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Objective: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine., Background: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain., Methods: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed., Results: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification., Conclusions: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed., (© 2024 American Headache Society.)

Spring viremia of carp virus (SVCV) is a rhabdovirus that primarily infects cyprinid finfishes and causes a disease notifiable to the World Organization for Animal Health. Amphibians, which are sympatric with cyprinids in freshwater ecosystems, are considered non-permissive hosts of rhabdoviruses. The potential host range expansion of SVCV in an atypical host species was evaluated by testing the susceptibility of amphibians native to the Pacific Northwest. Larval long-toed salamanders Ambystoma macrodactylum and Pacific tree frog Pseudacris regilla tadpoles were exposed to SVCV strains from genotypes Ia, Ib, Ic, or Id by either intraperitoneal injection, immersion, or cohabitation with virus-infected koi Cyprinus rubrofuscus . Cumulative mortality was 100% for salamanders injected with SVCV, 98-100% for tadpoles exposed to virus via immersion, and 0-100% for tadpoles cohabited with SVCV-infected koi. Many of the animals that died exhibited clinical signs of disease and SVCV RNA was found by in situ hybridization in tissue sections of immersion-exposed tadpoles, particularly in the cells of the gastrointestinal tract and liver. SVCV was also detected by plaque assay and RT-qPCR testing in both amphibian species regardless of the virus exposure method, and viable virus was detected up to 28 days after initial exposure. Recovery of infectious virus from naïve tadpoles cohabited with SVCV-infected koi further demonstrated that SVCV transmission can occur between classes of ectothermic vertebrates. Collectively, these results indicated that SVCV, a fish rhabdovirus, can be transmitted to and cause lethal disease in two amphibian species. Therefore, members of all five of the major vertebrate groups (mammals, birds, reptiles, fish, and amphibians) appear to be vulnerable to rhabdovirus infections. Future research studying potential spillover and spillback infections of aquatic rhabdoviruses between foreign and domestic amphibian and fish species will provide insights into the stressors driving novel interclass virus transmission events.

Background: Diapers represent a unique financial burden for those with young children. Pre-pandemic, approximately one in three U.S. households with young children reported diaper need or an insufficient supply of diapers. To support this population, policymakers, clinicians, and service providers need a better understanding of the groups most commonly affected and the ways that families cope with deprivation., Methods: An online survey was administered between February and July 2021 to a national sample of U.S. caregivers of at least one child aged 0-4 years in diapers (n = 881), investigating diaper need, diaper access, and how household expenses are balanced and prioritized vis-à-vis diapers. We use bivariate and multivariable models to assess factors associated with diaper need, and examine coping strategies, tradeoffs made to purchase diapers, and how caregivers would reallocate their money if diapers were accounted for., Findings: The prevalence of diaper need (46 %) exceeded pre-pandemic estimates. Diaper need was more prevalent among Hispanic respondents, lower income respondents, cloth diaper users, those with more than one child in diapers, caretakers with depression, and those with a negative financial change in the past year. Caretakers with diaper need were more likely to utilize a range of resources to access diapers and to use diapers for longer than desired to extend their supply. Those with diaper need also made more economic tradeoffs to afford diapers and indicated that they would reallocate resources to cover other unmet basic needs if they did not have to buy diapers., Interpretation: Our results indicate elevated levels of diaper need even after the U.S. economy had largely rebounded and raise concerns that inequities in diaper access may impact families' abilities to meet other basic needs. Diapers may be an important target for policies and interventions aimed at improving the well-being of families with young children., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 10.13039/100011633Emily H Belarmino reports financial support was provided by the University of Vermont’s Agricultural Experiment Station through the State of Vermont’s appropriation.. Emily H. Belarmino reports a relationship with US Department of Health and Human Services that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: To examine the associations between social determinants of health (SDOH) and prevalent overweight/obesity status and change in adiposity status among American Indian and Alaska Native (AI/AN) children. Methods: The study sample includes 23,950 AI/AN children 2-11 years of age, who used Indian Health Service (IHS) from 2010 to 2014. Multivariate generalized linear mixed models were used to examine the following: (1) cross-sectional associations between SDOH and prevalent overweight/obesity status and (2) longitudinal associations between SDOH and change in adiposity status over time. Results: Approximately 49% of children had prevalent overweight/obesity status; 18% had overweight status and 31% had obesity status. Prevalent severe obesity status was 20% in 6-11-year olds. In adjusted cross-sectional models, children living in counties with higher levels of poverty had 28% higher odds of prevalent overweight/obesity status. In adjusted longitudinal models, children 2-5 years old living in counties with more children eligible for free or reduced-priced lunch had 15% lower odds for transitioning from normal-weight status to overweight/obesity status. Conclusions: This work contributes to accumulating knowledge that economic instability, especially poverty, appears to play a large role in overweight/obesity status in AI/AN children. Research, clinical practice, and policy decisions should aim to address and eliminate economic instability in childhood.

There are two main approaches to how statistical patterns are extracted from sequences: The transitional probability approach proposes that statistical learning occurs through the computation of probabilities between items in a sequence. The chunking approach, including models such as PARSER and TRACX, proposes that units are extracted as chunks. Importantly, the chunking approach suggests that the extraction of full units weakens the processing of subunits while the transitional probability approach suggests that both units and subunits should strengthen. Previous findings using sequentially organized, auditory stimuli or spatially organized, visual stimuli support the chunking approach. However, one limitation of prior studies is that most assessed learning with the two-alternative forced-choice task. In contrast, this pre-registered experiment examined the two theoretical approaches in sequentially organized, visual stimuli using an online self-paced task-arguably providing a more sensitive index of learning as it occurs-and a secondary offline familiarity judgment task. During the self-paced task, abstract shapes were covertly organized into eight triplets (ABC) where one in every eight was altered (BCA) from the canonical structure in a way that disrupted the full unit while preserving a subunit (BC). Results from the offline familiarity judgment task revealed that the altered triplets were perceived as highly familiar, suggesting the learned representations were relatively flexible. More importantly, results from the online self-paced task demonstrated that processing for subunits, but not unit-initial stimuli, was impeded in the altered triplet. The pattern of results is in line with the chunking approach to statistical learning and, more specifically, the TRACX model., (© 2023 Cognitive Science Society LLC.)

