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Background people living with cognitive impairment commonly take multiple medications including potentially inappropriate medications (PIMs), which puts them at risk of medication related harms. Aims to explore willingness to have a medication deprescribed of older people living with cognitive impairment (dementia or mild cognitive impairment) and multiple chronic conditions and assess the relationship between willingness, patient characteristics and belief about medications. Methods cross-sectional study using results from the revised Patients’ Attitudes Towards Deprescribing questionnaire (rPATDcog) collected as baseline data in the OPTIMIZE study, a pragmatic, cluster-randomised trial educating patients and clinicians about deprescribing. Eligible participants were 65+, diagnosed with dementia or mild cognitive impairment, and prescribed at least five-long-term medications. Results the questionnaire was mailed to 1,409 intervention patients and 553 (39%) were returned and included in analysis. Participants had a mean age of 80.1 (SD 7.4) and 52.4% were female. About 78.5% (431/549) of participants said that they would be willing to have one of their medications stopped if their doctor said it was possible. Willingness to deprescribe was negatively associated with getting stressed when changes are made and with previously having a bad experience with stopping a medication (P Conclusion most older people living with cognitive impairment are willing to deprescribe. Addressing previous bad experiences with stopping a medication and stress when changes are made to medications may be key points to discuss during deprescribing conversations.

While the ICH E9(R1) Addendum on “Estimands and Sensitivity Analysis in Clinical Trials” was released in late 2019, the widespread implementation of defining and reporting estimands across clinical trials is still in progress and the engagement of non-statistical functions in this process is also in progress. Case studies are sought after, especially those with documented clinical and regulatory feedback. This paper describes an interdisciplinary process for implementing the estimand framework, devised by the Estimands and Missing Data Working Group (a group with clinical, statistical, and regulatory representation) of the International Society for CNS Clinical Trials and Methodology. This process is illustrated by specific examples using various types of hypothetical trials evaluating a treatment for major depressive disorder. Each of the estimand examples follows the same template and features all steps of the proposed process, including identifying the trial stakeholder(s), the decisions they need to make about the investigated treatment in their specific role and the questions that would support their decision making. Each of the five strategies for handling intercurrent events are addressed in at least one example; the featured endpoints are also diverse, including continuous, binary and time to event. Several examples are presented that include specifications for a potential trial design, key trial implementation elements needed to address the estimand, and main and sensitivity estimator specifications. Ultimately this paper highlights the need to incorporate multi-disciplinary collaborations into implementing the ICH E9(R1) framework.

Shock is common in critically ill and injured patients. Survival during shock is highly dependent on rapid restoration of tissue oxygenation with therapeutic goals based on cardiac output (CO) optimization. Despite the clinical availability of numerous minimally invasive monitors of CO, limited supporting performance data are available. Following approval of the University of Saskatchewan Animal Research Ethics Board, we assessed the performance and trending ability of PiCCOplus™, FloTrac™, and CardioQ-ODM™ across a range of CO states in pigs. In addition, we assessed the ability of invasive mean arterial blood pressure (iMAP) to follow changes in CO using a periaortic transit-time flow probe as the reference method. Statistical analysis was performed with function-fail, bias and precision, percent error, and linear regression at all flow, low-flow (> 1 standard deviation [SD] below the mean), and high-flow (> 1 SD above the mean) CO conditions. We made a total of 116,957 paired CO measurements. The non-invasive CO monitors often failed to provide a CO value (CardioQ-ODM: 40.6% failed measurements; 99% confidence interval [CI], 38.5 to 42.6; FloTrac: 9.6% failed measurements; 99% CI, 8.7 to 10.5; PiCCOplus: 4.7% failed measurements; 99% CI, 4.5 to 4.9; all comparisons, P < 0.001). The invasive mean arterial pressure provided zero failures, failing less often than any of the tested CO monitors (all comparisons, P < 0.001). The PiCCOplus was most interchangeable with the flow probe at all flow states: PiCCOplus (20% error; 99% CI, 19 to 22), CardioQ-ODM (25% error; 99% CI, 23 to 27), FloTrac (34% error; 99% CI, 32 to 38) (all comparisons, P < 0.001). At low-flow states, CardioQ-ODM (43% error; 99% CI, 32 to 63) and Flotrac (45% error; 99% CI, 33 to 70) had similar interchangeability (P = 0.07), both superior to PiCCOplus (48% error; 99% CI, 42 to 60) (P < 0.001). Regarding CO trending, the CardioQ-ODM (correlation coefficient, 0.82; 99% CI, 0.81 to 0.83) was statistically superior to other monitors including iMAP, but at low flows iMAP (correlation coefficient, 0.58; 99% CI, 0.58 to 0.60) was superior to all minimally invasive CO monitors (all comparisons P < 0.001). None of the minimally invasive monitors of CO performed well at all tested flows. Invasive mean arterial blood pressure most closely tracked CO change at critical flow states.

