Augmenting glutamatergic, but not dopaminergic, activity in the nucleus accumbens shell disrupts responding to a discrete alcohol cue in an alcohol context.

Discrete alcohol cues and contexts are relapse triggers for people with alcohol use disorder exerting particularly powerful control over behaviour when they co-occur. Here, we investigated the neural substrates subserving the capacity for alcohol-associated contexts to elevate responding to an alcohol-predictive conditioned stimulus (CS). Specifically, rats were trained in a distinct 'alcohol context' to respond by entering a fluid port during a discrete auditory CS that predicted the delivery of alcohol and were familiarized with a 'neutral context' wherein alcohol was never available. When conditioned CS responding was tested by presenting the CS without alcohol, we found that augmenting glutamatergic activity in the nucleus accumbens (NAc) shell by microinfusing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) reduced responding to an alcohol CS in an alcohol, but not neutral, context. Further, AMPA microinfusion robustly affected behaviour, attenuating the number, duration and latency of CS responses selectively in the alcohol context. Although dopaminergic inputs to the NAc shell were previously shown to be necessary for CS responding in an alcohol context, here, chemogenetic excitation of ventral tegmental area (VTA) dopamine neurons and their inputs to the NAc shell did not affect CS responding. Critically, chemogenetic excitation of VTA dopamine neurons affected feeding behaviour and elevated c-fos immunoreactivity in the VTA and NAc shell, validating the chemogenetic approach. These findings enrich our understanding of the substrates underlying Pavlovian responding for alcohol and reveal that the capacity for contexts to modulate responding to discrete alcohol cues is delicately underpinned by the NAc shell.

Evaluation of a Pharmacist-Led COVID-19 Vaccination Program in a Hospital Setting.

PURPOSE: A pharmacist-led COVID-19 vaccination screening and administration tool was implemented at a tertiary care hospital in the Upper Midwest, allowing pharmacists to determine if an inpatient is a candidate for the COVID-19 vaccination. The purpose of this observational study was to examine the feasibility of a pharmacist-led, COVID-19 vaccination administration workflow to the inpatient population in a tertiary care hospital. METHODS: This observational study was conducted at an Upper-Midwest facility and includes a study population of adult patients admitted to the hospital between 10/1/2021 - 1/1/2022. The primary outcome of this study was the number of COVID-19 vaccinations administered. Secondary outcomes included the number of attending physician approvals, pharmacist time dedicated to the vaccination program, patient demographics, and patient acceptance of vaccination. Group differences were evaluated using odds ratios, 95% confidence intervals, Pearson's chi-square test, the Mann-Whitney U test, and multivariate logistic regression. RESULTS: There were 715 patients eligible to receive COVID-19 vaccination. Of those, 23 (3.2%) patients received a COVID-19 vaccine while inpatient. After adjusting for sex at birth, age at admission, and length of hospital stay, compared to previously unvaccinated patients, those with their second dose due were 7.3 times more likely to have been given a vaccination (95% CI 1.3-42.1, P = 0.026), while patients with their booster due were 4 times more likely to have been given a vaccination (95% CI 1.3-12.3, P = 0.014). CONCLUSIONS: Although unvaccinated patients were successfully identified, only 23 were able to be vaccinated. Additional barriers need to be addressed to make this program successful.

Context-induced renewal of passive but not active coping behaviours in the shock-probe defensive burying task.

Renewal is the return of extinguished responding after removal from the extinction context. Renewal has been extensively studied using classical aversive conditioning procedures that measure a passive freezing response to an aversive conditioned stimulus. However, coping responses to aversive stimuli are complex and can be reflected in passive and active behaviours. Using the shock-probe defensive burying task, we investigated whether different coping responses are susceptible to renewal. During conditioning, male, Long-Evans rats were placed into a specific context (Context A) where an electrified shock-probe delivered a 3 mA shock upon contact. During extinction, the shock-probe was unarmed in either the same (Context A) or a different context (Context B). Renewal of conditioned responses was assessed in the conditioning context (ABA) or in a novel context (ABC or AAB). Renewal of passive coping responses, indicated by an increased latency and a decreased duration of shock-probe contacts, was observed in all groups. However, renewal of passive coping, measured by increased time spent on the side of the chamber opposite the shock-probe, was only found in the ABA group. Renewal of active coping responses linked to defensive burying was not observed in any group. The present findings highlight the presence of multiple psychological processes underlying even basic forms of aversive conditioning and demonstrate the importance of assessing a broader set of behaviours to tease apart these different underlying mechanisms. The current findings suggest that passive coping responses may be more reliable indicators for assessing renewal than active coping behaviours associated with defensive burying.