Nuclear inclusion X (NIX), the etiological agent of bacterial gill disease in Pacific razor clams Siliqua patula, was associated with host mortality events in coastal Washington State, USA, during the mid-1980s. Ongoing observations of truncated razor clam size distributions in Kalaloch Beach, Washington, raised concerns that NIX continues to impact populations. We conducted a series of spatial and longitudinal NIX surveillances, examined archived razor clam gill tissue, and used population estimates from stock assessments to test whether (1) the prevalence and intensity of NIX infections is higher at Kalaloch Beach relative to nearby beaches, (2) infected gill tissue has features consistent with historical descriptions of NIX-associated histopathology, and (3) annual clam survival is inversely related to NIX infection prevalence and intensity. NIX prevalence exceeded 85% at all sampled locations, and infection intensity was the highest at Kalaloch Beach by 0.9-2.6 orders of magnitude. Kalaloch Beach clams revealed histopathology consistent with previous NIX epidemics, including enlarged and/or rupturing branchial epithelial cells, branchial necrosis, and high hemocyte densities. Estimated annual survival was 22% at Kalaloch Beach, and ranged between 57 and 99% at other study sites. NIX infection intensity (via quantitative PCR) was not significantly correlated with annual survival; however, annual survival was lowest at Kalaloch Beach, where infection intensities were highest, suggesting that clams can tolerate infections up to a lethal threshold. Collectively these data support the hypothesis that high NIX intensities are associated with host mortality. NIX-associated mortality appears to be more pronounced at Kalaloch Beach relative to other Washington beaches.

There is ample evidence that humans and nonhuman animals can learn complex statistical regularities presented within various types of input. However, humans outperform their nonhuman primate counterparts when it comes to recognizing relationships that exist across one or several intervening stimuli (nonadjacent dependencies). This is especially true when the two elements in the dependency do not share any perceptual similarity (arbitrary associations). In the present study, we investigated whether manipulating the saliency of the predictive stimulus would enhance nonadjacent dependency learning in nonhuman primates. Rhesus macaques and tufted capuchins engaged in a computerized signal detection task that included sequences that were random in nature, included an adjacent dependency, or included a nonadjacent dependency. We manipulated the saliency of the predictive stimulus, such that the predictor jittered in place on the screen in some grammar blocks, as well as the transitional probability (the likelihood of the stimulus preceding the target to accurately predict the target's appearance) from block to block. Some monkeys evidenced learning of adjacent dependencies by faster response times to targets that followed a predictive stimulus compared to targets that were not preceded by a predictor. However, consistent with the body of evidence that indicates that nonhuman animals' statistical learning mechanisms are not at the same level of sophistication as humans', there was no evidence that monkeys learned nonadjacent dependencies of arbitrary associations, even when the salient cue was present., (© 2021. The Psychonomic Society, Inc.)

Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 ( 4 ), as a highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these, compounds 43 and 58 showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinal cord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties. Compound 58 , a central pyridine isomer of BMS-986176/LX-9211 ( 4 ), was 4-fold more potent than 4 in vitro and showed lower plasma exposure needed to achieve similar efficacy compared to 4 in the CCI rat model. However, both 43 and 58 showed an inferior preclinical toxicity profile compared to 4 .

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. ( S )-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) ( 34 ) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 ( 34 ) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 ( 34 ) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

One important aspect of human cognition involves the learning of structured information encountered in our environment, a phenomenon known as statistical learning. A growing body of research suggests that learning to read print is partially guided by learning the statistical contingencies existing between the letters within a word, and also between the letters and sounds to which the letters refer. Research also suggests that impairments to statistical learning ability may at least partially explain the difficulties experienced by individuals diagnosed with dyslexia. However, the findings regarding impaired learning are not consistent, perhaps partly due to the varied use of methodologies across studies - such as differences in the learning paradigms, stimuli used, and the way that learning is assessed - as well as differences in participant samples such as age and extent of the learning disorder. In this review, we attempt to examine the purported link between statistical learning and dyslexia by assessing a set of the most recent and relevant studies in both adults and children. Based on this review, we conclude that although there is some evidence for a statistical learning impairment in adults with dyslexia, the evidence for an impairment in children is much weaker. We discuss several suggestive trends that emerge from our examination of the research, such as issues related to task heterogeneity, possible age effects, the role of publication bias, and other suggestions for future research such as the use of neural measures and a need to better understand how statistical learning changes across typical development. We conclude that no current theoretical framework of dyslexia fully captures the extant research findings on statistical learning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Singh and Conway.)

