ReActiv8 Stimulation Therapy vs. Optimal Medical Management: A Randomized Controlled Trial for the Treatment of Intractable Mechanical Chronic Low Back Pain (RESTORE Trial Protocol).

INTRODUCTION: Chronic low back pain (CLBP) is the leading cause of years lived with disability globally. The role of restorative neurostimulation in the treatment of patients with refractory mechanical CLBP and multifidus muscle dysfunction has been established in one randomized controlled trial (RCT) and several clinical studies that demonstrated both safety and clinical benefit. This post-market trial provides a direct comparison to optimized medical management to test the hypothesis that the addition of restorative neurostimulation to current care paradigms results in significant improvements in back pain-related disability. METHODS AND ANALYSIS: This trial will include people who have reported significant levels of back pain and back pain-related disability with symptoms that have persisted for longer than 6 months prior to enrollment and resulted in pain on most days in the 12 months prior to enrollment. Eligible patients will be randomized to either optimal medical management or optimal medical management plus ReActiv8® restorative neurostimulation therapy. Patient-reported outcomes will be collected at regular intervals out to the 1-year primary endpoint, at which time the patients in the control arm will be offered implantation with the ReActiv8 system. Assessment of each group will continue for an additional year. ETHICS AND DISSEMINATION: The RESTORE trial follows the principles of the Declaration of Helsinki. The WCG IRB acts as the Central Institutional Review Board (IRB) for most sites and some sites will receive local IRB approval prior to enrollment of patients. Each IRB assessed the protocol and related documentation. The protocol complies with Good Clinical Practice (GCP). All patients provide written informed consent to participate in the trial. PROTOCOL VERSION: Version C, 07 Sep 2022. CLINICALTRIALS: gov registration number. NCT04803214 registered March 17, 2021.

Restorative neurostimulation is a treatment for intractable CLBP associated with dysfunction of the multifidus muscle, which normally provides functional stability to the lumbar spine. To date, ReActiv8^® (Mainstay Medical) is the only neurostimulator specifically developed and approved for this indication. Electrical stimulation of the muscle's nerve overrides the dysfunction and reactivates it. Several prior studies demonstrated that the most of participants experienced clinically substantial and durable symptom relief compared to baseline. This protocol describes a second RCT in which all participants are on individualized optimal medical management and half of them are randomly selected to be implanted with a ReActiv8 system to receive restorative neurostimulation. The purpose of this design is to measure if there is any clinical benefit of restorative neurostimulation over individualized optimal medical management alone over the course of a full year.

On the diversity and distribution of a data deficient habitat in a poorly mapped region: The case of Sabellaria alveolata L. in Ireland.

Data that can be used to monitor biodiversity through time are essential for conservation and management. The reef-forming worm, Sabellaria alveolata (L. 1767) is currently classed as 'Data Deficient' due to an imbalance in the spread of data on its distribution. Little is known about the distribution of this species around Ireland. Using data archaeology, we collated past and present distribution records and discovered that S. alveolata has a discontinuous distribution with large gaps between populations. Many regions lack data and should be targeted for sampling. Biodiversity surveys revealed that S. alveolata supported diverse epibiotic algal communities. Retrograding (declining) reefs supported greater infaunal diversity than prograding (growing) reefs or sand, suggesting that S. alveolata is a dynamic ecosystem engineer that has a lasting legacy effect. Similar research should be carried out for other Data Deficient species, habitats and regions. Such data are invaluable resources for management and conservation.

Physical Activity Assessment in the Charcot Population.

Charcot neuroarthropathy is a degenerative disorder that significantly impairs a patient's functional capacity. It has been reported that a Charcot patient's quality of life is significantly impacted by the disease state. The aim of this study is to compare measured energy expenditure to a patient's perceived quality of life and physical ability. The study enrolled 43 patients by set inclusion and exclusion criteria. Patients' total energy expenditure was measured with doubly labeled water. The patients also completed 2 quality of life assessments: 36-Item Short Form Survey (SF-36) and International Physical Activity Questionnaire-Long Form (IPAQ-LF). The measured energy expenditure was then compared to the patient's perceived functional capacity. Scores reaching statistical significance included general health (60 ± 21; p = .011), pain (62 ± 27; p = .025), emotional (61 ± 40; p < .017), physical limitation (45 ± 39; p < .0001), and physical function (50 ± 29; p < .001). SF-36 survey variables that did not reach statistical significance included mental (73 ± 26; p = .690), energy (55 ± 21; p = .205), and social (74 ± 26; p = .105). The IPAQ-LF and physical activity level (PAL) were compared. No identified variation was noted between the 2 test methods (p = .57). The patients' PAL was measured at 1.4 ± 0.42, which is comparable to the general population. Data from this study identify the Charcot population as comparable to the general population. The inferences taken from this study indicate that this population suffers from poor health outlooks compared with the general population but may be overestimating the level of perceived disability.

