Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis. METHODS: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. PRIMARY ENDPOINT: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12. RESULTS: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. PRIMARY ENDPOINT: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups. CONCLUSIONS: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib. TRIAL REGISTRATION NUMBERS: NCT03980483, NCT03970837.

Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: a phase III randomised trial (contRAst 3).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors. METHODS: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12. RESULTS: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups. CONCLUSIONS: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population. TRIAL REGISTRATION NUMBER: NCT04134728.

A Retrospective Application of the Arbon and Hartman Models to the Union Cycliste International Mountain Bike World Cup.

INTRODUCTION: Outdoor activities have accelerated in the past several years. The authors were tasked with providing medical care for the Union Cycliste International (UCI) mountain biking World Cup in Snowshoe, West Virginia (USA) in September 2021. The Hartman and Arbon models were designed to predict patient presentation and hospital transport rates as well as needed medical resources at urban mass-gathering events. However, there is a lack of standardized methods to predict injury, illness, and insult severity at rural mass gatherings. STUDY OBJECTIVE: This study aimed to determine whether the Arbon model would predict, within 10%, the number of patient presentations to be expected and to determine if the event classification provided by the Hartman model would adequately predict resources needed during the event. METHODS: Race data were collected from UCI event officials and injury data were collected from participants at time of presentation for medical care. Predicted presentation and transport rates were calculated using the Arbon model, which was then compared to the actual observed presentation rates. Furthermore, the event classification provided by the Hartman model was compared to the resources utilized during the event. RESULTS: During the event, 34 patients presented for medical care and eight patients required some level of transport to a medical facility. The Arbon predictive model for the 2021 event yielded 30.3 expected patient presentations. There were 34 total patient presentations during the 2021 race, approximately 11% more than predicted. The Hartman model yielded a score of four. Based on this score, this race would be classified as an "intermediate" event, requiring multiple Advanced Life Support (ALS) and Basic Life Support (BLS) personnel and transport units. CONCLUSION: The Arbon model provided a predicted patient presentation rate within reasonable error to allow for effective pre-event planning and resource allocation with only a four patient presentation difference from the actual data. While the Arbon model under-predicted patient presentations, the Hartman model under-estimated resources needed due to the high-risk nature of downhill cycling. The events staffed required physician skills and air medical services to safely care for patients. Further evaluation of rural events will be needed to determine if there is a generalized need for physician presence at smaller events with inherently risky activities, or if this recurring cycling event is an outlier.

Lessons on Mass Gatherings Learned From the 2019 Union Cycliste Internationale Mountain Bike World Cup.

The Union Cycliste Internationale (UCI) Mountain Bike World Cup in 2019 provided unique challenges for effective prehospital care. While on-site medical care has demonstrated improved outcomes along with reduced emergency department and emergency medical services (EMS) utilization, this aspect has not been well documented in the literature with respect to rural mass gathering events (MGEs). Conducted at a large mass gathering event in a geographically isolated area, this study aimed to assess the medical needs at this specific event and will hopefully assist in future coordination of similar events. All patients who were treated at the event clinic were included in the analysis. Primary investigators collected and recorded data while providing care. We believe the on-site clinic was successful in reducing barriers to healthcare by improving access, streamlining the treatment process, and optimizing resource utilization. This benefit extended to race participants, support staff, spectators, and the local EMS system.

Evaluating West Virginia's Emergency Medicine Workforce: A Longitudinal Observational Study.

Objective Although the urban emergency workforce is well studied, rural departments are less understood. This study seeks to further define the landscape of rural healthcare and expand on previous studies of the West Virginia (WV) workforce. Methods During the second quarter of 2019, surveys were sent via email to medical directors' professional IDs as anonymous survey links. Hard copies were also sent to directors at their hospital addresses. Responses were aggregated with hospitals stratified based on annual census and rural classification. Data was interpreted through descriptive analysis. Results Surveys were sent to 53 departments with a 55% response rate. Of the responding hospitals, 15 of 29 were identified as rural. The average state-wide annual hospital census was 29,500 visits with board-certified emergency medicine (EM)-trained physicians covering 67% of shifts. Rural departments have a smaller census and less specialized coverage. Full-time physicians are found to have the strongest ties to WV, with 65% attending medical school, residency, or growing up in the state. Conclusion Board-certified EM-trained physicians provide some level of coverage in most emergency departments in WV but remain underrepresented in rural locations. This specialized coverage has increased by 20% in the last 15 years. Additionally, a majority of hospitals have access to basic consulting services (surgery and primary care); however, other specialists are rare in rural WV.

