features at diagnosis and relapse, treatment and outcomes. The Kaplan-Meier method was used to estimate event-free and overall survival. RESULTS: Forty-seven of 306 (15%) patients with Ph- ALL had low-level BCR::ABL1 detected by RT-PCR. Most (77%) had B-cell ALL. The e1a2 transcript was detected most frequently, in 43 (91%) patients. BCR::ABL1 was quantifiable in 12/43 (28%) patients, with a median of 0.0008% (range 0.0003-0.095%). Seven patients (15%) relapsed. No patient with low-level BCR::ABL1 at diagnosis developed Ph + ALL at relapse. There was no difference in 5-year event-free (77% versus 81%, p = 0.407) or overall survival (86% versus 91%, p = 0.3) between children with low-level BCR::ABL1 (n = 47) and those without (n = 259). CONCLUSION: BCR::ABL1 low-level positivity in children with newly diagnosed Ph- ALL is a relatively common finding and did not adversely affect outcome for patients treated using a contemporary risk-adapted approach.

Data Analysis of Dynamics in Protein Solutions Using Quasi-Elastic Neutron Scattering─Important Insights from Polarized Neutrons.

Protein dynamics play a vital role in biology. Quasi elastic neutron scattering (QENS) is an ideal method to access these dynamics. To isolate protein dynamics, it is important to separate the signal of the buffer and the protein. Normally data analysis is performed based on the assumption that the scattering spectrum is incoherent. To observe the full range of protein dynamics, it is necessary to perform the experiments in solution. This solution is usually a fully deuterated buffer, while the protein remains protonated. It is generally assumed that subtracting the buffer contribution removes all coherent signal from the measured spectrum, and the rest can be considered as purely incoherent. Up until recently, there was no way to experimentally verify this assumption. Polarized QENS experiments allow for the coherent and incoherent contributions to be separated. By comparing the results from the polarized QENS experiment and the standard analysis method from unpolarized QENS, we are thus able to check this assumption experimentally. We show that the pure incoherent spectrum obtained from polarization analysis does not match the results for unpolarized QENS. We discuss the implications of this for data analysis and possible solutions to the problem, as well as mitigation techniques for standard QENS.

Paranasal sinus occupancy assessed from magnetic resonance images-associations with clinical indicators in patients with systemic lupus erythematosus.

OBJECTIVES: Nasal, paranasal sinus and mucosal disorders are common symptoms in autoimmune rheumatic diseases. Soft tissue changes and fluid accumulation in the osteomeatal complexes and paranasal sinuses manifest as opaqueness on radiological images which can be assessed using visual scoring and computational methods on CT scans, but their results do not always correlate. Using MRI, we investigate the applicability of different image analysis methods in SLE. METHODS: We assessed paranasal sinus opaqueness on MRI from 51 SLE patients, using three visual scoring systems and expert-delineated computational volumes, and examined their association with markers of disease activity, inflammation, endothelial dysfunction and common small vessel disease (SVD) indicators, adjusting for age and sex-at-birth. RESULTS: The average paranasal sinus volume occupation was 4.55 (6.47%) [median (interquartile range) = 0.67 (0.25-2.65) ml], mainly in the maxillary and ethmoid sinuses. It was highly correlated with Lund-Mackay (LM) scores modified at 50% opaqueness cut-off (Spearman's ρ: 0.71 maxillary and 0.618 ethmoids, P < 0.001 in all), and with more granular variations of the LM system. The modified LM scores were associated with SVD scores (0: B = 5.078, s.e. = 1.69, P = 0.0026; 2: B = -0.066, s.e. = 0.023, P = 0.0045) and disease activity (anti-dsDNA: B = 4.59, s.e. = 2.22, P = 0.045; SLEDAI 3-7: 2.86 < B < 4.30; 1.38 < s.e. < 1.63; 0.0083 ≤ P ≤ 0.0375). Computationally derived percent opaqueness yielded similar results. CONCLUSION: In patients with SLE, MRI computational assessment of sinuses opaqueness and LM scores modified at a 50% cut-off may be useful tools in understanding the relationships among paranasal sinus occupancy, disease activity and SVD markers.

Insurance-based Disparities in Outcomes and Extracorporeal Membrane Oxygenation Utilization for Hospitalized COVID-19 Patients.