A Curriculum to Increase Empathy and Reduce Burnout.

PURPOSE: Empathy is essential for good patient care. It underpins effective communication and high-quality, relationship-centered care. Empathy skills have been shown to decline with medical training, concordant with increasing physician distress and burnout. METHODS: We piloted a 6-month curriculum for interns (N = 27) during the 2015-2016 academic year at the University of Wisconsin-Madison. The course included: (1) review of literature on physician well-being and clinical empathy, (2) instruction on the neurobiology of empathy and compassion, (3) explanation of stress physiology and techniques for mitigating its effects, (4) humanities-informed techniques, and (5) introductions to growth mindset and mindful awareness. To measure effectiveness, we compared empathy and burnout scores before and after the course. RESULTS: The course was well-attended. Intern levels of burnout and empathy remained stable over the study period. In multivariable modeling, we found that for each session an intern attended, their emotional exhaustion declined by 3.65 points (P = 0.007), personal accomplishment increased by 2.69 points (P = 0.001), and empathic concern improved by 0.82 points (P = 0.066). The course was well-liked. Learners reported applying course content inside and outside of work and expressed variable preferences for content and teaching methods. CONCLUSION: Skills in empathic and self-care can be taught together to reduce the decline of empathy and well-being that has been seen during internship. In this single-center pilot, resident physicians reported using these skills both inside and outside of work. Our curriculum has the potential to be adopted by other residency programs.

Monitoring Procedural Pain and Distress in a Child With Rett Syndrome: A Case Report.

BACKGROUND AND PURPOSE: Whole body vibration training is a viable option for children with Rett syndrome; however, the positioning requirements and intense vibration may be interpreted as pain. CASE: A 13-year-old girl with a diagnosis of Rett syndrome, Stage IV, participated. The Individualized Numeric Rating Scale was developed in collaboration with the caregiver and scored by a physical therapist and student physical therapists during 16 sessions of whole body vibration training. OUTCOMES: The therapist and students reached 100% agreement on the Individualized Numeric Rating Scale ratings and successfully provided distractions to prevent pain and distress from reaching a level 5 out of 10 for 139 of 144 sessions. CONCLUSION: This is the first case in the literature to demonstrate use of the Individualized Numeric Rating Scale with a child who is nonverbal during a potentially painful physical therapy procedure.

Be part of the future.

One of the busiest university teaching hospitals in the north of England, the Royal Liverpool and Broadgreen University Hospitals NHS Trust provides a range of specialist services to more than 750,000 people a year.

Focus on fluid reasoning: The relationship between fluid reasoning and the Pattern of Strengths and Weaknesses model.

The purpose of this paper is to examine the Fluid Reasoning Index of the Wechsler Intelligence Test for Children, Fifth Edition (WISC-V), and determine how fluid-reasoning skills relate to academic skill acquisition in the classroom setting. We also examine the myriad of ways within which learning and learning disabilities can be defined. Also, we plan to examine a brief review of the definition of a Specific Learning Disability and review some of the leading theories related to the Pattern of Strengths and Weaknesses model.

Charcot Collapse: Does Collapse Pattern Dictate Osseous Metabolism?

Charcot fracture pattern (FP) and Charcot dislocation pattern (DP) are 2 distinct collapse patterns identified in Charcot neuroarthropathy of the foot and ankle. These patterns are believed to demonstrate relative differences in central bone mineral density (BMD), which has been theoretically extrapolated to describe local BMD. To assess variation in local bone composition of FP and DP patients, 10 patients, 5 DP and 5 FP were recruited. The patient's age, body mass index (BMI), radiographs, central BMD, local BMD, sRANKL (soluble receptor activator nuclear factor kappa-beta ligand), sRAGE (soluble receptors of advanced glycated end-products), and osteocalcin were measured to determined bone metabolic status and density. Central BMD was determined using DEXA (dual-energy X-ray absorptiometry) scans of the hip. peripheral BMD was determined using scans at the level of the ankle mortise and Chopart's joint, depending on the location of collapse. These scans were then compared with controls. Central and peripheral DEXA scans were significantly reduced in the FP ( P = .002 and P < .0001) when compared with healthy controls. Additionally, FP patients demonstrated statistically significant elevations in sRANKL ( P = .05) and sRAGE ( P = .002) when compared with DP. No significant difference was seen in osteocalcin ( P = 0.22); however, elevated values compared with normal reference ranges suggest increase bone production. These elevations combined with an osteoporotic profile may indicate difficulty of FP patients in repairing micro fracture. Results from this study emphasize the increased risk of nonunion during FP reconstruction, and highlight the variation in bone composition in these 2 Charcot subtypes. LEVELS OF EVIDENCE: Level III.