Several Francisella spp., including Francisella noatunensis, are regarded as important emerging pathogens of wild and farmed fish. However, very few studies have investigated the virulence factors that allow these bacterial species to be pathogenic in fish. The Francisella pathogenicity island (FPI) is a well-described, gene-dense region encoding major virulence factors for the genus Francisella. pdpA is a member of the pathogenicity-determining protein genes carried by the FPI that are implicated in the ability of the mammalian pathogen Francisella tularensis to escape and replicate in infected host cells. Using a sacB suicide approach, we generated pdpA knockouts to address the role of PdpA as a virulence factor for F. noatunensis . Because polarity can be an issue in gene-dense regions, we generated two different marker-based mutants in opposing polarity (the F. noatunensis subsp. orientalis Δ pdpA1 and Δ pdpA2 strains). Both mutants were attenuated ( P < 0.0001) in zebrafish challenges and displayed impaired intracellular replication ( P < 0.05) and cytotoxicity ( P < 0.05), all of which could be restored to wild-type (WT) levels by complementation for the Δ pdpA1 mutant. Importantly, differences were found for bacterial burden and induction of acute-phase and proinflammatory genes for the F. noatunensis subsp. orientalis Δ pdpA1 and Δ pdpA2 mutants compared to the WT during acute infection. In addition, neither mutant resulted in significant histopathological changes. Finally, immunization with the F. noatunensis subsp. orientalis Δ pdpA1 mutant led to protection ( P < 0.012) against an acute 40% lethal dose (LD 40 ) challenge with WT F. noatunensis in the zebrafish model of infection. Taken together, the results from this study further demonstrate physiological similarities within the genus Francisella relative to their phylogenetic relationships and the utility of zebrafish for addressing virulence factors for the genus.

In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The auditory scaffolding hypothesis states that early experience with sound underpins the development of domain-general sequence processing abilities, supported by studies observing impaired sequence processing in deaf or hard-of-hearing (DHH) children. To test this hypothesis, we administered a sequence processing task to 77 DHH children who use American Sign Language (ASL) and 23 hearing monolingual children aged 7-12 years and found no performance difference between them after controlling for age and nonverbal intelligence. Additionally, neither spoken language comprehension scores nor hearing loss levels predicted sequence processing scores in the DHH group, whereas ASL comprehension scores did. Our results do not indicate sequence processing deficits in DHH children and do not support the auditory scaffolding hypothesis; instead, these findings suggest that factors related to experience with and/or proficiency in an accessible language during development may be more important determinants of sequence processing abilities., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Preliminary evidence suggests that Chinook salmon Oncorhynchus tshawytscha from the Yukon River may be more susceptible to Ichthyophonus sp. infections than Chinook from stocks further south. To investigate this hypothesis in a controlled environment, we experimentally challenged juvenile Chinook from the Yukon River and from the Salish Sea with Ichthyophonus sp. and evaluated mortality, infection prevalence and infection load over time. We found that juvenile Chinook salmon from a Yukon River stock were more susceptible to ichthyophoniasis than were those from a Salish Sea stock. After feeding with tissues from infected Pacific herring Clupea pallasii, Chinook salmon from both stocks became infected. The infection was persistent and progressive in Yukon River stock fish, where infections sometimes progressed to mortality, and histological examinations revealed parasite dissemination and proliferation throughout the host tissues. In Salish Sea-origin fish, however, infections were largely transient; host mortalities were rare, and parasite stages were largely cleared from most tissues after 3-4 wk. Susceptibility differences were evidenced by greater cumulative mortality, infection prevalence, parasite density, proportion of fish demonstrating a cellular response, and intensity of the cellular response among fish from the Yukon River stock. These observed differences between Chinook salmon stocks were consistent when parasite exposures occurred in both freshwater and seawater. These results support the hypothesis that a longer-standing host-pathogen relationship, resulting in decreased disease susceptibility, exists among Salish Sea Chinook salmon than among Yukon River conspecifics.

Language is acquired in part through statistical learning abilities that encode environmental regularities. Language development is also heavily influenced by social environmental factors such as socioeconomic status. However, it is unknown to what extent statistical learning interacts with SES to affect language outcomes. We measured event-related potentials in 26 children aged 8-12 while they performed a visual statistical learning task. Regression analyses indicated that children's learning performance moderated the relationship between socioeconomic status and both syntactic and vocabulary language comprehension scores. For children demonstrating high learning, socioeconomic status had a weaker effect on language compared to children showing low learning. These results suggest that high statistical learning ability can provide a buffer against the disadvantages associated with being raised in a lower socioeconomic status household., Competing Interests: The authors have declared that no competing interests exist.

Background: Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine., Methods: We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9-12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638., Findings: Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9-12. The change from the observation period in mean number of migraine days per month during weeks 9-12 was -4·3 days (95% CI -4·8 to -3·9) with rimegepant and -3·5 days (-4·0 to -3·0) with placebo (least squares mean difference -0·8 days, 95% CI -1·46 to -0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died., Interpretation: Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted., Funding: Biohaven Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP K i  = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (F PO  = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP K i  = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat F PO  = 17%)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nuclear inclusion X (NIX) is a gamma proteobacteria that infects the nuclei of gill epithelial cells in Pacific razor clams. NIX has been associated with clam die-offs in coastal Washington. A quantitative PCR (qPCR) assay was developed to detect NIX in Pacific razor clams, and assay specificity was confirmed by chromogenic in situ hybridization (CISH). Both tests were applied to evaluate NIX infections in wild Pacific razor clams collected during spring 2019. Consistent with results from earlier histopathological assessments, qPCR and CISH indicated 100% prevalence in razor clams from two Washington beaches and 0% prevalence from two Alaskan beaches., (Published by Elsevier Inc.)

