Divergent transcriptional regulation of astrocyte reactivity across disorders.

Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.

Use of a Psychological Evaluation Tool as a Predictor of Spinal Cord Stimulation Outcomes.

INTRODUCTION: Preoperative work-up for spinal cord stimulation (SCS) includes a psychological assessment; however, no one psychological factor has correlated with poor outcomes across studies. We developed a Psychological Evaluation Tool for Spinal Cord Stimulation Candidacy (PETSCSC), which includes all factors in the literature found to correlate with outcomes. In this study, we examine whether PETSCSC correlates with postoperative outcomes. METHODS: Patients undergoing SCS were prospectively enrolled in this study. PETSCSC scores were obtained preoperatively. Numeric rating scale (NRS), global impression of change (GIC), pain catastrophizing scale (PCS), McGill pain questionnaire (MPQ), Oswestry disability index (ODI), and Beck Depression Inventory were assessed preoperatively and postoperatively. Outcomes were correlated with PETSCSC scores. RESULTS: Thirty-four SCS patients had a mean follow-up of 9.88 ± 2.91 months. At latest follow-up, we observed significant improvement in NRS, PCS, MPQ, and ODI. Total PETSCSC score exhibited significant correlation with GIC (p = 0.026, r = 0.380) and improvement in PCS total (p = 0.041, r = 0.351), and MPQ affective (p = 0.002, r = 0.517) scores. The PETSCSC emotive subset significantly correlated with GIC (p = 0.020, r = 0.395). The PETSCSC depression subset significantly correlated with improvement in PCS rumination (p = 0.009, r = 0.439), PCS helplessness (p = 0.021, r = 0.393), PCS total (p = 0.021, r = 0.394), and MPQ affective (p = 0.002, r = 0.501). The PETSCSC therapy subset significantly correlated with improvement in MPQ sensory (p = 0.026, r = -0.381) and MPQ affective (p < 0.001, r = 0.583). DISCUSSION: PETSCSC scores and subscores demonstrate significant correlation with pain outcomes used in assessment of SCS efficacy. Higher PETSCSC scores correlate with greater improvement in GIC, MPQ affective, and PCS scores. Stratification of these patients based on PETSCSC total and subset scores could help with prognostication.

Safety of Spinal Cord Stimulation in Patients Who Routinely Use Anticoagulants.

Objective: We assess the safety of performing the epidural placement or revision of spinal cord stimulation (SCS) in patients whose anticoagulation has been held (termed "anticoagulant-suspended" patients) in accordance with the 2017 Neurostimulation Appropriateness Consensus Committee (NACC) guidelines. Subjects: Patients undergoing SCS were included in this institutional review board-approved study. Design: A retrospective analysis of a prospectively collected database was performed. Any adverse event occurring within 90 days after SCS lead placement/revision was included. Results: A total of 225 patients who had a total of 239 surgeries including lead placement or lead revision were included; 182 patients were not on anticoagulants, 37 patients used one anticoagulant, and six patients used two or more anticoagulants. There were 13 adverse events. Anticoagulant use as a whole had no significant relationship to operative or postoperative adverse effects (χ2(1) = 1.613, P > 0.05). No anticoagulant on its own contributed significantly to adverse events; however, a small set of surgical cases showed a significantly greater incidence of adverse events for patients on enoxaparin used in combination with other anticoagulants (P < 0.05, N = 4). Conclusions: This study is the first to demonstrate that anticoagulant-suspended patients have no increased risk of perioperative hemorrhagic or thromboembolic adverse effects following SCS surgery compared with nonanticoagulated patients. The findings of this study validate the safety of neuromodulation in anticoagulation-suspended patients, concurring with the findings of previously described case studies, which anecdotally described neuromodulation outcomes in patients whose anticoagulation regimen had been temporarily held.

Pain Remission at One-Year Follow-Up With Spinal Cord Stimulation.

