D1 and D2 medium spiny neurons in the nucleus accumbens core have distinct and valence-independent roles in learning.

At the core of value-based learning is the nucleus accumbens (NAc). D1- and D2-receptor-containing medium spiny neurons (MSNs) in the NAc core are hypothesized to have opposing valence-based roles in behavior. Using optical imaging and manipulation approaches in mice, we show that neither D1 nor D2 MSNs signal valence. D1 MSN responses were evoked by stimuli regardless of valence or contingency. D2 MSNs were evoked by both cues and outcomes, were dynamically changed with learning, and tracked valence-free prediction error at the population and individual neuron level. Finally, D2 MSN responses to cues were necessary for associative learning. Thus, D1 and D2 MSNs work in tandem, rather than in opposition, by signaling specific properties of stimuli to control learning.

Early diagnosis of monomicrobial Clostridioides difficile bacteremia in a patient without colitis.

Bacteremia is a rare finding among Clostridioides difficile infections. We describe a case of a 67-year-old man with resected colorectal cancer with colostomy who presented with small bowel obstruction and was admitted for lysis of adhesions. On day 8 of admission, he developed leukocytosis and raised inflammatory markers with isolation of Gram-positive bacilli in several blood cultures, which was presumptively identified through blood culture pelleting and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) as C. difficile. The diagnosis was confirmed with conventional culture and reference lab identification and the patient demonstrated clinical response with parenteral then oral vancomycin that briefly worsened when therapy was switched to parenteral metronidazole and then improved once oral vancomycin was resumed. Our case was notable in that the combination of pelleting and MALDI-TOF offered early diagnosis in this patient whose positive blood cultures were suspicious for contamination and in whom there was an absence of diarrheal illness or features of colitis on abdominal imaging. Early diagnosis is critical for the timely initiation of therapy, implementation of infection prevention and control measures and in selection of appropriate therapy for antimicrobial stewardship.

La bactériémie est rare lors d'une infection à Clostridioides difficile. Les auteurs décrivent le cas d'un homme de 67 ans ayant une colostomie découlant de la résection d'un cancer colorectal, qui a consulté à cause d'une occlusion du grêle et a été hospitalisé pour traiter des adhésiolyses. Le huitième jour de l'hospitalisation, il a présenté une leucocytose et une augmentation des marqueurs inflammatoires, des bacilles à Gram positif ont été isolés dans plusieurs hémocultures, et un diagnostic provisoire de C. difficile a été posé par culot de sang et désorption/ionisation laser assistée par matrice par temps de vol (MALDI-TOF). Le diagnostic a été confirmé par une culture classique et par le laboratoire de référence, et le patient a affiché une réponse clinique à la vancomycine par voie parentérale, puis par voie orale. Son état s'est brièvement aggravé lors du passage au métronidazole par voie parentérale, puis s'est amélioré à la reprise de la vancomycine par voie orale. Le cas était remarquable parce que la combinaison du culot et de la MALDI-TOF a permis d'obtenir un diagnostic rapide chez ce patient dont les hémocultures positives ont suggéré une contamination dont l'imagerie abdominale ne révélait pas de maladie diarrhéique ni de caractéristiques de colite. Il est essentiel de poser un diagnostic précoce pour entreprendre le traitement rapidement, adopter des mesures de prévention et de contrôle des infections et sélectionner le traitement approprié à la gouvernance antimicrobienne.

A 20-year Study of Intracranial Pyogenic Complications of Sinusitis in Children.

BACKGROUND: Intracranial pyogenic complications of sinusitis in children can lead to serious sequelae. We characterize the clinical, epidemiologic and microbiologic characteristics of children with such complications over a 20-year period. METHODS: Single-center retrospective chart review. Cases were identified based on International Classification of Diseases diagnostic codes (ICD)-9 and ICD-10 depending on the year and by reviewing all intracranial microbiological samples. RESULTS: A total of 104 cases of complicated sinusitis were included after review of 1591 charts. Median age was 12 (IQR 9-14); 72 were male (69%). The most frequent complications were epidural empyema (n = 50, 48%), subdural empyema (n = 46, 44%) and Pott's puffy tumor (n = 27, 26%). 52% (n = 54) underwent neurosurgery and 46% (n = 48) underwent otolaryngological surgery. The predominant pathogen isolated from sterile site specimens was Streptococcus anginosus (n = 40, 63%), but polymicrobial growth was common (n = 24; 38%). The median duration of intravenous antibiotic therapy was 51 days (IQR 42-80). Persistent neurological sequelae (or death, n = 1) were found in 24% (n = 25) and were associated with the presence of cerebritis and extensive disease on neuroimaging ( P = 0.02 and P = 0.04, respectively). CONCLUSIONS: Intracranial complications of sinusitis continue to cause significant morbidity in children. Polymicrobial infections are common, which reinforces the need for broad-spectrum empiric antibiotic therapy and cautious adjustment of the antibiotic regimen based primarily on sterile site cultures. The association of neurologic sequelae with the presence of cerebritis and extensive intracranial involvement on neuroimaging suggest that delayed diagnosis may be a contributor to adverse outcome.