Objectives Friedreich ataxia (FRDA) is a rare disorder with progressive neurodegeneration and cardiomyopathy. Luvadaxistat (also known as TAK‐831; NBI‐1065844), an inhibitor of the enzyme d‐amino acid oxidase, has demonstrated beneficial effects in preclinical models relevant to FRDA. This phase 2, randomized, double‐blind, placebo‐controlled, parallel‐arm study evaluated the efficacy and safety of oral luvadaxistat in adults with FRDA. Methods Adult patients with FRDA were randomized 2:1:2 to placebo, luvadaxistat 75 mg twice daily (BID), or luvadaxistat 300 mg BID for 12 weeks. The primary endpoint changed from baseline at week 12 on the inverse of the time to complete the nine‐hole peg test (9‐HPT−1), a performance‐based measure of the function of the upper extremities and manual dexterity. Comparisons between luvadaxistat and placebo were made using a mixed model for repeated measures. Results Of 67 randomized patients, 63 (94%) completed the study. For the primary endpoint, there was no statistically significant difference in change from baseline on the 9‐HPT−1 (seconds−1) at week 12 between placebo (0.00029) and luvadaxistat 75 mg BID (−0.00031) or luvadaxistat 300 mg BID (−0.00059); least squares mean differences versus placebo (standard error) were −0.00054 (0.000746) for the 75 mg dose and −0.00069 (0.000616) for the 300 mg dose. Luvadaxistat was safe and well tolerated; the majority of reported adverse events were mild in intensity. Interpretation Luvadaxistat was safe and well tolerated in this cohort of adults with FRDA; however, it did not demonstrate efficacy as a treatment for this condition.

Communication between physicians who order, and clinicians who provide skilled home healthcare (SHHC), is critical to well-coordinated care. The views of SHHC staff on communication with physicians have not been well studied. The objective of this study was to explore how SHHC staff view the communication processes with physicians who order SHHC services. Using purposive and snowball sampling, we conducted semistructured interviews with 22 SHHC staff across multiple regions of the United States. Qualitative thematic content analysis was used to analyze the data. SHHC staff experienced significant barriers to effective communication with physicians, including not being able to communicate in a timely manner when necessary for patient care, and challenges identifying the correct physician to coordinate care and sign SHHC orders. Key strategies to enhance communication focused on creating standardized processes to streamline communication, setting expectations for response times in communication, and improving the Centers for Medicare & Medicaid Services Home Health Certification and Plan of Care form (commonly referred to as the "CMS-485"/Plan of Care). SHHC staff experience significant communication challenges with physicians who order SHHC services that can compromise care coordination and delivery. Modifications to workflows are urgently needed to improve efficiency and quality of communication, care coordination, and quality of care.

Ipsilateral corticospinal innervation is rare. No prior cases have described ipsilateral tumor-associated symptoms as the presentation of an uncrossed corticospinal tract. Herein, we describe a case associated with a left frontal tumor, presenting with transient ipsilateral hemiparesis and aphasia. Due to the fluctuating symptomatology, we suspected a cerebrovascular cause and initially performed a workup for stroke. Ipsilateral motor innervation was discovered with intraoperative monitoring during the resection of the tumor, and confirmed with postoperative diffusion tensor imaging (DTI). Neurosurgeons should be aware of uncrossed motor system, and include it in the differential of ipsilateral deficit in patients with intracranial tumors.

Refereed/Peer-reviewed Background: Individuals with dementia or mild cognitive impairment frequently have multiple chronic conditions (defined as ≥2 chronic medical conditions) and take multiple medications, increasing their risk for adverse outcomes. Deprescribing (reducing or stopping medications for which potential harms outweigh potential benefits) may decrease their risk of adverse outcomes. Objective: To examine the effectiveness of increasing patient and clinician awareness about the potential to deprescribe unnecessary or risky medications among patients with dementia or mild cognitive impairment. Design, Setting, and Participants: This pragmatic, patient-centered, 12-month cluster randomized clinical trial was conducted from April 1, 2019, to March 31, 2020, at 18 primary care clinics in a not-for-profit integrated health care delivery system. The study included 3012 adults aged 65 years or older with dementia or mild cognitive impairment who had 1 or more additional chronic medical conditions and were taking 5 or more long-term medications. Interventions: An educational brochure and a questionnaire on attitudes toward deprescribing were mailed to patients prior to a primary care visit, clinicians were notified about the mailing, and deprescribing tip sheets were distributed to clinicians at monthly clinic meetings. Main Outcomes and Measures: The number of prescribed long-term medications and the percentage of individuals prescribed 1 or more potentially inappropriate medications (PIMs). Analysis was performed on an intention-to-treat basis. Results: This study comprised 1433 individuals (806 women [56.2%]; mean [SD] age, 80.1 [7.2] years) in 9 intervention clinics and 1579 individuals (874 women [55.4%]; mean [SD] age, 79.9 [7.5] years) in 9 control clinics who met the eligibility criteria. At baseline, both groups were prescribed a similar mean (SD) number of long-term medications (7.0 [2.1] in the intervention group and 7.0 [2.2] in the control group), and a similar proportion of individuals in both groups were taking 1 or more PIMs (437 of 1433 individuals [30.5%] in the intervention group and 467 of 1579 individuals [29.6%] in the control group). At 6 months, the adjusted mean number of long-term medications was similar in the intervention and control groups (6.4 [95% CI, 6.3-6.5] vs 6.5 [95% CI, 6.4-6.6]; P = .14). The estimated percentages of patients in the intervention and control groups taking 1 or more PIMs were similar (17.8% [95% CI, 15.4%-20.5%] vs 20.9% [95% CI, 18.4%-23.6%]; P = .08). In preplanned subgroup analyses, adjusted differences between the intervention and control groups were –0.16 (95% CI, –0.34 to 0.01) for individuals prescribed 7 or more long-term medications at baseline (n = 1434) and –0.03 (95% CI, –0.20 to 0.13) for those prescribed 5 to 6 medications (n = 1578) (P = .28 for interaction; P = .19 for subgroup interaction for PIMs). Conclusions and Relevance: This large-scale educational deprescribing intervention for older adults with cognitive impairment taking 5 or more long-term medications and their primary care clinicians demonstrated small effect sizes and did not significantly reduce the number of long-term medications and PIMs. Such interventions should target older adults taking relatively more medications.

