Spinal cord stimulation attenuates paclitaxel-induced gait impairment and mechanical hypersensitivity via peripheral neuroprotective mechanisms in tumor-bearing rats.

BACKGROUND: Taxanes such as paclitaxel (PTX) induce dose-dependent chemotherapy-induced peripheral neuropathy (CIPN), which is associated with debilitating chronic pain and gait impairment. Increased macrophage-related proinflammatory activities have been reported to mediate the development and maintenance of neuropathic pain. While spinal cord stimulation (SCS) has been used for a number of pain conditions, the mechanisms supporting its use for CIPN remain to be elucidated. Thus, we aimed to examine whether SCS can attenuate Schwann cell-mediated and macrophage-mediated neuroinflammation in the sciatic nerve of Rowlette Nude (RNU) rats with PTX-induced gait impairment and mechanical hypersensitivity. METHODS: Adult male tumor-bearing RNU rats were used for this study examining PTX treatment and SCS. Gait and mechanical hypersensitivity were assessed weekly. Cytokines, gene expression, macrophage infiltration and polarization, nerve morphology and Schwann cells were examined in sciatic nerves using multiplex immunoassay, bulk RNA sequencing, histochemistry and immunohistochemistry techniques. RESULTS: SCS (50 Hz, 0.2 milliseconds, 80% motor threshold) attenuated the development of mechanical hypersensitivity (20.93±0.80 vs 12.23±2.71 grams, p<0.0096) and temporal gait impairment [swing (90.41±7.03 vs 117.27±9.71%, p<0.0076), and single stance times (94.92±3.62 vs 112.75±7.27%, p<0.0245)] induced by PTX (SCS+PTX+Tumor vs Sham SCS+PTX+Tumor). SCS also attenuated the reduction in Schwann cells, myelin thickness and increased the concentration of anti-inflammatory cytokine interleukin (IL)-10. Bulk RNA sequencing revealed differential gene expression after SCS, with 607 (59.2%) genes upregulated while 418 (40.8%) genes were downregulated. Notably, genes related to anti-inflammatory cytokines and neuronal growth were upregulated, while genes related to proinflammatory-promoting genes, increased M2γ polarization and decreased macrophage infiltration and Schwann cell loss were downregulated. CONCLUSION: SCS may attenuate PTX-induced pain and temporal gait impairment, which may be partly attributed to decreases in Schwann cell loss and macrophage-mediated neuroinflammation in sciatic nerves.

The Role of Early Life Gut Mycobiome on Child Health.

The human gut microbiota is composed of bacteria (microbiota or microbiome), fungi (mycobiome), viruses, and archaea, but most of the research is primarily focused on the bacterial component of this ecosystem. Besides bacteria, fungi have been shown to play a role in host health and physiologic functions. However, studies on mycobiota composition during infancy, the factors that might shape infant gut mycobiota, and implications to child health and development are limited. In this review, we discuss the factors likely shaping gut mycobiota, interkingdom interactions, and associations with child health outcomes and highlight the gaps in our current knowledge of this ecosystem.

Impact of psychosocial factors on the success of neuromodulation treatment for patients with persistent pain.

INTRODUCTION: Significant interindividual variability in spinal cord stimulation (SCS) outcomes exists. Due to its high cost and risks of complications, criteria to guide patient selection for SCS trials and their outcomes would be helpful. With increased focus on the use of patient-reported outcomes to improve care, we aim to evaluate the National Institute of Health Patient Reported Outcome Measurement Information System measures for an association with successful SCS trials in patients with persistent pain. METHODS: Our prospective, observational study enrolled 60 patients with persistent pain who underwent an SCS trial. Patients completed demographic and Patient Reported Outcome Measurement Information System computer adaptive test (PROMIS CAT) assessments to measure self-reported pain interference, depression, anxiety, physical functioning, and sleep disturbance at the time they presented for placement of their trial device. RESULTS: Of the 58 patients who underwent successful electrode placement, 11 had an unsuccessful trial. There were no differences in patient demographics between patients with a successful and an unsuccessful trial. Patients who had a successful SCS trial reported lower pre-trial levels of anxiety, depression, and sleep disturbance and decreased post-trial levels of depression, sleep disturbance, and pain interference. CONCLUSIONS: We found that patients with high levels of depression, anxiety, and sleep disturbance using the PROMIS CAT were predictive of unsuccessful trials. In addition, we found that patients with successful SCS trials reported lower levels of these domains on PROMIS CAT administered at the end of the trial.