Dopamine release at the time of a predicted aversive outcome causally controls the trajectory and expression of conditioned behavior.

Dopamine release in the nucleus accumbens (NAc) is causally linked to adaptive aversive learning, and its dysregulation is a core phenotype in anxiety and stress disorders. Here, we record NAc core dopamine during a task where mice learn to discriminate between cues signaling two types of outcomes: (1) footshock presentation and (2) footshock omission. We show that dopamine release is evoked by footshock omission. This dopamine response is largest when the omission is unexpected and decreases over learning, and artificially increasing this signal disrupts discrimination learning. Conversely, optogenetic inhibition of dopamine responses to the footshock itself impairs learning. Finally, theory-driven computational modeling suggests that these effects can be explained by dopamine signaling the perceived saliency of predicted aversive events. Together, we elucidate the role of NAc dopamine in aversive learning and offer potential avenues for understanding the neural mechanisms involved in anxiety and stress disorders.

Arthroscopic tissue biopsy as a preoperative diagnostic test for periprosthetic shoulder arthroplasty infections: a systematic review and meta-analysis.

BACKGROUND: The diagnosis of periprosthetic infection in shoulder arthroplasty remains a challenge. Conventional methods for evaluating periprosthetic joint infections are poor because of lower-virulence organisms affecting the shoulder. The aim of our systematic review was to evaluate the diagnostic accuracy of preoperative arthroscopic tissue cultures compared with tissue biopsy samples obtained at the time of revision surgery. MATERIALS AND METHODS: We conducted a systematic search of the MEDLINE, Embase, and Cochrane Central databases. The inclusion criteria consisted of studies that used arthroscopy to obtain preoperative tissue cultures for the diagnosis of shoulder arthroplasty infections. Studies were excluded if they obtained non-arthroscopic tissue samples. We reported the sensitivity, specificity, positive predictive value, and negative predictive value. Culture findings from the arthroscopic biopsy samples were also compared with conventional tests of fluoroscopy-guided joint aspiration and serum inflammatory marker testing (positive erythrocyte sedimentation rate or C-reactive protein) within the included studies. A meta-analysis was performed to assess the overall diagnostic accuracy of the studies. RESULTS: Our search strategy yielded 795 potentially relevant publications; 572 underwent title and abstract screening, and 14 studies underwent full-text review, of which 7 were included in our systematic review. The studies represented a balance of shoulder arthroplasty types, including anatomic total shoulder arthroplasty (n = 75, 38%), reverse total shoulder arthroplasty (n = 60, 30%), and hemiarthroplasty (n = 64, 32%). There were 56 of 120 arthroscopic procedures that returned positive tissue culture findings compared with 64 of 157 positive open biopsy culture findings obtained from revision surgery. The meta-analysis total for sensitivity and specificity for all studies combined indicated that arthroscopic tissue cultures (0.76 [95% confidence interval (CI), 0.57-0.88] and 0.91 [95% CI, 0.79-0.97], respectively) were superior to both aspiration (0.15 [95% CI, 0.03-0.48] and 0.93 [95% CI, 0.65-0.99], respectively) and a positive erythrocyte sedimentation rate or C-reactive protein level (0.14 [95% CI, 0.02-0.62] and 0.83 [95% CI, 0.56-0.95], respectively) in diagnosing periprosthetic shoulder infections. CONCLUSIONS: Our systematic review demonstrated that preoperative arthroscopic tissue biopsy used for microbiology cultures accurately predicts intraoperative culture findings obtained during revision surgery with high sensitivity and specificity. Additionally, arthroscopy appears to be superior to conventional techniques of joint aspiration and inflammatory marker testing. Therefore, arthroscopic tissue cultures may be an emerging useful tool to help guide the management of periprosthetic infections in shoulder arthroplasty.

Task parameters influence operant response variability in mice.