BACKGROUND: The objective of this study was to examine insurance-based disparities in mortality, nonhome discharges, and extracorporeal membrane oxygenation utilization in patients hospitalized with COVID-19. METHODS: Using a national database of U.S. academic medical centers and their affiliated hospitals, the risk-adjusted association between mortality, nonhome discharge, and extracorporeal membrane oxygenation utilization and (1) the type of insurance coverage (private insurance, Medicare, dual enrollment in Medicare and Medicaid, and no insurance) and (2) the weekly hospital COVID-19 burden (0 to 5.0%; 5.1 to 10%, 10.1 to 20%, 20.1 to 30%, and 30.1% and greater) was evaluated. Modeling was expanded to include an interaction between payer status and the weekly hospital COVID-19 burden to examine whether the lack of private insurance was associated with increases in disparities as the COVID-19 burden increased. RESULTS: Among 760,846 patients hospitalized with COVID-19, 214,992 had private insurance, 318,624 had Medicare, 96,192 were dually enrolled in Medicare and Medicaid, 107,548 had Medicaid, and 23,560 had no insurance. Overall, 76,250 died, 211,702 had nonhome discharges, 75,703 were mechanically ventilated, and 2,642 underwent extracorporeal membrane oxygenation. The adjusted odds of death were higher in patients with Medicare (adjusted odds ratio, 1.28 [95% CI, 1.21 to 1.35]; P < 0.0005), dually enrolled (adjusted odds ratio, 1.39 [95% CI, 1.30 to 1.50]; P < 0.0005), Medicaid (adjusted odds ratio, 1.28 [95% CI, 1.20 to 1.36]; P < 0.0005), and no insurance (adjusted odds ratio, 1.43 [95% CI, 1.26 to 1.62]; P < 0.0005) compared to patients with private insurance. Patients with Medicare (adjusted odds ratio, 0.47; [95% CI, 0.39 to 0.58]; P < 0.0005), dually enrolled (adjusted odds ratio, 0.32 [95% CI, 0.24 to 0.43]; P < 0.0005), Medicaid (adjusted odds ratio, 0.70 [95% CI, 0.62 to 0.79]; P < 0.0005), and no insurance (adjusted odds ratio, 0.40 [95% CI, 0.29 to 0.56]; P < 0.001) were less likely to be placed on extracorporeal membrane oxygenation than patients with private insurance. Mortality, nonhome discharges, and extracorporeal membrane oxygenation utilization did not change significantly more in patients with private insurance compared to patients without private insurance as the COVID-19 burden increased. CONCLUSIONS: Among patients with COVID-19, insurance-based disparities in mortality, nonhome discharges, and extracorporeal membrane oxygenation utilization were substantial, but these disparities did not increase as the hospital COVID-19 burden increased.

A Qualitative Analysis of Shared Values and Motivation for Change Expressed by Sexual Minority Men in Relationships: Use of the Personal Values Card Sort Activity During Motivational Interviewing Sessions Addressing Drug Use and Sexual Health.

The development of tailored interventions that address drug use and sexual risk taking among sexual minority men (SMM) in relationships has garnered increasing interest over the past 20 years. Motivational interviewing (MI) has demonstrated promise in both individual and couples-based applications. The Personal Values Card Sort activity is commonly employed in these interventions; however, relatively little is known about the content of client responses evoked by this intervention task. This study examined how SMM in relationships characterize their values; how their relationship partners influence value attainment; and how they situated drug use and sexual risk taking in the context of their values and primary relationships. A qualitative analysis of intervention transcripts from sessions with 47 SMM aged 18 to 34 was conducted. All respondents were HIV negative and indicated recent (past 30 days) drug use and sexual risk behavior. Participants' high priority values reflected a focus on clarifying personal identity and interpersonal relationships. Values manifested as realized, aspirational, or transformed. Participants described their partners as supporting goal attainment and as a companion with whom they cope with goal-related stressors. Consistent with interdependence theory, participants' responses indicated consideration of their partner and relationship when these aligned with and supported goal-attainment. Conversely, when partners were described as a barrier to realizing their values, participants characterized their relationship as being of lower quality. Implications of this content for the activation of motivation for health behavior are discussed with specific emphasis on applications with SMM in relationships.

Situational prevention: Pharmacotherapy during periods of increased risk for migraine attacks.