Historical comparisons reveal multiple drivers of decadal change of an ecosystem engineer at the range edge.

Biogenic reefs are important for habitat provision and coastal protection. Long-term datasets on the distribution and abundance of Sabellaria alveolata (L.) are available from Britain. The aim of this study was to combine historical records and contemporary data to (1) describe spatiotemporal variation in winter temperatures, (2) document short-term and long-term changes in the distribution and abundance of S. alveolata and discuss these changes in relation to extreme weather events and recent warming, and (3) assess the potential for artificial coastal defense structures to function as habitat for S. alveolata. A semi-quantitative abundance scale (ACFOR) was used to compare broadscale, long-term and interannual abundance of S. alveolata near its range edge in NW Britain. S. alveolata disappeared from the North Wales and Wirral coastlines where it had been abundant prior to the cold winter of 1962/1963. Population declines were also observed following the recent cold winters of 2009/2010 and 2010/2011. Extensive surveys in 2004 and 2012 revealed that S. alveolata had recolonized locations from which it had previously disappeared. Furthermore, it had increased in abundance at many locations, possibly in response to recent warming. S. alveolata was recorded on the majority of artificial coastal defense structures surveyed, suggesting that the proliferation of artificial coastal defense structures along this stretch of coastline may have enabled S. alveolata to spread across stretches of unsuitable natural habitat. Long-term and broadscale contextual monitoring is essential for monitoring responses of organisms to climate change. Historical data and gray literature can be invaluable sources of information. Our results support the theory that Lusitanian species are responding positively to climate warming but also that short-term extreme weather events can have potentially devastating widespread and lasting effects on organisms. Furthermore, the proliferation of coastal defense structures has implications for phylogeography, population genetics, and connectivity of coastal populations.

Calcium-Induced calcium release during action potential firing in developing inner hair cells.

In the mature auditory system, inner hair cells (IHCs) convert sound-induced vibrations into electrical signals that are relayed to the central nervous system via auditory afferents. Before the cochlea can respond to normal sound levels, developing IHCs fire calcium-based action potentials that disappear close to the onset of hearing. Action potential firing triggers transmitter release from the immature IHC that in turn generates experience-independent firing in auditory neurons. These early signaling events are thought to be essential for the organization and development of the auditory system and hair cells. A critical component of the action potential is the rise in intracellular calcium that activates both small conductance potassium channels essential during membrane repolarization, and triggers transmitter release from the cell. Whether this calcium signal is generated by calcium influx or requires calcium-induced calcium release (CICR) is not yet known. IHCs can generate CICR, but to date its physiological role has remained unclear. Here, we used high and low concentrations of ryanodine to block or enhance CICR to determine whether calcium release from intracellular stores affected action potential waveform, interspike interval, or changes in membrane capacitance during development of mouse IHCs. Blocking CICR resulted in mixed action potential waveforms with both brief and prolonged oscillations in membrane potential and intracellular calcium. This mixed behavior is captured well by our mathematical model of IHC electrical activity. We perform two-parameter bifurcation analysis of the model that predicts the dependence of IHCs firing patterns on the level of activation of two parameters, the SK2 channels activation and CICR rate. Our data show that CICR forms an important component of the calcium signal that shapes action potentials and regulates firing patterns, but is not involved directly in triggering exocytosis. These data provide important insights into the calcium signaling mechanisms involved in early developmental processes.

Creating a Culture of Mindfulness in Medicine.

