CCK+ Interneurons Contribute to Thalamus-Evoked Feed-Forward Inhibition in the Prelimbic Prefrontal Cortex.

Interneurons in the medial prefrontal cortex (PFC) regulate local neural activity to influence cognitive, motivated, and emotional behaviors. Parvalbumin-expressing (PV+) interneurons are the primary mediators of thalamus-evoked feed-forward inhibition across the mouse cortex, including the anterior cingulate cortex, where they are engaged by inputs from the mediodorsal (MD) thalamus. In contrast, in the adjacent prelimbic (PL) cortex, we find that PV+ interneurons are scarce in the principal thalamorecipient layer 3 (L3), suggesting distinct mechanisms of inhibition. To identify the interneurons that mediate MD-evoked inhibition in PL, we combine slice physiology, optogenetics, and intersectional genetic tools in mice of both sexes. We find interneurons expressing cholecystokinin (CCK+) are abundant in L3 of PL, with cells exhibiting fast-spiking (fs) or non-fast-spiking (nfs) properties. MD inputs make stronger connections onto fs-CCK+ interneurons, driving them to fire more readily than nearby L3 pyramidal cells and other interneurons. CCK+ interneurons in turn make inhibitory, perisomatic connections onto L3 pyramidal cells, where they exhibit cannabinoid 1 receptor (CB1R) mediated modulation. Moreover, MD-evoked feed-forward inhibition, but not direct excitation, is also sensitive to CB1R modulation. Our findings indicate that CCK+ interneurons contribute to MD-evoked inhibition in PL, revealing a mechanism by which cannabinoids can modulate MD-PFC communication.

Identifying infection in chronic wounds in a community setting: A systematic review of diagnostic test accuracy studies.

AIM: To determine the diagnostic accuracy of different methods currently available to identify infection in chronic wounds applicable to adult patients in a community setting. DESIGN: Systematic review of diagnostic test accuracy studies. REVIEW METHODS: Two authors independently completed screening, data extraction and quality and bias assessments (QUADAS2). Eligible studies compared a method (index test) for detecting infection (diagnosis of interest) with microscopy and culture of either deep tissue biopsy or wound swab (reference test) in adult patients with wounds of >4 weeks duration (participants). The results were synthesized narratively. DATA SOURCES: We systematically searched CINAHL, Embase and Medline from 2011 to April 2022. RESULTS: Four studies were included, all recruiting from secondary care wound clinics. Two studies assessed the diagnostic accuracy of Moleculight i:X, a bacterial fluorescence imaging device against deep tissue biopsy culture. One study assessed the diagnostic accuracy of the elevation of various enzymes detected in wound fluid against wound swab microscopy of culture. One study assessed the diagnostic accuracy of bacterial protease activity against wound swab microscopy and culture. Sensitivities of these methods ranged from 50 to 75% and specificities from 47 to 100%. CONCLUSION: Only a small number of studies were included in this systematic review due to our strict inclusion criteria. We have not identified any methods for diagnosing infection in chronic wounds with either a sufficient quality of evidence to recommend their use in community settings at present. Further research is needed to develop and evaluate appropriate diagnostics for this purpose. IMPACT: This study highlights the paucity of research into wound diagnostics in a community setting and should prompt further research in this area. Accurate diagnostic tests have the potential to improve community-based wound care by optimizing antibiotic use and potentially improving healing time. REPORTING METHOD: PRISMA-DTA checklist. PATIENT OR PUBLIC CONTRIBUTION: The PPI group for the NIHR Community Healthcare MIC were supportive of this topic of work.

Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior in fragile X syndrome model mice.

Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviors (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissect the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. Here, we report that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum reveals differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings uncover a cell-type-specific impact of the loss of fragile X messenger ribonucleoprotein (FMRP) on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS.

Complex Metabolism of the Novel Neurosteroid, Ganaxolone, in Humans: A Unique Challenge for Metabolites in Safety Testing Assessment.