The small molecule calcitonin gene-related peptide receptor antagonists (gepants) are the only drug class with medicines indicated for both the acute and preventive treatment of migraine. Given this dual capacity to both treat and prevent, along with their favorable tolerability profiles and lack of an association with medication-overuse headache, headache specialists have begun to use gepants in ways that transcend the traditional categories of acute and preventive treatment. One approach, called situational prevention, directs patients to treat during the interictal phase, before symptoms develop, in situations of increased risk for migraine attacks. Herein, we present three patients to illustrate scenarios of gepant use for situational prevention. In each case, a gepant was started in anticipation of a period of increased headache probability (vulnerability) and continued for a duration of 1 day to 5 consecutive days. Although this approach may expose patients to medication when headache may not have developed, the tolerability and safety profile and preventive effect of gepants may represent a feasible approach for some patients. Situational prevention is an emerging strategy for managing migraine before symptoms develop in individuals who can identify periods when the probability of headache is high. This paper is intended to increase awareness of this strategy and stimulate future randomized, placebo-controlled trials to rigorously assess this strategy.

CO2 storage and release in the deep Southern Ocean on millennial to centennial timescales.

The cause of changes in atmospheric carbon dioxide (CO2) during the recent ice ages is yet to be fully explained. Most mechanisms for glacial-interglacial CO2 change have centred on carbon exchange with the deep ocean, owing to its large size and relatively rapid exchange with the atmosphere1. The Southern Ocean is thought to have a key role in this exchange, as much of the deep ocean is ventilated to the atmosphere in this region2. However, it is difficult to reconstruct changes in deep Southern Ocean carbon storage, so few direct tests of this hypothesis have been carried out. Here we present deep-sea coral boron isotope data that track the pH-and thus the CO2 chemistry-of the deep Southern Ocean over the past forty thousand years. At sites closest to the Antarctic continental margin, and most influenced by the deep southern waters that form the ocean's lower overturning cell, we find a close relationship between ocean pH and atmospheric CO2: during intervals of low CO2, ocean pH is low, reflecting enhanced ocean carbon storage; and during intervals of rising CO2, ocean pH rises, reflecting loss of carbon from the ocean to the atmosphere. Correspondingly, at shallower sites we find rapid (millennial- to centennial-scale) decreases in pH during abrupt increases in CO2, reflecting the rapid transfer of carbon from the deep ocean to the upper ocean and atmosphere. Our findings confirm the importance of the deep Southern Ocean in ice-age CO2 change, and show that deep-ocean CO2 release can occur as a dynamic feedback to rapid climate change on centennial timescales.

Mesenteric blood flow and muscle sympathetic nerve activity during vasovagal syncope.

PURPOSE: Vasovagal syncope is thought to be mediated by a progressive fall in cardiac output secondary to venous pooling of blood in the splanchnic circulation. How and when this occurs before syncope has not been determined. METHODS: A total of 20 patients who became hypotensive during head-up tilt (age 40.9 ± 3.4 years; 10 females) were divided into two groups-the glyceryl trinitrate (GTN) group (n = 12) and the vasovagal syncope (VVS) group (n = 8) - on the basis of whether or not nitroglycerine provocation was required. They were compared with a control group (age 38.6 ± 3.3; 8 females; n = 13). Hemodynamics, including superior mesenteric artery blood flow (SMABF) and muscle sympathetic nerve activity (MSNA) were recorded continuously during early tilt, presyncope and recovery. We used pixel-weighting to calculate average velocity from the pulsed Doppler velocity envelope. RESULTS: During baseline and early tilt, resistance to mesenteric blood flow was lower in the VVS group: 0.30 ± 0.02 to 0.30 ± 0.02 mmHg/ml/min versus controls 0.30 ± 0.03 to 0.38 ± 0.04 mmHg/ml/min (p = 0.05). During presyncope, as blood pressure and stroke volume gradually fell, SMABF was higher in the VVS group, falling from 370 ± 46 to 248 ± 35 ml/min, versus controls, falling from 342 ± 51 to 233 ± 19 (p = 0.03). At this time, MSNA was lower in the VVS group than controls: 39 ± 4 to 34 ± 3 bursts/min versus 45 ± 2 to 48 ± 3 (p = 0.001). CONCLUSION: During presyncope, increased splanchnic blood flow may pool more blood in capacitance vessels resulting in decreased venous return and cardiac output. This may be secondary to decreased vasoconstrictor sympathetic activity.

Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions.

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies. MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment. CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Confinement of Fractional Excitations in a Triangular Lattice Antiferromagnet.