Enhancer-activated RET confers protection against oxidative stress to KMT2A-rearranged acute myeloid leukemia.

Ectopic activation of rearranged during transfection (RET) has been reported to facilitate lineage differentiation and cell proliferation in different cytogenetic subtypes of acute myeloid leukemia (AML). Herein, we demonstrate that RET is significantly (p < 0.01) upregulated in AML subtypes containing rearrangements of the lysine methyltransferase 2A gene (KMT2A), commonly referred to as KMT2A-rearranged (KMT2A-r) AML. Integrating multi-epigenomics data, we show that the KMT2A-MLLT3 fusion induces the development of CCCTC-binding (CTCF)-guided de novo extrusion enhancer loop to upregulate RET expression in KMT2A-r AML. Based on the finding that RET expression is tightly correlated with the selective chromatin remodeler and mediator (MED) proteins, we used a small-molecule inhibitor having dual inhibition against RET and MED12-associated cyclin-dependent kinase 8 (CDK8) in KMT2A-r AML cells. Dual inhibition of RET and CDK8 restricted cell proliferation by producing multimodal oxidative stress responses in treated cells. Our data suggest that epigenetically enhanced RET protects KMT2A-r AML cells from oxidative stresses, which could be exploited as a potential therapeutic strategy.

Identification of Regulatory Elements in Primary Sensory Neurons Involved in Trauma-Induced Neuropathic Pain.

Chronic pain is a significant public health issue that is often refractory to existing therapies. Here we use a multiomic approach to identify cis-regulatory elements that show differential chromatin accessibility and reveal transcription factor (TF) binding motifs with functional regulation in the rat dorsal root ganglion (DRG), which contain cell bodies of primary sensory neurons, after nerve injury. We integrated RNA-seq to understand how differential chromatin accessibility after nerve injury may influence gene expression. Using TF protein arrays and chromatin immunoprecipitation-qPCR, we confirmed C/EBPγ binding to a differentially accessible sequence and used RNA-seq to identify processes in which C/EBPγ plays an important role. Our findings offer insights into TF motifs that are associated with chronic pain. These data show how interactions between chromatin landscapes and TF expression patterns may work together to determine gene expression programs in rat DRG neurons after nerve injury.

Erratum: Complete head cerebral sensitivity mapping for diffuse correlation spectroscopy using subject-specific magnetic resonance imaging models: errata.

[This corrects the article on p. 1131 in vol. 13, PMID: 35414976.].

Implementing Best Practices for Decreasing Nurse Hesitancy to Call the Rapid Response Team: An Evidence-Based Quality Improvement Initiative.

BACKGROUND: Nurses, regardless of experience, sometimes wait for the Modified Early Warning Score to indicate physiological decline before initiating the hospital's Rapid Response Team (RRT). The goal of this quality improvement initiative was to reduce nurse hesitancy to call the RRT, as indicated by the monthly number of proactive calls before the Modified Early Warning Score increased and triggered an automated page. METHOD: Education, planned handoff communication, debriefing, and good catch emails were the educational strategies used in the implementation of the quality improvement initiatives, encouraging RRT calls sooner. Increasing RRT knowledge and communication is an evidence-based practice strategy to reduce nurse reluctance to call the RRT. RESULTS: After implementation, monthly proactive RRT calls increased (χ2 [1, n = 1,964] = 14.6085, p = .000159). Bedside interventions, unscheduled transfers, and Acute Physiologic and Chronic Health Evaluation scores did not differ. CONCLUSION: Education, structured handoff communication, and acknowledging good catches reduced nurses' reluctance to call the RRT proactively. [J Contin Educ Nurs. 2023;54(6):281-288.].

Spinal Cord Stimulation Increases Chemoefficacy and Prevents Paclitaxel-Induced Pain via CX3CL1.

