Efficacy and Safety of Erenumab for Nonopioid Medication Overuse Headache in Chronic Migraine: A Phase 4, Randomized, Placebo-Controlled Trial.

Importance: Patients with chronic migraine and medication overuse headaches (CM-MOH) represent a particularly burdened subpopulation. This trial provides first, to our knowledge, American Academy of Neurology class I evidence for a preventive therapy in CM-MOH. Objective: To assess erenumab efficacy and safety in patients with nonopioid CM-MOH. Design, Settings, and Participants: This randomized, double-blind, parallel-group, placebo-controlled trial took place at 67 centers in North America, Europe, and Australia from October 7, 2019, to November 2, 2022. This report reflects the primary analysis conducted in January 2023, using a database snapshot from December 1, 2022, which contains the complete dataset of the double-blind treatment period (DBTP). Participants included adults with CM-MOH who had 1 or more preventive treatment failure(s). There were 992 participants screened and 620 participants enrolled (584 in nonopioid cohort and 36 in opioid cohort). Interventions: Erenumab, 70 mg, 140 mg, or placebo, once monthly for 24 weeks. Main Outcomes and Measures: The primary end point was MOH remission at month 6. Secondary end points included change from baseline in mean monthly acute headache medication days (AHMD) at month 6 and sustained MOH remission throughout the DBTP. Safety end points were adverse events and changes in vital signs. Results: The primary analysis population included 584 participants in the nonopioid-treated cohort with a mean age of 44 years and 482 participants were female (82.5%). Baseline demographics and disease characteristics were balanced across groups. At month 6, 134 participants in the erenumab, 140 mg group (69.1%) (odds ratio [OR], 2.01; 95% CI, 1.33-3.05; P < .001 vs placebo) and 117 in the erenumab, 70 mg group (60.3%) (OR, 1.37; 95% CI, 0.92-2.05; P = .13 vs placebo) achieved MOH remission vs 102 participants in the placebo group (52.6%). AHMD use was also reduced in the erenumab groups vs placebo. Least squares mean (standard error) change from baseline in average monthly AHMD was -9.4 (0.4) days in the erenumab, 140 mg group (difference from placebo, -2.7; 95% CI, -3.9 to -1.6; P < .001) and -7.8 (0.4) days in the erenumab, 70 mg group (difference from placebo, -1.2; 95% CI, -2.4 to -0.1; P = .03), vs -6.6 (0.4) days in the placebo group. MOH remission throughout the DBTP was sustained in 119 participants (61.3%,) 96 participants (49.5%), and 73 participants (37.6%) in the erenumab, 140 mg, 70 mg, and placebo groups, respectively. Adverse events were consistent with the known safety profile of erenumab. Treatment-emergent adverse events incidence in the combined erenumab group was 66.8% (259 participants; constipation 15.2% (59 participants) and COVID-19 13.9% (54 participants) were most common. Conclusions and Relevance: In this study, monthly, 140 mg, erenumab injections safely and effectively achieved MOH remission in patients with nonopioid CM-MOH within 6 months. Trial Registration: ClinicalTrials.gov Identifier: NCT03971071.

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.

Long-term outcomes by lobular versus ductal histology in four NSABP adjuvant breast cancer trials.

We evaluated differences in long-term outcomes of invasive lobular carcinoma (ILC) vs breast cancers of no special type (NST) treated with anthracycline-based adjuvant chemotherapy using 4 National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized phase III trials (B-22, B-25, B-28, B-30). Our cohort included 11,251 patients with NST and 1,231 with ILC. Patients with ILC were older, had larger and more often estrogen receptor-positive tumors, and more positive lymph nodes. During early follow-up (0-5 years), patients with ILC had fewer recurrences (HR: 0.797; 95% confidence interval [CI] 0.685-0.929) and deaths (HR: 0.756; 95% CI 0.623-0.917). After 5 years patients with ILC had more recurrences (HR: 1.30; 95% CI 1.085-1.558) and deaths (HR: 1.044; 95% CI 0.898-1.214). Conditional probability analysis showed significant interactions between time-period and histologic type for recurrences (p < .001) and deaths (p < .001). Patients with ILC have elevated risk of late recurrence and death compared to patients with NST.

Treatment patterns of patients with migraine eligible for anti-CGRP pathway monoclonal antibodies.

