Exploring clinical markers of Axon degeneration processes in Chemotherapy-induced peripheral neuropathy among young adults receiving vincristine or paclitaxel.

BACKGROUND: Approximately 70% of patients receiving neurotoxic chemotherapy (e.g., paclitaxel or vincristine) will develop chemotherapy-induced peripheral neuropathy. Despite the known negative effects of CIPN on physical functioning and chemotherapy dosing, little is known about how to prevent CIPN. The development of efficacious CIPN prevention interventions is hindered by the lack of knowledge surrounding CIPN mechanisms. Nicotinamide adenine dinucleotide (NAD+) and cyclic-adenosine diphosphate ribose (cADPR) are potential markers of axon degeneration following neurotoxic chemotherapy, however, such markers have been exclusively measured in preclinical models of chemotherapy-induced peripheral neuropathy (CIPN). The overall objective of this longitudinal, observational study was to determine the association between plasma NAD+, cADPR, and ADPR with CIPN severity in young adults receiving vincristine or paclitaxel. METHODS: Young adults (18-39 years old) beginning vincristine or paclitaxel were recruited from Dana-Farber Cancer Institute. Young adults completed the QLQ-CIPN20 sensory and motor subscales and provided a blood sample prior to starting chemotherapy (T1) and at increasing cumulative vincristine (T2: 3-5 mg, T3: 7-9 mg) and paclitaxel (T2: 300-500 mg/m2, T3: 700-900 mg/m2) dosages. NAD+, cADPR, and ADPR were quantified from plasma using mass spectrometry. Metabolite levels and QLQ-CIPN20 scores over time were compared using mixed-effects linear regression models and/or paired two-sample tests. RESULTS: Participants (N = 50) were mainly female (88%), white (80%), and receiving paclitaxel (78%). Sensory and motor CIPN severity increased from T1-T3 (p < 0.001). NAD+ (p = 0.28), cADPR (p = 0.62), and ADPR (p = 0.005) values decreased, while cADPR/NAD+ ratio increased from T1-T3 (p = 0.50). There were no statistically significant associations between NAD + and QLQ-CIPN20 scores over time. CONCLUSIONS: To our knowledge, this is the first study to measure plasma NAD+, cADPR, and ADPR among patients receiving neurotoxic chemotherapy. Although, no meaningful changes in NAD+, cADPR, or cADPR/NAD+ were observed among young adults receiving paclitaxel or vincristine. Future research in an adequately powered sample is needed to explore the clinical utility of biomarkers of axon degeneration among patients receiving neurotoxic chemotherapy to guide mechanistic research and novel CIPN treatments.

Investigating the efficiency of electrocoagulation using similar/dissimilar electrodes for the detoxification of Coralene Rubine dye: a cost effective approach.

Efficient treatment of textile dyeing wastewater can be achieved through electrocoagulation (EC) with minimal sludge production; however, the selection of the appropriate electrode is essential in lowering overall costs. Also, the reuse of the treated aqueous azo dye solution from this process has not been explored in detail. With these objectives, this study aims to treat synthetic azo dye solutions and achieve high colour removal efficiency (CRE%) using similar (Ti-Ti) and dissimilar (Ti-Cu) metal electrodes through EC with an attempt to reduce the cost. The aqueous Coralene Rubine GFL azo dye was used to examine the efficiency and cost of the EC process. X-Ray Photoelectron Spectroscopy was used to study the EC mechanism, while High Performance Liquid Chromatography was used to analyse the degradation of the dye and the formation of intermediate compounds. The concentration of metal ions in the treated dye solution was quantified using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), with Ti-Ti treated solution having 14.20 mg/L concentration of Ti and Ti-Cu treated solution having 0.078 mg/L of Ti and 0.001 mg/L of Cu, respectively. Colour removal efficiency of 99.49% was obtained for both electrode sets, with a lower operating time and voltage for dissimilar metal combination. Ecotoxicity studies showed negligible toxicity of Ti-Cu treated dye samples compared to untreated solutions. Survival rate, protein estimation, and catalase activity was used to validate the treatment method's efficacy. The study found that the dissimilar electrode material exhibited reduced toxicity due to the presence of heavy metals below the permissible limit.