INTRODUCTION: Despite increasing utilization of spinal cord stimulation (SCS), its effects on chemoefficacy, cancer progression, and chemotherapy-induced peripheral neuropathy (CIPN) pain remain unclear. Up to 30% of adults who are cancer survivors may suffer from CIPN, and there are currently no effective preventative treatments. MATERIALS AND METHODS: Through a combination of bioluminescent imaging, behavioral, biochemical, and immunohistochemical approaches, we investigated the role of SCS and paclitaxel (PTX) on tumor growth and PTX-induced peripheral neuropathy (PIPN) pain development in T-cell-deficient male rats (Crl:NIH-Foxn1rnu) with xenograft human non-small cell lung cancer. We hypothesized that SCS can prevent CIPN pain and enhance chemoefficacy partially by modulating macrophages, fractalkine (CX3CL1), and inflammatory cytokines. RESULTS: We show that preemptive SCS enhanced the antitumor efficacy of PTX and prevented PIPN pain. Without SCS, rats with and without tumors developed robust PIPN pain-related mechanical hypersensitivity, but only those with tumors developed cold hypersensitivity, suggesting T-cell dependence for different PIPN pain modalities. SCS increased soluble CX3CL1 and macrophages and decreased neuronal and nonneuronal insoluble CX3CL1 expression and inflammation in dorsal root ganglia. CONCLUSION: Collectively, our findings suggest that preemptive SCS is a promising strategy to increase chemoefficacy and prevent PIPN pain via CX3CL1-macrophage modulation.

Why They Stay and Why They Leave: Stay Interviews With Registered Nurses to Hear What Matters the Most.

Registered nurse retention is declining, with a national turnover rate in 2021 of 27%. After implementing a toolkit, nursing leaders in 1 organization completed 75 stay interviews with nurses in a cardiothoracic telemetry and a cardiothoracic surgical intensive care unit. Nurses reported that unit culture, team/peers, and scheduling were important in decisions to stay in their positions, but respondents considered leaving for salary, growth/development, and traveling opportunities. The stay interview process affords nurse leaders an opportunity to examine why nurses stay or leave and supports the development of targeted retention strategies.

Using the Culex pipiens sperm proteome to identify elements essential for mosquito reproduction.

Mature sperm from Culex pipiens were isolated and analyzed by mass spectrometry to generate a mature sperm proteome dataset. In this study, we highlight subsets of proteins related to flagellar structure and sperm motility and compare the identified protein components to previous studies examining essential functions of sperm. The proteome includes 1700 unique protein IDs, including a number of uncharacterized proteins. Here we discuss those proteins that may contribute to the unusual structure of the Culex sperm flagellum, as well as potential regulators of calcium mobilization and phosphorylation pathways that regulate motility. This database will prove useful for understanding the mechanisms that activate and maintain sperm motility as well as identify potential molecular targets for mosquito population control.

Ensuring Rapid Response Team Care Aligns With Patients' Limitations of Medical Therapy: A Quality Improvement Project.

BACKGROUND: Rapid response teams (RRTs) are designed to improve patient care during deterioration in clinical condition. LOCAL PROBLEM: Patients' desired limitations of medical therapy (LOMTs) were not documented or communicated to the RRT, and patients received care not aligned with their wishes. METHODS: A multidisciplinary team developed a process for improving documentation, communication of LOMTs, and care delivery on 3 medical cardiology units. The team implemented 3 Plan-Do-Study-Act (PDSA) cycles over 6 months. INTERVENTIONS: In cycle 1, team members taught the unit nurses, RRT members, and physicians to share LOMTs during handoff communications. Cycle 2 engaged case managers in LOMT documentation. In cycle 3, unit-based RRT simulation was conducted. RESULTS: All care delivered by the RRT aligned with the documented LOMTs. Documentation of LOMTs increased from 76% to 82.5% ( P = .014). CONCLUSIONS: Education, scripting, and simulation were successful strategies to ensure that care given during RRT events aligned with patients' wishes.

De novo methylation of histone H3K23 by the methyltransferases EHMT1/GLP and EHMT2/G9a.