Retrospective review of results from a prospectively collected Canadian cohort in comparison to published literature.(1) To investigate whether patients in a universal health care system have different outcomes than those in a multitier health care system in surgical management of degenerative spondylolisthesis (DS). (2) To identify independent factors predictive of outcome in surgical DS patients.Canada has a national health insurance program with unique properties. It is a single-payer system, coverage is universal, and access to specialist care requires referral by the primary care physician. The United States on the other hand is a multitier public/private payer system with more rapid access for insured patients to specialist care.Surgical DS patients treated between 2013 and 2016 in Canada were identified through the Canadian Spine Outcome Research Network (CSORN) database, a national registry that prospectively enrolls consecutive patients with spinal pathology from 16 tertiary care academic hospitals. This population was compared with the surgical DS arm of patients treated in the Spine Patients Outcome Research Trial (SPORT) study. We compared baseline demographics, spine-related, and health-related quality of life (HRQOL) outcomes at 3 months and 1 year. Multivariate analysis was used to identify factors predictive of outcome in surgical DS patients.The CSORN cohort of 213 patients was compared with the SPORT cohort of 248 patients. Patients in the CSORN cohort were younger (mean age 60.1 vs. 65.2; p.001), comprised fewer females (60.1% vs. 67.7%; p=.09), and had a higher proportion of smokers (23.3% vs. 8.9%; p.001). The SPORT cohort had more patients receiving compensation (14.6% vs. 7.7%; p.001). The CSORN cohort consisted of patients with slightly greater baseline disability (Oswestry disability index scores: 47.7 vs. 44.0; p=.008) and had more patients with symptom duration of greater than 6 months (93.7% vs. 62.1%; p.001). The CSORN cohort showed greater satisfaction with surgical results at 3 months (91.1% vs. 66.1% somewhat or very satisfied; p.01) and 1 year (88.2% vs. 71.0%, p.01). Improvements in back and leg pain were similar comparing the two cohorts. On multivariate analysis, duration of symptoms, treatment group (CSORN vs. SPORT) or insurance type (public/Medicare/Medicaid vs. Private/Employer) predicted higher level of postoperative satisfaction. Baseline depression was also associated with worse Oswestry disability index at 1-year postoperative follow-up in both cohorts.Surgical DS patients treated in Canada (CSORN cohort) reported higher levels of satisfaction than those treated in the United States (SPORT cohort) despite similar to slightly worse baseline HRQOL measures. Symptom duration and insurance type appeared to impact satisfaction levels. Improvements in other patient-reported health-related quality of life measures were similar between the cohorts.

Communication between physicians who order, and clinicians who provide skilled home healthcare (SHHC), is critical to well-coordinated care. The views of SHHC staff on communication with physicians have not been well studied. The objective of this study was to explore how SHHC staff view the communication processes with physicians who order SHHC services. Using purposive and snowball sampling, we conducted semistructured interviews with 22 SHHC staff across multiple regions of the United States. Qualitative thematic content analysis was used to analyze the data. SHHC staff experienced significant barriers to effective communication with physicians, including not being able to communicate in a timely manner when necessary for patient care, and challenges identifying the correct physician to coordinate care and sign SHHC orders. Key strategies to enhance communication focused on creating standardized processes to streamline communication, setting expectations for response times in communication, and improving the Centers for MedicareMedicaid Services Home Health Certification and Plan of Care form (commonly referred to as the "CMS-485"/Plan of Care). SHHC staff experience significant communication challenges with physicians who order SHHC services that can compromise care coordination and delivery. Modifications to workflows are urgently needed to improve efficiency and quality of communication, care coordination, and quality of care.

Objective: To subjectively identify low-risk ST-elevation myocardial infarction (STEMI) patients and triage this low-risk population to an intermediate level of care. Background: Many patients with STEMI are admitted to the intensive care unit (ICU), however, a large portion do not merit ICU admission. We sought to examine whether, among post-STEMI patients admitted to the ICU, if an easily obtainable subjective scoring system could predict low-risk patients and safely triage them to an intermediate level of care. Methods: Retrospective observational study at Christiana Hospital, a 900-bed regional referral center. Data were defined by the ACTION Registry and CathPCI Registry. Acute Physiology and Chronic Health Evaluation (APACHE) predictions were retrieved for all patients with STEMI and were analyzed for complications, length of stay, and inhospital mortality. We then examined subjective criteria to triage patients with STEMI out of the ICU. Results: Among 253 patients with STEMI, 179 (70.75%) were classified as low risk (intermediate level care appropriate) and 74 (29.25%) were classified as high risk (ICU appropriate). The mean age was 64.95 years. The APACHE III score was right skewed with a mean of 36.97 and a median of 31. There was a significant difference between the APACHE III score of low-risk patients and the APACHE III score of high-risk patients (P < .001). Conclusion: In conclusion, patients characterized as low risk, as defined by our criteria, had low APACHE III scores and a low likelihood of complications post-STEMI. This low-risk population could potentially be admitted to an intermediate level of care, avoiding the ICU altogether.