BACKGROUND: Well-documented challenges faced by primary care clinicians have brought growing awareness to the issues of physician wellness and burnout and the potential subsequent impact on patients. Research has identified mindfulness as a tool to increase clinician well-being and enhance clinician characteristics associated with a more patient-centered orientation to clinical care. OBJECTIVE: The overall goal of our intervention was to promote the cultivation of mindful awareness throughout our health system, creating a culture of mindfulness in medicine. METHODS: We developed a systems-level strategy to promote health and resilience for clinicians and patients by preparing a group of clinician leaders to serve as catalysts to practice and teach mindfulness. The strategy involved 3 steps: (1) select 5 primary care leaders to help foster mindfulness within both health care delivery and education; (2) provide funds for these leaders to attend advanced mindfulness training designed specifically for clinicians; and (3) foster mindfulness within our health system and beyond via collaborative planning meetings and seed money for implementation of projects. RESULTS: All 5 leaders endorsed the personal value of the mindfulness training, with some describing it as life-changing. Within 8 months, 4 of the leaders fostered a wide variety of mindfulness activities benefitting colleagues, medical students, and patients across our state and beyond. CONCLUSION: We found that the value received from our investment in mindfulness far exceeded our relatively low cost, although further evaluation is needed to prove this.

Making time for nurses to reduce patient falls.

Patient falls in hospitals are a serious problem and can cause long delays in their recovery. One-to-one nursing reduces the number of serious falls that occur, but nursing staff are often busy with routine clerical duties and do not have time to sit with patients constantly. Electronic health records make these clerical duties quicker to complete, giving nurses more time to spend with patients and reducing the likelihood of serious falls occurring. This article describes the steps taken by The Walton Centre to reduce falls and provides an evaluation of the programme.

Loss of RAGE defense: a cause of Charcot neuroarthropathy?

OBJECTIVE: This study investigated the relationship between circulating soluble receptor for advanced glycation end products (sRAGE) and parameters of bone health in patients with Charcot neuroarthropathy (CNA). RESEARCH DESIGN AND METHODS: Eighty men (aged 55.3±9.0 years), including 30 healthy control subjects, 30 type 2 diabetic patients without Charcot, and 20 type 2 diabetic patients with stage 2 (nonacute) CNA, underwent evaluations of peripheral and autonomic neuropathy, nerve conduction, markers of bone turnover, bone mineral density, and bone stiffness of the calcaneus. RESULTS: CNA patients had worse peripheral and autonomic neuropathy and a lower bone stiffness index than diabetic or control individuals (77.1, 103.3, and 105.1, respectively; P<0.05), but no difference in bone mineral density (P>0.05). CNA subjects also had lower sRAGE levels than control (162 vs. 1,140 pg/mL; P<0.01) and diabetic (162 vs. 522 pg/mL; P<0.05) subjects, and higher circulating osteocalcin levels. CONCLUSIONS: CNA patients had significantly lower circulating sRAGE, with an accompanying increase in serum markers of bone turnover, and reduced bone stiffness in the calcaneus not accompanied by reductions in bone mineral density. These data suggest a failure of RAGE defense mechanisms against oxidative stress in diabetes. Future studies should determine if medications that increase sRAGE activity could be useful in mitigating progression to CNA.

Measuring quality: how to empower staff to take control.

A vast amount of information relating to standards of patient care is collated from hospital wards, yet there is not always evidence that this information is discussed or acted upon by ward staff. Involving ward staff in setting up systems to monitor performance and then deciding how to address shortcomings uses their insights into care provision and gives them ownership over standards of care. The balanced scorecard is an effective tool for monitoring quality that can be applied to healthcare. This article discusses how to use it to develop and implement systems of measuring the quality of care.

Postsynaptic recordings at afferent dendrites contacting cochlear inner hair cells: monitoring multivesicular release at a ribbon synapse.

The afferent synapse between the inner hair cell (IHC) and the auditory nerve fiber provides an electrophysiologically accessible site for recording the postsynaptic activity of a single ribbon synapse. Ribbon synapses of sensory cells release neurotransmitter continuously, the rate of which is modulated in response to graded changes in IHC membrane potential. Ribbon synapses have been shown to operate by multivesicular release, where multiple vesicles can be released simultaneously to evoke excitatory postsynaptic currents (EPSCs) of varying amplitudes. Neither the role of the presynaptic ribbon, nor the mechanism underlying multivesicular release is currently well understood. The IHC is innervated by 10-20 auditory nerve fibers, and every fiber contacts the IHC with a unmyelinated single ending to form a single ribbon synapse. The small size of the afferent boutons contacting IHCs (approximately 1 µm in diameter) enables recordings with exceptional temporal resolution to be made. Furthermore, the technique can be adapted to record from both pre- and postsynaptic cells simultaneously, allowing the transfer function at the synapse to be studied directly. This method therefore provides a means by which fundamental aspects of neurotransmission can be studied, from multivesicular release to the elusive function of the ribbon in sensory cells.