A Comparison of Internal Dispositions and Career Trajectories after Collaborative versus Apprenticed Research Experiences for Undergraduates.

Undergraduate research experiences confer benefits on students bound for science, technology, engineering, and mathematics (STEM) careers, but the low number of research professionals available to serve as mentors often limits access to research. Within the context of our summer research program (BRAIN), we tested the hypothesis that a team-based collaborative learning model (CLM) produces student outcomes at least as positive as a traditional apprenticeship model (AM). Through stratified, random assignment to conditions, CLM students were designated to work together in a teaching laboratory to conduct research according to a defined curriculum led by several instructors, whereas AM students were paired with mentors in active research groups. We used pre-, mid-, and postprogram surveys to measure internal dispositions reported to predict progress toward STEM careers, such as scientific research self-efficacy, science identity, science anxiety, and commitment to a science career. We are also tracking long-term retention in science-related career paths. For both short- and longer-term outcomes, the two program formats produced similar benefits, supporting our hypothesis that the CLM provides positive outcomes while conserving resources, such as faculty mentors. We discuss this method in comparison with course-based undergraduate research and recommend its expansion to institutional settings in which mentor resources are scarce.

Neural distribution of vasotocin receptor mRNA in two species of songbird.

The neurohypophyseal hormones vasopressin and oxytocin are produced and released within the mammalian brain, where they act via multiple receptor subtypes. The neural distributions of these receptors, for example, V1a and oxytocin receptors, have been well described in many mammals. In birds, the distribution of binding sites for the homologous neuropeptides, vasotocin (VT) and mesotocin, has been studied in several species by using synthetic radioligands designed to bind to mammalian receptors. Such binding studies, however, may not reveal the specific distributions of each receptor subtype. To identify and map the receptors likely to bind VT and mesotocin, we generated partial cDNA sequences for four VT receptor subtypes, VT1, VT2 (V1b), VT3 (oxytocin-like), and VT4 (V1a), in white-throated sparrow (Zonotrichia albicollis) and zebra finch (Taeniopygia guttata). These genes shared high sequence identity with the homologous avian and mammalian neurohypophyseal peptide receptors, and we found evidence for VT1, VT3, and VT4 receptor mRNA expression throughout the brains of both species. As has been described in rodents, there was striking interspecific and intraspecific variation in the densities and distribution of these receptors. For example, whereas the VT1 receptor mRNA was more widespread in zebra finch brain, the VT3 (oxytocin-like) receptor mRNA was more prevalent in the sparrow brain. Although VT2 (V1b) receptor mRNA was abundant in the pituitary, it was not found in the brain. Because of their association with brain regions implicated in social behavior, the VT1, VT3, and VT4 receptors are all likely candidates for mediating the behavioral effects of VT.

Neural distribution of nonapeptide binding sites in two species of songbird.

Vasotocin (VT) and its mammalian homologue, vasopressin (VP), modulate many social behaviors in a variety of vertebrate species. In songbirds, the effects of centrally administered VT vary according to species, which may reflect species-specific distributions of VT binding sites. Different radioligands used to map receptors in previous autoradiographical studies have revealed nonoverlapping distributions of VT binding, suggesting a heterogeneous population of more than one type of VT receptor. For two model songbird species, the white-throated sparrow (Zonotrichia albicollis) and zebra finch (Taeniopygia guttata), we labeled putative VT receptors with two radioligands, [(125)I]ornithine vasotocin analog ([(125)I]OVTA) and [(125)I]linear VP antagonist ([(125)I]HO-LVA). Competitive binding assays in the lateral septum showed that both ligands were effectively displaced by both VT and a related nonapeptide, mesotocin (MT), showing that these radioligands, which were developed to label mammalian nonapeptide receptors, label at least one population of related receptors in songbirds. [(125)I]OVTA labeled receptors throughout the telencephalon, diencephalon, midbrain, and brainstem, with a similar distribution in both species. In contrast, the binding of [(125)I]HO-LVA was restricted to the septal area, dorsal arcopallium, and optic tectum in sparrow and was essentially undetectable in zebra finch. Because the avian brain is likely to express multiple types of VT receptors, we hypothesize that the binding patterns of these radioligands represent a heterogeneous receptor population.