In the last decade, a number of initiatives to define good practices for projects involving modeling and simulation have been put forward. No proposal for best practice in modeling and simulation, however, has been generally and consciously adopted in the pharmaceutical world. This perspective aims to highlight these recent proposals (Marshall et al., 2016; O'Kelly et al., 2017) with respect to the use of modeling and simulation in the drug development and regulatory approval process. Both groups define Model-Informed Drug Discovery and Development (MID3) inclusively so as to potentially include the whole community of users of modeling and simulation. Applications in both communities (pharmacometrics and statistics) have many similarities in tools and methods to be used for model building, assumption testing, qualification versus available data and sensitivity analysis, albeit with a different focus. Both communities are emphatic that the same good practices could apply across the wide range of mo...

Highlights • Signal processing of the SSEP obtained during treatment of carotid artery disease. • Differences between control and unoperated and operated sides. • Differences between treatment with open or endovascular approach., Objective To describe the changes in the shape and topology of the somatosensory evoked potential (SSEP) during carotid endarterectomy, with particular reference to the time of clamping. Methods Routine intraoperative monitoring was performed on 30 patients undergoing carotid endarterectomy (15) or undergoing stenting (15) using median nerve SSEPs. Post-operatively the first and second derivatives of the potential were examined. Separate analysis of the SSEP using wavelets was also performed. Results In no instances did changes in the SSEP reach clinical significance. The first derivative showed significant changes that were temporally related to the clamp period. After clamping the ‘velocity’ was higher than baseline. There were changes in the wavelets related to the clamp period with more marked spectral edges at the conclusion of the procedure than baseline. In all instances the patient had a good clinical outcome. Conclusions Wavelet and derivative analysis of evoked potentials show changes that are not apparent with measures of amplitude and latency. The clinical relevance of these changes remains uncertain and await larger studies. Significance Increased velocity and spectral edges may be markers of increased cerebral blood flow, at least in the setting of pre-existing carotid stenosis.

SUMMARY Using a previously described technique that measures the "velocity" of the upswing of the median nerve SSEP, we identified an ischemic event during a carotid surgery that did not meet traditional alarm criteria. Mechanical thrombectomy successfully removed a thrombus, and the patient experienced a good recovery. Analysis of the SSEP waveform may allow for the detection of events missed with traditional alarm criteria.

The article Is the new ASNM intraoperative neuromonitoring supervision "guideline" a trustworthy guideline? A commentary, written by Stanley A. Skinner, Elif Ilgaz Aydinlar, Lawrence F. Borges, Bob S. Carter, Bradford L. Currier, Vedran Deletis, Charles Dong, John Paul Dormans, Gea Drost, Isabel Fernandez‑Conejero, E. Matthew Hoffman, Robert N. Holdefer, Paulo Andre Teixeira Kimaid, Antoun Koht, Karl F. Kothbauer, David B. MacDonald, John J. McAuliffe III, David E. Morledge, Susan H. Morris, Jonathan Norton, Klaus Novak, Kyung Seok Park, Joseph H. Perra, Julian Prell, David M. Rippe, Francesco Sala, Daniel M. Schwartz, Martín J. Segura, Kathleen Seidel, Christoph Seubert, Mirela V. Simon, Francisco Soto, Jeffrey A. Strommen, Andrea Szelenyi, Armando Tello, Sedat Ulkatan, Javier Urriza and Marshall Wilkinson, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 05 January 2019 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 30 January 2019 to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The original article has been corrected.

Introduction MEDI-565, a bispecific, single-chain antibody targeting human carcinoembryonic antigen on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex, showed antitumor activity in carcinoembryonic antigen-expressing tumors in murine models. Patients and Methods This phase I, multicenter, open-label dose escalation study enrolled adults with gastrointestinal adenocarcinomas. MEDI-565 was given intravenously over 3 hours on days 1 through 5 in 28-day cycles, with 4 single-patient (0.75-20 μg) and 5 standard 3 + 3 escalation (60 μg-3 mg; 1.5-7.5 mg with dexamethasone) cohorts. Primary objective was determining maximum tolerated dose; secondary objectives were evaluating pharmacokinetics, antidrug antibodies, and antitumor activity. Results Thirty-nine patients were enrolled (mean age, 59 years; 56% male; 72% colorectal cancer). Four patients experienced dose-limiting toxicities (2 at 3 mg; 2 at 7.5 mg + dexamethasone): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Five patients reported grade 3 treatment-related adverse events: diarrhea, CRS, increased alanine aminotransferase, hypertension (all, n = 1), and hypoxia (n = 2); 6 experienced treatment-related serious adverse events: diarrhea, vomiting, pyrexia, CRS (all, n = 1), and hypoxia (n = 2). MEDI-565 pharmacokinetics was linear and dose-proportional, with fast clearance and short half-life. Nineteen patients (48.7%) had antidrug antibodies; 5 (12.8%) had high titers, 2 with decreased MEDI-565 concentrations. No objective responses occurred; 11 (28%) had stable disease as best response. Conclusions The maximum tolerated dose of MEDI-565 in this patient population was 5 mg administered over 3 hours on days 1 through 5 every 28 days, with dexamethasone. Pharmacokinetics were linear. No objective responses were observed.

When providing advice on a medical product, a major task for FDA advisory committee members is to determine whether or not the benefits of the product under discussion outweigh its risks. Thoughtful and creative utilization of analysis methods and visualization tools often helps the sponsors and the FDA to clearly and succinctly deliver the key message, that is, whether the benefit-risk profile is favorable or unfavorable. In this article, we summarize a review of analysis methods and visual tools that were included in recent (during 2011–2014) FDA advisory committee meeting materials. We summarize the key findings related to benefit-risk (B-R) evaluations. Illustrative examples of analysis and visualization tools are provided along with potential refinements to provide readers' proper context for the appropriate use of various B-R tools in practice when evaluating the B-R balance of medical products.