Two modes of release shape the postsynaptic response at the inner hair cell ribbon synapse.

Cochlear inner hair cells (IHCs) convert sounds into receptor potentials and via their ribbon synapses into firing rates in auditory nerve fibers. Multivesicular release at individual IHC ribbon synapses activates AMPA-mediated EPSCs with widely ranging amplitudes. The underlying mechanisms and specific role for multivesicular release in encoding sound are not well understood. Here we characterize the waveforms of individual EPSCs recorded from afferent boutons contacting IHCs and compare their characteristics in immature rats (postnatal days 8-11) and hearing rats (postnatal days 19-21). Two types of EPSC waveforms were found in every recording: monophasic EPSCs, with sharp rising phases and monoexponential decays, and multiphasic EPSCs, exhibiting inflections on rising and decaying phases. Multiphasic EPSCs exhibited slower rise times and smaller amplitudes than monophasic EPSCs. Both types of EPSCs had comparable charge transfers, suggesting that they were activated by the release of similar numbers of vesicles, which for multiphasic EPSCs occurred in a less coordinated manner. On average, a higher proportion of larger, monophasic EPSCs was found in hearing compared to immature rats. In addition, EPSCs became significantly faster with age. The developmental increase in size and speed could improve auditory signaling acuity. Multiphasic EPSCs persisted in hearing animals, in some fibers constituting half of the EPSCs. The proportion of monophasic versus multiphasic EPSCs varied widely across fibers, resulting in marked heterogeneity of amplitude distributions. We propose that the relative contribution of two modes of multivesicular release, generating monophasic and multiphasic EPSCs, may underlie fundamental characteristics of auditory nerve fibers.

Hair cell afferent synapses.

This review will cover advances in the study of hair cell afferent synaptic function occurring between 2005 and 2008. During this time, capacitance measurements of vesicular fusion have continued to be refined, optical methods have added insights regarding vesicle trafficking, and paired intracellular recordings have established the transfer function of the afferent synapse at high resolution. Further, genes have been identified with forms of deafness known as auditory neuropathy, and their role in afferent signaling explored in mouse models. With these advances, our view of the hair cell afferent synapse has continued to be refined, and surprising properties have been revealed that emphasize the unique role of this structure in neural function.

Calcium- and calmodulin-dependent inactivation of calcium channels in inner hair cells of the rat cochlea.

Modulation of voltage-gated calcium channels was studied in inner hair cells (IHCs) in an ex vivo preparation of the apical turn of the rat organ of Corti. Whole cell voltage clamp in the presence of potassium channel blockers showed inward calcium currents with millisecond activation and deactivation kinetics. When temperature was raised from 22 to 37 degrees C, the calcium currents of immature IHCs [<12 days postnatal (P12)] increased threefold in amplitude, and developed more pronounced inactivation. This was determined to be calcium-dependent inactivation (CDI) on the basis of its reliance on external calcium (substitution with barium), sensitivity to internal calcium-buffering, and voltage dependence (reflecting the calcium driving force). After the onset of hearing at P12, IHC calcium current amplitude and the extent of inactivation were greatly reduced. Although smaller than in prehearing IHCs, CDI remained significant in the mature IHC near the resting membrane potential. CDI in mature IHCs was enhanced by application of the endoplasmic calcium pump blocker, benzo-hydroquinone. Conversely, CDI in immature IHCs was reduced by calmodulin inhibitors. Thus voltage-gated calcium channels in mammalian IHCs are subject to a calmodulin-mediated process of CDI. The extent of CDI depends on the balance of calcium buffering mechanisms and may be regulated by calmodulin-specific processes. CDI provides a means for the rate of spontaneous transmitter release to be adjusted to variations in hair cell resting potential and steady state calcium influx.

Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.

The expression of unconventional vesicular glutamate transporter VGLUT3 by neurons known to release a different classical transmitter has suggested novel roles for signaling by glutamate, but this distribution has raised questions about whether the protein actually contributes to glutamate release. We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway. The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing. In addition, the mice exhibit primary, generalized epilepsy that is accompanied by remarkably little change in ongoing motor behavior. The glutamate release conferred by expression of VGLUT3 thus has an essential role in both function and development of the auditory pathway, as well as in the control of cortical excitability.