The expression of motion shows strong crosslinguistic variability; however, less is known about speakers' expectancies for lexicalizations of motion at the neural level. We examined event-related brain potentials (ERPs) in native English or Spanish speakers while they read grammatical sentences describing animations involving manner and path components of motion that did or did not violate language-specific patterns of expression. ERPs demonstrated different expectancies between speakers: Spanish speakers showed higher expectancies for motion verbs to encode path and English speakers showed higher expectancies for motion verbs to encode manner followed by a secondary path expression. Interestingly, grammatical but infrequent motion expressions (manner verbs in Spanish, path verbs and secondary manner expressions in English) elicited semantic P600 rather than the expected N400 effects-with or without post-N400 positivities-that are typically associated with semantic processing. Overall, our findings provide the first empirical evidence for the effect of crosslinguistic variation in processing motion event descriptions at the neural level., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. However, prior studies have employed measures of working memory that include processing speed and attention. We examined the relationships between the RC-LF WMI and processing speed, attention, and working memory to clarify the relationship of RC-LF WMI with a specific cognitive function. Right superior longitudinal fasciculus II (SLF II) WMI and visual attention were included as a negative control tract and task to demonstrate a double dissociation., Methods: Adult survivors of childhood brain tumors [n = 29, age: M = 22 years (SD = 5), 45% female] and demographically matched controls were recruited (n = 29). Tests of auditory attention span, working memory, and visual attention served as cognitive measures. Participants completed a 3-T MRI diffusion-weighted imaging scan. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. Partial correlations between WMI and cognitive scores included controlling for type of treatment., Results: A correlational double dissociation was found. RC-LF WMI was associated with auditory attention (FA: r = .42, p = .03; RD: r = -.50, p = .01) and was not associated with visual attention (FA: r = -.11, p = .59; RD: r = -.11, p = .57). SLF II FA WMI was associated with visual attention (FA: r = .44, p = .02; RD: r = -.17, p = .40) and was not associated with auditory attention (FA: r = .24, p = .22; RD: r = -.10, p = .62)., Conclusions: The results show that RC-LF WMI is associated with auditory attention span rather than working memory per se and provides evidence for a specificity based on the correlational double dissociation.

Objective: Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine., Background: The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs)., Methods: This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks., Results: The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal., Conclusion: Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings., (© 2020 Biohaven Pharmaceutical Holding Company Ltd. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC, on behalf of American Headache Society.)

The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This Perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments that have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine.

Piscine orthoreovirus genotype 1 (PRV-1) is the causative agent of heart and skeletal muscle inflammation (HSMI) in farmed Atlantic salmon (Salmo salar L.). The virus has also been found in Pacific salmonids in western North America, raising concerns about the risk to native salmon and trout. Here, we report the results of laboratory challenges using juvenile Chinook salmon, coho salmon and rainbow trout injected with tissue homogenates from Atlantic salmon testing positive for PRV-1 or with control material. Fish were sampled at intervals to assess viral RNA transcript levels, haematocrit, erythrocytic inclusions and histopathology. While PRV-1 replicated in all species, there was negligible mortality in any group. We observed a few erythrocytic inclusion bodies in fish from the PRV-1-infected groups. At a few time points, haematocrits were significantly lower in the PRV-1-infected groups relative to controls, but in no case was anaemia noted. The most common histopathological finding was mild, focal myocarditis in both the non-infected controls and PRV-1-infected fish. All cardiac lesions were judged mild, and none were consistent with those of HSMI. Together, these results suggest all three species are susceptible to PRV-1 infection, but in no case did infection cause notable disease in these experiments., (© Published 2020. This article is a U.S. Government work and is in the public domain in the USA. Journal of Fish Diseases published by John Wiley & Sons Ltd.)

Objective: To provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine., Methods: Case reports are presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588). After Food and Drug Administration approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol., Results: Patients were women 44 and 36 years of age with ≥2 decades of self-reported suboptimal response to multiple migraine medications. Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly. Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic. Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with rimegepant responded. She stopped near-daily use of injectable ketorolac and diphenhydramine. While using rimegepant alone or together with erenumab, patients reported no related adverse events., Conclusions: Rimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration. The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study., Clinicaltrialsgov Identifier: NCT03266588., Classification of Evidence: This study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Despite a growing body of research devoted to the study of how humans encode environmental patterns, there is still no clear consensus about the nature of the neurocognitive mechanisms underpinning statistical learning nor what factors constrain or promote its emergence across individuals, species, and learning situations. Based on a review of research examining the roles of input modality and domain, input structure and complexity, attention, neuroanatomical bases, ontogeny, and phylogeny, ten core principles are proposed. Specifically, there exist two sets of neurocognitive mechanisms underlying statistical learning. First, a "suite" of associative-based, automatic, modality-specific learning mechanisms are mediated by the general principle of cortical plasticity, which results in improved processing and perceptual facilitation of encountered stimuli. Second, an attention-dependent system, mediated by the prefrontal cortex and related attentional and working memory networks, can modulate or gate learning and is necessary in order to learn nonadjacent dependencies and to integrate global patterns across time. This theoretical framework helps clarify conflicting research findings and provides the basis for future empirical and theoretical endeavors., Competing Interests: Declarations of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The ability to learn and process sequential dependencies is essential for language acquisition and other cognitive domains. Recent studies suggest that the learning of adjacent (e.g., "A-B") versus nonadjacent (e.g., "A-X-B") dependencies have different cognitive demands, but the neural correlates accompanying such processing are currently underspecified. We developed a sequential learning task in which sequences of printed nonsense syllables containing both adjacent and nonadjacent dependencies were presented. After incidentally learning these grammatical sequences, twenty-one healthy adults (age M = 22.1, 12 females) made familiarity judgments about novel grammatical sequences and ungrammatical sequences containing violations of the adjacent or nonadjacent structure while in a 3T MRI scanner. Violations of adjacent dependencies were associated with increased BOLD activation in both posterior (lateral occipital and angular gyrus) as well as frontal regions (e.g., medial frontal gyrus, inferior frontal gyrus). Initial results indicated no regions showing significant BOLD activations for the violations of nonadjacent dependencies. However, when using a less stringent cluster threshold, exploratory analyses revealed that violations of nonadjacent dependencies were associated with increased activation in subcallosal cortex, paracingulate cortex, and anterior cingulate cortex (ACC). Finally, when directly comparing the adjacent condition to the nonadjacent condition, we found significantly greater levels of activation for the right superior lateral occipital cortex (BA 19) for the adjacent relative to nonadjacent condition. In sum, the detection of violations of adjacent and nonadjacent dependencies appear to involve distinct neural networks, with perceptual brain regions mediating the processing of adjacent but not nonadjacent dependencies. These results are consistent with recent proposals that statistical-sequential learning is not a unified construct but depends on the interaction of multiple neurocognitive mechanisms acting together., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine., Methods: In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual., Findings: Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3 × the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2 × the upper limit of normal were reported. Treated participants reported no serious adverse events., Interpretation: In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns., Funding: Biohaven Pharmaceuticals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment., Methods: In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered., Results: A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection., Conclusions: Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.)., (Copyright © 2019 Massachusetts Medical Society.)