Epigenetic modifications to histone proteins serve an important role in regulating permissive and repressive chromatin states, but despite the identification of many histone PTMs and their perceived role, the epigenetic writers responsible for generating these chromatin signatures are not fully characterized. Here, we report that the canonical histone H3K9 methyltransferases EHMT1/GLP and EHMT2/G9a are capable of catalyzing methylation of histone H3 lysine 23 (H3K23). Our data show that while both enzymes can mono- and di-methylate H3K23, only EHMT1/GLP can tri-methylate H3K23. We also show that pharmacologic inhibition or genetic ablation of EHMT1/GLP and/or EHMT2/G9a leads to decreased H3K23 methylation in mammalian cells. Taken together, this work identifies H3K23 as a new direct methylation target of EHMT1/GLP and EHMT2/G9a, and highlights the differential activity of these enzymes on H3K23 as a substrate.

Oxygen extraction efficiency and white matter lesion burden in older adults exhibiting radiological evidence of capillary shunting.

White matter lesions (WML) have been linked to cognitive decline in aging as well as in Alzheimer's disease. While hypoperfusion is frequently considered a cause of WMLs due to the resulting reduction in oxygen availability to brain tissue, such reductions could also be caused by impaired oxygen exchange. Here, we tested the hypothesis that venous hyperintense signal (VHS) in arterial spin labeling (ASL) magnetic resonance imaging (MRI) may represent a marker of impaired oxygen extraction in aging older adults. In participants aged 60-80 years (n = 30), we measured cerebral blood flow and VHS with arterial spin labeling, maximum oxygen extraction fraction (OEFmax) with dynamic susceptibility contrast, and WML volume with T1-weighted MRI. We found a significant interaction between OEFmax and VHS presence on WML volume (p = 0.02), where lower OEFmax was associated with higher WML volume in participants with VHS, and higher OEFmax was associated with higher WML volume in participants without VHS. These results indicate that VHS in perfusion-weighted ASL data may represent a distinct cerebrovascular aging pattern involving oxygen extraction inefficiency as well as hypoperfusion.

Improving PACU Throughput Using an Electronic Dashboard: A Quality Improvement Initiative.

PURPOSE: Patients boarding in a 14-bed postanesthesia care unit (PACU) impacted throughput in a large university hospital in West Virginia. The PACU and operating room (OR) boarder rate in 2019 was 12% (n = 1241) and 5% (n = 503), respectively. The purpose of this initiative was to improve PACU throughput by developing an efficient and evidence-based handoff communication process between the PACU and the medical-surgical floors. DESIGN: The design of the project was evidence-based quality improvement. METHODS: An interprofessional team created a nursing patient dashboard in the electronic medical record to be used during handoff communication between the PACU and medical-surgical floor nurses. The dashboard displayed real-time vital signs, patient history, medications, and laboratory results. When the patient met Aldrete score requirements for transfer, PACU nurses notified the floor that the patient was ready for transfer. After allowing 20 minutes for the floor nurse to view the dashboard, the PACU nurse and floor nurse spoke on the phone to discuss any outstanding questions. PACU and OR boarder rates were obtained from the electronic medical record 12 months before and after implementing the nursing patient dashboard. User feedback was gathered via plan-do-study-act cycles, posters, and interviews. FINDINGS: The electronic dashboard was a successful strategy to improve handoff communication between the PACU and receiving units. The dashboard was accepted by the staff with 70% (n = 24) of the comments being positive. A significant decrease in the number of PACU (χ2(1, n = 20,608) =122.63, P < .00001) and OR boarding (χ2 (1, n = 20,283) =14.55, P = .000136) of patients was found in the C-year compared to 2019. For patients who were boarded in the PACU, no significant difference in PACU delay duration was found (t(11) =1.49, P = .149) with the mean in 2019 of 166.96 (SD = 68.38) and the C-Year mean 132.84 (SD = 39.74). For patients who boarded in the OR, there was a significant difference (t(11) =15.590162, P <.00001) between groups for average duration of boarding with the mean in 2019 of 19.06 minutes (SD = 3.72) compared to 1.62 (SD = 1.1) in C-year. However, in July 2020 the PACU intermittently opened 2 flexible beds when the PACU was full, suggesting that OR boarding was not a reliable measure, but PACU boarding remained an accurate measure. CONCLUSIONS: The findings of this evidence-based quality improvement project demonstrated the usefulness of an electronic dashboard tool combined with verbal report to improve patient throughput by decreasing the number of patients boarding in the PACU.