Estradiol modulates neural responses to song in a seasonal songbird.

Social behaviors such as courtship, parenting, and aggression depend primarily on two factors: a social signal to trigger the behavior, and a hormonal milieu that facilitates or permits it. Gonadal steroids may alter the valence or perceived context of the signal so that the same pheromone, vocalization, or visual display may elicit very different responses depending on the receiver's plasma hormone level. The neural processes underlying this phenomenon, however, are not well understood. Here, we describe how hormones modulate neural responses to social signals in female white-throated sparrows listening to recordings of male song. While manipulating levels of the ovarian steroid estradiol, we mapped and quantified sound-induced expression of the immediate early gene egr-1 in nine brain regions that constitute a social behavior network in vertebrates. In most regions of interest, hearing male song induced more expression than hearing tones or silence, and this selectivity for song was seen only in birds with estradiol levels typical of the breeding season. In females with regressed ovaries and no exogenous estradiol, neural responses were selective for song over tones only in the lateral portion of the ventromedial hypothalamus, not in the rest of the network. Because the effects of hormone treatment on neural responses are not identical in each region, the overall pattern of activation across the network changes with estradiol level and thus with season and breeding context. Our results demonstrate a possible mechanism by which gonadal steroids may alter the processing of social signals and affect social decision-making.

Rapid neuroendocrine responses to auditory courtship signals.

In many species, courtship signals enhance reproductive function in the receiver. How these social signals are processed by the brain, particularly how they induce an endocrine response, is not well understood. Songbirds provide an ideal model in which to study this phenomenon because of the large existing literature on both their auditory neurobiology and the control of their reproductive physiology by environmental cues. To date, all of the relevant studies on songbirds have involved measuring the effects of male vocalizations on ovarian function over a period of weeks, a time course that precludes detailed analysis of the neuroendocrine mechanisms operating during song perception. We played recordings of conspecific male song to laboratory-housed female white-throated sparrows and quantified the resulting rapid changes in LH as well as the induction of the immediate early gene Egr-1 in the GnRH system and mediobasal hypothalamus (MBH). Hearing song for 42 min induced LH release and Egr-1 expression in the MBH, but did not alter Egr-1 expression in GnRH neurons. The time course of LH release and the pattern of Egr-1 expression together suggest that song acts as a trigger to induce GnRH release in a manner resembling photostimulation. The Egr-1 response in the MBH was qualitatively distinguishable from the responses to either photostimulation or pharmacologically induced LH release but seemed to involve overlapping neuronal populations. Song-induced Egr-1 expression in the MBH was correlated with the expression in midbrain and forebrain auditory centers, further supporting a role for the MBH in processing social information.

Estradiol modulates brainstem catecholaminergic cell groups and projections to the auditory forebrain in a female songbird.

In songbirds, hearing conspecific song induces robust expression of the immediate early gene zenk in the auditory forebrain. This genomic response to song is well characterized in males and females of many species, and is highly selective for behaviorally relevant song. In white-throated sparrows, the selectivity of the zenk response requires breeding levels of estradiol; we previously showed that in non-breeding females with low levels of plasma estradiol, the zenk response to hearing song is no different than the response to hearing frequency-matched tones. Here, we investigated the role of brainstem catecholaminergic cells groups, which project to the forebrain, in estradiol-dependent selectivity. First, we hypothesized that estradiol treatment affects catecholaminergic innervation of the auditory forebrain as well as its possible sources in the brainstem. Immunohistochemical staining of tyrosine hydroxylase revealed that estradiol treatment significantly increased the density of catecholaminergic innervation of the auditory forebrain as well as the number of catecholaminergic cells in the locus coeruleus (A6) and the ventral tegmental area (A10), both of which are known to contain estrogen receptors in songbirds. Second, we hypothesized that during song perception, catecholaminergic cell groups of the brainstem actively participate in auditory selectivity via estrogen-dependent changes in activity. We found that hearing songs did not induce the expression of zenk, a putative marker of activity, within catecholaminergic neurons in any of the cell groups quantified. Together, our results suggest that estradiol induces changes in brainstem catecholaminergic cell groups that may play a neuromodulatory role in behavioral and auditory selectivity.

