Association of Race and Ethnicity With COVID‐19 Outcomes in Rheumatic Disease: Data From the COVID‐19 Global Rheumatology Alliance Physician Registry

OBJECTIVE: Racial/ethnic minorities experience more severe outcomes of COVID-19 in the general United States (US) population. The aim of this study was to examine the association between race/ethnicity and COVID-19 hospitalization, ventilation status, and mortality in people with rheumatic disease. METHODS: US patients with rheumatic disease and COVID-19 entered into the COVID-19 Global Rheumatology Alliance physician registry March 24 - August 26, 2020 were included. Race/ethnicity was defined as white, Black, Latinx, Asian and other/mixed race. Outcomes included hospitalization, requirement for ventilatory support, and death. Multivariable regression models were used to estimate odds ratios (OR) and 95% confidence intervals controlling for age, sex, smoking, rheumatic disease diagnosis, comorbidities, medications taken prior to infection, and rheumatic disease activity. RESULTS: A total of 1,324 patients were included, of whom 36% were hospitalized and 6% died; 26% of hospitalized patients required mechanical ventilation. In multivariable models, Black (OR=2.74, 95% CI 1.90, 3.95), Latinx (OR=1.71, 95% CI 1.18, 2.49), and Asian (OR=2.69, 95% CI 1.16, 6.24) patients had higher odds of being hospitalized compared to white patients. Latinx patients also had three-fold increased odds of requiring ventilatory support (OR=3.25, 95% CI 1.75, 6.05). No differences in mortality based on race/ethnicity were found, though power may have been limited to detect associations. CONCLUSION: Similar to findings in the general US population, racial/ethnic minorities with rheumatic disease and COVID-19 had increased odds of hospitalization and ventilatory support. These results illustrate significant health disparities related to COVID-19 in people with rheumatic diseases. The rheumatology community should proactively address the needs of patients currently experiencing inequitable health outcomes during the pandemic

The Role of Stimulus Salience and Attentional Capture Across the Neural Hierarchy in a Stop-Signal Task

Inhibitory motor control is a core function of cognitive control. Evidence from diverse experimental approaches has linked this function to a mostly right-lateralized network of cortical and subcortical areas, wherein a signal from the frontal cortex to the basal ganglia is believed to trigger motor-response cancellation. Recently, however, it has been recognized that in the context of typical motor-control paradigms those processes related to actual response inhibition and those related to the attentional processing of the relevant stimuli are highly interrelated and thus difficult to distinguish. Here, we used fMRI and a modified Stop-signal task to specifically examine the role of perceptual and attentional processes triggered by the different stimuli in such tasks, thus seeking to further distinguish other cognitive processes that may precede or otherwise accompany the implementation of response inhibition. In order to establish which brain areas respond to sensory stimulation differences by rare Stop-stimuli, as well as to the associated attentional capture that these may trigger irrespective of their task-relevance, we compared brain activity evoked by Stop-trials to that evoked by Go-trials in task blocks where Stop-stimuli were to be ignored. In addition, region-of-interest analyses comparing the responses to these task-irrelevant Stop-trials, with those to typical relevant Stop-trials, identified separable activity profiles as a function of the task-relevance of the Stop-signal. While occipital areas were mostly blind to the task-relevance of Stop-stimuli, activity in temporo-parietal areas dissociated between task-irrelevant and task-relevant ones. Activity profiles in frontal areas, in turn, were activated mainly by task-relevant Stop-trials, presumably reflecting a combination of triggered top-down attentional influences and inhibitory motor-control processes

Association between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death among Patients with Immune-Mediated Inflammatory Disease and COVID-19

Importance: Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective: To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants: This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures: Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures: The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results: A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P =.006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P =.001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P <.001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P =.004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P =.33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. Conclusions and Relevance: In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs

Discrimination Training with Multimodal Stimuli Changes Activity in the Mushroom Body of the Hawkmoth Manduca sexta