Complete head cerebral sensitivity mapping for diffuse correlation spectroscopy using subject-specific magnetic resonance imaging models.

We characterize cerebral sensitivity across the entire adult human head for diffuse correlation spectroscopy, an optical technique increasingly used for bedside cerebral perfusion monitoring. Sixteen subject-specific magnetic resonance imaging-derived head models were used to identify high sensitivity regions by running Monte Carlo light propagation simulations at over eight hundred uniformly distributed locations on the head. Significant spatial variations in cerebral sensitivity, consistent across subjects, were found. We also identified correlates of such differences suitable for real-time assessment. These variations can be largely attributed to changes in extracerebral thickness and should be taken into account to optimize probe placement in experimental settings.

Erratum: Improved accuracy of cerebral blood flow quantification in the presence of systemic physiology cross-talk using multi-layer Monte Carlo modeling.

[This corrects the article DOI: 10.1117/1.NPh.8.1.015001.].

CCAAT enhancer binding protein gamma (C/EBP-γ): An understudied transcription factor.

The CCAAT enhancer binding protein (C/EBP) family of transcription factors are important transcriptional mediators of a wide range of physiologic processes. C/EBP-γ is the shortest C/EBP protein and lacks a canonical activation domain for the recruitment of transcriptional machinery. Despite its ubiquitous expression and ability to dimerize with other C/EBP proteins, C/EBP-γ has been studied far less than other C/EBP proteins, and, to our knowledge, no review of its functions has been written. This review seeks to integrate the current knowledge about C/EBP-γ and its physiologic roles, especially in cell proliferation, the integrated stress response, oncogenesis, hematopoietic and nervous system development, and metabolism, as well as to identify areas for future research.

Global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain.

BACKGROUND: Efforts to understand genetic variability involved in an individual's susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. METHODS: To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by chronic constriction injury (CCI) of the sciatic nerve and intra-plantar injection of complete Freund's adjuvant (CFA) in rats. RESULTS: Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of chromatin accessibility changes in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naïve and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models. CONCLUSIONS: Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG.

Implementing Trauma-Informed Strategies for Mothers of Infants with Neonatal Abstinence Syndrome.

PURPOSE: To improve outcomes of infants with neonatal abstinence syndrome (NAS) by implementing an evidence-based approach to care. METHODS: An interdisciplinary team developed and implemented an educational module about the elements and principles of trauma-informed care (TIC) and standardized education on NAS for mothers with substance use disorder (SUD). The team collaborated with community behavioral health professionals to secure the services of a certified recovery specialist. Primary outcome measures of average length of stay (LOS) and admissions to special care nursery (SCN) for NAS infants were analyzed. RESULTS: Following health care team education on TIC and implementation of the standardized NAS brochure, average LOS decreased significantly from 6.5 to 5.1 days from baseline period (January-December 2019) to the implementation period (February-June 2020; p = 0.03). There was no difference in SCN admission from the baseline period (February-June 2019) to the implementation period (February-June 2020). Referrals to certified recovery specialists did not change. CLINICAL IMPLICATIONS: Education on the impact of trauma on new mothers with SUD can promote collaboration between them and the neonatal team. Standardizing education for new mothers of infants with NAS can help to engage families of infants with NAS and improve clinical outcomes.

Critical Thinking Tools for Quality Improvement Projects.

TOPIC: This article explores the use of 4 quality improvement tools and 2 evidence-based practice tools that, when used within the nursing process, encourage critical thinking about quality issues. CLINICAL RELEVANCE: Patients and families expect to receive patient-centered, high-quality, and cost-effective care. Caring for critically ill patients is challenging and requires nurses to engage in quality improvement efforts to ensure that they provide evidence-based care. PURPOSE OF PAPER: To explore the use of critical thinking tools and evidence-based practice tools in assessing and diagnosing quality issues in the clinical setting. CONTENT COVERED: The nursing process serves as the framework for problem solving. Some commonly used critical thinking tools for assessing and diagnosing quality issues are described, including the Spaghetti Diagram, the 5 Whys, the Cause and Effect Diagram, and the Pareto chart.