Electrocoagulation using Ti/Ti for the remediation and reuse of aqueous Dispersive Blue-79.

The entire ecology is contaminated by the synthetic dyes that are widely utilised in the textile industries. They can be handled using a variety of technologies, but an eco-friendly method called electrocoagulation has been used to prevent additional contamination. Textile wastewater containing disperse dyes are successfully treated in Electrocoagulation (EC) utilizing Al, Fe, and Stainless Steel (SS), but it is not cost effective, also the treated water contains certain mg/L of the metals used, along with dye components, which obstructs the reuse of the same. The effects of initial pH, applied voltage, dye concentration, supporting electrolyte, and treatment time on the colour removal efficiency (CRE) and consumption of energy were examined in EC process followed by activated charcoal filtration (hybrid process) with a monopolar Ti/Ti electrode on the remediation of aqueous solution of Dispersive Blue-79 (dye 3G). The maximum CREobtained was 99.4%, chemical oxygen demand (COD) 93%, and biological oxygen demand (BOD) 85%, under the following optimized operating conditions, applied voltage 15 V, pH = 7, concentration of dye, electrolyte 110 mg/L, 0.2 g/L and time = 15 min. The overall operating cost for the treatment of aqueous dye 3G was 0.455US/m3. The mechanism of EC was studied using XPS analysis in the sludge obtained. For the purpose of the reuse, FTIR, AAS, and ICP-OES analysis were done and compared with the aqueous dye 3G, after EC and hybrid process to ensure the maximum removal of the degraded dye components and metal. ICP-OES results showed that there were no traces of metal in the treated aqueous dye 3G using this method. Throughout the study, the experimental outcomes indicated that the hybrid process upgraded the quality of the treated aqueous dye 3G.

Advanced Nursing Practice and Advanced Practice Nursing roles within low and lower-middle-income countries.

INTRODUCTION: Population health initiatives rely on the availability and skills of an appropriate workforce to meet required goals. One global workforce initiative with demonstrated ability to expand health care services and improve access to care is the development of Advanced Nursing Practice and Advanced Practice Nursing roles. Given the sparse published information about these roles in Low and Lower-Middle-Income countries, this study seeks to describe their development and application in these countries. DESIGN: The researchers developed a descriptive cross-sectional multilingual survey for online distribution to nursing experts within the targeted countries. Survey questions addressed demographic information on the population served, Advanced Nursing Practice and Advanced Practice Nursing titles, the time frame and rationale for creating the title, and how the roles relate to the International Council of Nurses' Advanced Practice Nursing guidelines characteristics of education, practice, and regulation. RESULTS: Of the 167 responses received, only 24 participants met the inclusion criteria. This represented five low-income countries and nineteen lower-middle-income countries from four World Bank regions. Seventy-one roles were identified. Roles emerged predominantly over the last 20 years, focusing on care for underserved populations, with an almost even spread across primary and acute care settings. There were differences in education, practice, and regulation amongst the roles. Roles that required a master's education or higher with practice-related characteristics had a broader scope of practice, which is consistent with international guidelines. CONCLUSION: This paper describes how Advanced Nursing Practice and Advanced Practice Nursing roles from Low and Lower Middle-Income Countries have been implemented to address gaps in service and highlights disparities in education, practice and regulation compared to international guidelines. Maintaining and increasing support from organizations and universities internationally may be required to assist in developing and expanding educational programs for advanced nursing roles in these countries. CLINICAL RELEVANCE: Understanding how these advanced nursing roles are operationalized in relation to education, practice, and regulation in Low and Lower-Middle-Income countries can provide baseline information that will inform workforce development policies to address healthcare needs in similar jurisdictions.