Although control for multiplicity is recognized as a cornerstone of proper statistical inference, the topic has rarely been addressed in the specific context of benefit–risk assessment for medical products. This article raises key questions and provides opinions and recommendations. Topics include the symmetry between efficacy and safety endpoints, the proper stage to adjust for multiple endpoints, when and how to adjust for multiple subgroups, when a drug can be approved based on a favorable benefit–risk result in a subgroup, and multiplicity considerations arising from re-analysis of data.

INTRODUCTION: Odontoid fractures in young children are rare. Most authors advocate for closed reduction and external stabilization as first line treatment. Unlike adults, young children are much less amenable to an awake reduction for real-time assessment of neurological function. We used spinal cord monitoring, as used in spine surgery, to assess the function of the spinal cord during the closed reduction in our 31-month-old patient. CASE PRESENTATION: A 31-month-old male presented with a displaced odontoid fracture and ASIA C spinal cord injury. Given his age, closed reduction and halo application were completed under general anesthesia guided by neuromonitoring. A less-than-ideal reduction initially was accepted due to a decline in motor-evoked potentials. Subsequently, there was no change in neurological status. The reduction was repeated under anesthesia, with monitoring, a number of times until good correction was achieved. Ultimately, a surgical fusion was required due to ligamentous instability. The child achieved a very good neurological outcome and a stable spine. DISCUSSION: Neuromonitoring is an important adjunct to closed reductions when complete and reliable neurological assessment is not possible.

The article Is the new ASNM intraoperative neuromonitoring supervision “guideline” a trustworthy guideline? A commentary, written by Stanley A. Skinner, Elif Ilgaz Aydinlar, Lawrence F. Borges, Bob S. Carter, Bradford L. Currier, Vedran Deletis, Charles Dong, John Paul Dormans, Gea Drost, Isabel Fernandez‑Conejero, E. Matthew Hoffman, Robert N. Holdefer, Paulo Andre Teixeira Kimaid, Antoun Koht, Karl F. Kothbauer, David B. MacDonald, John J. McAuliffe III, David E. Morledge, Susan H. Morris, Jonathan Norton, Klaus Novak, Kyung Seok Park, Joseph H. Perra, Julian Prell, David M. Rippe, Francesco Sala, Daniel M. Schwartz, Martín J. Segura, Kathleen Seidel, Christoph Seubert, Mirela V. Simon, Francisco Soto, Jeffrey A. Strommen, Andrea Szelenyi, Armando Tello, Sedat Ulkatan, Javier Urriza and Marshall Wilkinson, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 05 January 2019 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 30 January 2019 to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The original article has been corrected.

Intraoperative neuromonitoring is a specialized skill set performed in the operating room to reduce the risk of neurologic injury. There appears to be a shortage of qualified personnel and a lack of Canadian guidelines on the performance of the task. We distributed a web-based survey on the attitude of the surgeons to the interpretation of intraoperative neuromonitoring data among surgeons who use the technique. At present, most of the interpretation is performed by either technologists or by the surgeons themselves. Most surgeons would prefer professional oversight from a neurologist or neurophysiologist at the doctoral level. There is a lack of personnel in Canada with the appropriate training and expertise to interpret intraoperative neuromonitoring data.

Assessing the neural function in acute stroke patients in a timely manner is important to identify time sensitive treatment. While a hospital may have clinical neurophysiology machines, these are complex to use and crucially expensive to own. A low-cost point-of-care system for assessing the neural function in such patients would have value in many clinical centers, and also potentially with EMS teams. A study to determine the effectiveness of such an approach, especially with a limited number of EEG channels, requires suitable devices to provide this functionality. This paper focuses on the design and performance considerations for such a system which will be used in this study. Of interest is the use of the devices the clinicians already have (e.g. smartphone, tablet) to access and control the system as well as real-time performance of sampling on low-cost commodity hardware and the provision of an extensible platform that can be upgraded and take advantage of cloud computing resources.

Objective: To develop a standardized paediatric protocol for acquiring simultaneous chest wall kinematics and surface electromyography (EMG) of chest wall muscles during maximum performance and speech tasks. Patients and Methods: Eighteen healthy participants included: (a) a younger age group (n = 6; ages 4.0-6.5 years), (b) an older age group (n = 6; ages 7.0-10.5 years), and (c) an adult group (n = 8; ages 21-33 years). A child (age 10 years) with spastic-type cerebral palsy (CP) served as a ‘proof of protocol feasibility'. Chest wall kinematics and surface EMGs (intercostals, rectus abdominus, external oblique, latissimus dorsi, and erector spinae) were acquired during maximum performance and speech tasks. Results: Successful calibration of the EMG signal and reliable detection of muscle activation onset, offset, and amplitude relative to vital capacity and percent maximum voluntary contraction in children were demonstrated. Kinematic and surface EMG measurements were sensitive to non-speech and speech tasks, age, and neurological status (i.e. CP). Conclusion: The simultaneous measurement of kinematics and EMG of the chest wall muscle groups provides a more comprehensive description of speech breathing in children. This protocol can be used for the observation and interpretation of clinical outcomes seen in children with motor speech disorders following treatments that focus on increasing overall respiratory and vocal effort.