High-resolution neutron and THz spectroscopies are used to study the magnetic excitation spectrum of Cs_{2}CoBr_{4}, a distorted-triangular-lattice antiferromagnet with nearly XY-type anisotropy. What was previously thought of as a broad excitation continuum [L. Facheris et al., Phys. Rev. Lett. 129, 087201 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.087201] is shown to be a series of dispersive bound states reminiscent of "Zeeman ladders" in quasi-one-dimensional Ising systems. At wave vectors where interchain interactions cancel at the mean field level, they can indeed be interpreted as bound finite-width kinks in individual chains. Elsewhere in the Brillouin zone their true two-dimensional structure and propagation are revealed.

Does the definition of a novel environment affect the ability to detect cryptic genetic variation?

Anthropogenic change exposes populations to environments that have been rare or entirely absent from their evolutionary past. Such novel environments are hypothesized to release cryptic genetic variation, a hidden store of variance that can fuel evolution. However, support for this hypothesis is mixed. One possible reason is a lack of clarity in what is meant by 'novel environment', an umbrella term encompassing conditions with potentially contrasting effects on the exposure or concealment of cryptic variation. Here, we use a meta-analysis approach to investigate changes in the total genetic variance of multivariate traits in ancestral versus novel environments. To determine whether the definition of a novel environment could explain the mixed support for a release of cryptic genetic variation, we compared absolute novel environments, those not represented in a population's evolutionary past, to extreme novel environments, those involving frequency or magnitude changes to environments present in a population's ancestry. Despite sufficient statistical power, we detected no broad-scale pattern of increased genetic variance in novel environments, and finding the type of novel environment did not explain any significant variation in effect sizes. When effect sizes were partitioned by experimental design, we found increased genetic variation in studies based on broad-sense measures of variance, and decreased variation in narrow-sense studies, in support of previous research. Therefore, the source of genetic variance, not the definition of a novel environment, was key to understanding environment-dependant genetic variation, highlighting non-additive genetic variance as an important component of cryptic genetic variation and avenue for future research.

Downsized: gray whales using an alternative foraging ground have smaller morphology.

Describing individual morphology and growth is key for identifying ecological niches and monitoring the health and fitness of populations. Eastern North Pacific ((ENP), approximately 16 650 individuals) gray whales primarily feed in the Arctic/sub-Arctic regions, while a small subgroup called the Pacific Coast Feeding Group (PCFG, approximately 212 individuals) instead feeds between northern California, USA and British Columbia, Canada. Evidence suggests PCFG whales have lower body condition than ENP whales. Here we investigate morphological differences (length, skull, and fluke span) and compare length-at-age growth curves between ENP and PCFG whales. We use ENP gray whale length-at-age data comprised of strandings, whaling, and aerial photogrammetry (1926-1997) for comparison to data from PCFG whales collected through non-invasive techniques (2016-2022) to estimate age (photo identification) and length (drone-based photogrammetry). We use Bayesian methods to incorporate uncertainty associated with morphological measurements (manual and photogrammetric) and age estimates. We find that while PCFG and ENP whales have similar growth rates, PCFG whales reach smaller asymptotic lengths. Additionally, PCFG whales have relatively smaller skulls and flukes than ENP whales. These findings represent a striking example of morphological adaptation that may facilitate PCFG whales accessing a foraging niche distinct from the Arctic foraging grounds of the broader ENP population.

Sustained response of galcanezumab in migraine prevention: Patient-level data from a post hoc analysis in patients with episodic or chronic migraine.