The mushroom bodies of the insect brain play an important role in olfactory processing, associative learning and memory. The mushroom bodies show odor-specific spatial patterns of activity and are also influenced by visual stimuli.Functional imaging was used to investigate changes in the in vivo responses of the mushroom body of the hawkmoth Manduca sexta during multimodal discrimination training. A visual and an odour stimulus were presented either together or individually. Initially, mushroom body activation patterns were identical to the odour stimulus and the multimodal stimulus. After training, however, the mushroom body response to the rewarded multimodal stimulus was significantly lower than the response to the unrewarded unimodal odour stimulus, indicating that the coding of the stimuli had changed as a result of training. The opposite pattern was seen when only the unimodal odour stimulus was rewarded. In this case, the mushroom body was more strongly activated by the multimodal stimuli after training. When no stimuli were rewarded, the mushroom body activity decreased for both the multimodal and unimodal odour stimuli. There was no measurable response to the unimodal visual stimulus in any of the experiments. These results can be explained using a connectionist model where the mushroom body is assumed to be excited by olfactory stimulus components, and suppressed by multimodal configurations.Discrimination training with multimodal stimuli consisting of visual and odour cues leads to stimulus specific changes in the in vivo responses of the mushroom body of the hawkmoth

Event-Related Potential Correlates of Performance-Monitoring in a Lateralized Time-Estimation Task

Performance-monitoring as a key function of cognitive control covers a wide range of diverse processes to enable goal directed behavior and to avoid maladjustments. Several event-related brain potentials (ERP) are associated with performance-monitoring, but their conceptual background differs. For example, the feedback-related negativity (FRN) is associated with unexpected performance feedback and might serve as a teaching signal for adaptational processes, whereas the error-related negativity (ERN) is associated with error commission and subsequent behavioral adaptation. The N2 is visible in the EEG when the participant successfully inhibits a response following a cue and thereby adapts to a given stop-signal. Here, we present an innovative paradigm to concurrently study these different performance-monitoring-related ERPs. In 24 participants a tactile time-estimation task interspersed with infrequent stop-signal trials reliably elicited all three ERPs. Sensory input and motor output were completely lateralized, in order to estimate any hemispheric processing preferences for the different aspects of performance monitoring associated with these ERPs. In accordance with the literature our data suggest augmented inhibitory capabilities in the right hemisphere given that stop-trial performance was significantly better with left- as compared to right-hand stop-signals. In line with this, the N2 scalp distribution was generally shifted to the right in addition to an ipsilateral shift in relation to the response hand. Other than that, task lateralization affected neither behavior related to error and feedback processing nor ERN or FRN. Comparing the ERP topographies using the Global Map Dissimilarity index, a large topographic overlap was found between all considered components.With an evenly distributed set of trials and a split-half reliability for all ERP components ≥.85 the task is well suited to efficiently study N2, ERN, and FRN concurrently which might prove useful for group comparisons, especially in clinical populations

Spatial Learning and Action Planning in a Prefrontal Cortical Network Model

The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive “insight” capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates

Anti-relapse neurons in the infralimbic cortex of rats drive relapse-suppression by drug omission cues

Drug addiction is a chronic relapsing disorder of compulsive drug use. Studies of the neurobehavioral factors that promote drug relapse have yet to produce an effective treatment. Here we take a different approach and examine the factors that suppress – rather than promote – relapse. Adapting Pavlovian procedures to suppress operant drug response, we determined the anti-relapse action of environmental cues that signal drug omission (unavailability) in rats. Under laboratory conditions linked to compulsive drug use and heightened relapse risk, drug omission cues suppressed three major modes of relapse-promotion (drug-predictive cues, stress, and drug exposure) for cocaine and alcohol. This relapse-suppression is partially driven by omission cue-reactive neurons, which constitute small subsets of glutamatergic and GABAergic cells, in the infralimbic cortex. Future studies of such neural activity-based cellular units (neuronal ensembles/memory engram cells) for relapse-suppression can be used to identify alternate targets for addiction medicine through functional characterization of anti-relapse mechanisms

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry.

