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Background Women with endometriosis are more likely to have migraine. The mechanisms underlying this co-morbidity are unknown. Prolactin, a neurohormone secreted and released into circulation from the anterior pituitary, can sensitize sensory neurons from female, but not male, rodents, monkeys and human donors. Methods We used a syngeneic model of endometriosis to determine whether elevated prolactin levels can sensitize trigeminal ganglion neurons and increase vulnerability to migraine pain. Results Mice with endometriotic lesions showed increased serum prolactin levels and developed persistent abdominal, but not cephalic, allodynia. However, inhalation of a transient receptor potential ankyrin 1 agonist, umbellulone, a known environmental trigger of headache in some patients, elicited cephalic allodynia in mice with endometriosis but not sham controls, suggesting that endometriosis can promote sensitization of trigeminal neurons and migraine attacks. Endometriosis dysregulated the expression of prolactin receptor isoforms in trigeminal neurons and increased their excitability measured by in vitro patch clamp electrophysiology. Inhibition of pituitary prolactin following a 2-week treatment with a dopamine receptor agonist, cabergoline, prevented cephalic allodynia elicited by activation of trigeminal afferents with umbellulone. Cabergoline treatment also normalized the expression of prolactin receptor isoforms in trigeminal ganglia and the hyperexcitability of trigeminal neurons. Conclusions These data demonstrate that circulating prolactin in endometriosis promotes vulnerability to migraine through sensitization of trigeminal afferents. Clinically available dopamine receptor agonists or novel monoclonal antibodies targeting prolactin signaling may be effective for migraine prevention in women with endometriosis.

AbstractBackgroundMayo Test DRIVE (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based multi‐device (smartphone, tablet, personal computer) platform optimized for remote self‐administered cognitive assessment that includes a computer‐adaptive word list memory test (Stricker Learning Span; SLS), a measure of processing speed/executive functioning (Symbols Test) and a score combining both the memory and processing speed/executive functioning measures (MTD Composite). We aimed to determine the reliability of MTD measures across follow‐up sessions.MethodIndividuals participating in this ancillary study who completed at least two and up to four complete MTD sessions were included, resulting in 1,293 participants (mean age = 70.6, SD = 11.6; mean education = 15.6, SD = 2.3; 48.6% male; 96.9% White; 99.1% non‐Hispanic; 97.1% cognitively unimpaired) from parent studies (see Table 1). MTD raw scores were winsorized at 1% and 99% to minimize the impact of outliers. Test‐retest reliability was assessed using single‐rating, absolute‐agreement, and two‐way mixed ICCs and results are described using descriptives from Koo et al. (2016). ICCs for in‐person‐administered traditional neuropsychological measures are also reported alongside MTD for a subset of participants newly enrolled into the MCSA (to ensure participants were test naïve to both MTD and in‐person tests).ResultReliability was good for the MTD Composite raw [total ICC = 0.78; see Table 2 for session‐to‐session ICCs and 95% CIs], and moderate‐to‐good for the primary outcome variables for each subtest [total ICC = 0.74 for both SLS and Symbols]. Weighting by accuracy negatively impacted reliability of Symbols and the Composite; without this weighting, MTD Composite and Symbols variables showed higher reliability (MTD Composite z total ICC = 0.80; Symbols response time total ICC = 0.84; see Table 2). Alternative methods of defining response time on Symbols showed nearly identical reliability values. SLS sum of trials (primary variable) had subtly higher reliability than separate measures of learning (1‐5 correct, max span) or delay. Reliability of remote MTD and in‐person‐administered measures and select comparisons are provided in Table 3.ConclusionMTD showed moderate to good reliability, similar to in‐person‐administered traditional neuropsychological tests. Future work will examine the effect of demographics, device type, and session interference on reliability.

AbstractBackgroundFew normative data for computerized measures administered in unsupervised remote environments are available. We aimed to determine what variables to include in normative models for remote self‐administered assessments, develop normative data for measures administered through Mayo Test Drive (MTD, a multi‐device remote cognitive assessment platform) and evaluate application of norms.Method1240 adults ages 33‐100 (96% White) from the Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center met normative sample inclusion criteria that included a concordant Cognitively Unimpaired (CU) diagnosis (3 independent raters all diagnosed CU) and CDR = 0 (see Table 1 for sample characteristics). Raw test scores were converted to normalized scaled scores. We derived regression‐based normative data that adjusted for age, age2, sex and education (base model); alternative models are also provided (age+age2+sex; age+ age2). We evaluated whether additional model terms beyond the base model were needed using an a priori cut‐off of 1% variance improvement in adjusted R2 over and above the base model. We examined rates of low test performance defined as performance below ‐1 SD in independent validation samples (n = 167 concordant CU, n = 64 mild cognitive impairment (MCI), n = 14 dementia). Rates are considered significantly different than expected when 95% confidence intervals (CIs) do not include the expected 14.7% base rate frequency.ResultNo additional potential model terms met our a priori cut‐off for inclusion beyond the base model (see Table 2), including other quadratic and cubic terms or interactions, device type, response input type, potential session interference, and national area deprivation index (ADI available in subset; N = 776). Application of norms showed expected rates of low test performance among CU participants (95% CI includes expected base rate) and significantly greater than expected rates of low test performance for all variables in MCI (e.g., 62.5% for composite) and dementia (e.g., 71.4% for composite; see Table 3).ConclusionTypical normative models appear appropriate for remote self‐administered measures and are sensitive to cognitive impairment. Device type and response input did not explain enough variance to warrant inclusion in normative models but are important for individual level interpretation. Future work will improve representation of individuals from under‐represented groups.