OBJECTIVES: Spinal Cord Stimulation (SCS) is an effective treatment for chronic pain. How often pain remission follows SCS has not been evaluated. This is a retrospective analysis of patients who underwent an implantation of spinal cord stimulators for various chronic pain conditions. The objective of the study was to elucidate characteristics and features of patients with pain relief greater than 80% after one year of treatment. METHODS: A total of 86 patients with thoracic SCS and 12-month follow-up data were identified. Patients were divided into a remission group (>80% improvement in Numeric Pain Rating Scale [NRS] pain scale), average responders (20-80% improvement) and a non-responder group (less than 20% improvement). These patient groups were compared via the following outcome measures: NRS, Oswestry Disability Index (ODI), Pain Catastrophizing Scale (PCS), McGill Pain Questionnaire (MPQ), and Insomnia Severity Index (ISI). Correlations with age, body mass index (BMI), tobacco and alcohol usage, patient satisfaction with SCS, disability status, and opioid usage were assessed. RESULTS: Nineteen of 86 patients (22%) were remitters at one year follow-up, including 17 patients who had an NRS = 0 at that time. Upon analyzing the three patient groups (non-responders, average responders, and remitters), remitter patients showed the greatest change over the one-year post-operative period in ODI (F(2) = 8.101, p < 0.01) and PCS (F(2) = 7.607, p < 0.01). Moreover, remission was less likely when the patients were on disability prior to implant (χ2 (2) = 6.469, p < 0.05) and on opioids pre-operatively (χ2 (2) = 17.688, p < 0.01). CONCLUSIONS: Our study demonstrates a remission rate of 22% with SCS at one-year follow with a total of 19.8% of our total patient cohort having an NRS of 0. Greater decreases in PCS and ODI correlate with remission. Further, pre-operative disability and opioid use correlate with lower likelihood of remission.

King's Parkinson's Disease Pain Scale for Assessment of Pain Relief Following Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: Pain is a prevalent and debilitating nonmotor symptom of Parkinson's disease (PD) that is often inadequately managed. Deep brain stimulation (DBS) has been shown to relieve pain in PD but an effective method of identifying which types of PD pain respond to DBS has not been established. We examine the effects of DBS on different types of PD pain using the King's Parkinson's disease pain scale (KPDPS), the only validated scale of PD pain. METHODS: We prospectively followed 18 PD patients undergoing subthalamic nucleus (STN) or Globus pallidus interna (GPi) DBS. Subjects completed the KPDPS, low back disability index (LBDI), and McGill pain questionnaire (MPQ), preoperatively and at six months postoperatively. Subjects underwent the unified Parkinson's disease rating scale-III (UPDRS-III) with preoperative scores ON medication and postoperative scores ON medication/DBS stimulation. RESULTS: Of the 18 patients, a total of 12 subjects had STN DBS and 6 had GPi DBS. As a group, subjects showed improvement in total KPDPS score at six-month postoperative follow-up (p = 0.004). Fluctuation and nocturnal pain were most significantly improved (p = 0.006, 0.01, respectively). Significant improvements were found in fluctuation-related pain domain following GPi DBS. CONCLUSIONS: In this pilot study, we are the first group to employ KPDPS to monitor pain relief following DBS in PD patients. We demonstrate that fluctuation-related pain and nocturnal pain significantly improve with DBS. Use of the KPDPS in the future will allow better understanding of how STN and GPi DBS treat PD pain over time.

Prospective Evaluation of Patient Usage of Above and Below Threshold Waveforms With Traditional Spinal Cord Stimulation Devices.