Optogenetic stimulation of infralimbic cortex projections to the paraventricular thalamus attenuates context-induced renewal.

Contexts associated with prior reinforcement can renew extinguished conditioned responding. The prelimbic (PL) and infralimbic (IL) cortices are thought to mediate the expression and suppression of conditioned responding, respectively. Evidence suggests that PL inputs to the paraventricular nucleus of the thalamus (PVT) drive the expression of cue-induced reinstatement of drug seeking and that IL inputs to the PVT mediate fear extinction retrieval. However, the role of these projections in renewal of appetitive Pavlovian conditioned responding is unknown. We trained male and female Long-Evans rats to associate a conditioned stimulus (CS; 10 s white noise) with delivery of a 10% sucrose unconditioned stimulus (US; .2 ml/CS) to a fluid port in a distinct context (Context A). We then extinguished responding by presenting the CS without the US in a different context (Context B). At test, rats were returned to Context A, and optogenetic stimulation was delivered to either the IL-to-PVT or PL-to-PVT pathway during CS presentations. Optically stimulating the IL-to-PVT, but not the PL-to-PVT pathway, attenuated ABA renewal of CS port entries, and this effect was similar in males and females. Further, rats self-administered optical stimulation of the IL-to-PVT but not the PL-to-PVT pathway suggesting that activation of the IL-to-PVT pathway is reinforcing. The effectiveness of optical stimulation parameters to activate neurons in the IL, PL and PVT was confirmed using Fos immunohistochemistry. These findings provide evidence for novel neural mechanisms in renewal of responding to a sucrose-predictive CS, as well as more generally in contextual processing and appetitive associative learning.

Learning processes in relapse to alcohol use: lessons from animal models.

RATIONALE: Alcohol use is reliably preceded by discrete and contextual stimuli which, through diverse learning processes, acquire the capacity to promote alcohol use and relapse to alcohol use. OBJECTIVE: We review contemporary extinction, renewal, reinstatement, occasion setting, and sex differences research within a conditioning framework of relapse to alcohol use to inform the development of behavioural and pharmacological therapies. KEY FINDINGS: Diverse learning processes and corresponding neurobiological substrates contribute to relapse to alcohol use. Results from animal models indicate that cortical, thalamic, accumbal, hypothalamic, mesolimbic, glutamatergic, opioidergic, and dopaminergic circuitries contribute to alcohol relapse through separable learning processes. Behavioural therapies could be improved by increasing the endurance and generalizability of extinction learning and should incorporate whether discrete cues and contexts influence behaviour through direct excitatory conditioning or occasion setting mechanisms. The types of learning processes that most effectively influence responding for alcohol differ in female and male rats. CONCLUSION: Sophisticated conditioning experiments suggest that diverse learning processes are mediated by distinct neural circuits and contribute to relapse to alcohol use. These experiments also suggest that gender-specific behavioural and pharmacological interventions are a way towards efficacious therapies to prevent relapse to alcohol use.

Neural correlates of recall and extinction in a rat model of appetitive Pavlovian conditioning.

Extinction is a fundamental form of inhibitory learning that is important for adapting to changing environmental contingencies. While numerous studies have investigated the neural correlates of extinction using Pavlovian fear conditioning and appetitive operant reward-seeking procedures, less is known about the neural circuitry mediating the extinction of appetitive Pavlovian responding. Here, we aimed to generate an extensive brain activation map of extinction learning in a rat model of appetitive Pavlovian conditioning. Male Long-Evans rats were trained to associate a conditioned stimulus (CS; 20 s white noise) with the delivery of a 10% sucrose unconditioned stimulus (US; 0.3 ml/CS) to a fluid port. Control groups also received CS presentations, but sucrose was delivered either during the inter-trial interval or in the home-cage. After conditioning, 1 or 6 extinction sessions were conducted in which the CS was presented but sucrose was withheld. We performed Fos immunohistochemistry and network connectivity analyses on a set of cortical, striatal, thalamic, and amygdalar brain regions. Neural activity in the prelimbic cortex, ventral orbitofrontal cortex, nucleus accumbens core, and paraventricular nucleus of the thalamus was greater during recall relative to extinction. Conversely, prolonged extinction following 6 sessions induced increased neural activity in the infralimbic cortex, medial orbitofrontal cortex, and nucleus accumbens shell compared to home-cage controls. All these structures were similarly recruited during recall on the first extinction session. These findings provide novel evidence for the contribution of brain areas and neural networks that are differentially involved in the recall versus extinction of appetitive Pavlovian conditioned responding.