OBJECTIVE: To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). METHODS: We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. RESULTS: Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. CONCLUSIONS: People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people

Cognitive and Socio-Emotional Deficits in Platelet-Derived Growth Factor Receptor-β Gene Knockout Mice

Platelet-derived growth factor (PDGF) is a potent mitogen. Extensive in vivo studies of PDGF and its receptor (PDGFR) genes have reported that PDGF plays an important role in embryogenesis and development of the central nervous system (CNS). Furthermore, PDGF and the β subunit of the PDGF receptor (PDGFR-β) have been reported to be associated with schizophrenia and autism. However, no study has reported on the effects of PDGF deletion on mice behavior. Here we generated novel mutant mice (PDGFR-β KO) in which PDGFR-β was conditionally deleted in CNS neurons using the Cre/loxP system. Mice without the Cre transgene but with floxed PDGFR-β were used as controls. Both groups of mice reached adulthood without any apparent anatomical defects. These mice were further examined by conducting several behavioral tests for spatial memory, social interaction, conditioning, prepulse inhibition, and forced swimming. The test results indicated that the PDGFR-β KO mice show deficits in all of these areas. Furthermore, an immunohistochemical study of the PDGFR-β KO mice brain indicated that the number of parvalbumin (calcium-binding protein)-positive (i.e., putatively γ-aminobutyric acid-ergic) neurons was low in the amygdala, hippocampus, and medial prefrontal cortex. Neurophysiological studies indicated that sensory-evoked gamma oscillation was low in the PDGFR-β KO mice, consistent with the observed reduction in the number of parvalbumin-positive neurons. These results suggest that PDGFR-β plays an important role in cognitive and socioemotional functions, and that deficits in this receptor may partly underlie the cognitive and socioemotional deficits observed in schizophrenic and autistic patients

Altering the Motivational Function of Nicotine through Conditioning Processes

The collection of chapters in this 55th Nebraska Symposium on Motivation Volume clearly highlights that effective strategies for reducing compulsive tobacco use will require a multifaceted approach in which genetic, neurobiological, individual, and cultural factors are considered. It is difficult, if not impossible, to predict where the next important breakthrough will come from (Bevins & Bardo, 2004; Dethier, 1966; Laidler, 1998). Accordingly, further research that extends and challenges current theory and practice at each of these levels of analysis is needed. The continuing focus of our research program, and the topic of the present chapter, is on the role of Pavlovian conditioning processes involving nicotine. Theoretical and empirical approaches to nicotine dependence that include Pavlovian conditioning processes have lead to important advances in our understanding and treatment of chronic tobacco use (e.g., see Rose, Chapter 8 and Tiffany, Warthen, & Goedecker, Chapter 10 in current Volume). These approaches conceptualize the drug as an unconditioned stimulus (US) or reinforcer. That is, the pharmacological effects of the drug (e.g., reward, analgesia, psychomotor stimulation) enter into an association with stimuli that reliably co-occur with these effects (e.g., paraphernalia, situational cues). Later exposure to these conditioned stimuli (CSs) can evoke conditioned responses (CRs) that increase the chances an individual will seek drug. More recently, we have suggested that the interoceptive stimulus effects of nicotine might also serve as a CS for other appetitive non-drug outcomes (i.e., USs) and/or a stimulus that occasions whether other CS-US associations will or will not occur (i.e., an occasion setter or facilitator; see Bevins & Palmatier, 2004). We have further suggested that such an associative learning history could impact the tenacity of nicotine addiction—e.g., shorten the time between experimentation and dependence, increase the difficulty of quitting, make sustaining abstinence more difficult, etc. At the current time these suggestions are speculative. With this in mind, the present chapter will review the research in this area, as well as highlight some of its historical precursors and suggest some possible future directions for research. In doing so, hopefully the reader will gain an appreciation for how this approach might lead to further insight into how Pavlovian conditioning processes can alter the motivational function of nicotine in a manner that contributes to chronic tobacco use