The human pharmacokinetics, metabolism, and excretion of [14C]-ganaxolone (GNX) were characterized in healthy male subjects (n = 8) following a single 300-mg (150 µCi) oral dose. GNX exhibited a short half-life of 4 hours in plasma, whereas total radioactivity had a half-life of 413 hours indicating extensive metabolism to long-lived metabolites. Identification of the major GNX circulating metabolites required extensive isolation and purification for liquid chromatography-tandem mass spectrometry analysis, together with in vitro studies, NMR spectroscopy, and synthetic chemistry support. This revealed that the major routes of GNX metabolism involved hydroxylation at the 16α-hydroxy position, stereoselective reduction of the 20-ketone to afford the corresponding 20α-hydroxysterol, and sulfation of the 3α-hydroxy group. This latter reaction yielded an unstable tertiary sulfate, which eliminated the elements of H2SO4 to introduce a double bond in the A ring. A combination of these pathways, together with oxidation of the 3ß-methyl substituent to a carboxylic acid and sulfation at the 20α position, led to the major circulating metabolites in plasma, termed M2 and M17. These studies, which led to the complete or partial identification of no less than 59 metabolites of GNX, demonstrated the high complexity of the metabolic fate of this drug in humans and demonstrated that the major circulating products in plasma can result from multiple sequential processes that may not be easily replicated in animals or with animal or human in vitro systems. SIGNIFICANCE STATEMENT: Studies on the metabolism of [14C]-ganaxolone in humans revealed a complex array of products that circulated in plasma, the two major components of which were formed via an unexpected multi-step pathway. Complete structural characterization of these (disproportionate) human metabolites required extensive in vitro studies, along with contemporary mass spectrometry, NMR spectroscopy, and synthetic chemistry efforts, which served to underscore the limitations of traditional animal studies in predicting major circulating metabolites in man.

Grievance-fueled sexual violence.

The grievance fueled violence paradigm encompasses various forms of targeted violence but has not yet been extended to the theoretical discussion of sexual violence. In this article, we argue that a wide range of sexual offenses can be usefully conceptualized as forms of grievance fueled violence. Indeed, our assertion that sexual violence is often grievance fueled is unoriginal. More than 40 years of sexual offending research has discussed the pseudosexual nature of much sexual offending, and themes of anger, power, and control - themes that draw clear parallels to the grievance fueled violence paradigm. Therefore, we consider the opportunities for theoretical and practical advancement through the merging of ideas and concepts from the two fields. We examine the scope of grievance in the context of understanding sexual violence, and we look to the role of grievance in the trajectory toward both sexual and nonsexual violence, as well as factors that might distinguish grievance fueled sexual from nonsexual violence. Finally, we discuss future research directions and make recommendations for clinical practice. Specifically, we suggest that grievance represents a promising treatment target where risk is identified for both sexual and nonsexual violence.

What is the Diagnostic Accuracy of Novel Urine Biomarkers for Urinary Tract Infection?

Background: Urinary tract infection (UTI) affects half of women at least once in their lifetime. Current diagnosis involves urinary dipstick and urine culture, yet both methods have modest diagnostic accuracy, and cannot support decision-making in patient populations with high prevalence of asymptomatic bacteriuria, such as older adults. Detecting biomarkers of host response in the urine of hosts has the potential to improve diagnosis. Objectives: To synthesise the evidence of the diagnostic accuracy of novel biomarkers for UTI, and of their ability to differentiate UTI from asymptomatic bacteriuria. Design: A systematic review. Data Sources and Methods: We searched MEDLINE, EMBASE, CINAHL and Web of Science for studies of novel biomarkers for the diagnosis of UTI. We excluded studies assessing biomarkers included in urine dipsticks as these have been well described previously. We included studies of adult patients (≥16 years) with a suspected or confirmed urinary tract infection using microscopy and culture as the reference standard. We excluded studies using clinical signs and symptoms, or urine dipstick only as a reference standard. Quality appraisal was performed using QUADAS-2. We summarised our data using point estimates and data accuracy statistics. Results: We included 37 studies on 4009 adults measuring 66 biomarkers. Study quality was limited by case-control design and study size; only 4 included studies had a prospective cohort design. IL-6 and IL-8 were the most studied biomarkers. We found plausible evidence to suggest that IL-8, IL-6, GRO-a, sTNF-1, sTNF-2 and MCR may benefit from more rigorous evaluation of their potential diagnostic value for UTI. Conclusions: There is insufficient evidence to recommend the use of any novel biomarker for UTI diagnosis at present. Further evaluation of the more promising candidates, is needed before they can be recommended for clinical use.

