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.

piRNA expression patterns in high vs. low fertility bovine sperm.

PIWI-interacting RNAs (piRNAs) are 24-32 nucleotide RNA sequences primarily expressed in germ cells and developing embryos that suppress transposable element expression to protect genomic integrity during epigenetic reprogramming events. We characterized the expression of piRNA sequences and their encoding clusters in sperm samples from an idiopathic fertility model of Holstein bulls with high and low Sire Conception Rates. The piRNA populations were determined to be mostly similar between fertility conditions when investigated by principal component and differential expression analysis, suggesting that a high degree of conservation in the piRNA system is likely necessary for the production of viable sperm. Both fertility conditions demonstrated evidence of 'ping-pong' activity - a secondary biogenesis pathway associated with active transposable element targeting and suppression. Most sperm-borne piRNAs were between 29-30 nucleotides in length and originated from 226 clusters across the genome, with the exception of chromosome 20. Mapping analysis revealed abundant targeting of several transposable element families, suggesting a suppressive function of sperm piRNAs consistent with their established roles. Expression of genes targeted by sperm-borne piRNAs is significantly reduced throughout early embryogenesis compared to the mRNA population. Limited transposable element expression is known to be essential for spermatogenesis, thus epigenetic regulation of this pathway is likely to influence sperm quality and fertilizing capacity.

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.

Morphological characterization of Iris hymenospatha and Iris histrio populations in Iran: implications for conservation and breeding.

The native populations of Iris hymenospatha and Iris histrio, two endangered bulbous species within the large Iris genus in Iridaceae, are threatened with extinction due to mining and other industrial activities in their natural habitats in Central Asia, including Iran. These species not only have a significant economic impact on the global horticultural industry due to their versatility and attractive phenotypic traits, but also have significant ecological value that necessitates their conservation. In this study, we examined the morphological and functional diversity between individuals within these two species, which exhibit high tolerance to environmental stresses. Our study examined 10 populations of I. hymenospatha and two populations of I. histrio based on bulb, flower, and leaf characteristics throughout Iran. We recognized a gradation of five different leaf shapes among I. hymenospatha populations with significant differences between some populations, including "Arak-Khomain" and "Arak-Gerdo". The "Jaro", "Natanz-Karkas", "Ardestan-Taleghan", "Arak-Rahjerd", "Arak-Gerdo", "Ganjnameh", and "Abas-Abad" populations of I. hymenospatha displayed maximal values in leaf width, stem diameter under flower, crown diameter, flower number, leaf number, and bulb diameter. The I. histrio "Velian" population had a significantly larger flower size, a longer stem length, a larger style width, a longer flowering date, and a higher plant height compared to the "Ganjnameh" population of I. histrio. Such characteristics of both species make them remarkable ornamental plants. Our study also revealed that I. hymenospatha populations grow on different soils and elevations and have the ability to adapt to different growing conditions. Given the threats they face, conservation through horticultural selection and propagation offers a viable conservation strategy for both species. This approach not only preserves the genetic diversity of these species, but also enables their further contribution to the horticultural industry.

Addressing weight bias in reproductive medicine: a call to revisit body mass index restrictions for in vitro fertilization treatment.

The prevalence of obesity has doubled among reproductive-age adults in the US over the past 40 years and is projected to impact half of the population by 2030. Obesity is associated with a twofold to threefold increase in infertility, largely because of anovulation, and is associated with a lower rate of pregnancy with ovulation induction among anovulatory women. As a result of these trends and associations, in vitro fertilization (IVF) care will need to be adapted to provide safe, effective, and equitable access for patients with obesity. Research over the past 10 years has demonstrated safe sedation practices and effective procedure modifications for oocyte retrievals and embryo transfers in patients with obesity undergoing IVF treatment. We encourage IVF medical directors to revisit body mass index restrictions for IVF treatment in favor of individualized patient risk assessments to minimize weight bias and provide timely access to safe and effective IVF care for patients with obesity and infertility.

A Prospective Trial of Single-Fraction Radiation to the Tumor Bed with a Novel Breast-Specific Stereotactic Radiation Therapy Device: The GammaPod.