Comparing ABA, AAB, and ABC Renewal of Appetitive Pavlovian Conditioned Responding in Alcohol- and Sucrose-Trained Male Rats.

Conditioned responding can be renewed by re-exposure to the conditioning context following extinction in a different context (ABA renewal) or by removal from the extinction context (AAB or ABC renewal). ABA renewal is robust in Pavlovian and operant conditioning paradigms. However, fewer studies have investigated AAB and ABC renewal of appetitive conditioning, and those that did predominantly used operant conditioning tasks. Renewal has theoretical relevance for extinction and for exposure-based treatments for substance use disorders that aim to extinguish reactivity to drug-predictive cues. We therefore investigated ABA, AAB, and ABC renewal of Pavlovian conditioned responding to cues that predicted either alcohol or sucrose. Male, Long-Evans rats (Charles River) were exposed to either 15% ethanol (Study 1: "alcohol") or 10% sucrose (Study 2: "sucrose") in their home cages. Next, they were trained to discriminate between two auditory stimuli (white noise and clicker; 10 s) in conditioning chambers equipped with distinct olfactory, visual, and tactile contextual stimuli (context A). One conditioned stimulus (CS+) was paired with fluid delivery (0.2 ml/CS+; 3.2 ml/session; alcohol or sucrose in separate experiments), and the second CS (CS-) was not. In all sessions (conditioning, extinction, and test), each CS was presented 16 times/session on a variable-time 67-s schedule, and entries into the fluid port were recorded. CS+ port entries were then extinguished by withholding fluid delivery either in context A or in a second, different context (context B). Next, we assessed ABA, AAB, and ABC renewal in the absence of fluid delivery. During extinction, CS+ port entries were initially elevated in context A relative to context B. ABA renewal of CS+ port entries occurred in both alcohol- and sucrose-trained rats. ABC renewal approached statistical significance when data from both experiments were combined. No AAB renewal was observed, and, in fact, alcohol-trained rats showed AAB suppression. These results corroborate the reliability of ABA renewal and suggest that ABC renewal is a modest effect that may require greater statistical power to detect. From a treatment perspective, the lack of AAB renewal suggests that exposure-based treatments for substance use disorders might benefit from implementation in real-world, drug-use contexts.

6'-Methoxy Raloxifene-analog enhances mouse bone properties with reduced estrogen receptor binding.

Raloxifene (RAL) is an FDA-approved drug used to treat osteoporosis in postmenopausal women. RAL suppresses bone loss primarily through its role as a selective estrogen receptor modulator (SERM). This hormonal estrogen therapy promotes unintended side effects, such as hot flashes and increased thrombosis risk, and prevents the drug from being used in some patient populations at-risk for fracture, including children with bone disorders. It has recently been demonstrated that RAL can have significant positive effects on overall bone mechanical properties by binding to collagen and increasing bone tissue hydration in a cell-independent manner. A Raloxifene-Analog (RAL-A) was synthesized by replacing the 6-hydroxyl substituent with 6-methoxy in effort to reduce the compound's binding affinity for estrogen receptors (ER) while maintaining its collagen-binding ability. It was hypothesized that RAL-A would improve the mechanical integrity of bone in a manner similar to RAL, but with reduced estrogen receptor binding. Molecular assessment showed that while RAL-A did reduce ER binding, downstream ER signaling was not completely abolished. In-vitro, RAL-A performed similarly to RAL and had an identical concentration threshold on osteocyte cell proliferation, differentiation, and function. To assess treatment effect in-vivo, wildtype (WT) and heterozygous (OIM+/-) female mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL or RAL-A from 8 weeks to 16 weeks of age. There was an untreated control group for each genotype as well. Bone microarchitecture was assessed using microCT, and mechanical behavior was assessed using 3-point bending. Results indicate that both compounds produced analogous gains in tibial trabecular and cortical microarchitecture. While WT mechanical properties were not drastically altered with either treatment, OIM+/- mechanical properties were significantly enhanced, most notably, in post-yield properties including bone toughness. This proof-of-concept study shows promising results and warrants the exploration of additional analog iterations to further reduce ER binding and improve fracture resistance.

Open source electronic health records and chronic disease management.