Introduction: Migraine is a debilitating neurological disorder, with a wide range of symptoms and disease burden, underscoring the heterogeneity of patients' disease characteristics and treatment needs. To characterize the profile of migraine patients in the US who may be eligible for preventive treatment with an anti-CGRP pathway mAb and to better understand treatment patterns and real-world use of acute and preventive medications for migraine, we conducted a retrospective cohort study of adult patients. Methods: These patients were identified as having migraine using diagnosis codes or migraine-specific medication use (first = index) in the IQVIA PharMetrics® Plus database. Patients were required to have ≥ 12 months of continuous enrollment in medical and pharmacy benefits prior to index (baseline) and after index (follow-up). Patients were stratified into chronic migraine (CM) and non-chronic migraine (non-CM) by diagnosis codes. Based on acute migraine-specific medication dispensing data in the follow-up period, non-CM patients were divided into 3 cohorts: highest, middle, and lowest tertile of total units of dispensed acute migraine-specific medication (gepants, ditans, ergot derivatives, and triptans). Migraine medication use was captured in the baseline and follow-up periods. Results: A total of 22,584 CM and 216,807 non-CM patients (72,269 patients in each tertile) were identified and included in the study. Over the follow-up, CM patients had a mean of 70 units of acute migraine-specific medications dispensed, while the highest, middle, and lowest tertile of non-CM patients had a mean of 92, 29, and 10 units, respectively. Anti-calcitonin gene-related peptide pathway mAbs were dispensed for 28.9% of CM patients, and for 6.9%, 4.1%, and 2.9% of non-CM patients in the highest, middle, and lowest tertiles, respectively. Conclusion: A lower proportion of non-CM patients had use of anti-calcitonin gene-related peptide pathway mAbs compared to CM patients, confirming the unmet need with appropriate preventive medication. There appears to be a persistent gap in management of patients without a diagnosis of CM who are dispensed high quantities of acute migraine-specific medications.

Incident Infarcts in Patients With Stroke and Cerebral Small Vessel Disease: Frequency and Relation to Clinical Outcomes.

BACKGROUND AND OBJECTIVES: Factors associated with cerebral small vessel disease (SVD) progression, including incident infarcts, are unclear. We aimed to determine the frequency of incident infarcts over 1 year after minor stroke and their relation to baseline SVD burden, vascular risks, and recurrent stroke and cognitive outcomes. METHODS: We recruited patients with lacunar or nondisabling cortical stroke. After diagnostic imaging, we repeated structural MRI at 3-6 monthly intervals for 12 months, visually assessing incident infarcts on diffusion-weighted imaging or FLAIR. We used logistic regression to determine associations of baseline vascular risks, SVD score, and index stroke subtype with subsequent incident infarcts. We assessed cognitive and functional outcomes at 1 year using Montreal Cognitive Assessment (MoCA) and modified Rankin scale (mRS), adjusting for baseline age, mRS, MoCA, premorbid intelligence, and SVD score. RESULTS: We recruited 229 participants, mean age 65.9 (SD 11.1). Over half of all participants, 131 of 229 (57.2%) had had an index lacunar stroke. From baseline to 1-year MRI, we detected 117 incident infarcts in n = 57/229 (24.8%) participants. Incident infarcts were mainly of the small subcortical (86/117 [73.5%] in n = 38/57 [66.7%]) vs cortical infarct subtype (n = 19/57 [33.3%]). N = 39/57 participants had incident infarcts at 1 visit; 18 of 57 at 2 or more visits; and 19 of 57 participants had multiple infarcts at a single visit. Only 7 of 117 incident infarcts corresponded temporally to clinical stroke syndromes. The baseline SVD score was the strongest predictor of incident infarcts (adjusted odds ratio [OR] 1.87, 95% CI 1.39-2.58), while mean arterial pressure was not associated. All participants with incident infarcts were prescribed an antiplatelet or anticoagulant. Lower 1-year MoCA was associated with lower baseline MoCA (ß 0.47, 95% CI 0.33-0.61), lower premorbid intelligence, and older age. Higher 1-year mRS was associated with higher baseline mRS only (OR 5.57 [3.52-9.10]). Neither outcome was associated with incident infarcts. DISCUSSION: In the year after stroke in a population enriched for lacunar stroke, incident infarcts occurred in one-quarter and were associated with worse baseline SVD. Most incident infarcts detected on imaging did not correspond to clinical stroke/transient ischemic attack. Worse 1-year cognition and function were not associated with incident infarcts.

Measurement of Physical Activity Using Fitness Trackers Before and After Midurethral Sling.