INTRODUCTION: Spondyloarthritis (SpA), the most common extraintestinal manifestation of inflammatory bowel disease (IBD), is reported in up to 39% of patients with IBD. Despite this high prevalence, risk factors of developing SpA in patients with IBD are not well described. In this study, we aimed to determine the factors associated with SpA symptoms and their prevalence in an IBD cohort. METHODS: Two validated screening questionnaires for the detection of SpA in IBD (DETAIL = DETection of Arthritis in Inflammatory boweL diseases, IBIS-Q = IBD Identification of Spondyloarthritis Questionnaire) were administered to patients with IBD without a prior diagnosis of SpA in 6 US academic medical centers. Demographic data, IBD characteristics, and medication history were recorded. RESULTS: Screening questionnaires were completed by 588 patients (220 ulcerative colitis, 349 Crohn's disease, and 19 IBD-unclassified), with a median age of 40 years (interquartile range 30–53) and median disease duration of 12 years (interquartile range 6–22). The number of positive screens was 130 (22%) for DETAIL, 196 (33%) for IBIS-Q, and 204 (35%) for either DETAIL or IBIS-Q. Age, female sex, history of smoking, prior bowel surgery, and history of any biologic or targeted small molecule exposure were associated with a positive screen on univariate analysis. After multivariate analysis, female sex (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.41–2.93), older age (OR 1.02, 95% CI 1.01–1.04), history of smoking (OR 1.67, 95% CI 1.04–2.69), and history of any biologic or targeted small molecule exposure (OR 2.27, 95% CI 1.34–3.84) were independently associated with positive screens. Higher number of biologic exposures was associated with higher risk of positive screens, with the highest risk seen with 3 or more exposures (OR 3.25, 95% CI 1.75–6.03). DISCUSSION: A substantial number of patients with IBD screen positive for SpA symptoms, indicating a potentially high burden of undiagnosed illness. Factors associated with SpA symptoms include older age, female sex, and more severe disease (based on increased number of advanced therapies or prior surgery), whereas IBD phenotype does not independently increase the risk of a positive SpA screen. Further studies are needed to confirm these findings and better characterize SpA in IBD.

Background Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD). Methods To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety. Results Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30–67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%. Conclusions In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.

ABSTRACTIntroduction/AimsGlucocorticoid (GC)‐related adverse reactions and risks are commonly seen during the treatment of immune‐mediated and inflammatory neuromuscular disorders. There is wide variation in the management of associated complications. The aim of this study is to develop international consensus guidance on the management of GC‐related complications in neuromuscular disorders.MethodsThrough the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), an international task force of 15 experts was convened to develop clinical guidance for the management of GC‐related complications in neuromuscular patients. The RAND/UCLA appropriateness method (RAM) was used to develop consensus guidance statements. Initial guidance statements were crafted after a thorough literature review and were modified after anonymous panel input, with up to three rounds of voting via email to achieve consensus.ResultsStatements were developed and achieved consensus for general care, monitoring of patients while on GC, osteoporosis prevention, vaccinations, infection screening, and Pneumocystis jiroveci pneumonia prophylaxis. A multidisciplinary approach to the management of GC‐related complications was emphasized.DiscussionThese formal consensus statements provide guidance to clinicians who use GC in the treatment of neuromuscular diseases regarding prevention and management of the more common associated adverse events and risks that arise with long and short‐term GC use and serve as a springboard for investigation and updates.