OBJECTIVE: To study and report on the use of open source electronic health records (EHR) to assist with chronic care management within safety net medical settings, such as community health centers (CHC). METHODS AND MATERIALS: The study was conducted by NORC at the University of Chicago from April to September 2010. The NORC team undertook a comprehensive environmental scan, including a literature review, a dozen key informant interviews using a semistructured protocol, and a series of site visits to CHC that currently use an open source EHR. RESULTS: Two of the sites chosen by NORC were actively using an open source EHR to assist in the redesign of their care delivery system to support more effective chronic disease management. This included incorporating the chronic care model into an CHC and using the EHR to help facilitate its elements, such as care teams for patients, in addition to maintaining health records on indigent populations, such as tuberculosis status on homeless patients. DISCUSSION: The ability to modify the open-source EHR to adapt to the CHC environment and leverage the ecosystem of providers and users to assist in this process provided significant advantages in chronic care management. Improvements in diabetes management, controlled hypertension and increases in tuberculosis vaccinations were assisted through the use of these open source systems. CONCLUSIONS: The flexibility and adaptability of open source EHR demonstrated its utility and viability in the provision of necessary and needed chronic disease care among populations served by CHC.

The use of open source electronic health records within the federal safety net.

OBJECTIVE: To conduct a federally funded study that examines the acquisition, implementation and operation of open source electronic health records (EHR) within safety net medical settings, such as federally qualified health centers (FQHC). METHODS AND MATERIALS: The study was conducted by the National Opinion Research Center (NORC) at the University of Chicago from April to September 2010. The NORC team undertook a comprehensive environmental scan, including a literature review, a dozen key informant interviews using a semistructured protocol, and a series of site visits to West Virginia, California and Arizona FQHC that were currently using an open source EHR. RESULTS: Five of the six sites that were chosen as part of the study found a number of advantages in the use of their open source EHR system, such as utilizing a large community of users and developers to modify their EHR to fit the needs of their provider and patient communities, and lower acquisition and implementation costs as compared to a commercial system. DISCUSSION: Despite these advantages, many of the informants and site visit participants felt that widespread dissemination and use of open source was restrained due to a negative connotation regarding this type of software. In addition, a number of participants stated that there is a necessary level of technical acumen needed within the FQHC to make an open source EHR effective. CONCLUSIONS: An open source EHR provides advantages for FQHC that have limited resources to acquire and implement an EHR, but additional study is needed to evaluate its overall effectiveness.

Governance typology: a consensus classification of state-local health department relationships.

CONTEXT: Public health practitioners and researchers often refer to state public health systems as being centralized, decentralized, shared, or mixed. These categories refer to governance of the local public health units within the state and whether they operate under the authority of the state government, local government, shared state and local governance, or a mix of governance structures within the state. OBJECTIVE: This article describes the development of an objective method of classifying states as centralized, decentralized, shared, or mixed. We also discuss some initial analyses that have been conducted to identify how public health resources and activities vary across states with different classifications. DESIGN: Cross-sectional study. SETTING: State health agencies. PARTICIPANTS: Survey respondents were organizational leaders from all 50 state health agencies. MAIN OUTCOME MEASURE(S): Total full-time equivalent employees, total health agency expenditures, expenditures on clinical services, and provision of clinical services. RESULTS: Centralized state health agencies employ more full-time equivalent employees, have higher total expenditures, and provide more clinical services than decentralized state health agencies. Although higher expenditures on clinical services were observed, these differences were not statistically significant. CONCLUSIONS: It is important to take governance classification into account when investigating variation in services, resources, or performance of governmental public health systems. As public health systems and services researchers seek to identify best practices in the organization of public health systems, consistent definition of different types of organization is critical. This system provides an objective and reliable system for classifying governance relationships that allows for comparisons that are meaningful to both practitioners and researchers.

Dyspnoea and pulmonary consolidation in a cat with T-cell lymphoma.

A 13-year-old male neutered domestic shorthair cat presented with an acute onset of dyspnoea. Thoracic radiographs revealed marked, bilateral, caudal lung lobe consolidation. A diagnosis of anatomically mixed T-cell lymphoma with pulmonary, renal and alimentary involvement was confirmed on histopathology. Pulmonary involvement in cases of feline lymphoma is uncommon and the radiographic appearance of pulmonary lymphoma is highly variable. Lung lobe consolidation has been described with primary lung tumours in cats, but not previously in association with pulmonary lymphoma. This unusual presentation serves to alert practitioners to the possibility of lymphoma as a cause of severe bronchopulmonary disease in the cat.