Rehabilitation Support via Postcard (RSVP): A Randomised Controlled Trial of a Postcard to Promote Uptake of Cardiac Rehabilitation.

PURPOSE: The aim was to increase cardiac rehabilitation (CR) uptake using a novel intervention, Rehabilitation Support Via Postcard (RSVP), among patients with acute myocardial infarction discharged from two major hospitals in Hunter New England Local Health District (HNELHD), New South Wales, Australia. METHODS: The RSVP trial was evaluated using a two-armed randomised controlled trial design. Participants (N=430) were recruited from the two main hospitals in HNELHD, and enrolled and randomised to either the intervention (n=216) or control (n=214) group over a six-month period. All participants received usual care; however, the intervention group received postcards promoting CR attendance between January and July 2020. The postcard was ostensibly written as an invitation from the patient's admitting medical officer to promote timely and early uptake of CR. The primary outcome was CR attendance at outpatient HNELHD CR services in the 30-days post-discharge. RESULTS: Fifty-four percent (54%) of participants who received RSVP attended CR, compared to 46% in the control group; however this difference was not statistically significant (odds ratio [OR]=1.4, 95% confidence interval [CI]=0.9-2.0, p=0.11). Exploratory post-hoc analysis among four sub-groups (i.e., Indigeneity, gender, age and rurality), found that the intervention significantly increased attendance in males (OR=1.6, 95%CI=1.0-2.6, p=0.03) but had no significant impact on attendance for other sub-groups. CONCLUSIONS: While not statistically significant, postcards increased overall CR attendance by 8%. This strategy may be useful to increase attendance, particularly in men. Alternative strategies are necessary to increase CR uptake among women, Indigenous people, older people and people from regional and remote locations.

The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.

During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates a critical threonine (T410) in the activation loop. Thus, Eya1 inactivates aPKC, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation. Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants.

Cardiac rehabilitation in the acute care setting: Integrative review.

BACKGROUND: Phase one cardiac rehabilitation (CR) is an essential component of care for patients with coronary heart disease. With optimal program delivery, health outcomes can be improved. OBJECTIVES: To conduct an integrative review that explores Phase one CR for patients hospitalised with coronary heart disease. DESIGN: Integrative literature review (2003-2014) Data sources: The literature search included Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Experta Medica Database (EMBASE), Psycinfo, Clinical Practice Guidelines Portal, Cochrane Library, Clinical Evidence (BMJ) and Google Scholar. REVIEW METHODS: The Joanna Briggs Institute critical appraisal tools relevant to study methodology were utilised. Studies included for review were peer reviewed, published in English. Studies included Phase one CR intervention/s or the provision of education to patients diagnosed with coronary heart disease in the acute care setting prior to hospital discharge. RESULTS: In the past decade cardiac researchers have predominantly focused on patients and health professionals perceptions, CR interventions, and patient education. Factors that impede delivery of Phase one CR, such as time, workload etc. were also reported. CONCLUSIONS: The implementation of Phase one CR delivery requires optimisation to enable patients with coronary heart disease to achieve positive health outcomes post hospitalisation. Future interventions should address the factors that impede delivery of Phase one CR.

Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration.

Establishment of neuronal circuitry depends on both formation and refinement of neural connections. During this process, target-derived neurotrophins regulate both transcription and translation to enable selective axon survival or elimination. However, it is not known whether retrograde signaling pathways that control transcription are coordinated with neurotrophin-regulated actions that transpire in the axon. Here we report that target-derived neurotrophins coordinate transcription of the antiapoptotic gene bclw with transport of bclw mRNA to the axon, and thereby prevent axonal degeneration in rat and mouse sensory neurons. We show that neurotrophin stimulation of nerve terminals elicits new bclw transcripts that are immediately transported to the axons and translated into protein. Bclw interacts with Bax and suppresses the caspase6 apoptotic cascade that fosters axonal degeneration. The scope of bclw regulation at the levels of transcription, transport, and translation provides a mechanism whereby sustained neurotrophin stimulation can be integrated over time, so that axonal survival is restricted to neurons connected within a stable circuit.

Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as Sonic Hedgehog co-receptors to promote proliferation.

Sonic Hedgehog (Shh) signaling is crucial for growth, cell fate determination, and axonal guidance in the developing nervous system. Although the receptors Patched (Ptch1) and Smoothened (Smo) are required for Shh signaling, a number of distinct co-receptors contribute to these critical responses to Shh. Several membrane-embedded proteins such as Boc, Cdo, and Gas1 bind Shh and promote signaling. In addition, heparan sulfate proteoglycans (HSPGs) have also been implicated in the initiation of Shh responses. However, the attributes of HSPGs that function as co-receptors for Shh have not yet been defined. Here, we identify HSPGs containing a glypican 5 core protein and 2-O-sulfo-iduronic acid residues at the nonreducing ends of the glycans as co-receptors for Shh. These HSPG co-receptors are expressed by cerebellar granule cell precursors and promote Shh binding and signaling. At the subcellular level, these HSPG co-receptors are located adjacent to the primary cilia that act as Shh signaling organelles. Thus, Shh binds to HSPG co-receptors containing a glypican 5 core and 2-O-sulfo-iduronic acid to promote neural precursor proliferation.

Medical futility in the care of non-competent terminally ill patient: nursing perspectives and responsibilities.

BACKGROUND: Debate continues on the use of medical technology to prolong life independent of the quality of the outcomes. As a consequence, acute care nurses often find themselves in situations where they are asked to carry out physician's orders, in the context of a patient's deteriorating condition, which may be at odds with professional and personal ethical standards. This can cause nurses to become distressed when struggling with the ethical dilemmas involved with medical futility. PURPOSE: This paper is a perspective on nursing considerations of our Code of Ethics and the concept of medical futility in acute nursing care. The utility of the Code is examined through a clinical vignette. METHOD: A database search using the keywords medical futility and acute care limited to 2008 to 2012 and a secondary hand search of these references identified thirty journal publications. The Code of Ethics was examined via a clinical scenario pertinent to an acute environment. FINDINGS: This paper examines the ethical principles that underpin nursing and illustrates how the code of ethics may serve as sign posts when faced with caring for a terminally ill patient that is inappropriately managed. CONCLUSION: Understanding how individual nurses may address ethical dilemmas when faced with medical futility can better enable the nurse to fulfil their role as patient advocate, health promoter and alleviator of suffering. Ongoing education and communication to decrease any ambiguity or anguish associated with a patient's impending death optimises apt outcomes.

Management of the acute cardiac patient in the Australian rural setting: a 12 month retrospective study.

BACKGROUND: Rural cardiac patients may require transfer to tertiary health services for ongoing acute cardiac management. The time required to transfer is a consideration in determining appropriate clinical care. There is little published data reporting acute cardiac management in the Australian regional setting that reviews factors determining transfer to a tertiary centre. PURPOSE: This paper reports the findings of a quantitative, retrospective study conducted to identify demographic differences and potential predictors to urban transfer for ongoing acute cardiac management for patients presenting to a regional hospital with suspected acute myocardial infarction. METHODS: Using a purpose designed tool an audit of 204 files from June 2009 to July 2010 was conducted for all patients admitted to a regional hospital having a discharge diagnosis of acute myocardial infarction or angina. Patient demographics, clinical outcomes, concordance with treatment guidelines, and possible predictors of treatment decisions were investigated. FINDINGS: Patients younger than 65 years (p<0.001), unemployed (p<0.01) and with acute electrocardiograph changes (p<0.01) were more likely to be transferred to a tertiary centre. Treatment guidelines concordance for acute cardiac care ranged from 70% to 79% for all patients. CONCLUSIONS: Although presenting patients were treated in a timely manner consistent with national guidelines, to be younger, unemployed or have electrocardiograph changes was a greater predictor to urban transfer. It is unknown if these differences in transferring or not to a tertiary centre contribute to poorer long-term cardiac outcomes for rural patients. Further evaluations are warranted.