AbstractBackgroundPrior longitudinal studies among older adults have documented associations between hearing loss and changes in brain morphology. Whether interventions involving hearing aids can reduce age‐related atrophy is unknown. A substudy within the Aging and Cognitive Health Evaluation in Elders (ACHIEVE, Clinicaltrials.gov Identifier: NCT03243422) randomized controlled trial tested the effect of a best‐practices hearing intervention versus health education control on three‐year change in cortical thickness among older adults with hearing loss.MethodThe ACHIEVE study enrolled 977 community‐dwelling adults aged 70‐84 years at baseline (2018‐2019) with untreated hearing loss (better ear pure tone average [0.5‐4 kHz] ≥30 and <70 dB HL) and without substantial cognitive impairment from four sites across the U.S. (Jackson, MS, Forsyth County, NC, Minneapolis, MN, Washington County, MD). Participants were randomized to a hearing intervention (provision of hearing aids and related technologies, counseling, and education) or a health education control (individual sessions with a health educator covering topics relevant to chronic disease and disability prevention). Three‐dimensional magnetic resonance imaging was performed on 3 Tesla Siemens scanners in a subsample of 445 participants at the ACHIEVE baseline and three‐year follow‐up. Linear mixed effects models were used in intention‐to‐treat analyses to estimate three‐year change in cortical thickness. All models adjusted for baseline measures of hearing loss, recruitment source, site, age, sex, and education. Missing outcome and covariate data was imputed to mitigate bias caused by informative attrition.ResultAt baseline, 224 participants were women (50.3%), 52 participants were Black (11.7%), and the mean (SD) age was 76.4 (4.0) years old (Table 1). Compared to the health education control, the hearing intervention exhibited a nominally protective effect on three‐year change in average cortical thickness (Figure 1). The greatest effect size for cortical thickness was observed in the occipital lobe, while the smallest effect size was detected in the temporal lobe. Statistically significant effects were detected in the pars orbitalis, rostral anterior cingulate, posterior cingulate, and isthmus cingulate (Figure 2).ConclusionHearing aid use may reduce decline in cortical thickness among older adults. The effects of hearing aids may be greatest in regions other than those associated with the auditory cortex.

AbstractBackgroundFew normative data for computerized measures administered in unsupervised remote environments are available. We aimed to determine what variables to include in normative models for remote self‐administered assessments, develop normative data for measures administered through Mayo Test Drive (MTD, a multi‐device remote cognitive assessment platform) and evaluate application of norms.Method1240 adults ages 33‐100 (96% White) from the Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center met normative sample inclusion criteria that included a concordant Cognitively Unimpaired (CU) diagnosis (3 independent raters all diagnosed CU) and CDR = 0 (see Table 1 for sample characteristics). Raw test scores were converted to normalized scaled scores. We derived regression‐based normative data that adjusted for age, age2, sex and education (base model); alternative models are also provided (age+age2+sex; age+ age2). We evaluated whether additional model terms beyond the base model were needed using an a priori cut‐off of 1% variance improvement in adjusted R2 over and above the base model. We examined rates of low test performance defined as performance below ‐1 SD in independent validation samples (n = 167 concordant CU, n = 64 mild cognitive impairment (MCI), n = 14 dementia). Rates are considered significantly different than expected when 95% confidence intervals (CIs) do not include the expected 14.7% base rate frequency.ResultNo additional potential model terms met our a priori cut‐off for inclusion beyond the base model (see Table 2), including other quadratic and cubic terms or interactions, device type, response input type, potential session interference, and national area deprivation index (ADI available in subset; N = 776). Application of norms showed expected rates of low test performance among CU participants (95% CI includes expected base rate) and significantly greater than expected rates of low test performance for all variables in MCI (e.g., 62.5% for composite) and dementia (e.g., 71.4% for composite; see Table 3).ConclusionTypical normative models appear appropriate for remote self‐administered measures and are sensitive to cognitive impairment. Device type and response input did not explain enough variance to warrant inclusion in normative models but are important for individual level interpretation. Future work will improve representation of individuals from under‐represented groups.

ObjectiveSpondyloarthritis (SpA) is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). The application of screening tools to detect SpA in patients with IBD may lead to earlier recognition of SpA and affect treatment decisions.MethodsA combination of two previously described SpA screening questionnaires, the Detection of Arthritis in Inflammatory Bowel Disease (DETAIL) and IBD Identification of Spondyloarthritis Questionnaire (IBIS‐Q), was administered to consecutive patients with IBD attending IBD specialty clinics in six US academic medical centers. Demographic data, IBD, and rheumatology history were extracted by chart review.ResultsA total of 669 patients were analyzed. The median age was 40 years (interquartile range [IQR] 30–54) with a median disease duration of 12 years (IQR 6–22) and moderate to severe IBD based on medication exposure and history of bowel surgery. A total of 81 patients (12%) carried a diagnosis of an inflammatory rheumatic disease, whereas 75 (11%) had consulted a rheumatologist during the previous year. Using published cutoffs, 180 out of 669 patients (27%) screened positive with DETAIL, 266 (40%) with IBIS‐Q, and 275 (41%) with either questionnaire. Axial symptoms were more frequently reported than peripheral musculoskeletal complaints. Notably, 189 out of 275 (69%) screen‐positive patients had neither a documented inflammatory rheumatic disease diagnosis nor a visit with a rheumatologist within the past year.ConclusionA substantial proportion of patients with IBD have symptoms suggestive of SpA, and many of these may have undiagnosed SpA. The IBIS‐Q questionnaire appears to identify more potential SpA cases than DETAIL. Strategies are needed to prioritize rheumatology consultations for those patients with IBD who are most likely to benefit.

This nonrandomized clinical trial reports outcomes for children with low-risk relapsed Hodgkin lymphoma treated with second-line chemotherapy and involved-field radiotherapy without autologous stem cell transplant.