Object The authors conducted a study to determine the neurophysiological capacity of the neural placode in spina bifida neonates and to determine if the spinal nerve roots in these neonates had normal stimulation. Methods The authors present a case series of 2 neonates born with open neural tube defects who underwent neural tube closure within 24 hours of birth. Neurophysiological monitoring and electrical stimulation of the placode and nerve roots was performed before and after closure of the neural tube. Results Stimulation of nerve roots resulted in evoked electromyographic responses in distinct muscle groups, indicative of the myotome innervation pattern. Stimulation threshold did not change significantly after closure of the placode. Stimulation within the placode generated an alternating pattern of activity in the left and right legs. Conclusions Closure of the neural tube did not affect the stimulation threshold of the nerve roots, which remained easily excitable. The viability of the nerve roots suggests that they may be candidates for neural prostheses in the future. The neural placode contains basic neural elements for generating a locomotor-like pattern in response to tonic neural inputs.

A novel method for simultaneously visualizing beneft and risk over time is presented. The underlying model represents a subject’s beneft-risk state at a given time as one of fve discrete clinical states, one being premature study withdrawal. The new graphic uses colors to represent each subject’s changing state over the course of the clinical trial. The user can quickly grasp how a treatment affects subjects in aggregate, then further examine how individuals are affected. It is possible to tell whether the benefcial and harmful outcomes are correlated. The method is particularly appropriate for treatments that provide only symptomatic relief. An approved drug for chronic pain is presented as a worked example.

Little has been included in the medical literature about the involvement of industry representatives in transcatheter aortic valve replacement (TAVR) procedures. Multidetector computed tomography (MDCT) is commonly used, and plays an integral role, to assess the aortic annulus and other parameters

Afferent inputs are known to modulate the activity of locomotor central pattern generators, but their role in the generation of locomotor patterns remains uncertain. This study sought to investigate the importance of afferent input for producing bilateral, coordinated hindlimb stepping in adult cats. Following complete spinal transection, animals were trained to step on the moving belt of a treadmill until proficient, weight-bearing stepping of the hindlimbs was established. Selective dorsal rhizotomies of roots reaching various segments of the lumbosacral enlargement were then conducted, and hindlimb stepping capacity was reassessed. Depending on the deafferented lumbosacral segments, stepping was either abolished or unaffected. Deafferentation of mid-lumbar (L3/L4) or lower-lumbar (L5-S1) segments abolished locomotion. Locomotor capacity in these animals could not be restored with the administration of serotonergic or adrenergic agonists. Deafferentation of L3, L6, or S1 had mild effects on locomotion. This suggested that critical afferent inputs pertaining to hip position (mid-lumbar) and limb loading (lower-lumbar) play an important role in the generation of locomotor patterns after spinal cord injury.

Introduction Children with Down Syndrome frequently have surgical procedures including those that might require intraoperative neuromonitoring, most frequently in our centre using somatosensory and motor evoked potentials, (SSEPs and MEPs). The SSEP is recorded at both peripheral, spinal and cortical sites. The amplitude of the response is dependent on the size of the sensory volley. Under anesthesia, during surgical procedures, each patient serves as their own control, and comparisons to control subjects are not valid. Methods We age matched 7 ‘healthy’ children with and without Down Syndrome undergoing spinal surgery. We compared the amplitude of the cortical and peripheral responses for ‘equivalent’ stimulation currents. We also measured the voltage required to generate similar amplitude MEPs in the muscles using transcranial electrical stimulation. Stimulation parameters (frequency, train length etc) were constant between Down Syndrome and other children. Results The amplitude of the peripheral responses of the SSEP did not vary between groups, but the amplitude of the cortical potentials was 12 times higher in Down Syndrome than control subjects. The voltage required to produce a MEP in the tibialis anterior muscle of 100 μV in a Down Syndrome child was 1/3–1/4 of that required in a control child. We did not observe any differences in latencies between the groups. Conclusion Individuals with Down Syndrome show higher amplitude cortical somatosensory evoked potentials and a lower threshold for eliciting potentials that originate in the cortex. These two observations may be related to the well established, higher incidence of epilepsy in Down Syndrome. These findings indicate a higher degree of cortical excitability in Down Syndrome. Possible reasons for this may be changes in the mechanism of inhibition in the cortex or a true increase in the excitability of the cortex. Other studies have indicated that Down Syndrome has a higher degree of cortical connectivity, across many brain regions. The evoked potential changes may also be a reflection of this connectivity, but we do not understand the mechanism at present.

Introduction Lumbo-sacral root stimulation while able to generate FES-cycling lacked the specificity to allow standing and stepping. The LARSI system (1) had electrodes placed on the L2-S2 anterior nerve roots bilaterally. Crucially it was not able to separate out non-synergistic joint moments in particular hip flexion from knee extension. Advances in micro-electronics such as ‘Active-Books’ (2) and our understanding of neural plasticity and stimulation led us to investigate whether stimulation of nerve rootlets would decouple these joint moments. This reports an animal study and intra-operative recordings from patients. Methods With ethical committee approval 15 rats were studied and all roots from L1 to Co1 were stimulated and subsequently divided into rootlets. In all cases a bipolar stimulator probe was used and EMG recorded from leg muscles. Results Each root easily divided into 4 strands in the lumbar and cervical spine. Using the terminology for threshold ratio developed in (3): we measured the K1 and K2 values for both root and rootlets. The rootlets’ ratios were higher than the roots (an average increase from 8.2 ± 4.5 to 18.3 ± 5.1). Conclusion Placing electrodes at the cauda equina is advantageous, compared to the peripheral nerves, all the electrodes are in one surgical field and there they are protected by the spine. Rootlet stimulation offers more selectivity than root stimulation and an increase in the number of channels of stimulation available, so it should allow better function. Whether it would allow satisfactory FES-walking or standing is not easily assessed in the acute setting.