OBJECTIVES: Spinal cord stimulation (SCS) is an efficacious therapy used to treat chronic pain. The type of SCS programming is important in improving patients' quality of life and overall satisfaction. In this study, 19 patients who underwent SCS with traditional devices were given between 4 and 6 programs including programs with stimulation below sensory threshold and above sensory threshold. Usage patterns and preferences were assessed. METHODS: SCS patients were given 4-6 programs, some above sensory threshold and some below threshold immediately postoperatively after permanent implantation. Usage patterns of different programs were documented, including percent of time that the settings were used and preference for above threshold vs. below threshold settings during sleeping, walking, sitting, and vigorous activity. Improvements at three months in Oswestry disability index (ODI), numeric rating scale (NRS), Beck depression inventory (BDI), McGill pain questionnaire (MPQ), pain catastrophizing scale (PCS), insomnia severity index (ISI), and Epworth sleepiness scale (ESS) were evaluated. RESULTS: Patients were all trialed on above sensory threshold programs. Six weeks after implantation, most patients preferred above threshold stimulation (74%) vs. below threshold waveforms (21%). Patient diagnosis, type/location of lead or recharging burden played no role in patient preference. Above threshold patients had significantly better improvement in BDI scores than did below threshold patients (p < 0.05) at three-month follow-up but also had worse ESS scores (p < 0.05). Above threshold stimulation was preferred for walking and sitting (p < 0.05). CONCLUSIONS: Results indicate that when given the option between waveforms inducing paresthesias and those that do not, SCS patients tend to prefer waveforms that induce paresthesias. Among users of above threshold waveforms, there was preference for these settings during walking and sitting. There was a trend for below threshold preference in vigorous activity and sleeping.

Understanding bladder management on a palliative care unit: a grounded theory study.

BACKGROUND: Research regarding factors associated with nursing-initiated changes to bladder management at end-of-life is sparse. OBJECTIVES: To explore the process of Palliative Care Unit (PCU) nurses' approach to bladder management changes. METHODS: Nursing staff from one PCU in London, Canada were interviewed regarding bladder management care practices. A constructivist grounded theory was generated. RESULTS: Four interconnected themes emerged: humanity (compassionate support of patients); journey (making the most of a finite timeline); health condition (illness, functional decline); and context (orders, policies, supplies). These overlapping themes must be considered in light of ongoing changes which prompt recycling through the framework. While bladder management necessitates shared decision-making and individualised care, nurses' phronetic experience may serve to detect the presence of change and the need to consider other alternatives. CONCLUSION: End-of-life bladder management requires nurses to continually reconsider the significance of humanity, journey, health condition and context in light of ongoing changes.

Comparison of bacteriological culture and PCR for detection of bacteria in ovine milk--sheep are not small cows.

Mastitis, inflammation of the mammary gland, is an important cause of disease, mortality, and production losses in dairy and meat sheep. Mastitis is commonly caused by intramammary infection with bacteria, which can be detected by bacterial culture or PCR. PathoProof (Thermo Fisher Scientific Ltd., Vantaa, Finland) is a commercially available real-time PCR system for the detection of bovine mastitis pathogens. Sheep differ from cattle in the bacterial species or bacterial strains that cause mastitis, as well as in the composition of their milk. The aim of this study was to evaluate whether the PathoProof system was suitable for detection of mastitis pathogens in sheep milk. Milk samples were collected aseptically from 219 udder halves of 113 clinically healthy ewes in a single flock. Aliquots were used for bacteriological culture and real-time PCR-based detection of bacteria. For species identified by culture, the diagnosis was confirmed by species-specific conventional PCR or by sequencing of a housekeeping gene. The majority of samples were negative by culture (74.4% of 219 samples) and real-time PCR (82.3% of 192 samples). Agreement was observed for 138 of 192 samples. Thirty-four samples were positive by culture only, mostly due to presence of species that are not covered by primers in the PCR system (e.g., Mannheimia spp.). Two samples were positive for Streptococcus uberis by culture but not by PCR directly from the milk samples. This was not due to inability of the PCR primers to amplify ovine Streptococcus uberis, as diluted DNA extracts from the same samples and DNA extracts from the bacterial isolates were positive by real-time PCR. For samples containing Staphylococcus spp., 11 samples were positive by culture and PCR, 9 by culture only, and 20 by PCR only. Samples that were negative by either method had lower bacterial load than samples that were positive for both methods, whereas no clear relation with species identity was observed. This study provides proof of principle that real-time PCR can be used for detection of mastitis pathogens in ovine milk. Routine use in sheep may require inclusion of primer sets for sheep-specific mastitis pathogens.