Purpose: Radiation therapy for early-stage breast cancer is typically delivered in a hypofractionated regimen to the whole breast followed by a tumor bed boost. This results in a treatment course of approximately 4 weeks. In this study, the tumor bed boost was delivered in a single fraction as part of a safety and feasibility study for FDA clearance of the device. Methods and Materials: Eligible women with early-stage breast cancer underwent lumpectomy followed by radiation therapy. Patients underwent breast immobilization using a system specific to the GammaPod followed by CT simulation, boost treatment planning, and boost treatment delivery all in a single treatment day. Patients then started whole-breast radiation therapy within 1 week of the boost treatment. Patients and treatments were assessed for safety and feasibility. Acute toxicities were recorded. Results: A single-fraction boost of 8 Gy was delivered to the tumor bed before a course of whole-breast radiation. The GammaPod treatment was successfully delivered to 14 of 17 enrolled patients. Acute toxicities from all radiation therapy, inclusive of the boost and whole-breast radiation, were limited to grade 1 events. Conclusions: The GammaPod device successfully delivered a single-fraction boost treatment to the tumor bed with no change in expected acute toxicities. The results of this study led to FDA clearance of the device through the Investigational Device Exemption process at the FDA. The GammaPod is in clinical use at 4e institutions nationally and internationally, with additional sites pending in 2023.

Odevixibat: A Novel Bile Salt Inhibitor Treatment for Pruritus in Progressive Familial Intrahepatic Cholestasis.

Chronic pruritus is defined as an itch lasting greater than six weeks. It can manifest from a wide variety of etiologies, as many different substances can act as pruritogens, such as steroids, histamine, progesterone, endogenous opioids, and serotonin. In the setting of cholestatic liver disease, increased bile acids play a major role in chronic pruritus. The itching in cholestatic liver disease is worsened in intensity at night and localized frequently to the palms, soles, knees, and other pressure sites. It can be hard to manage, affecting the quality of sleep and causing irritability, poor attention, and, in some cases, depression. One such disease that results from chronic pruritus is progressive familial intrahepatic cholestasis (PFIC), a group of uncommon hereditary disorders that affects the formation of bile and its outflow from the liver. Previously, the drug ursodeoxycholic acid was used to help manage pruritus or surgical procedures, e.g., partial external biliary diversion or partial internal biliary diversion, to help control complications of the disease. This literature review will discuss three clinical studies covering the effectiveness of odevixibat in treating pruritus in patients with PFIC. Odevixibat (Bylvay) is an oral drug that has been FDA-approved to treat pruritus in patients three months of age and older with PFIC. Odevixibat prevents the reabsorption of bile salts in the intestines, resulting in decreased levels of bile salts via their excretion in stool. Several studies have determined that the drug is well tolerated and provides a nonsurgical, pharmacological treatment alternative for those with PFIC.

Preterm infant with necrotizing enterocolitis and arteritis secondary to streptococcus gallolyticus subspecies pasteurianus.

 Streptococcus gallolyticus subspecies pasteurianus is a subtype of Streptococcus bovis (S. bovis) that has become increasingly recognized as a sepsis-causing pathogen in neonates. It is well documented that S. bovis species have a predilection to both cardiac and gastrointestinal tissue, and in adult populations, isolating these organisms in the bloodstream often triggers further evaluation for co-morbid complications such as colon cancer or endocarditis. However, no such guidance currently exists in neonatal literature. We present a case of a preterm infant with S. gallolyticus subsp. pasteurianus bacteremia presenting as necrotizing enterocolitis (NEC) not previously described in the literature. Furthermore, through a complete diagnostic evaluation, including an echocardiogram, our patient was found to have the rare complication of endocarditis.

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.

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.

Management of medication overuse headache.

Medication overuse headache (MOH) is a secondary headache characterized by frequent use of acute or symptomatic migraine medications at a sufficient frequency to transform patients from episodic to chronic migraine. MOH represents a significant medical problem, with a serious burden on patients' lives and on society as a whole. MOH patients often have additional comorbidities, and the clinical challenge of helping patients reduce acute medication use and revert to episodic headache can be marked. Treatment includes education and prevention; withdrawal programs; pharmacological prophylaxis; multidisciplinary therapies with behavioral and noninvasive neuromodulation options; and scheduled, frequent follow-up to prevent relapses. The advent of anti-CGRP therapy monoclonal antibodies may provide an alternative to more extensive programs for less complex patients. This review also provides guidance for which patients may benefit most from coordinated integrated programs.

State Resident Handedness, Ideology, and Political Party Preference: U.S. Presidential Election Outcomes Over the Past 60 Years.

