Deletion of endocannabinoid synthesizing enzyme DAGLα from cerebellar Purkinje cells decreases social preference and elevates anxiety.

The endocannabinoid (eCB) signaling system is robustly expressed in the cerebellum starting from the embryonic developmental stages to adulthood. There it plays a key role in regulating cerebellar synaptic plasticity and excitability, suggesting that impaired eCB signaling will lead to deficits in cerebellar adjustments of ongoing behaviors and cerebellar learning. Indeed, human mutations in DAGLα are associated with neurodevelopmental disorders. In this study, we show that selective deletion of the eCB synthesizing enzyme diacylglycerol lipase alpha (Daglα) from mouse cerebellar Purkinje cells (PCs) alters motor and social behaviors, disrupts short-term synaptic plasticity in both excitatory and inhibitory synapses, and reduces Purkinje cell activity during social exploration. Our results provide the first evidence for cerebellar-specific eCB regulation of social behaviors and implicate eCB regulation of synaptic plasticity and PC activity as the neural substrates contributing to these deficits.

How do soundboard-trained dogs respond to human button presses? An investigation into word comprehension.

Past research on interspecies communication has shown that animals can be trained to use Augmentative Interspecies Communication (AIC) devices, such as soundboards, to make simple requests of their caretakers. The recent uptake in AIC devices by hundreds of pet owners around the world offers a novel opportunity to investigate whether AIC is possible with owner-trained family dogs. To answer this question, we carried out two studies to test pet dogs' ability to recognise and respond appropriately to food-related, play-related, and outside-related words on their soundboards. One study was conducted by researchers, and the other by citizen scientists who followed the same procedure. Further, we investigated whether these behaviours depended on the identity of the person presenting the word (unfamiliar person or dog's owner) and the mode of its presentation (spoken or produced by a pressed button). We find that dogs produced contextually appropriate behaviours for both play-related and outside-related words regardless of the identity of the person producing them and the mode in which they were produced. Therefore, pet dogs can be successfully taught by their owners to associate words recorded onto soundboard buttons to their outcomes in the real world, and they respond appropriately to these words even when they are presented in the absence of any other cues, such as the owner's body language.

Musculoskeletal and Neuropathic Pain in COVID-19.

Chronic pain constitutes a significant disease burden globally and accounts for a substantial portion of healthcare spending. The COVID-19 pandemic contributed to an increase in this burden as patients presented with musculoskeletal or neuropathic pain after contracting COVID-19 or had their chronic pain symptoms exacerbated by the virus. This extensive literature review analyzes the epidemiology of pain pre-pandemic, the costs associated with the COVID-19 pandemic, the impact of the virus on the body, mechanisms of pain, management of chronic pain post-pandemic, and potential treatment options available for people living with chronic pain who have had or are currently infected with COVID-19.

Factors Influencing Parental Willingness to Consent to a Survey Study for Patients in the Pediatric Emergency Department.

OBJECTIVE: To identify factors that impact parental willingness to consent to research studies conducted for their children during visits to pediatric emergency departments (EDs). METHODS: Parents and guardians of children receiving care in our pediatric ED were approached and asked if they would be willing to let their child participate in a research study requiring the child to complete an electronic questionnaire. No such questionnaire existed, however, because the primary purpose was to ascertain the parent's willingness to let their child participate. All parents were debriefed and informed of the true purpose of the study and asked to complete a survey themselves to help understand factors that influenced their initial decision of whether to consent. Bivariate tests and logistic regression were used to evaluate unadjusted and adjusted associations between parent and patient characteristics and parental consent decision. RESULTS: We approached 431 eligible parents about the hypothetical research study involving their children, and 386 (89.6%) consented for their children to participate. After the debriefing, 392 (91.0%) parents consented to complete the parental survey. We observed statistically significant associations between shorter length of ED stay to approach for consent for the study ( P = 0.048) as well as longer travel time ( P = 0.03) and willingness to consent in bivariate analysis, though this did not hold in regression analysis. Regression analysis revealed parents of children who have previously participated in research had 79 times lower odds of consenting to participate in our study adjusted for parent race, ethnicity, actual and perceived length of stay, travel time to the ED, and altruism. CONCLUSIONS: A high proportion of parents consented to their child participating in research in our ED with previous child participation in research being associated with lower odds of parental consent even when adjusted for other factors. Our findings may inform future research practices and studies investigating parental perceptions and motivations surrounding research studies.