This study investigated the role of sequential processing in spoken language outcomes for children who are deaf or hard of hearing (DHH), ages 5;3-11;4, by comparing them to children with typical hearing (TH), ages 6;3-9;7, on sequential learning and memory tasks involving easily nameable and difficult-to-name visual stimuli. Children who are DHH performed more poorly on easily nameable sequencing tasks, which positively predicted receptive vocabulary scores. Results suggest sequential learning and memory may underlie delayed language skills of many children who are DHH. Implications for language development in children who are DHH are discussed.

Both adjacent and non-adjacent dependencies (AD and NAD) are present in natural language and other domains, yet the learning of non-adjacent sequential dependencies generally only occurs under favorable circumstances. It is currently unknown to what extent adults can learn AD and NAD, presented concurrently in spatial and verbal sequences during a single session, and whether a second session improves performance. In addition, the relationship between AD and NAD learning and other theoretically related cognitive and language processes has not yet been fully established. In this study, participants reproduced two types of sequences generated from an artificial grammar: visuo-spatial sequences with stimuli presented in four spatial locations, and visuo-verbal sequences with printed syllables. Participants were tested for incidental learning by reproducing novel sequences, half consistent with the grammar and half containing violations of either AD or NAD. The procedure was repeated on a second day. Results showed that both AD and NAD were learned in both visuo-spatial and visuo-verbal tasks, although AD learning was better than NAD and learning of NAD decreased over time. Furthermore, NAD learning for both spatial and verbal tasks was positively correlated with a language measure, whereas AD learning for both spatial and verbal tasks was negatively associated with working memory measures in the opposite domain. These results demonstrate that adults can learn both AD and NAD within a single session, but NAD learning is more easily disrupted than AD and both types of learning are sub-served by partially distinct cognitive processes. These findings increase our understanding of the processes governing the learning of AD and NAD in verbal and spatial domains.

Statistical learning plays an important role in the acquisition of spoken and written language. It has been proposed that impaired or atypical statistical learning may be linked with language difficulties in developmental disabilities. However, research on statistical learning in individuals with developmental disabilities such as autism spectrum disorder, dyslexia, and specific language impairment, and in individuals with cochlear implants, has produced divergent findings. It is unclear whether, and to what extent, statistical learning is impaired or atypical in each of these developmental disabilities. We suggest that these disparate findings point to several critical issues that must be addressed before we can evaluate the role of statistical learning in atypical child development. While the issues we outline are interrelated, we propose four key points relating to (a) the nature of statistical learning, (b) the myriad of ways in which statistical learning can be measured, (c) our lack of understanding regarding the developmental trajectory of statistical learning, and (d) the role of individual differences. We close by making suggestions that we believe will be helpful in moving the field forward and creating new synergies among researchers, clinicians, and educators to better support language learners., Competing Interests: Declaration of Conflicting Interests: The author(s) declared that there were no conflicts of interest with respect to the authorship or the publication of this article.

It has been suggested that external and/or internal limitations paradoxically may lead to superior learning, that is, the concepts of starting small and less is more (Elman, ; Newport, ). In this paper, we explore the type of incremental ordering during training that might help learning, and what mechanism explains this facilitation. We report four artificial grammar learning experiments with human participants. In Experiments 1a and 1b we found a beneficial effect of starting small using two types of simple recursive grammars: right-branching and center-embedding, with recursive embedded clauses in fixed positions and fixed length. This effect was replicated in Experiment 2 (N = 100). In Experiment 3 and 4, we used a more complex center-embedded grammar with recursive loops in variable positions, producing strings of variable length. When participants were presented an incremental ordering of training stimuli, as in natural language, they were better able to generalize their knowledge of simple units to more complex units when the training input "grew" according to structural complexity, compared to when it "grew" according to string length. Overall, the results suggest that starting small confers an advantage for learning complex center-embedded structures when the input is organized according to structural complexity., (© 2018 The Authors. Cognitive Science - A Multidisciplinary Journal published by Wiley Periodicals, Inc. on behalf of Cognitive Science Society.)