IMPORTANCE: Urinary incontinence can be a barrier to performing physical activities for many women. A midurethral sling (MUS) has shown symptom improvement for women experiencing stress urinary incontinence (SUI), suggesting the hypothesis that physical activity rates should increase after treatment. OBJECTIVE: The aim of this study was to determine the change in objectively measured physical activity levels in women following placement of MUS for SUI. STUDY DESIGN: In this prospective cohort study, patients undergoing MUS placement, with or without concomitant pelvic reconstructive surgery, were provided a commercial activity tracker. Physical activity was tracked for at least 1 week preoperatively and up to 6 months postoperatively. Participants were required to wear the tracker for at least 2 weeks in the postoperative period. The primary outcome, mean caloric daily expenditure (MCDE), was compared preoperatively and postoperatively. RESULTS: Seventy-two patients met criteria for data inclusion. The device was worn for a mean of 18.4 ± 12.1 days preoperatively and 91.7 ± 53.3 days postoperatively. Mean participant age was 51.9 ± 9.4 years. The MCDE was significantly higher postoperatively (preoperatively: 1,673 kcal/d vs postoperatively: 2,018 kcal/d; P < 0.01). There were no significant differences in postoperative MCDE in participants who had only MUS as the primary procedure versus participants who also had a concomitant procedure (2,020 ± 216 kcal/d vs 2,015 ± 431 kcal/d; P = 0.95). Of participants with class II/III obesity, 45% had at least a 500 kcal/d increase postoperatively. CONCLUSIONS: Treatment of SUI with MUS is associated with a significantly greater caloric expenditure in the postoperative period.

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.

Prevalence, incidence and determinants of QuantiFERONTM positivity in South African schoolchildren.

BACKGROUND: TB control requires the understanding and disruption of TB transmission. We describe prevalence, incidence and risk factors associated with childhood TB infection in Cape Town, South Africa. METHODS: We report cross-sectional baseline and prospective incidence data from a large trial among primary school children living in high TB burden communities. Prevalent infection was defined as QuantiFERON™-TB Gold Plus (QFT-Plus) positivity as assessed at baseline. Subsequent conversion to QFT-Plus positivity was measured 3 years later among those QFT-Plus-negative at baseline. Multivariable logistic regression models examined factors associated with TB infection. RESULTS: QuantiFERON-positivity at baseline (prevalence: 22.6%, 95% CI 20.9-24.4), was independently associated with increasing age (aOR 1.24 per additional year, 95% CI 1.15-1.34) and household exposure to TB during the participant's lifetime (aOR 1.87, 95% CI 1.46-2.40). QFT-Plus conversion at year 3 (12.2%, 95% CI 10.5-14.0; annual infection rate: 3.95%) was associated with household exposure to an index TB case (aOR 2.74, 95% CI 1.05-7.18). CONCLUSION: Rates of QFT-diagnosed TB infection remain high in this population. The strong association with household TB exposure reinforces the importance of contact tracing, preventative treatment and early treatment of infectious disease to reduce community transmission.

CONTEXTE: La lutte contre la TB nécessite la compréhension et la perturbation de la transmission de la TB. Nous décrivons la prévalence, l'incidence et les facteurs de risque associés à l'infection tuberculeuse infantile au Cap, en Afrique du Sud. MÉTHODES: Nous rapportons des données transversales de référence et d'incidence prospective provenant d'un vaste essai mené auprès d'enfants d'écoles primaires vivant dans des communautés à forte charge de morbidité tuberculeuse. La prévalence de l'infection a été définie comme la positivité au QuantiFERON™-TB Gold Plus (QFT-Plus) telle qu'évaluée au départ. La conversion subséquente en QFT-Plus positif a été mesurée 3 ans plus tard chez les QFT-Plus négatifs au départ. Des modèles de régression logistique multivariée ont examiné les facteurs associés à l'infection tuberculeuse. RÉSULTATS: La positivité QuantiFERON-au départ (prévalence : 22,6%, IC à 95% 20,9­24,4), était indépendamment associée à l'augmentation de l'âge (aOR 1,24 par année supplémentaire, IC à 95% 1,15­1,34) et à l'exposition du ménage à la TB au cours de la vie du participant (aOR 1,87 ; IC à 95% 1,46­2,40). La conversion QFT-Plus à l'année 3 (12,2%, IC à 95% 10,5­14,0 ; taux d'infection annuel : 3,95%) était associée à l'exposition du ménage à un cas de tuberculose index (aOR 2,74 ; IC à 95% 1,05­7,18). CONCLUSION: Les taux d'infection tuberculeuse diagnostiquée par QFT restent élevés dans cette population. La forte association avec l'exposition à la TB dans les ménages renforce l'importance de la recherche des contacts, du traitement préventif et du traitement précoce des maladies infectieuses pour réduire la transmission communautaire.

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.

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.

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.

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.

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.

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.

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.

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).