Sequential Targeted Therapy for Advanced, Metastatic, and Recurrent Cervical Cancer: A Cost-Effectiveness Analysis of the Patient Journey.

OBJECTIVES: To evaluate outcomes and cost-effectiveness of targeted therapy sequencing for metastatic and recurrent cervical cancer. METHOD: Models were simulated based on phase II and III trials on bevacizumab (bev) from GOG-240, cemiplimab (cemi) from GOG 3016, pembrolizumab (pembro) from KEYNOTE-826, and tisotumab vedotin (tiso) from GOG 3023. Costs were based on IBM Micromedex RED BOOK™ and company listed costs. RESULTS: For [chemo + bev → chemo], total cost was $125,918.04, with median overall survival (mOS) of 21.8 months, and cost-effectiveness ratio (CER) of $119,835.79. For [chemo + bev → cemi], total cost was $187,562.99 with mOS of 28.5 months and CER of $162,039.16. For [chemo + bev + pembro → chemo], total cost was $319,963.78 with mOS 32.9 months and CER of $249,930.10. For [chemo + bev + pembro → tiso], total cost was $455,204.45, with mOS 36.5 months and CER of $320,072.99. CONCLUSION: The combination of immunotherapies and biologics have significantly increased overall survival, but with associated higher costs, primarily related to drug costs.

No evidence from complementary data sources of a direct glutamatergic projection from the mouse anterior cingulate area to the hippocampal formation.

The connectivity and interplay between the prefrontal cortex and hippocampus underpin various key cognitive processes, with changes in these interactions being implicated in both neurodevelopmental and neurodegenerative conditions. Understanding the precise cellular connections through which this circuit is organised is, therefore, vital for understanding these same processes. Overturning earlier findings, a recent study described a novel excitatory projection from anterior cingulate area to dorsal hippocampus. We sought to validate this unexpected finding using multiple, complementary methods: anterograde and retrograde anatomical tracing, using anterograde and retrograde adeno-associated viral vectors, monosynaptic rabies tracing, and the Fast Blue classical tracer. Additionally, an extensive data search of the Allen Projection Brain Atlas database was conducted to find the stated projection within any of the deposited anatomical studies as an independent verification of our own results. However, we failed to find any evidence of a direct, monosynaptic glutamatergic projection from mouse anterior cingulate cortex to the hippocampus proper.

Feasibility of outpatient hybrid brachytherapy for cervical cancer with minimal sedation: Results from a single-institutional protocol.

Purpose: Pain control techniques during high-dose-rate hybrid intracavitary-interstitial brachytherapy (HBT) for cervical cancer vary widely, with many centers opting for general anesthesia (GA) or conscious sedation (CS). Here, we describe a single-institutional series of patients treated with HBT and ASA-defined minimal sedation, utilizing oral analgesic and anxiolytic medications in substitution for GA or CS. Material and methods: The charts of patients who underwent HBT treatments for cervical cancer from June 2018 to May 2020 were retrospectively reviewed. Prior to HBT, all patients underwent an exam under anesthesia (EUA), and Smit sleeve placement under general anesthesia or deep sedation. Oral lorazepam and oxycodone/acetaminophen were administered between 30-90 minutes before HBT procedure for minimal sedation. HBT placement was performed on computed tomography (CT) table, with needle advancement under CT-guidance. Results: Treatments with minimal sedation were attempted in 63 patients. A total of 244 interstitial implants with 453 needles were placed via CT-guidance. Sixty-one patients (96.8%) tolerated the procedure without any additional intervention, while two patients (3.2%) required the use of epidural anesthesia. None of the patients in the series required a transition to general anesthesia for the procedure. Bleeding, which resolved with short-term vaginal packing, occurred in 22.1% of insertions. Conclusions: In our series, the treatment of HBT for cervical cancer with minimal sedation was feasible at a high percentage (96.8%). The ability to perform HBT without GA or CS could be a reasonable option to provide image-guided adaptive brachytherapy (IGABT) with limited resources, allowing for more widespread use. Further investigations using this technique are warranted.

Use of Augmentative Interspecies Communication devices in animal language studies: A review.