Rostral and caudal basolateral amygdala engage distinct circuits in the prelimbic and infralimbic prefrontal cortex.

Connections from the basolateral amygdala (BLA) to medial prefrontal cortex (PFC) regulate memory and emotion and become disrupted in neuropsychiatric disorders. The diverse roles attributed to interactions between the BLA and PFC may reflect multiple circuits nested within a wider network. To examine these circuits, we first used retrograde and anterograde anatomy to show that the rostral BLA (rBLA) and caudal BLA (cBLA) differentially project to prelimbic (PL) and infralimbic (IL) subregions of the mouse PFC. Using ex vivo whole-cell recordings and optogenetics, we then assessed which neuronal subtypes are targeted, showing that rBLA preferentially drives layer 2 (L2) cortico-amygdalar (CA) neurons in PL, whereas cBLA drives layer 5 (L5) pyramidal tract (PT) neurons in IL. We next combined in vivo silicon probe recordings and optogenetics to confirm that cBLA mainly influences IL L5, whereas rBLA primarily activates PL L2, but also evokes polysynaptic activity in PL L5. Lastly, we used soma-tagged optogenetics to explore the local circuits linking superficial and deep layers of PL, showing how rBLA can engage L2 CA neurons to impact L5 PT neuron activity. Together, our findings delineate how subregions of the BLA target distinct networks within the PFC and differentially influence output from PL and IL.

Factors associated with occurrence and severity of acute kidney injury in patients with Sepsis - A retrospective database study.

PURPOSE: Sepsis remains the most common cause of acute kidney injury (AKI) and is associated with a high mortality. This study aims to identify laboratory, clinical and demographic factors that are associated with the different stages of AKI in sepsis. METHODS: We studied patients >18 years who met Sepsis-3 criteria between July 10, 2009 and September 7, 2019 using ordinal logistic regression to determine the factors associated with different stages of AKI. Sensitivity analyses for development of any stage vs no AKI and, separately, the factors associated with receipt of kidney replacement therapy were also done. RESULTS: Of 31,228 patients meeting Sepsis-3 criteria, 4684 (15%) developed AKI. Of the AKI patients, 53% were KDIGO stage 1, 9% stage 2, and 37% stage 3, with 27% of AKI patients receiving kidney replacement therapy (Stage 3b). Several comorbidities, mechanical ventilation, and pre-sepsis creatinine levels were associated with AKI occurrence and severity. Positive blood culture was associated with a higher risk (OR 1.10 [1.06, 1.15], p < 0.001), while positive respiratory, urine, and wound cultures were associated with lower risks of developing AKI and with lower severity. CONCLUSION: Presepsis creatinine levels, mechanical ventilation, comorbidities, and positive blood cultures were associated with AKI.

Scoping review to evaluate the effects of peer support on the mental health of young adults.

OBJECTIVES: Young adults report disproportionality greater mental health problems compared with the rest of the population with numerous barriers preventing them from seeking help. Peer support, defined as a form of social-emotional support offered by an individual with a shared lived experience, has been reported as being effective in improving a variety of mental health outcomes in differing populations. The objective of this scoping review is to provide an overview of the literature investigating the impact of peer support on the mental health of young adults. DESIGN: A scoping review methodology was used to identify relevant peer-reviewed articles in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across six databases and Google/Google Scholar. Overall, 17 eligible studies met the inclusion criteria and were included in the review. RESULTS: Overall, studies suggest that peer support is associated with improvements in mental health including greater happiness, self-esteem and effective coping, and reductions in depression, loneliness and anxiety. This effect appears to be present among university students, non-student young adults and ethnic/sexual minorities. Both individual and group peer support appear to be beneficial for mental health with positive effects also being present for those providing the support. CONCLUSIONS: Peer support appears to be a promising avenue towards improving the mental health of young adults, with lower barriers to accessing these services when compared with traditional mental health services. The importance of training peer supporters and the differential impact of peer support based on the method of delivery should be investigated in future research.