OBJECTIVE: To evaluate, at population and individual patient levels, the sustained response of reduction in migraine headache days in patients with migraine treated with galcanezumab. METHODS: This was a post hoc analysis of double-blind galcanezumab studies in patients with migraine: two 6-month episodic migraine (EM; EVOLVE-1/EVOLVE-2), one 3-month chronic migraine (CM; REGAIN), and one 3-month treatment-resistant migraine (CONQUER). Patients received monthly subcutaneous galcanezumab 120 mg (after 240 mg initial loading dose), galcanezumab 240 mg, or placebo. In the EM and CM studies, the proportions of patients with ≥50% and ≥75% (EM only) reduction from baseline in average monthly migraine headache days from Months 1 to 3 and Months 4 to 6 were evaluated. A mean monthly response rate was estimated. The sustained effect was defined as maintaining ≥50% response for ≥3 consecutive months in the patient-level data for EM and CM. RESULTS: A total of 3348 patients with EM or CM from the EVOLVE-1/EVOLVE-2 (placebo, n = 894, galcanezumab, n = 879), REGAIN (placebo, n = 558, galcanezumab, n = 555), and CONQUER (EM: placebo, n = 132, galcanezumab, n = 137; CM: placebo, n = 98, galcanezumab, n = 95) studies were included. Patients were predominantly female, White, and had monthly migraine headache day averages ranging from 9.1 to 9.5 days (EM) and 18.1 to 19.6 days (CM). In patients with EM and CM, 19.0% and 22.6% of galcanezumab-treated patients, respectively, had significantly higher maintenance of ≥50% response for all months in the double-blind period compared to 8.0% and 1.5% of placebo-treated patients. The odds ratios (OR) of achieving clinical response for EM and CM were double with galcanezumab (OR = 3.0 [95% CI 1.8, 4.8] and OR = 6.3 [95% CI 1.7, 22.7], respectively). At the individual patient level, of patients who had ≥75% response at Month 3 in the galcanezumab 120 and 240 mg dose groups and placebo group, 39.9% (55/138) and 43.0% (61/142), respectively, of galcanezumab-treated patients maintained ≥75% response during Months 4-6 compared to 32.7% (51/156) with placebo. CONCLUSION: More galcanezumab-treated patients achieved ≥50% response within the first 3 months of treatment compared to placebo; responses were sustained during Months 4-6. The odds of achieving ≥50% response were double with galcanezumab.

Once-daily oral atogepant for the long-term preventive treatment of migraine: Findings from a multicenter, randomized, open-label, phase 3 trial.

OBJECTIVE: To assess long-term safety, tolerability, and efficacy of once-daily oral atogepant 60 mg in adults with migraine. BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of episodic migraine. METHODS: A 52-week, multicenter, randomized, open-label trial of adults (18-80 years) with migraine. Lead-in trial completers or newly enrolled participants with 4-14 migraine days/month were enrolled and randomized (5:2) to atogepant 60 mg once daily or oral standard care (SC) migraine preventive medication. The primary objective was to evaluate the safety and tolerability of atogepant; safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, and Columbia-Suicide Severity Rating Scale scores. Efficacy assessments (atogepant only) included change from baseline in mean monthly migraine days (MMDs) and the proportion of participants with reductions from baseline of ≥50%, ≥75%, and 100% in MMDs. RESULTS: The trial included 744 participants randomized to atogepant 60 mg (n = 546) or SC (n = 198). The atogepant safety population was 88.2% female (n = 479/543) with a mean (standard deviation) age of 42.5 (12.0) years. TEAEs occurred in 67.0% (n = 364/543) of participants treated with atogepant 60 mg. The most commonly reported TEAEs (≥5%) were upper respiratory tract infection (10.3%; 56/543), constipation (7.2%; 39/543), nausea (6.3%; 34/543), and urinary tract infection (5.2%; 28/543). Serious TEAEs were reported in 4.4% (24/543) for atogepant. Mean (standard error) change in MMDs for atogepant was -3.8 (0.1) for weeks 1-4 and -5.2 (0.2) at weeks 49-52. Similarly, the proportion of participants with ≥50%, ≥75%, and 100% reductions in MMDs increased from 60.4% (310/513), 37.2% (191/513), and 20.7% (106/513) at weeks 1-4 to 84.2% (282/335), 69.9% (234/335), and 48.4% (162/335), at weeks 49-52. CONCLUSION: Daily use of oral atogepant 60 mg for preventive treatment of migraine during this 1-year, open-label trial was safe, well tolerated, and efficacious.

Healthcare costs and resource utilization in patients with migraine treated with erenumab: A retrospective, non-interventional study using claims data from the United States.