Purpose: Statistical learning-the ability to learn patterns in environmental input-is increasingly recognized as a foundational mechanism necessary for the successful acquisition of spoken language. Spoken language is a complex, serially presented signal that contains embedded statistical relations among linguistic units, such as phonemes, morphemes, and words, which represent the phonotactic and syntactic rules of language. In this review article, we first review recent work that demonstrates that, in typical language development, individuals who display better nonlinguistic statistical learning abilities also show better performance on different measures of language. We next review research findings that suggest that children who are deaf and use cochlear implants may have difficulties learning sequential input patterns, possibly due to auditory and/or linguistic deprivation early in development, and that the children who show better sequence learning abilities also display improved spoken language outcomes. Finally, we present recent findings suggesting that it may be possible to improve core statistical learning abilities with specialized training and interventions and that such improvements can potentially impact and facilitate the acquisition and processing of spoken language., Method: We conducted a literature search through various online databases including PsychINFO and PubMed, as well as including relevant review articles gleaned from the reference sections of other review articles used in this review. Search terms included various combinations of the following: sequential learning, sequence learning, statistical learning, sequence processing, procedural learning, procedural memory, implicit learning, language, computerized training, working memory training, statistical learning training, deaf, deafness, hearing impairment, hearing impaired, DHH, hard of hearing, cochlear implant(s), hearing aid(s), and auditory deprivation. To keep this review concise and clear, we limited inclusion to the foundational and most recent (2005-2018) relevant studies that explicitly included research or theoretical perspectives on statistical or sequential learning. We here summarize and synthesize the most recent and relevant literature to understanding and treating language delays in children using cochlear implants through the lens of statistical learning., Conclusions: We suggest that understanding how statistical learning contributes to spoken language development is important for understanding some of the difficulties that children who are deaf and use cochlear implants might face and argue that it may be beneficial to develop novel language interventions that focus specifically on improving core foundational statistical learning skills.

Previous research suggests that individuals with developmental dyslexia perform below typical readers on non-linguistic cognitive tasks involving the learning and encoding of statistical-sequential patterns. However, the neural mechanisms underlying such a deficit have not been well examined. The aim of the present study was to investigate the event-related potential (ERP) correlates of sequence processing in a sample of children diagnosed with dyslexia using a non-linguistic visual statistical learning paradigm. Whereas the response time data suggested that both typical and atypical readers learned the statistical patterns embedded in the task, the ERP data suggested otherwise. Specifically, ERPs of the typically developing children (n = 12) showed a P300-like response indicative of learning, whereas the children diagnosed with a reading disorder (n = 8) showed no such ERP effects. These results may be due to intact implicit motor learning in the children with dyslexia but delayed attention-dependent predictive processing. These findings are consistent with other evidence suggesting that differences in statistical learning ability might underlie some of the reading deficits observed in developmental dyslexia.

Humans and nonhuman primates can learn about the organization of stimuli in the environment using implicit sequential pattern learning capabilities. However, most previous artificial grammar learning studies with nonhuman primates have involved relatively simple grammars and short input sequences. The goal in the current experiments was to assess the learning capabilities of monkeys on an artificial grammar-learning task that was more complex than most others previously used with nonhumans. Three experiments were conducted using a joystick-based, symmetrical-response serial reaction time task in which two monkeys were exposed to grammar-generated sequences at sequence lengths of four in Experiment 1, six in Experiment 2, and eight in Experiment 3. Over time, the monkeys came to respond faster to the sequences generated from the artificial grammar compared to random versions. In a subsequent generalization phase, subjects generalized their knowledge to novel sequences, responding significantly faster to novel instances of sequences produced using the familiar grammar compared to those constructed using an unfamiliar grammar. These results reveal that rhesus monkeys can learn and generalize the statistical structure inherent in an artificial grammar that is as complex as some used with humans, for sequences up to eight items long. These findings are discussed in relation to whether or not rhesus macaques and other primate species possess implicit sequence learning abilities that are similar to those that humans draw upon to learn natural language grammar.

A current controversy in the area of implicit statistical learning (ISL) is whether this process consists of a single, central mechanism or multiple modality-specific ones. To provide insight into this question, the current study involved three ISL experiments to explore whether multimodal input sources are processed separately in each modality or are integrated together across modalities. In Experiment 1, visual and auditory ISL were measured under unimodal conditions, with the results providing a baseline level of learning for subsequent experiments. Visual and auditory sequences were presented separately, and the underlying grammar used for both modalities was the same. In Experiment 2, visual and auditory sequences were presented simultaneously with each modality using the same artificial grammar to investigate whether redundant multisensory information would result in a facilitative effect (i.e., increased learning) compared to the baseline. In Experiment 3, visual and auditory sequences were again presented simultaneously but this time with each modality employing different artificial grammars to investigate whether an interference effect (i.e., decreased learning) would be observed compared to the baseline. Results showed that there was neither a facilitative learning effect in Experiment 2 nor an interference effect in Experiment 3. These findings suggest that participants were able to track simultaneously and independently two sets of sequential regularities under dual-modality conditions. These findings are consistent with the theories that posit the existence of multiple, modality-specific ISL mechanisms rather than a single central one.

Statistical learning is the ability to extract predictive patterns from structured input. A common assumption is that statistical learning is a type of implicit learning that does not result in explicit awareness of learned patterns. However, there is also some evidence that statistical learning may involve explicit processing to some extent. The purpose of this study was to examine the effect of pattern awareness on behavioral and neurophysiological correlates of visual statistical learning. Participants completed a visual learning task while behavioral responses and event-related potentials were recorded. Following the completion of the task, awareness of statistical patterns was assessed through a questionnaire scored by three independent raters. Behavioral findings indicated learning only for participants exhibiting high pattern awareness levels. Neurophysiological data indicated that only the high-pattern awareness group showed expected P300 event-related potential learning effects, although there was also some indication that the low awareness groups showed a sustained mid- to late-latency negativity. Linear mixed-model analyses confirmed that only the high awareness group showed neurophysiological indications of learning. Finally, source estimation results revealed left hemispheric activation was associated with statistical learning extending from frontal to occipital and parietal regions. Further analyses suggested that left insula, left parahippocampal, and right precentral regions showed different levels of activation based on pattern awareness. To conclude, we found that pattern awareness, a dimension associated with explicit processing, strongly influences the behavioral and neurophysiological correlates of visual statistical learning.