Lesion-remote astrocytes govern microglia-mediated white matter repair.

Spared regions of the damaged central nervous system undergo dynamic remodeling and exhibit a remarkable potential for therapeutic exploitation. Here, lesion-remote astrocytes (LRAs), which interact with viable neurons, glia and neural circuitry, undergo reactive transformations whose molecular and functional properties are poorly understood. Using multiple transcriptional profiling methods, we interrogated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury (SCI). We show that LRAs acquire a spectrum of molecularly distinct, neuroanatomically restricted reactivity states that evolve after SCI. We identify transcriptionally unique reactive LRAs in degenerating white matter that direct the specification and function of local microglia that clear lipid-rich myelin debris to promote tissue repair. Fueling this LRA functional adaptation is Ccn1 , which encodes for a secreted matricellular protein. Loss of astrocyte CCN1 leads to excessive, aberrant activation of local microglia with (i) abnormal molecular specification, (ii) dysfunctional myelin debris processing, and (iii) impaired lipid metabolism, culminating in blunted debris clearance and attenuated neurological recovery from SCI. Ccn1 -expressing white matter astrocytes are specifically induced by local myelin damage and generated in diverse demyelinating disorders in mouse and human, pointing to their fundamental, evolutionarily conserved role in white matter repair. Our findings show that LRAs assume regionally divergent reactivity states with functional adaptations that are induced by local context-specific triggers and influence disorder outcome. Astrocytes tile the central nervous system (CNS) where they serve vital roles that uphold healthy nervous system function, including regulation of synapse development, buffering of neurotransmitters and ions, and provision of metabolic substrates 1 . In response to diverse CNS insults, astrocytes exhibit disorder-context specific transformations that are collectively referred to as reactivity 2-5 . The characteristics of regionally and molecularly distinct reactivity states are incompletely understood. The mechanisms through which distinct reactivity states arise, how they evolve or resolve over time, and their consequences for local cell function and CNS disorder progression remain enigmatic. Immediately adjacent to CNS lesions, border-forming astrocytes (BFAs) undergo transcriptional reprogramming and proliferation to form a neuroprotective barrier that restricts inflammation and supports axon regeneration 6-9 . Beyond the lesion, spared but dynamic regions of the injured CNS exhibit varying degrees of synaptic circuit remodeling and progressive cellular responses to secondary damage that have profound consequences for neural repair and recovery 10,11 . Throughout these cytoarchitecturally intact, but injury-reactive regions, lesion-remote astrocytes (LRAs) intermingle with neurons and glia, undergo little to no proliferation, and exhibit varying degrees of cellular hypertrophy 7,12,13 . The molecular and functional properties of LRAs remain grossly undefined. Therapeutically harnessing spared regions of the injured CNS will require a clearer understanding of the accompanying cellular and molecular landscape. Here, we leveraged integrative transcriptional profiling methodologies to identify multiple spatiotemporally resolved, molecularly distinct states of LRA reactivity within the injured spinal cord. Computational modeling of LRA-mediated heterotypic cell interactions, astrocyte-specific conditional gene deletion, and multiple mouse models of acute and chronic CNS white matter degeneration were used to interrogate a newly identified white matter degeneration-reactive astrocyte subtype. We define how this reactivity state is induced and its role in governing the molecular and functional specification of local microglia that clear myelin debris from the degenerating white matter to promote repair.

Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse.

Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.

Implementing standardized diversity, equity, and inclusion approaches within scientific communities.