OBJECTIVE: To assess healthcare costs and healthcare resource utilization (HCRU) among adult patients who newly initiated erenumab in the United States. METHODS: This retrospective, non-interventional analysis included adult patients (aged ≥18 years) newly initiating erenumab and who had three consecutive monthly claims for erenumab (11/1/2017-9/1/2019) from the Komodo Health database. Outcomes included migraine-related and all-cause costs, use of other preventive/acute migraine medications, and HCRU. All outcomes were compared during the 180-day pre- versus the 180-day post-index periods. Cost outcomes were also assessed for longer periods including post-index Days 91-270 and monthly mean post-index costs for the longest time of continuous insurance enrollment. RESULTS: Overall, 1839 patients with migraine were included for analysis. Compared to the 180-day pre-index period, an increase in total migraine-related costs (+$2639; p < 0.0001), migraine-related prescription costs (+$3435, p < 0.0001), all-cause total costs (+$2977; p < 0.001), and all-cause prescription costs (+$4102; p < 0.0001) were observed during the 180-day post-index period after adjusting for covariates. Conversely, reduction in migraine-related medical costs (-$896; p < 0.0001), and significantly lower odds of migraine-related emergency room visits (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.44-0.82; p = 0.001), migraine-related office visits (OR 0.58, 95% CI 0.53-0.64; p < 0.0001), and migraine-related neurologist visits (OR 0.69, 95% CI 0.63-0.75; p < 0.0001) were observed during the 180-days post-index period. There were significant decreases in the odds of having overall preventive migraine medications (OR 0.81, 95% CI 0.75-0.87; p < 0.0001), acute-migraine medications (OR 0.92, 95% CI 0.85-1.00; p = 0.038), and triptan (OR 0.79, 95% CI 0.73-0.85; p < 0.0001) during the 180-day post-index period. Sensitivity analyses on cost outcomes found no statistically significant differences in pre-index migraine-related costs compared to post-index migraine-related costs when assessing longer post-index follow-up periods. CONCLUSION: Initiation of therapy with a novel treatment is often associated with an increase in overall healthcare costs due to the entrance costs associated with novel therapy. For a chronic condition such as migraine, cost versus health benefits should be evaluated over a long period (e.g., ≥2 years) to better understand the true benefits of therapy. Data from this study suggest that the entrance cost for erenumab, the primary driver of the high post-index prescription costs gets mitigated by reduced medical costs over long-term follow-up. The results indicate better disease management in adult patients with migraine, which should be an important consideration for both patients and payors, as these findings have shown an offset between migraine-related prescription and medical costs.

Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial.

OBJECTIVE: To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine. BACKGROUND: Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary. RESULTS: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval -3.9 to -1.5], p < 0.001). The significance was maintained when analyzing the episodic (-3.2 ± 3.4 vs. -1.0 ± 3.6, p = 0.003) and chronic (-4.7 ± 4.4 vs. -1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group. CONCLUSION: Applied every other day, REN is effective and safe for the prevention of migraine.

Long-term efficacy and safety of erenumab in patients with chronic migraine and acute medication overuse: A subgroup analysis.

OBJECTIVE: Assess the long-term efficacy and safety of erenumab in patients with chronic migraine with acute medication overuse. BACKGROUND: Overuse of acute medication in patients with chronic migraine has been linked to greater pain intensity and disability and may diminish the effectiveness of preventive therapies. METHODS: This 52-week open-label extension study followed a 12-week double-blind placebo-controlled study in which patients with chronic migraine were randomized 3:2:2 to placebo or once-monthly erenumab 70 mg or 140 mg. Patients were stratified by region and medication overuse status. Patients received erenumab 70 mg or 140 mg throughout or switched from erenumab 70 to 140 mg (based on protocol amendment to augment safety data at higher dose). Efficacy was assessed in patients with and without medication overuse at parent study baseline. RESULTS: Of 609 patients enrolled in the extension study, 252/609 (41.4%) met the criteria for medication overuse at parent study baseline. At Week 52, the mean change in monthly migraine days from parent study baseline was -9.3 (95% confidence interval: -10.4, -8.1 days) in the medication overuse subgroup versus -9.3 (-10.1, -8.5 days) in the non-medication overuse subgroup (combined erenumab doses); proportion of patients achieving ≥50% reduction in monthly migraine days at Week 52 was 55.9% (90/161; 48.2%, 63.3%) versus 61.3% (136/222; 54.7%, 67.4%), respectively. Among baseline users of acute migraine-specific medication, the mean change in monthly migraine-specific medication days at Week 52 was -7.4 (-8.3, -6.4 days) in the medication overuse subgroup versus -5.4 (-6.1, -4.7 days) in the non-medication overuse subgroup. Most patients (197/298; 66.1%) in the medication overuse subgroup transitioned to non-overuse status by Week 52. Erenumab 140 mg was associated with numerically greater efficacy than erenumab 70 mg across all endpoints. No new safety signals were identified. CONCLUSION: Long-term erenumab treatment demonstrated sustained efficacy and safety in patients with chronic migraine with and without acute medication overuse.