Timely treatment for acute myocardial infarction and health outcomes: an integrative review of the literature.

BACKGROUND: Coronary heart disease is the most common condition affecting Australians. The time sensitive nature of treating ST-segment elevation myocardial infarction (STEMI) has been the subject of extensive research for several years. Despite important advances in strategies to reduce time to treatment, time continues to represent a major determinant of mortality and morbidity. Door to balloon time (DTBT) is a key indicator of quality of care for STEMI. Nurses play a pivotal role in streamlining the care processes to influence timely management of STEMI. PURPOSE: The aim of this paper is to review the evidence on the time to treat STEMI, the associated factors impacting upon health outcomes and explore systems of care that reduce time to treatment, using an integrative review approach. METHOD: Established databases were searched from 2000 to 2012. The search terms 'myocardial infarction', 'emergency medicine', 'angioplasty balloon', 'time factors', 'treatment outcome', 'mortality', 'prognosis', 'female', 'age factors', and 'readmission', were used in various combinations. Research studies that addressed the aims of this paper were examined. FINDINGS: Twenty-nine papers were included in this integrative review. The literature demonstrates a strong relationship between shorter DTBT and reduced in-hospital mortality. Factors such as age, gender, time of presentation and co-morbid condition were associated with increased in-hospital mortality. There is sparse literature examining the effect timely reperfusion has on longer-term mortality and other longer-term outcomes such as readmission rates and occurrence of heart failure. Additionally, strategies that effectively reduced DTBT were identified, yet little has been reported on the impact reduced DTBT has had upon health outcomes and whether these improvements were sustained. CONCLUSION: Whilst the importance of timely reperfusion is now well recognised, additional efforts to streamline the process of care and demonstrate sustained improvement for STEMI patients is required. Nurses in the areas of emergency medicine and cardiac care, play an essential role in facilitating this.

Spiritual care for older people living in the community: A scoping review.

BACKGROUND: The population of older people should be supported to enjoy optimal quality of life. Health professionals should consider a range of interventions that support the older population to maintain their quality of life. One such interventional approach involves spiritual care. OBJECTIVE: To explore what is known about spiritual care approaches for older people living in the community. METHODS: Scoping review informed by Joanna Briggs Institute guidelines. Eight electronic databases were searched: CINAHL, Ageline, PubMed, ProQuest Nursing & Allied Health, PsycINFO, Scopus, Garuda, and Neliti. The review included quantitative and qualitative primary peer-reviewed research studies focusing on spiritual care interventions for older people living in the community published between 2011 and 2021 in English or Bahasa Indonesia. The search was uploaded into an electronic citation manager and imported into Covidence for screening. RESULTS: A total of 29 studies were included in the review. While the studies were conducted in five continents, most were reported from the Asian continent. Five key issues based on the outcome of interventions were found namely psychological, physical, spiritual, multidisciplinary approach, and social connection. CONCLUSION: This scoping review identifies spiritual interventions conducted across many countries have been implemented for older people living in the community. Although there are review limitations and further research is needed, these spiritual interventions, both faith-based and non-faith-based, are identified as useful to support the well-being of older people.

Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor.

BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining "staple" and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.

Satellite glial contact enhances differentiation and maturation of human iPSC-derived sensory neurons.

Sensory neurons generated from induced pluripotent stem cells (iSNs) are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop a pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for investigating human peripheral neuropathies.

A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma.

Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1-38 functioned as an EYA antagonist and opposed SHH signaling. DS-1-38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB. SIGNIFICANCE: Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain cancer.

Sensory neuropathy attributable to loss of Bcl-w.