RATIONALE: During operant conditioning, animals associate actions with outcomes. However, patterns and rates of operant responding change over learning, which makes it difficult to distinguish changes in learning from general changes in performance or movement. Thus, understanding how task parameters influence movement execution is essential. OBJECTIVES: To understand how specific operant task parameters influenced the repetition of future operant responses, we investigated the ability of operant conditioning schedules and contingencies to promote reproducible bouts of five lever presses in mice. METHODS: Mice were trained on one of the four operant tasks to test three distinct hypotheses: (1) whether a cue presented concurrently with sucrose delivery influenced the pattern of lever pressing; (2) whether requiring animals to collect earned sucrose promoted the organization of responses into bouts; and (3) whether only reinforcing bouts where interresponse time (IRT) variances were below a target promoted reproducible patterns of operant behavior. RESULTS: (1) Signaling reinforcer delivery with a cue increased learning rates but resulted in mice pressing the lever in fast succession until the cue turned on, rather than executing discrete bouts. (2) Requiring mice to collect the reinforcer between bouts had little effect on behavior. (3) A training strategy that directly reinforced bouts with low variance IRTs was not more effective than a traditional fixed ratio schedule at promoting reproducible action execution. CONCLUSIONS: Together, our findings provide insights into the parameters of behavioral training that promote reproducible actions and that should be carefully selected when designing operant conditioning experiments.

Dopamine signaling in the nucleus accumbens core mediates latent inhibition.

Studies investigating the neural mechanisms by which associations between cues and predicted outcomes control behavior often use associative learning frameworks to understand the neural control of behavior. These frameworks do not always account for the full range of effects that novelty can have on behavior and future associative learning. Here, in mice, we show that dopamine in the nucleus accumbens core is evoked by novel, neutral stimuli, and the trajectory of this response over time tracked habituation to these stimuli. Habituation to novel cues before associative learning reduced future associative learning, a phenomenon known as latent inhibition. Crucially, trial-by-trial dopamine response patterns tracked this phenomenon. Optogenetic manipulation of dopamine responses to the cue during the habituation period bidirectionally influenced future associative learning. Thus, dopamine signaling in the nucleus accumbens core has a causal role in novelty-based learning in a way that cannot be predicted based on purely associative factors.

A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies.

A large body of work has focused on understanding stimulus-driven behavior, sex differences in these processes, and the neural circuits underlying them. Many preclinical mouse models present rewarding or aversive stimuli in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes. In addition, the context (or reinforcement schedule under) in which stimuli are encountered can engender different behavioral responses to the same stimulus. Thus, delineating neural control of behavior requires a dissociation between stimulus valence and stimulus-driven behavior. We developed the Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence in mice. First, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. Next, discriminative stimuli are presented concurrently allowing for parsing innate behavioral strategies based on reward seeking and avoidance. Lastly, responding in the face of punishment is assessed, thus examining  how positive and negative outcomes are relatively valued. First, we identified sex-specific behavioral strategies, showing that females prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. Next, we show that chemogenetically inhibiting D1 medium spiny neurons (MSNs) in the nucleus accumbens-a population that has been linked to reward-driven behavior-reduces positive and increases negative reinforcement learning rates. Thus, D1 MSNs modulate stimulus processing, rather than motivated responses or the reinforcement process itself. Together, the MCOAT has broad utility for understanding complex behaviors as well as the definition of the discrete information encoded within cellular populations.

Granulocyte-Colony Stimulating Factor Alters the Pharmacodynamic Properties of Cocaine in Female Mice.

Addiction to psychostimulants is a major public health crisis that leads to significant morbidity and mortality, for which there are currently no FDA-approved pharmacotherapies. Female subjects have increased propensity to develop pathological substance use disorders after initial use, suggesting the possibility of different pathophysiological mechanisms between males and females. Recently, we identified the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) as a key mediator of neuronal and behavioral plasticity in response to cocaine in male mice. Here, we found that G-CSF potentiated the rewarding effects of cocaine in female mice as well; however, the dopaminergic mechanism linked to these effects was highly dependent on the ovarian hormone cycle. G-CSF treatment enhanced the ability of cocaine to inhibit dopamine clearance; however, this effect was observed specifically during pro/estrus, when circulating ovarian hormone levels were high. These findings demonstrate important sex differences in the synaptic effects of this translationally relevant neuroimmune modulator.

Zebrafish cancer and metastasis models for in vivo drug discovery.

There is a great need for more efficient methods to discover new cancer therapeutics, as traditional drug development processes are slow and expensive. The use of zebrafish as a whole-organism screen is a time and cost-effective means of improving the efficiency and efficacy of drug development. This review features zebrafish genetic and cell transplantation models of cancer and metastasis, and current imaging and automation technologies that, together, will significantly advance the field of anti-cancer drug discovery.