Hippocampal-evoked inhibition of cholinergic interneurons in the nucleus accumbens.

Cholinergic interneurons (ChIs) in the nucleus accumbens (NAc) play a central role in motivated behaviors and associated disorders. However, while the activation of ChIs has been well studied in the dorsal striatum, little is known about how they are engaged in the NAc. Here, we find that the ventral hippocampus (vHPC) and the paraventricular nucleus of the thalamus (PVT) are the main excitatory inputs to ChIs in the NAc medial shell. While the PVT activates ChIs, the vHPC evokes a pronounced pause in firing through prominent feedforward inhibition. In contrast to the dorsal striatum, this inhibition reflects strong connections onto ChIs from local parvalbumin interneurons. Our results reveal the mechanisms by which different long-range inputs engage ChIs, highlighting fundamental differences in local connectivity across the striatum.

Enhancing the inpatient ward learning environment: A practical guide.

Inpatient ward placements are rich with practical learning opportunities for medical students; however, many such opportunities go overlooked and underused. Newly qualified doctors often feel underprepared for work on wards; improving student experience on ward placements can address this. Although this requires an active effort from both students and clinical educators, it is not arduous and has mutual benefit: improving medical education while simultaneously reducing staff workload. Here, we present a guide for both teachers and students highlighting three key areas of ward learning that may be improved: strategies to drive active learning, integration of students into the ward team and underutilised resources to develop a patient-centred approach.

Genome-Wide Association Study of Waterlogging Tolerance in Barley (Hordeum vulgare L.) Under Controlled Field Conditions.

Waterlogging is one of the main abiotic stresses severely reducing barley grain yield. Barley breeding programs focusing on waterlogging tolerance require an understanding of genetic loci and alleles in the current germplasm. In this study, 247 worldwide spring barley genotypes grown under controlled field conditions were genotyped with 35,926 SNPs with minor allele frequency (MAF) > 0.05. Significant phenotypic variation in each trait, including biomass, spikes per plant, grains per plant, kernel weight per plant, plant height and chlorophyll content, was observed. A genome-wide association study (GWAS) based on linkage disequilibrium (LD) for waterlogging tolerance was conducted. Population structure analysis divided the population into three subgroups. A mixed linkage model using both population structure and kinship matrix (Q+K) was performed. We identified 17 genomic regions containing 51 significant waterlogging-tolerance-associated markers for waterlogging tolerance response, accounting for 5.8-11.5% of the phenotypic variation, with a majority of them localized on chromosomes 1H, 2H, 4H, and 5H. Six novel QTL were identified and eight potential candidate genes mediating responses to abiotic stresses were located at QTL associated with waterlogging tolerance. To our awareness, this is the first GWAS for waterlogging tolerance in a worldwide barley collection under controlled field conditions. The marker-trait associations could be used in the marker-assisted selection of waterlogging tolerance and will facilitate barley breeding.

Circuit organization of the rodent medial prefrontal cortex.

The prefrontal cortex (PFC) orchestrates higher brain function and becomes disrupted in many mental health disorders. The rodent medial PFC (mPFC) possesses an enormous variety of projection neurons and interneurons. These cells are engaged by long-range inputs from other brain regions involved in cognition, motivation, and emotion. They also communicate in the local network via specific connections between excitatory and inhibitory cells. In this review, we describe the cellular diversity of the rodent mPFC, the impact of long-range afferents, and the specificity of local microcircuits. We highlight similarities with and differences between other cortical areas, illustrating how the circuit organization of the mPFC may give rise to its unique functional roles.

"We Boil at Different Degrees": Factors Associated With Severity of Attack in Sexual Killing.