Within the global scientific community, there are disparate approaches to diversity, equity, and inclusion (DEI) practices, leading to inequalities that hinder progress. Here, we frame this problem through historical perspectives in the global north and propose a DEI framework adaptable by institutions regardless of location, improving the academic environment for researchers globally.

Developing a fast-track discharge protocol for patients with cerebral aneurysms treated via neuroendovascular techniques.

INTRODUCTION: As we emerge from the current pandemic, hospitals, staff, and resources will need to continue to adjust to meet ongoing healthcare demands. Lessons learned during past shortages can be used to optimize peri-procedural protocols to safely improve the utilization of hospital resources. METHODS: Retrospective review of patients who underwent elective endovascular intracranial aneurysm treatment was performed. Multivariable logistic regression was used to identify factors associated with patients who were able to be discharged within 24 h of elective procedures. Rates of complications (particularly readmission) were determined. RESULTS: 330 patients underwent elective endovascular aneurysm treatment with 86 (26.1%) discharged within 24 h. Factors associated with earlier discharge included procedure years (2019-2021) and male sex. Patients were more likely to be discharged later (after 24 h) if they underwent stent-coil embolization or flow-diversion. There was no association between discharge timing and likelihood of readmission. DISCUSSION: Our review highlights the safety of earlier discharge and allowed us to prepare a fast-track protocol for same-day discharge in these patients. This protocol will be studied prospectively in the next phase of this study. As we gain more comfort with emerging, minimally invasive endovascular therapies, we hope to safely achieve same-day discharge on a protocolized and routine basis, reducing the demand of elective aneurysm treatments on our healthcare system. CONCLUSION: We retrospectively demonstrate that early discharge following elective aneurysm treatment is safe in our cohort and provide a fast-track pathway based on these findings for other centers developing similar protocols.

Molecular profiling of enteric nervous system cell lineages.

The enteric nervous system (ENS) is an extensive network of enteric neurons and glial cells that is intrinsic to the gut wall and regulates almost all aspects of intestinal physiology. While considerable advancement has been made in understanding the genetic programs regulating ENS development, there is limited understanding of the molecular pathways that control ENS function in adult stages. One of the limitations in advancing the molecular characterization of the adult ENS relates to technical difficulties in purifying healthy neurons and glia from adult intestinal tissues. To overcome this, we developed novel methods for performing transcriptomic analysis of enteric neurons and glia, which are based on the isolation of fluorescently labeled nuclei. Here we provide a step-by-step protocol for the labeling of adult mouse enteric neuronal nuclei using adeno-associated-virus-mediated gene transfer, isolation of the labeled nuclei by fluorimetric analysis, RNA purification and nuclear RNA sequencing. This protocol has also been adapted for the isolation of enteric neuron and glia nuclei from myenteric plexus preparations from adult zebrafish intestine. Finally, we describe a method for visualization and quantification of RNA in myenteric ganglia: Spatial Integration of Granular Nuclear Signals (SIGNS). By following this protocol, it takes ~3 d to generate RNA and create cDNA libraries for nuclear RNA sequencing and 4 d to carry out high-resolution RNA expression analysis on ENS tissues.

Development of a reference standard for the detection and quantification of Mycobacterium avium subsp. paratuberculosis by quantitative PCR.