Countless discussions have been generated by the animal language studies, specifically those utilizing mechanical interfaces, termed here Augmentative Interspecies Communication (AIC) devices (e.g., lexigrams; magnetic chips; keyboards). Overall, three concerns dominate the field: (1) claims that AIC device using animals manifest linguistic skills remain nebulous, and simpler alternative mechanisms have been proposed (e.g., associative learning); (2) such methodology may be unsuitable as some theorize AIC device interfaces are not sufficiently ecologically relevant to foster meaningful use; (3) data may be considered dubious due to potential cueing from experimenters and lack of systematicity in reporting training and performance. Despite such controversy-which eventually led to the field's deterioration around the last quarter of the twentieth century-this research also saw important successes, such as improvements in captive animal welfare, the outcomes of which hold promise for future interspecies communication work. This article is categorized under: Linguistics > Evolution of Language.

Advances in Spinal Cord Stimulation.

Neuromodulation, specifically spinal cord stimulation (SCS), has become a staple of chronic pain management for various conditions including failed back syndrome, chronic regional pain syndrome, refractory radiculopathy, and chronic post operative pain. Since its conceptualization, it has undergone several advances to increase safety and convenience for patients and implanting physicians. Current research and efforts are aimed towards novel programming modalities and modifications of existing hardware. Here we review the recent advances and future directions in spinal cord stimulation including a brief review of the history of SCS, SCS waveforms, new materials for SCS electrodes (including artificial skins, new materials, and injectable electrodes), closed loop systems, and neurorestorative devices.

Seeing Things: A Community Science Investigation into Motion Illusion Susceptibility in Domestic Cats (Felis silvestris catus) and Dogs (Canis lupus familiaris).

Illusions-visual fields that distort perception-can inform the understanding of visual perception and its evolution. An example of one such illusion, the Rotating Snakes illusion, causes the perception of motion in a series of static concentric circles. The current study investigated pet dogs' and cats' perception of the Rotating Snakes illusion in a community science paradigm. The results reveal that neither species spent significantly more time at the illusion than at either of the controls, failing to indicate susceptibility to the illusion. Specific behavioral data at each stimulus reveal that the most common behaviors of both species were Inactive and Stationary, while Locomotion and Pawing were the least common, supporting the finding that susceptibility may not be present. This study is the first to examine susceptibility to the Rotating Snakes illusion in dogs, as well as to directly compare the phenomenon between dogs and cats. We suggest future studies might consider exploring alternative methods in testing susceptibility to motion illusions in non-human animals.

Contrafreeloading in kea (Nestor notabilis) in comparison to Grey parrots (Psittacus erithacus).

Contrafreeloading-working to access food that could be freely obtained-is rarely exhibited and poorly understood. Based on data from Grey parrots (Psittacus erithacus), researchers proposed a correlation between contrafreeloading and play: that contrafreeloading is more likely when subjects view the task as play. We tested that hypothesis by subjecting a relatively more playful parrot species, the kea (Nestor notabilis), to the same experimental tasks. Experiment 1 presented eight kea with container pairs holding more- or less-preferred free or enclosed food items, and examined three types of contrafreeloading: calculated (working to access preferred food over less-preferred, freely available food); classic (working to access food identical to freely available food); and super (working to access less-preferred food over preferred, freely available food). At the group level, the kea behaved similarly to the Greys: They significantly preferred calculated contrafreeloading, performed classic contrafreeloading at chance, and significantly failed to super contrafreeload. However, overall kea engaged in more contrafreeloading than Greys. Experiment 2 examined a potentially more ecologically relevant task, a choice between shelled and unshelled walnuts. No kea contrafreeloaded for nuts, whereas two of five Greys significantly preferred nut contrafreeloading and one chose at chance. We examine proximate and adaptive explanations for the performances of these differentially playful parrot species to further elucidate the role of play in contrafreeloading.

ß Bursting in the Retrosplenial Cortex Is a Neurophysiological Correlate of Environmental Novelty Which Is Disrupted in a Mouse Model of Alzheimer's Disease.