A class of hierarchical Bayesian models is proposed for adverse birth outcomes such as preterm birth, which are assumed to follow a conditional binomial distribution. The log-odds of an adverse outcome in a particular county, logit(pi), follow a linear model that includes observed covariates and normally-distributed random effects. Spatial dependence between neighboring regions is allowed for by including an intrinsically autoregressive (IAR) prior or an IAR convolution prior in the linear predictor. Temporal dependence is incorporated by including a temporal IAR term also. It is shown that the variance parameters underlying these random effects (IAR, convolution, convolution plus temporal IAR) are identifiable. The Deviance Information Criterion (DIC) is considered as a way to compare spatial hierarchical models. Simulations are performed to test whether the DIC can identify whether binomial outcomes come from a hierarchical model that includes different combinations of random and fixed effects. Having v...

Changes in the strength of corticospinal projections to muscles in the upper and lower limbs are induced in conscious humans after paired associative stimulation (PAS) to the motor cortex. We tested whether an intervention of PAS consisting of 90 low-frequency (0.1-Hz) stimuli to the common peroneal nerve combined with suprathreshold transcranial magnetic stimulation (TMS) produces specific changes to the motor-evoked potentials (MEPs) in lower leg muscles if the afferent volley from peripheral stimulation is timed to arrive at the motor cortex after TMS-induced firing of corticospinal neurons. Unlike PAS in the hand, MEP facilitation in the leg was produced when sensory inputs were estimated to arrive at the motor cortex over a range of 15 to 90 ms after cortical stimulation. We examined whether this broad range of facilitation occurred as a result of prolonged subthreshold excitability of the motor cortex after a single pulse of suprathreshold TMS so that coincident excitation from sensory inputs arriving many milliseconds after TMS can occur. We found that significant facilitation of MEP responses (>200%) occurred when the motor cortex was conditioned with suprathreshold TMS tens of milliseconds earlier. Likewise, it was possible to induce strong MEP facilitation (85% at 60 min) when afferent inputs were directly paired with subthreshold TMS. We argue that in the leg motor cortex, facilitation of MEP responses from PAS occurred over a large range of interstimulus intervals as a result of the paired activation of sensory inputs with sustained, subthreshold activity of cortical neurons that follow a pulse of suprathreshold TMS.

OBJECT The diagnosis of tethered cord syndrome (TCS) remains difficult, and the decision to operate is even more complex. The objective of this study was to examine how detailed examination of neurophysiological test results can affect the diagnosis for patients undergoing a surgical cord release. METHODS Patients undergoing tethered spinal cord releases were matched by age and sex with control patients undergoing scoliosis correction in the absence of spinal cord pathology. The latency and width of the P37 peak of the posterior tibial nerve somatosensory evoked potential (SSEP) and the motor evoked potential (MEP) latencies were examined. Immediate changes as a result of the surgical procedure were reported. RESULTS The width of the P37 response differed significantly between TCS and control patients and changed significantly during the surgical procedure. Nonsignificant trends were seen in SSEP and MEP latencies. CONCLUSIONS The width of the P37 response may be a useful marker for TCS and may play a role in presurgical decision making.

Intermuscular coherence analysis can be used to assess the common drive to muscles. Coherence in the β-frequency band (15–35 Hz) is thought to arise from common cortical sources. Intermuscular coherence analysis is a potentially attractive tool for the investigation of motor cortical excitability changes because it is non-invasive and can be done relatively quickly. We carried out this study to test the hypothesis that intermuscular coherence analysis was able to detect cortical excitability changes in healthy subjects following transcranial direct current stimulation (tDCS). tDCS has been shown to increase (anodal stimulation) or decrease (cathodal stimulation) the size of the muscle potential evoked by TMS. We found that anodal tDCS caused an increase in motor evoked potential (MEP) size that was paralleled by an increase in β-band intermuscular coherence. Similarly, the reduction in MEP size produced by cathodal tDCS was paralleled by a reduction in β-band intermuscular coherence, while sham stimulation did not result in any change in either MEP amplitude or β-band intermuscular coherence. The similar pattern of change observed for MEP and intermuscular coherence may indicate similar mechanisms of action, although this cannot be assumed without further investigation. These changes do suggest that at least some of the action of tDCS is on cortical networks, and that combined tDCS and intermuscular coherence analysis may be useful in the diagnosis of pathologies affecting motor cortical excitability.

It is commonly accepted that locomotor-related neuronal circuitry resides in the lumbosacral spinal cord. Pharmacological agents, epidural electrical stimulation, and sensory stimulation can be used to activate these instrinsic networks in in vitro neonatal rat and in vivo cat preparations. In this study, we investigated the use of low-level tonic intraspinal microstimulation (ISMS) as a means of activating spinal locomotor networks in adult cats with complete spinal transections. Trains of low-amplitude electrical pulses were delivered to the spinal cord via groups of fine microwires implanted in the ventral horns of the lumbosacral enlargement. In contrast to published reports, tonic ISMS applied through microwires in the caudal regions of the lumbosacral enlargement (L7-S1) was more effective in eliciting alternating movements in the hindlimbs than stimulation in the rostral regions. Possible mechanisms of action of tonic ISMS include depolarization of locally oscillating networks in the lumbosacral cord, backfiring of primary afferents, or activation of propriospinal neurons.