Degree of injury, as measured by the Homicide Injury Scale (HIS), was examined to advance understanding of the dynamics of sexual killing. A total of 350 nonserial, male sexual killers were included, and the different ways that the sexual element of their offenses and the act of killing were connected was accounted for by determining that cases were either directly sexual (the sexual element and killing were closely bound), or indirectly sexual (killing was not a source of sexual stimulation). The two groups, direct and indirect sexual killers, were each subjected to multiple linear regression analyses to examine the group-specific relationship between level of injury and predictor variables previously found to be associated with increased severity of attack. No differences in the mean total HIS scores between the indirect and the direct cases were found, suggesting a comparable emotional intensity between the groups. However, given that the groups differed in terms of the functional role of fatal violence, severity of attack could not be sufficiently explained as driven by anger. In line with this hypothesis, different predictors appeared to be associated with increased degree of injury sustained by victims of indirect compared with direct sexual killers. As such, situational components appear to play a role in the behavior of indirect sexual killers, whereas the behavior of direct perpetrators tends to be linked with the enactment of existing deviant fantasies. The role of anger in sexual homicide is discussed further, and overall, it is argued that irrespective of whether violence was initially driven by anger, evidence of sexual arousal to severe violence must be scrutinized within sexual homicide research as well as in psycholegal contexts.

Mediodorsal and Ventromedial Thalamus Engage Distinct L1 Circuits in the Prefrontal Cortex.

Interactions between the thalamus and prefrontal cortex (PFC) play a critical role in cognitive function and arousal. Here, we use anatomical tracing, electrophysiology, optogenetics, and 2-photon Ca2+ imaging to determine how ventromedial (VM) and mediodorsal (MD) thalamus target specific cell types and subcellular compartments in layer 1 (L1) of mouse PFC. We find thalamic inputs make distinct connections in L1, where VM engages neuron-derived neurotrophic factor (NDNF+) cells in L1a and MD drives vasoactive intestinal peptide (VIP+) cells in L1b. These separate populations of L1 interneurons participate in different inhibitory networks in superficial layers by targeting either parvalbumin (PV+) or somatostatin (SOM+) interneurons. NDNF+ cells also inhibit the apical dendrites of L5 pyramidal tract (PT) cells to suppress action potential (AP)-evoked Ca2+ signals. Lastly, NDNF+ cells mediate a unique form of thalamus-evoked inhibition at PT cells, selectively blocking VM-evoked dendritic Ca2+ spikes. Together, our findings reveal how two thalamic nuclei differentially communicate with the PFC through distinct L1 micro-circuits.

Hippocampal inputs engage CCK+ interneurons to mediate endocannabinoid-modulated feed-forward inhibition in the prefrontal cortex.

Connections from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) regulate cognition, emotion, and memory. These functions are also tightly controlled by inhibitory networks in the PFC, whose disruption is thought to contribute to mental health disorders. However, relatively little is known about how the vHPC engages different populations of interneurons in the PFC. Here we use slice physiology and optogenetics to study vHPC-evoked feed-forward inhibition in the mouse PFC. We first show that cholecystokinin (CCK+), parvalbumin (PV+), and somatostatin (SOM+) expressing interneurons are prominent in layer 5 (L5) of infralimbic PFC. We then show that vHPC inputs primarily activate CCK+ and PV+ interneurons, with weaker connections onto SOM+ interneurons. CCK+ interneurons make stronger synapses onto pyramidal tract (PT) cells over nearby intratelencephalic (IT) cells. However, CCK+ inputs undergo depolarization-induced suppression of inhibition (DSI) and CB1 receptor modulation only at IT cells. Moreover, vHPC-evoked feed-forward inhibition undergoes DSI only at IT cells, confirming a central role for CCK+ interneurons. Together, our findings show how vHPC directly engages multiple populations of inhibitory cells in deep layers of the infralimbic PFC, highlighting unexpected roles for both CCK+ interneurons and endocannabinoid modulation in hippocampal-prefrontal communication.

To What Extent Does Clinically Assisted Nutrition and Hydration Have a Role in the Care of Dying People?