Small fiber sensory neuropathy is a common disorder in which progressive degeneration of small-diameter nociceptors causes decreased sensitivity to thermal stimuli and painful sensations in the extremities. In the majority of patients, the cause of small fiber sensory neuropathy is unknown, and treatment options are limited. Here, we show that Bcl-w (Bcl-2l2) is required for the viability of small fiber nociceptive sensory neurons. Bcl-w(-/-) mice demonstrate an adult-onset progressive decline in thermosensation and a decrease in nociceptor innervation of the epidermis. This denervation occurs without cell body loss, indicating that lack of Bcl-w results in a primary axonopathy. Consistent with this phenotype, we show that Bcl-w, in contrast to the closely related Bcl-2 and Bcl-xL, is enriched in axons of sensory neurons and that Bcl-w prevents the dying back of axons. Bcl-w(-/-) sensory neurons exhibit mitochondrial abnormalities, including alterations in axonal mitochondrial size, axonal mitochondrial membrane potential, and cellular ATP levels. Collectively, these data establish bcl-w(-/-) mice as an animal model of small fiber sensory neuropathy and provide new insight regarding the role of Bcl-w and of mitochondria in preventing axonal degeneration.

Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN.

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN).

An evaluation of a structured learning programme as a component of the clinical practicum in final year bachelor of nursing programme: a pre-post-test analysis.

AIM AND OBJECTIVE: To evaluate the impact of a structured learning programme as a component of the clinical practicum in final year bachelor of nursing course on the student's report of their anxiety and self-efficacy pre-post programme participation. BACKGROUND: Student anxiety and low levels of self-efficacy are known to affect the quality of clinical learning. A three-day structured learning programme at the commencement of an acute care clinical placement was designed to reduce student anxiety and enhance self-efficacy. DESIGN: A pre-post test design. OUTCOME MEASURES: The hospital anxiety and depression scale (The HAD) and the general self-efficacy scale (GSES-12) were administered prior to the commencement of the structured learning programme (time one) and at the end of the programme (time two). RESULTS: One hundred and twenty final year students undertaking an acute care clinical placement participated in the programme in three cohorts and completed the questionnaires at time one and 118 at time two. FINDINGS: Students levels of anxiety >8 with The HAD pre-post programme 53 vs. 30% (p < 0·001). Levels of self-efficacy <40 with the GSES-12 pre-post programme were 7 vs. 4% (p < 0·001). CONCLUSIONS: Participation in the structured learning programme resulted in a statistically significant reduction in student anxiety and increase in self-efficacy across the three cohort groups. This effect can be achieved with the development of a relatively low cost/low technology structured learning programme that is part of an acute care clinical placement. RELEVANCE TO CLINICAL PRACTICE: Nurse educators should not assume that students are less anxious about their acute care clinical placements as the semester proceeds. There is a typical correlation between increased anxiety and decreased self-efficacy which is likely to impact on student learning in the clinical setting. Significant results can be achieved with a relatively low cost and a low technology enabling intervention.

Diversity of developing peripheral glia revealed by single-cell RNA sequencing.

The peripheral nervous system responds to a wide variety of sensory stimuli, a process that requires great neuronal diversity. These diverse neurons are closely associated with glial cells originating from the neural crest. However, the molecular nature and diversity among peripheral glia are not understood. Here, we used single-cell RNA sequencing to profile developing and mature glia from somatosensory dorsal root ganglia and auditory spiral ganglia. We found that glial precursors (GPs) in these two systems differ in their transcriptional profiles. Despite their unique features, somatosensory and auditory GPs undergo convergent differentiation to generate molecularly uniform myelinating and non-myelinating Schwann cells. By contrast, somatosensory and auditory satellite glial cells retain system-specific features. Lastly, we identified a glial signature gene set, providing new insights into commonalities among glia across the nervous system. This survey of gene expression in peripheral glia constitutes a resource for understanding functions of glia across different sensory modalities.