We investigated where telemedicine sites were placed in a telemedicine network to assist high-risk pregnancies in Arkansas. There were 14 telemedicine sites in 75 counties, excluding the central site in Pulaski county. Logistic regression was used to examine site placement. Five potential predictors of site placement were examined: (1) the logarithm of the number of births in the county (LOGBIRTHS); (2) an indicator of whether a county had an abnormal rate of low birthweight babies (HIGHLBW); (3) the proportion of the county population below the government's poverty level; (4) the ratio of black to white births; (5) an indicator of whether the county bordered the telemedicine hub site county. The results suggested that telemedicine sites were placed where there were more births (LOGBIRTHS, P = 0.001) and more low birthweight babies (HIGHLBW, P = 0.004). After controlling for these variables, the county poverty level did not reduce the likelihood of site placement. Thus telemedicine sites had been established in those areas where the need was great both in terms of immediate risk (rate of low birthweight babies) and in terms of the continuing pressure of large numbers of births. This is significant in view of the concentration of poor minorities in certain areas, which historically have not been matched by past distribution of resources.

The purpose was to examine the organizational impact of a state-wide high-risk pregnancy telemedical system, Antenatal and Neonatal Guidelines, Education and Learning System (ANGELS), after the first year of its roll out. The focus is on several aspects of system organization, including the volume and diversity of patient-based telemedical consultations and weekly telemedical case discussions, telephone consultations, and changes in the pattern of birth-related patient transports. Individual data on patient transports and associated hospital days, provider-specialist telephone calls, and telemedical consultations were collected for two time periods: December 2002-May 2003 (prior to initiation of ANGELS), and December 2003-May 2004 (postinitiation of ANGELS). Different statistical tests were constructed to compare the two periods as appropriate. Significant increases were observed in the volume and geographic diversity of telemedical consultations and the volume of telephone consultations. There was a moderate, but nonsignificant decrease in the number of maternal transports to University of Arkansas School of Medical Sciences (UAMS), and the average length of stay decreased. The type of specialist-provider and specialist-patient contact has changed as the ANGELS high-risk pregnancy telemedical system has evolved over the first year. We conclude that the rollout of the ANGELS program is changing the shape of high-risk patient care in Arkansas, and we attribute that to an evolving collegial network between specialists and generalists.

Objective To investigate the maturation of the auditory cortex by non-invasive recording of auditory evoked magnetic fields in human fetuses and newborns with the relatively novel and completely non-invasive technology of MEG. Methods Serial recordings were performed every 2 weeks on 18 fetuses beginning from week 27 of gestational age until term with a follow-up recording on the newborn. Auditory stimulation consisted of tone bursts in an oddball design with standard tones and deviant tones. Results In 52 of 63 fetal and in all of the neonatal recordings an auditory evoked magnetic field was obtained. A decrease in latency with increasing age of the subjects was observed in the combined analysis of fetuses and neonates. Conclusions With advanced study using MEG, 83% of the measurements showed auditory evoked fields in fetuses that correspond with existing literature in electrophysiology in the past. These findings indicate that MEG is a technique that can be used to investigate maturation of the auditory cortex based on auditory evoked fields in fetuses and neonates. Significance Maturational changes have been examined in the past. With the use of this novel technique, applied to a serial study, it is possible to trace the development of auditory responses in utero and newborns.

We have measured some oscillatory properties of severe lower limb spasms experienced by a low-thoracic complete paraplegic during assisted standing. Electromyograms (EMG) were recorded from the leg muscles while the patient stood passively in a standing frame. The patient also stood using functional electrical stimulation (FES) while ground and handle reaction force vectors were measured together with EMG activity. During passive standing, spasms appeared simultaneously in all leg muscle groups on one side. The interval between spasms varied between 3 and 30 seconds. Within the spasms, there was a tendency of repetitive grouped discharge of motor units as well as a strong 10-Hz component in the EMG that was coherent across ipsilateral muscle groups. Thus, the spasms were inherently oscillatory. During FES-assisted standing, clinically similar spasms were observed. However, the interspasm interval became relatively fixed at around 16 seconds, which may indicate entraining of the spasm cycle by FES. There are similarities between this patient's spasms and the pathological motor activities seen in other movement disorders that may also be of spinal origin.

We describe a novel method of measuring the mass properties of the limbs, specifically legs. We use the method to obtain the mass and centre of mass of the legs which enables us to calculate the leg joint moments from measurements of ground reaction forces using force plates. The data are obtained by using a 3D whole body scanner to obtain a data set representing the surface of both legs. The bones are significantly denser than the soft tissue so their mass is calculated. Textbook values for the densities of bone and soft tissue are used. The actual bones are approximated by stretching appropriate bone shapes to fit the X-ray of the subject. Numerical integration is then used to obtain the mass and centre of mass of the limb. The system is fast and reliable and allows an individual's mass properties to be measured rather than relying upon population surveys which may be biased, particularly, when the subject is atypical by being disabled. Paraplegics can be measured in the scanner using a modified Oswestry standing frame. When compared with a water displacement method, for 10 legs the errors in the total leg volume using this method are less than 1% and in the location of the centre of mass are less than 4%.