Quantitative PCR (qPCR) has become a frequently employed direct method for the detection and quantification of Mycobacterium avium subsp. paratuberculosis (MAP). The quantity of MAP determined by qPCR, however, may be affected by the type of qPCR quantification standard used (PCR product, plasmid, genomic DNA) and the way in which standard DNA quantity is determined (absorbance, fluorescence). In practice, this can be reflected in the inability to properly compare quantitative data from the same qPCR assays in different laboratories. Thus, the aim of this study was to prepare a prototype of an international MAP reference standard, which could be used to calibrate routinely used qPCR quantification standards in various laboratories to promote clinical data comparability. Considering stability, storage and shipment issues, a lyophilised fecal suspension artificially contaminated with a MAP reference strain was chosen as the most suitable form of the standard. The effect of five types of lyophilisation matrices on standard stability was monitored on 2-weeks interval basis for 4 months by F57 qPCR. The lyophilisation matrix with 10% skimmed milk provided the best recovery and stability in time and was thus selected for subsequent comparative testing of the standard involving six diagnostic and research laboratories, where DNA isolation and qPCR assay procedures were performed with the parallel use of the identical supplied genomic DNA solution. Furthermore, the effect of storage conditions on the standard stability was tested for at least 6 months. The storage at room temperature in the dark and under light, at + 4 °C, - 20 °C and - 80 °C showed no significant changes in the stability, and also no substantial changes in MAP viability were found using phage amplification assay. The prepared MAP quantification standard provided homogeneous and reproducible results demonstrating its suitability for utilisation as an international reference qPCR standard.

Deficiency of Microglial Autophagy Increases the Density of Oligodendrocytes and Susceptibility to Severe Forms of Seizures.

Excessive activation of mTOR in microglia impairs CNS homeostasis and causes severe epilepsy. Autophagy constitutes an important part of mTOR signaling. The contribution of microglial autophagy to CNS homeostasis and epilepsy remains to be determined. Here, we report that ATG7KO mice deficient for autophagy in microglia display a marked increase of myelination markers, a higher density of mature oligodendrocytes (ODCs), and altered lengths of the nodes of Ranvier. Moreover, we found that deficiency of microglial autophagy (ATG7KO) leads to increased seizure susceptibility in three seizure models (pilocarpine, kainic acid, and amygdala kindling). We demonstrated that ATG7KO mice develop severe generalized seizures and display nearly 100% mortality to convulsions induced by pilocarpine and kainic acid. In the amygdala kindling model, we observed significant facilitation of contralateral propagation of seizures, a process underlying the development of generalized seizures. Taken together, our results reveal impaired microglial autophagy as a novel mechanism underlying altered homeostasis of ODCs and increased susceptibility to severe and fatal generalized seizures.

Enteric glia as a source of neural progenitors in adult zebrafish.

The presence and identity of neural progenitors in the enteric nervous system (ENS) of vertebrates is a matter of intense debate. Here, we demonstrate that the non-neuronal ENS cell compartment of teleosts shares molecular and morphological characteristics with mammalian enteric glia but cannot be identified by the expression of canonical glial markers. However, unlike their mammalian counterparts, which are generally quiescent and do not undergo neuronal differentiation during homeostasis, we show that a relatively high proportion of zebrafish enteric glia proliferate under physiological conditions giving rise to progeny that differentiate into enteric neurons. We also provide evidence that, similar to brain neural stem cells, the activation and neuronal differentiation of enteric glia are regulated by Notch signalling. Our experiments reveal remarkable similarities between enteric glia and brain neural stem cells in teleosts and open new possibilities for use of mammalian enteric glia as a potential source of neurons to restore the activity of intestinal neural circuits compromised by injury or disease.

Spinal Cord Stimulation for the Treatment of Chronic Pain Reduces Opioid Use and Results in Superior Clinical Outcomes When Used Without Opioids.