Background: Optimal management of chronic diseases, such as type 2 diabetes and hypertension, often include prescription medications. Medication adherence (MA) is one component of self-management. Optimization through digital health-eHealth and mHealth-could enhance patient awareness and/or communication between the patient and provider., Objective: Medication adherence is a major issue that affects 50%-60% of chronically ill adults. Digital health refers to eHealth and mHealth, collectively, and as these technologies become more accessible, remote health delivery is increasingly available as an adjunct to improve medication adherence; communicate with patients and providers; and provide education to patients, families, and communities. The objective of this integrative review was to examine the types of digital health technologies that targeted medication adherence in the adult population with diabetes or hypertension., Methods: An integrative review was conducted using databases within EBSCOhost, PubMed, and Scopus. Eligible studies available as of September 2016 had to be written in English, had to contain digital health interventions to improve medication adherence to prescription medications in adults 18 years or older, and had to focus on diabetes or hypertension., Results: Of the 337 located studies, 13 (3.9%) used a digital health intervention for medication adherence to prescribed medications for diabetes or hypertension and were assessed according to the Chronic Care Model., Conclusions: The 13 studies included in this review found no conclusive evidence of improved medication adherence using digital health interventions such as interactive voice response (IVR), short message service (SMS) text messaging, telemonitoring, and interactive software technology. Among the 13 studies were digital health interventions that foster medication adherence via one-way communication to the patient or two-way communication between the patient and health care provider for adjunct medication adherence strategies. More research is needed to determine which digital health interventions are most beneficial for individuals with diabetes or hypertension., (©Cheryl Moseley Conway, Teresa J Kelechi. Originally published in JMIR Diabetes (http://diabetes.jmir.org), 16.08.2017.)

An asymmetric synthesis of the major metabolite of the calcitonin gene-related peptide recepotor antagonist BMS-846372 is presented. The variously substituted cyclohepta[b]pyridine ring system represents an underexplored ring system and showed some unexpected chemistry. Reactivities of epoxide and ketone functional groups on the cycloheptane ring were extensively controlled by a remote bulky TIPS group. The rate difference of the hydrogenolysis between two diastereomeric epoxide intermediates shed some light on the mechanism of epoxide hydrogenolysis, and further, deuterium labeling studies revealed more mechanistic details on this well-known chemical transformation for the first time.

The superficial dorsal horn is the synaptic termination site for many peripheral sensory fibers of the somatosensory system. A wide range of sensory modalities are represented by these fibers, including pain, itch, and temperature. Because the involvement of local inhibition in the dorsal horn, specifically that mediated by the inhibitory amino acids GABA and glycine, is so important in signal processing, we investigated regional inhibitory control of excitatory interneurons under control conditions and peripheral inflammation-induced mechanical allodynia. We found that excitatory interneurons and projection neurons in lamina I and IIo are dominantly inhibited by GABA while those in lamina IIi and III are dominantly inhibited by glycine. This was true of identified neuronal subpopulations: neurokinin 1 receptor-expressing (NK1R+) neurons in lamina I were GABA-dominant while protein kinase C gamma-expressing (PKCγ+) neurons at the lamina IIi-III border were glycine-dominant. We found this pattern of synaptic inhibition to be consistent with the distribution of GABAergic and glycinergic neurons identified by immunohistochemistry. Following complete Freund's adjuvant injection into mouse hindpaw, the frequency of spontaneous excitatory synaptic activity increased and inhibitory synaptic activity decreased. Surprisingly, these changes were accompanied by an increase in GABA dominance in lamina IIi. Because this shift in inhibitory dominance was not accompanied by a change in the number of inhibitory synapses or the overall postsynaptic expression of glycine receptor α1 subunits, we propose that the dominance shift is due to glycine receptor modulation and the depressed function of glycine receptors is partially compensated by GABAergic inhibition. SIGNIFICANCE STATEMENT Pain associated with inflammation is a sensation we would all like to minimize. Persistent inflammation leads to cellular and molecular changes in the spinal cord dorsal horn, including diminished inhibition, which may be responsible for enhance excitability. Investigating inhibition in the dorsal horn following peripheral inflammation is essential for development of improved ways to control the associated pain. In this study, we have elucidated regional differences in inhibition of excitatory interneurons in mouse dorsal horn. We have also discovered that the dominating inhibitory neurotransmission within specific regions of dorsal horn switches following peripheral inflammation and the accompanying hypersensitivity to thermal and mechanical stimuli. Our novel findings contribute to a more complete understanding of inflammatory pain., (Copyright © 2017 the authors 0270-6474/17/372337-13$15.00/0.)

Statistical learning (SL) is believed to enable language acquisition by allowing individuals to learn regularities within linguistic input. However, neural evidence supporting a direct relationship between SL and language ability is scarce. We investigated whether there are associations between event-related potential (ERP) correlates of SL and language abilities while controlling for the general level of selective attention. Seventeen adults completed tests of visual SL, receptive vocabulary, grammatical ability, and sentence completion. Response times and ERPs showed that SL is related to receptive vocabulary and grammatical ability. ERPs indicated that the relationship between SL and grammatical ability was independent of attention while the association between SL and receptive vocabulary depended on attention. The implications of these dissociative relationships in terms of underlying mechanisms of SL and language are discussed. These results further elucidate the cognitive nature of the links between SL mechanisms and language abilities., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A novel virus, rainbow trout orthomyxovirus (RbtOV), was isolated in 1997 and again in 2000 from commercially-reared rainbow trout (Oncorhynchus mykiss) in Idaho, USA. The virus grew optimally in the CHSE-214 cell line at 15°C producing a diffuse cytopathic effect; however, juvenile rainbow trout exposed to cell culture-grown virus showed no mortality or gross pathology. Electron microscopy of preparations from infected cell cultures revealed the presence of typical orthomyxovirus particles. The complete genome of RbtOV is comprised of eight linear segments of single-stranded, negative-sense RNA having highly conserved 5' and 3'-terminal nucleotide sequences. Another virus isolated in 2014 from steelhead trout (also O. mykiss) in Wisconsin, USA, and designated SttOV was found to have eight genome segments with high amino acid sequence identities (89-99%) to the corresponding genes of RbtOV, suggesting these new viruses are isolates of the same virus species and may be more widespread than currently realized. The new isolates had the same genome segment order and the closest pairwise amino acid sequence identities of 16-42% with Infectious salmon anemia virus (ISAV), the type species and currently only member of the genus Isavirus in the family Orthomyxoviridae. However, pairwise comparisons of the predicted amino acid sequences of the 10 RbtOV and SttOV proteins with orthologs from representatives of the established orthomyxoviral genera and a phylogenetic analysis using the PB1 protein showed that while RbtOV and SttOV clustered most closely with ISAV, they diverged sufficiently to merit consideration as representatives of a novel genus. A set of PCR primers was designed using conserved regions of the PB1 gene to produce amplicons that may be sequenced for identification of similar fish orthomyxoviruses in the future., (Published by Elsevier B.V.)