The question over whether to administer clinically assisted nutrition and hydration (CANH) to a dying patient is controversial, with much debate concerning this sensitive issue. The administration of CANH poses clinical and ethical dilemmas, with supporting and opposing views. Proposed positive effects of CANH include preventing thirst, delirium, hypercalcemia, and opioid toxicity. However, CANH has been shown to increase the risk of aspiration, pressure ulcers, infections, and hospital admissions as well as potentially causing discomfort to the patient. Guidance from several national bodies generally advises that the risks and burdens of CANH outweigh the benefits in the dying patient. However, an individualized approach is needed, and the patient's wishes regarding CANH need consideration if they have capacity and can communicate. Otherwise, sensitive discussions are required with the family, enquiring about the patient's prior wishes if there is no advanced care plan and acting in the patient's best interests. The ethical principles of autonomy, beneficence, non-maleficence, and justice need to be applied being mindful of any cultural and religious beliefs and potential misperceptions.

Genome-Wide Analysis of Gene Expression Provides New Insights into Waterlogging Responses in Barley (Hordeum vulgare L.).

Waterlogging is a major abiotic stress causing oxygen depletion and carbon dioxide accumulation in the rhizosphere. Barley is more susceptible to waterlogging stress than other cereals. To gain a better understanding, the genome-wide gene expression responses in roots of waterlogged barley seedlings of Yerong and Deder2 were analyzed by RNA-Sequencing. A total of 6736, 5482, and 4538 differentially expressed genes (DEGs) were identified in waterlogged roots of Yerong at 72 h and Deder2 at 72 and 120 h, respectively, compared with the non-waterlogged control. Gene Ontology (GO) enrichment analyses showed that the most significant changes in GO terms, resulted from these DEGs observed under waterlogging stress, were related to primary and secondary metabolism, regulation, and oxygen carrier activity. In addition, more than 297 transcription factors, including members of MYB, AP2/EREBP, NAC, WRKY, bHLH, bZIP, and G2-like families, were identified as waterlogging responsive. Tentative important contributors to waterlogging tolerance in Deder2 might be the highest up-regulated DEGs: Trichome birefringence, α/ß-Hydrolases, Xylanase inhibitor, MATE efflux, serine carboxypeptidase, and SAUR-like auxin-responsive protein. The study provides insights into the molecular mechanisms underlying the response to waterlogging in barley, which will be of benefit for future studies of molecular responses to waterlogging and will greatly assist barley genetic research and breeding.

A comparison of displacement and reinforcer potency for typically developing children.

Previous researchers found that individuals with intellectual and developmental disabilities tend to prefer edible over leisure stimuli, although leisure stimuli may still function as reinforcers. We replicated and extended previous research in a 2-part experiment with typically developing children. In Experiment 1, we evaluated 15 children's preference for leisure and edible stimuli. Five of 15 participants preferred edible over leisure stimuli, 3 of 15 participants preferred leisure over edible stimuli, and the remaining 7 of 15 participants did not show a preference for a stimulus class. In Experiment 2, we compared the reinforcer potency of the top-ranked stimulus from each class with 7 of the 8 participants who showed displacement of one stimulus class. Four of 7 participants allocated more responding to the task associated with the top-ranked stimulus and 3 of 7 participants showed no differences in responding to the task regardless of the stimulus rank.

The Projection Targets of Medium Spiny Neurons Govern Cocaine-Evoked Synaptic Plasticity in the Nucleus Accumbens.

We examine synaptic connectivity and cocaine-evoked plasticity at specific networks within the nucleus accumbens (NAc). We identify distinct subpopulations of D1+ medium spiny neurons (MSNs) that project to either the ventral pallidum (D1+VP) or the ventral tegmental area (D1+VTA). We show that inputs from the ventral hippocampus (vHPC), but not the basolateral amygdala (BLA), are initially biased onto D1+VTA MSNs. However, repeated cocaine exposure eliminates the bias of vHPC inputs onto D1+VTA MSNs, while strengthening BLA inputs onto D1+VP MSNs. Our results reveal that connectivity and plasticity depend on the specific inputs and outputs of D1+ MSNs and highlight the complexity of cocaine-evoked circuit level adaptations in the NAc.