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory and is functionally disrupted in the early stages of Alzheimer's disease (AD). In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake and freely moving male mice, comparing neural activity between wild-type and J20 mice, a transgenic model of AD-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials (LFPs) were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of ß (20-30 Hz) oscillations (ß bursts), which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of ß bursts. Additionally, θ-α/ß cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during ß bursts. Finally, excessive ß bursting was seen in J20 mice, including increased ß bursting during novelty and familiarity, yet a loss of coupling between ß bursts and spiking activity. These findings support the concept that ß bursting may be responsible for the activation and reactivation of neuronal ensembles underpinning the formation and maintenance of cortical representations, and that disruptions to this activity in J20 mice may underlie cognitive impairments seen in these animals.SIGNIFICANCE STATEMENT The retrosplenial cortex (RSC) is thought to be involved in the formation, recall and consolidation of contextual memory. The discovery of bursts of ß oscillations in this region, which are associated with increased neuronal spiking and strongly upregulated while mice explore novel environments, provides a potential mechanism for the activation of neuronal ensembles, which may underlie the formation of cortical representations of context. Excessive ß bursting in the RSC of J20 mice, a mouse model of Alzheimer's disease (AD), alongside the disassociation of ß bursting from neuronal spiking, may underlie spatial memory impairments previously shown in these mice. These findings introduce a novel neurophysiological correlate of spatial learning and memory, and a potentially new form of AD-related cortical dysfunction.

Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure.

Heart failure represents a major cause of morbidity and mortality worldwide. Single-cell transcriptomics have revolutionized our understanding of cell composition and associated gene expression. Through integrated analysis of single-cell and single-nucleus RNA-sequencing data generated from 27 healthy donors and 18 individuals with dilated cardiomyopathy, here we define the cell composition of the healthy and failing human heart. We identify cell-specific transcriptional signatures associated with age and heart failure and reveal the emergence of disease-associated cell states. Notably, cardiomyocytes converge toward common disease-associated cell states, whereas fibroblasts and myeloid cells undergo dramatic diversification. Endothelial cells and pericytes display global transcriptional shifts without changes in cell complexity. Collectively, our findings provide a comprehensive analysis of the cellular and transcriptomic landscape of human heart failure, identify cell type-specific transcriptional programs and disease-associated cell states and establish a valuable resource for the investigation of human heart failure.

Real-world outcomes in patients with advanced endometrial cancer: A retrospective cohort study of US electronic health records.

OBJECTIVES: To characterize clinical outcomes of women with advanced/recurrent endometrial cancer (AEC) in routine practice using electronic health records from a real-world database. METHODS: Adult women diagnosed with AEC (stage III/IV, or early stage with locoregional/distant recurrence) between January 1, 2013 and September 30, 2020, inclusive, were eligible provided they received platinum-based chemotherapy at any time following diagnosis and had ≥2 clinical visits. Follow-up was from initiation of systemic treatment after advanced diagnosis (index) until March 30, 2021, last available follow-up, or death, whichever occurred first. Outcomes, by histological subtype, included Kaplan-Meier estimates of overall survival (OS) and time to first subsequent therapy or death (TFST). RESULTS: Of the 2202 women with AEC, most were treated in a community setting (82.7%) and presented with stage III/IV disease at initial diagnosis (74.0%). The proportion with endometrioid carcinoma, uterine serous carcinoma (USC), and other AEC subtypes was 59.8%, 25.0%, and 15.2%, respectively. The most common first systemic treatment following advanced/recurrent diagnosis was platinum-based combination chemotherapy (82.0%). Median OS (95% CI) from initiation of first systemic treatment was shorter with USC (31.3 [27.7-34.3] months) and other AECs (29.4 [21.4-43.9] months) versus endometrioid carcinoma (70.8 [60.5-83.2] months). Similar results were observed for TFST. Black/African American women had worse OS and TFST than white women. CONCLUSIONS: Women with AEC had poor survival outcomes, demonstrating the requirement for more effective therapies. To our knowledge, this is the most comprehensive evaluation of contemporary treatment of AEC delivered in a community setting to date.

DNA Damage Repair Inhibitors-Combination Therapies.

ABSTRACT: DNA damage response and repair (DDR) is responsible for ensuring genomic integrity. It is composed of intricate, complex pathways that detect various DNA insults and then activate pathways to restore DNA fidelity. Mutations in this network are implicated in many malignancies but can also be exploited for cancer therapies. The advent of inhibitors of poly(ADP-ribose) polymerase has led to the investigation of other DDR inhibitors and combinations to address high unmet needs in cancer therapeutics. Specifically, regimens, often in combination with chemotherapy, radiation, or other DDR inhibitors, are being investigated. This review will focus on 4 main DDR pathways-ATR/CHK1, ATM/CHK2, DNA-PKcs, and polymerase θ-and the current state of clinical research and use of the inhibitors of these pathways with other DDR inhibitors.

Initial evidence for eliciting contrafreeloading in grey parrots (Psittacus erithacus) via the opportunity for playful foraging.