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans., (Copyright © 2016 The Author(s).)

Objective: Most predictive models of kidney disease progression have not incorporated structural data. If structural variables have been used in models, they have generally been only semi-quantitative., Methods: We examined the predictive utility of quantitative structural parameters measured on the digital images of baseline kidney biopsies from the NEPTUNE study of primary proteinuric glomerulopathies. These variables were included in longitudinal statistical models predicting the change in estimated glomerular filtration rate (eGFR) over up to 55 months of follow-up., Results: The participants were fifty-six pediatric and adult subjects from the NEPTUNE longitudinal cohort study who had measurements made on their digital biopsy images; 25% were African-American, 70% were male and 39% were children; 25 had focal segmental glomerular sclerosis, 19 had minimal change disease, and 12 had membranous nephropathy. We considered four different sets of candidate predictors, each including four quantitative structural variables (for example, mean glomerular tuft area, cortical density of patent glomeruli and two of the principal components from the correlation matrix of six fractional cortical areas-interstitium, atrophic tubule, intact tubule, blood vessel, sclerotic glomerulus, and patent glomerulus) along with 13 potentially confounding demographic and clinical variables (such as race, age, diagnosis, and baseline eGFR, quantitative proteinuria and BMI). We used longitudinal linear models based on these 17 variables to predict the change in eGFR over up to 55 months. All 4 models had a leave-one-out cross-validated R2 of about 62%., Conclusions: Several combinations of quantitative structural variables were significantly and strongly associated with changes in eGFR. The structural variables were generally stronger than any of the confounding variables, other than baseline eGFR. Our findings suggest that quantitative assessment of diagnostic renal biopsies may play a role in estimating the baseline risk of succeeding loss of renal function in future clinical studies, and possibly in clinical practice.

At the present time, there is no question that cochlear implants (CIs) work and often work very well in quiet listening conditions for many profoundly deaf children and adults. The speech and language outcomes data published over the last two decades document quite extensively the clinically significant benefits of CIs. Although there now is a large body of evidence supporting the "efficacy" of CIs as a medical intervention for profound hearing loss in both children and adults, there still remain a number of challenging unresolved clinical and theoretical issues that deal with the "effectiveness" of CIs in individual patients that have not yet been successfully resolved. In this paper, we review recent findings on learning and memory, two central topics in the field of cognition that have been seriously neglected in research on CIs. Our research findings on sequence learning, memory and organization processes, and retrieval strategies used in verbal learning and memory of categorized word lists suggests that basic domain-general learning abilities may be the missing piece of the puzzle in terms of understanding the cognitive factors that underlie the enormous individual differences and variability routinely observed in speech and language outcomes following cochlear implantation.

The progression of external signs of Ichthyophonus infection in Pacific herring Clupea pallasii Valenciennes was highly variable and asynchronous after intraperitoneal injection with pure parasite preparations; however, external signs generally persisted through the end of the study (429 days post-exposure). Observed signs included papules, erosions and ulcers. The prevalence of external signs plateaued 35 days post-exposure and persisted in 73-79% of exposed individuals through the end of the first experiment (147 days post-exposure). Among a second group of infected herring, external signs completely resolved in only 10% of the fish after 429 days. The onset of mortality preceded the appearance of external signs. Histological examination of infected skin and skeletal muscle tissues indicated an apparent affinity of the parasite for host red muscle. Host responses consisted primarily of granulomatous inflammation, fibrosis and necrosis in the skeletal muscle and other tissues. The persistence and asynchrony of external signs and host response indicated that they were neither a precursor to host mortality nor did they provide reliable metrics for hindcasting on the date of exposure. However, the long-term persistence of clinical signs in Pacific herring may be useful in ascertaining the population-level impacts of ichthyophoniasis in regularly observed populations., (© 2015 John Wiley & Sons Ltd.)

Recent studies have demonstrated participants' ability to learn cross-modal associations during statistical learning tasks. However, these studies are all similar in that the cross-modal associations to be learned occur simultaneously, rather than sequentially. In addition, the majority of these studies focused on learning across sensory modalities but not across perceptual categories. To test both cross-modal and cross-categorical learning of sequential dependencies, we used an artificial grammar learning task consisting of a serial stream of auditory and/or visual stimuli containing both within- and cross-domain dependencies. Experiment 1 examined within-modal and cross-modal learning across two sensory modalities (audition and vision). Experiment 2 investigated within-categorical and cross-categorical learning across two perceptual categories within the same sensory modality (e.g., shape and color; tones and non-words). Our results indicated that individuals demonstrated learning of the within-modal and within-categorical but not the cross-modal or cross-categorical dependencies. These results stand in contrast to the previous demonstrations of cross-modal statistical learning, and highlight the presence of modality constraints that limit the effectiveness of learning in a multimodal environment.