Pearson correlation, partial correlation, and multiple regression strategies determined the degree to which estimates of the level of left-handedness in each of the 48 contiguous American states related to citizen political ideology and to Democratic-Republican presidential popular vote over the past 60 years. Higher state levels of left-handedness were associated significantly with liberal ideology in each of the presidential election years from 1964 to 2016. Comparable ideology data were not available for 2020. Higher state levels of left-handedness also were associated with a greater degree of Democratic candidate popular vote support in each of the presidential election years from 1964 to 2020 except for 1976. The mean size of these 28 significant Pearson correlations involving the two political criteria was .62 (SD = .12) with a range of .38-.80, indicating handedness alone could account for a mean of 40.1% (SD = 14.9) of the variance in the two political preference variables. Corresponding multiple regressions showed that when state-level Big Five personality, White population percent, urbanization, and income variables were given the opportunity to enter the equations, handedness still emerged with a significant regression coefficient in 26 of the 28 equations. The two exceptions occurred for 1968 with either political preference criterion. It is speculated that such relations are grounded in hypothesized but poorly understood genetic links between handedness, personality, and political beliefs and attitudes, and, that a foundational genetic predisposition to left-handedness in a population may have much greater impact on correlates than overt levels of left-handedness.

Eptinezumab Demonstrated Efficacy Regardless of Prior Preventive Migraine Treatment Failure Type: Post Hoc Analyses of the DELIVER Study.

INTRODUCTION: In the DELIVER study, eptinezumab reduced monthly migraine days (MMDs) more than placebo in patients with 2-4 prior preventive migraine treatment failures. This post hoc analysis evaluated the efficacy of eptinezumab across the 24-week placebo-controlled period of the DELIVER study in subgroups defined by prior treatment failure type. METHODS: DELIVER (NCT04418765) randomized adults with migraine to eptinezumab 100 mg, 300 mg, or placebo, administered intravenously every 12 weeks. Changes from baseline in MMDs and percentages of patients with ≥ 50% reduction from baseline in MMDs (≥ 50% migraine responder rates [MRRs]) were summarized in subgroups of patients defined by prior treatment failure type. Subgroups were not mutually exclusive and included patients for whom topiramate, beta blockers (metoprolol, propranolol), amitriptyline, and/or flunarizine had failed. RESULTS: Across Weeks 1-12 in all subgroups, patients treated with eptinezumab experienced greater reductions from baseline in MMDs than those receiving placebo (reductions ranged from 4.5-5.5 vs 1.6-2.4, respectively), with larger reductions over Weeks 13-24. Similarly, ≥ 50% MRRs were consistently higher with eptinezumab than placebo and increased following a second infusion. CONCLUSION: In all subgroups, regardless of prior preventive treatment failure type, eptinezumab demonstrated greater reductions in MMDs and higher MRRs compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765).

Single-Cell mRNA-sncRNA Co-sequencing of Preimplantation Embryos.

The development of single-cell multiomics has provided the ability to systematically investigate cellular diversity and heterogeneity in different biological systems via comprehensive delineations of individual cellular states. Single-cell RNA sequencing in particular has served as a powerful tool to the study of the molecular circuitries underlying preimplantation embryonic development in both the mouse and human. Here we describe a method to elucidate the cellular dynamics of the embryo further by performing both single-cell RNA sequencing (Smart-Seq2) and single-cell small non-coding RNA sequencing (Small-Seq) on the same individual embryonic cell.

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.

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.

Characterizing the Neurobiological Mechanisms of Action of Exercise and Cognitive-Behavioral Interventions for Rheumatoid Arthritis Fatigue: A Magnetic Resonance Imaging Brain Study.

OBJECTIVE: Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive-behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. METHODS: A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). RESULTS: Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ßAverage = -0.46, SD 0.61; ßAverage = -0.32, SD 0.47, respectively). CONCLUSION: The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting.

A horizon scan of global biological conservation issues for 2024.

We present the results of our 15th horizon scan of novel issues that could influence biological conservation in the future. From an initial list of 96 issues, our international panel of scientists and practitioners identified 15 that we consider important for societies worldwide to track and potentially respond to. Issues are novel within conservation or represent a substantial positive or negative step-change with global or regional extents. For example, new sources of hydrogen fuel and changes in deep-sea currents may have profound impacts on marine and terrestrial ecosystems. Technological advances that may be positive include benchtop DNA printers and the industrialisation of approaches that can create high-protein food from air, potentially reducing the pressure on land for food production.