BACKGROUND: Chronic pain causes a significant burden to the US health care system, is difficult to treat, and remains a significant contributor to increased opioid use in the United States. Spinal cord stimulation (SCS) has been FDA approved for the treatment of chronic pain. OBJECTIVE: To evaluate the hypothesis that SCS reduces opioid use, and alone maintains clinical outcome measures of pain and psychosocial determinants of health. METHODS: In this prospective cohort study, we evaluated 86 patients undergoing SCS surgery for the treatment of chronic pain between September 2012 and August 2015. Preoperatively and postoperatively, patients completed the Numerical Rating Scale (NRS), McGill Pain Questionnaire (MPQ), Pain Catastrophizing Scale (PCS), Oswestry Disability Index (ODI), and Beck's Depression Inventory (BDI). VAS scores were retrospectively analyzed. RESULTS: Fifty-three patients used opioids before SCS implantation. The 33 nonusers had lower mean VAS, NRS, and ODI scores than both opioid groups at 1 yr and improved significantly at 1 yr on the VAS (P < .001), NRS (P < .001), MPQ (P = .002), PCS (P < .001), BDI (P = .04), and ODI (P = .002). After surgery, 41.5% remained opioids and 58.5% reduced/eliminated use. Discontinued (n = 29) or reduced (n = 2) use resulted in VAS, NRS, total MPQ, and ODI score reduction (P < .001, P = .002, P = .002, and P = .009 respectively). At 1 yr, survey scores in opioid users were unchanged. There was no difference between groups in revision or failure rates. CONCLUSION: Sixty-four percent of patients who were using opioids prior to SCS reduced (n = 2) or eliminated opioid use (n = 29) at 1 yr postoperatively. Patients who eliminated opioid use or never used opioids had superior clinical outcomes to those who continued use.

Enhanced methamphetamine self-administration in a neurodevelopmental rat model of schizophrenia.

RATIONALE: Substance abuse is more prevalent among patients with schizophrenia than in the general population. The considerable overlap in neurobiological disruptions thought to underlie each condition suggests that addictive behavior may represent a primary symptom of schizophrenia. OBJECTIVE: This study investigated drug-seeking in a neurodevelopmental animal model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. MATERIALS AND METHODS: At postnatal day 7, rats received an excitotoxic ventral hippocampus lesion or a sham procedure and were trained as adults to self-administer methamphetamine (0.1 mg/kg/infusion) or respond for natural reinforcement (water or food). RESULTS: NVHL rats were faster than shams to acquire the operant response for either drug self-administration or water reinforcement, suggesting that simple instrumental learning may be enhanced in these animals. NVHL and sham rats displayed no differences in fixed-ratio (FR) responding for either methamphetamine or food, and both groups of animals were equally sensitive to methamphetamine dose changes (0.05, 0.1, or 0.2 mg/kg/infusion). However, under a progressive-ratio (PR) schedule, NVHL animals reached significantly higher break points (NVHL 18 infusions; sham 12 infusions) for methamphetamine but not food reinforcement, suggesting enhanced motivation to acquire drug and/or elevated incentive value of the drug that did not generalize to another form of reinforcement. CONCLUSIONS: These data indicate that developmental disruption of the hippocampus elevates rats' vulnerability to drug-seeking behavior under PR conditions. Furthermore, drug self-administration in the NVHL animal emulates addictive behavior in schizophrenia, making this model useful for investigating the mechanisms of dual diagnosis, including the neurobiological and behavioral similarities between addiction and schizophrenia.

Using MMI Comments for Medical School Admissions Decision-Making.

This article was migrated. The article was marked as recommended. Introduction Multiple mini-interview (MMI) comments can help to reveal an underlying personality or behavioral flaw that the numerical scores are not designed to illustrate. The importance of the comments provided by interviewers has not been documented in the literature. This study sought to examine whether MMI comments influenced admission committee decision-making. Methods Five thousand de-identified interview comments from a subset of 625 medical school applicants were reviewed by study raters who followed a rubric that outlined scoring assignments based upon the number of positive and negative statements made by MMI interviewers. The presence of extremely negative MMI comments was also evaluated. Results MMI score strongly correlated with MMI comment score assigned by the raters and contributed to overall committee score and decision for acceptance or rejection to medical school. The presence of one negative outlier comment score alone did not impact committee score or acceptance; however, when extremely negative attributes were identified by study raters within an outlier comment, this was associated with a reduction of final committee score and higher incidence of rejection. Conclusions A strong correlation existed between the MMI comments and overall MMI score. Both MMI comments and MMI scores predict acceptance to medical school. The additional value of the MMI comments lies in the extremely negative outlier comments.