Amaranth decoloration by Trametes versicolor in a rotating biological contacting reactor.

Sequential batch and continuous operation of a rotating biological contacting (RBC) reactor and the effects of dissolved oxygen on the decoloration of amaranth by Trametes versicolor were evaluated. Amaranth belongs to the group of azo dyes which are potential carcinogens and/or mutagens that can be transformed into toxic aryl amines under anaerobic conditions. Cultivation of T. versicolor in a stirred tank reactor was found to be unsuitable for amaranth decoloration due to significant biomass fouling and increase in medium viscosity. Assuming that decoloration follows first-order kinetics, amaranth was decolorized more rapidly when T. versicolor was immobilized on jute twine in a RBC reactor operated either in a sequential batch (k=0.25 h(-1)) or in a continuous (0.051 h(-1)) mode compared to a stirred tank reactor (0.015 h(-1)). Oxygen was found to be essential for decoloration with the highest decoloration rates occurring at oxygen saturation. Although longer retention times resulted in more decoloration when the RBC was operated in the continuous mode (about 33% amaranth decoloration), sequential batch operation gave better results (>95%) under similar nutrient conditions. Our data indicate that the fastest decoloration should occur in the RBC using nitrogen-free Kirk's medium with 1 g/l glucose in sequential batch operation at rotational speeds and/or aeration rates which maintain oxygen saturation in the liquid phase.

Estrogen-dependent selectivity of genomic responses to birdsong.

Behavioral responses to sociosexual signals often depend on gonadal steroid hormones, which are thought to modulate behavior by acting on motivational systems in the brain. There is mounting evidence that sex steroids may also modulate perception of sociosexual signals by affecting sensory processing. In seasonally breeding songbirds such as the white-throated sparrow (Zonotrichia albicollis), the female's behavioral response to hearing male song depends on her plasma levels of estradiol (E2). Here, we examined whether plasma E2 also affects the selectivity of the song-induced zenk (egr-1) response in the auditory forebrain, which is known to vary according to the behavioral relevance of song stimuli. Non-breeding females were held on a winter-like photoperiod and implanted with silastic capsules containing either no hormone or E2. E2-treated birds hearing 42 min of conspecific song had more cells immunoreactive for the protein product of zenk in the auditory forebrain than did those hearing frequency-matched synthetic tones. In birds not treated with E2, however, the zenk response to song did not differ from that to tones. We found similar effects in the avian homolog of the inferior colliculus, indicating that E2 may affect the processing of auditory information upstream of the forebrain. Our data suggest that in females, zenk induction in the auditory system is selective for song only when plasma E2 exceeds non-breeding levels. E2-dependent plasticity of auditory pathways and processing centres may promote recognition of and attention to conspecific song during the breeding season.

Neuroendocrine correlates of behavioral polymorphism in white-throated sparrows.

Interspecific differences in the neuropeptide systems of the lateral septum (LS) often parallel differences in social behavior. In rodents, some closely related species that differ in aggressive behavior also differ according to the level of vasopressin (VP) innervation of the LS. In songbirds, the neuropeptides vasotocin (VT) and vasoactive intestinal peptide (VIP) affect aggression when administered directly to the LS. Here, we tested whether the density of VT or VIP innervation of the LS reflects patterns of intraspecific behavioral polymorphism in male and female white-throated sparrows (Zonotrichia albicollis), in which the "white-stripe" (WS) morph behaves more aggressively than the "tan-stripe" (TS) morph. We found that the WS birds had more VT-immunoreactivity (IR) than the TS birds in the ventrolateral subdivision of the caudal LS (LSc.vl) and in the medial portion of the bed nucleus of the stria terminalis (BSTm). In addition, the TS birds had more densely stained VIP-IR in the LSc.vl than the WS birds. Males had more VT-IR than females in the LSc.vl and BSTm, and more VIP-IR in the LSc.vl. We also report sex and morph differences in VIP-IR in the basal hypothalamus, where VIP is synthesized and released into the portal vasculature. Males had nearly twice as many VIP-immunoreactive (ir) neurons in the infundibular nucleus than did females, and birds of the WS morph had more densely stained VIP-IR in the median eminence than TS birds. Our results support the hypothesis that differences in these neuropeptide systems underlie inter- and intraspecific differences in social behavior across vertebrates.