Influence of threshold selection and image sequence in in-vivo segmentation of enlarged perivascular spaces.

BACKGROUND: Growing interest surrounds perivascular spaces (PVS) as a clinical biomarker of brain dysfunction given their association with cerebrovascular risk factors and disease. Neuroimaging techniques allowing quick and reliable quantification are being developed, but, in practice, they require optimisation as their limits of validity are usually unspecified. NEW METHOD: We evaluate modifications and alternatives to a state-of-the-art (SOTA) PVS segmentation method that uses a vesselness filter to enhance PVS discrimination, followed by thresholding of its response, applied to brain magnetic resonance images (MRI) from patients with sporadic small vessel disease acquired at 3 T. RESULTS: The method is robust against inter-observer differences in threshold selection, but separate thresholds for each region of interest (i.e., basal ganglia, centrum semiovale, and midbrain) are required. Noise needs to be assessed prior to selecting these thresholds, as effect of noise and imaging artefacts can be mitigated with a careful optimisation of these thresholds. PVS segmentation from T1-weighted images alone, misses small PVS, therefore, underestimates PVS count, may overestimate individual PVS volume especially in the basal ganglia, and is susceptible to the inclusion of calcified vessels and mineral deposits. Visual analyses indicated the incomplete and fragmented detection of long and thin PVS as the primary cause of errors, with the Frangi filter coping better than the Jerman filter. COMPARISON WITH EXISTING METHODS: Limits of validity to a SOTA PVS segmentation method applied to 3 T MRI with confounding pathology are given. CONCLUSIONS: Evidence presented reinforces the STRIVE-2 recommendation of using T2-weighted images for PVS assessment wherever possible. The Frangi filter is recommended for PVS segmentation from MRI, offering robust output against variations in threshold selection and pathology presentation.

Long-term effectiveness of eptinezumab in patients with migraine and prior preventive treatment failures: extension of a randomized controlled trial.

BACKGROUND: Eptinezumab demonstrated efficacy in adults with migraine and prior preventive treatment failures in the placebo-controlled phase of the DELIVER clinical trial; its long-term effectiveness in this population has not yet been reported. The objective of this study was to evaluate the long-term effectiveness of eptinezumab in a migraine patient population during the 48-week extension phase of DELIVER. METHODS: DELIVER was conducted June 1, 2020 to September 15, 2022. 865 adults with migraine, with documented evidence of 2-4 prior preventive migraine treatment failures and with completion of the 24-week placebo-controlled period of DELIVER received eptinezumab (100 or 300 mg) during the dose-blinded extension, either continuing their randomized dose or, if originally receiving placebo, were randomized 1:1 to an eptinezumab dose (100 or 300 mg). A mixed model for repeated measures was used to evaluate changes from baseline in the number of monthly migraine days (MMDs). RESULTS: Of 865 patients entering the extension (eptinezumab 100 mg, n = 433; 300 mg, n = 432), 782 (90.4%) completed and 11 (1.3%) discontinued due to an adverse event. Eptinezumab was associated with early and sustained reductions in migraine frequency. Mean MMDs at baseline were approximately 14 days across groups. Mean (standard error) change from baseline in MMDs over the final dosing interval (weeks 61-72) was -6.4 (0.50) with placebo/eptinezumab 100 mg, -7.3 (0.49) with placebo/eptinezumab 300 mg, -7.1 (0.39) with eptinezumab 100 mg, and -7.0 (0.39) with eptinezumab 300 mg. During weeks 61-72, 63-70% of patients demonstrated ≥ 50% reduction in MMDs, and 36-45% demonstrated ≥ 75% reduction. Headache severity and acute medication use reductions, and patient-reported improvements in most bothersome symptom, disease status, quality of life, and work productivity, were observed. Adverse events were generally mild, transient, and similar in frequency/type to previous eptinezumab trials. CONCLUSIONS: The long-term effectiveness and safety/tolerability of eptinezumab in patients with migraine and 2-4 prior preventive treatment failures was demonstrated by high completion rates and migraine-preventive benefits sustained for up to 18 months, implying that eptinezumab is a viable long-term treatment option for patients still seeking successful migraine treatments. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765; URL: https://www. CLINICALTRIALS: gov/ct2/show/NCT04418765 ); EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25 ).