Contrafreeloading is the choice to perform a physical task to access food over freely available food, a behavior pattern contrary to the predictions of both optimal foraging and learning theories. This study examined the presence and degree of contrafreeloading in Grey parrots (Psittacus erithacus) and the possible interpretation of such behavior in the context of play. Experiment 1 presented 4 subjects, Griffin, Athena, Franco and Pepper, with container pairs holding more- or less-preferred free or enclosed food items. Degrees of contrafreeloading were classified as follows: calculated contrafreeloading (working to access preferred food over less-preferred, freely available food); classic contrafreeloading (working to access food equal in value to freely available food); and super contrafreeloading (working to access a less-preferred food over preferred, freely available food). Of these three, Griffin significantly preferred classic and calculated contrafreeloading; Athena, Pepper, and Franco significantly preferred calculated contrafreeloading. Experiment 2 examined a more ecologically relevant contrafreeloading task in 5 parrots, Griffin, Athena, Lucci, Pepper, and Franco, using shelled and unshelled nuts. Athena and Franco significantly preferred cracking the shell to obtain the nut (contrafreeloading); Griffin and Lucci did not; Pepper chose at chance. We examine numerous possible explanations for their behavior and suggest that individual differences in contrafreeloading among the Grey parrots could relate to which task each considers some form of play. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Acute, but not longer-term, exposure to environmental enrichment attenuates Pavlovian cue-evoked conditioned approach and Fos expression in the prefrontal cortex in mice.

Exposure to environmental enrichment can modify the impact of motivationally relevant stimuli. For instance, previous studies in rats have found that even a brief, acute (~1 day), but not chronic, exposure to environmentally enriched (EE) housing attenuates instrumental lever pressing for sucrose-associated cues in a conditioned reinforcement setup. Moreover, acute EE reduces corticoaccumbens activity, as measured by decreases in expression of the neuronal activity marker "Fos." Currently, it is not known whether acute EE also reduces sucrose seeking and corticoaccumbens activity elicited by non-contingent or "forced" exposure to sucrose cues, which more closely resembles cue exposure encountered in daily life. We therefore measured the effects of acute/intermittent (1 day or 6 day of EE prior to test day) versus chronic (EE throughout conditioning lasting until test day) EE on the ability of a Pavlovian sucrose cue to elicit sucrose seeking (conditioned approach) and Fos expression in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), and nucleus accumbens (NAc) in mice. One day, but not 6 day or chronic EE , reduced sucrose seeking and Fos in the deep layers of the dorsal mPFC. By contrast, 1 day, 6 day, and chronic EE all reduced Fos in the shallow layers of the OFC. None of the EE manipulations modulated NAc Fos expression. We reveal how EE reduces behavioral reactivity to sucrose cues by reducing activity in select prefrontal cortical brain areas. Our work further demonstrates the robustness of EE in its ability to modulate various forms of reward-seeking across species.

Extinction of cue-evoked food-seeking recruits a GABAergic interneuron ensemble in the dorsal medial prefrontal cortex of mice.

Animals must quickly adapt food-seeking strategies to locate nutrient sources in dynamically changing environments. Learned associations between food and environmental cues that predict its availability promote food-seeking behaviors. However, when such cues cease to predict food availability, animals undergo "extinction" learning, resulting in the inhibition of food-seeking responses. Repeatedly activated sets of neurons, or "neuronal ensembles," in the dorsal medial prefrontal cortex (dmPFC) are recruited following appetitive conditioning and undergo physiological adaptations thought to encode cue-reward associations. However, little is known about how the recruitment and intrinsic excitability of such dmPFC ensembles are modulated by extinction learning. Here, we used in vivo 2-Photon imaging in male Fos-GFP mice that express green fluorescent protein (GFP) in recently behaviorally activated neurons to determine the recruitment of activated pyramidal and GABAergic interneuron dmPFC ensembles during extinction. During extinction, we revealed a persistent activation of a subset of interneurons which emerged from a wider population of interneurons activated during the initial extinction session. This activation pattern was not observed in pyramidal cells, and extinction learning did not modulate the excitability properties of activated pyramidal cells. Moreover, extinction learning reduced the likelihood of reactivation of pyramidal cells activated during the initial extinction session. Our findings illuminate novel neuronal activation patterns in the dmPFC underlying extinction of food-seeking, and in particular, highlight an important role for interneuron ensembles in this inhibitory form of learning.