Feasibility of gabapentin as an intervention for neurorecovery after an acute spinal cord injury: Protocol.

Introduction: This protocol is describing the first ever prospective, mock-efficacy, dose exploration trial design testing the feasibility of administering gabapentin in the acute setting as an intervention for neurorecovery. Gabapentin is an FDA-approved medication for treating seizures and postherpetic neuralgia and is used broadly off-label for neuropathic pain management for many conditions, including spinal cord injury. Emerging data suggests that when given early after spinal cord injury onset and in low-medium doses, gabapentin may have properties that promote recovery of neurological function. The objective of this trial is to assess the feasibility of conducting an efficacy trial in which gabapentin is started early after injury, is restricted in its dose, and is not used for pain management. Methods and analysis: Forty-two people aged 18 years or older with any level and any severity of spinal cord injury induced by a trauma will be enrolled, randomized, and have the first dose of study medication by 120 h post-injury onset. Participants will be randomly assigned to one of three groups: 600, 1,800 mg/day gabapentin, or placebo. Study medication will be given for a 90-day duration. Blinded assessments will be obtained at 7 days post-injury (baseline), 30 days post-injury (interim), after the 90-day treatment duration/approximately 3 months post-injury (end of treatment), and at 6 months post-injury (end of study). The key analysis parameters will evaluate feasibility of recruitment of target population, delivery of drug treatment protocol, maintenance of blinding, and retention of participants. Discussion: Outputs from this trial will inform research and clinical practice on the effects of manipulating gabapentin for non-pain management purposes in the acute setting and will guide the development of a properly powered efficacy trial of gabapentin as an intervention for neurorecovery in spinal cord injury. Ethics and dissemination: The study was approved by the MetroHealth Institutional Review Board (IRB21-00609) and registered at clinicaltrials.gov prior to enrolling any participants. Dissemination will include peer-reviewed publications, presentations at professional conferences and in the community, and through other healthcare and public venues. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05302999; protocol version 1.1 approved 05/23/2022. Trial funding: National Institute on Disability, Independent Living and Rehabilitation Research.

Multi-center, single-blind randomized controlled trial comparing functional electrical stimulation therapy to conventional therapy in incomplete tetraplegia.

Background: Loss of upper extremity function after tetraplegia results in significant disability. Emerging evidence from pilot studies suggests that functional electrical stimulation (FES) therapy may enhance recovery of upper extremity function after tetraplegia. The aim of this trial was to determine the effectiveness of FES therapy delivered by the Myndmove stimulator in people with tetraplegia. Methods: A multi-center, single-blind, parallel-group, two-arm, randomized controlled trial was conducted comparing FES to conventional therapy in adults (≥18 years) with C4-C7 traumatic incomplete tetraplegia between 4 and 96 months post-injury, and with a baseline spinal cord injury independence measure III -self-care (SCIM III-SC) score of ≤10. Participants were enrolled at four SCI-specialized neurorehabilitation centers in the U.S. and Canada. Participants were stratified by center and randomized in a 1:1 ratio to receive either 40 sessions of FES or conventional therapy targeting upper extremities over a 14-week period. Blinded assessors measured SCIM III, Toronto Rehabilitation Institute Hand Function Test, and Graded Redefined Assessment of Strength, Sensibility, and Prehension at baseline, after 20th session, after 40th session or 14 weeks after 1st session, and at 24 weeks after 1st session. The primary outcome measure was change in SCIM III-SC from baseline to end of the treatment. Based on the primary outcome measure, a sample size of 60 was calculated. Seventeen participants' progress in the study was interrupted due to the COVID-19 lockdown. The protocol was modified for these participants to allow them to complete the study. Results: Between June 2019 to August 2021, 51 participants were randomized to FES (n = 27) and conventional therapy (n = 24). Both groups gained a mean of 2 points in SCIM-SC scores at the end of treatment, which was a clinically meaningful change. However, there was no statistically significant difference between the groups on any outcomes. Conclusion: Forty sessions of FES therapy delivered by the MyndMove stimulator are as effective as conventional therapy in producing meaningful functional improvements that persist after therapy is completed. Limitations of this study include the impact of COVID-19 limiting the ability to recruit the target sample size and per-protocol execution of the study in one-third of the participants. Registration: This trial is registered at www.ClinicalTrials.gov, NCT03439319.

Improving chemotherapy infusion operations through the simulation of scheduling heuristics: a case study.

Over the last decade, chemotherapy treatments have dramatically shifted to outpatient services such that nearly 90% of all infusions are now administered outpatient. This shift has challenged oncology clinics to make chemotherapy treatment as widely available as possible while attempting to treat all patients within a fixed period of time. Historical data from a Veterans Affairs chemotherapy clinic in the United States and staff input informed a discrete event simulation model of the clinic. The case study examines the impact of altering the current schedule, where all patients arrive at 8:00 AM, to a schedule that assigns patients to two or three different appointment times based on the expected length of their chemotherapy infusion. The results identify multiple scheduling policies that could be easily implemented with the best solutions reducing both average patient waiting time and average nurse overtime requirements.

Multicentre, single-blind randomised controlled trial comparing MyndMove neuromodulation therapy with conventional therapy in traumatic spinal cord injury: a protocol study.

INTRODUCTION: This protocol is describing a multicentre, single-blind randomised controlled trial. The objective is to compare the efficacy of MyndMove therapy versus conventional therapy (CT) in improving upper extremity function in individuals with C4-C7 traumatic, incomplete spinal cord injury (SCI). It is being conducted in two US and two Canadian SCI rehabilitation centres. METHODS AND ANALYSIS: Sixty people aged 18 years or older with a C4-C7 incomplete (AIS B-D) SCI between 4 months and 8 years postinjury are randomised to receive 40 sessions of MyndMove neuromodulation therapy or CT within a 14-week period of time. Therapy sessions are 1 hour in duration with a dose of 3-5 sessions per week. Assessments occur prior to randomisation, after 20 sessions, after 40 sessions and 10 weeks after the last session. The primary outcome measure is the efficacy of MyndMove therapy versus CT in improving upper extremity function as measured by Spinal Cord Independence Measure III: Self-Care subscore after 40 sessions. Secondary outcomes include: (1) improvements in the SCIM mobility subscore; (2) upper limb functions measured by Graded Redefined Assessment of Strength, Sensibility and Prehension and (3) Toronto Rehab Institute Hand Function Test; (4) To assess safety as measured by serious and non-serious adverse events recorded for participants in both groups of the study population over the duration of the study; (5) to compare the change in quality of life as measured by the Spinal Cord Injury-Quality of Life; and (6) to evaluate the impact on healthcare resource utilisation. ETHICS AND DISSEMINATION: All ethical approvals were obtained prior to enrolling any participants. Dissemination of the results of the study will be made at peer-reviewed academic meetings and through peer-reviewed medical journals TRIAL REGISTRATION NUMBER: NCT03439319.

Management of the Patient with Chronic Spinal Cord Injury.

Individuals with spinal cord injuries or disorders (SCI/D), whether of traumatic or nontraumatic cause, require multidisciplinary management by their care team to achieve optimal health outcomes. SCI/D is relatively rare in the general population and primary care providers (PCPs) may not have extensive experience managing people with these disorders. Spinal cord injuries, impair the body's autonomic and biomechanical performance by interrupting the communications to and from major bodily systems. This article provides a framework to help PCPs understand how these changes impact their patient's physiologic function and subsequent risks for health complications with guidance for initial treatment approaches.

Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper.

A new non-cytotoxic [(+)-17ß-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na+/K+-ATPase. Compound 3 docks deeply in the Na+/K+-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na+/K+-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na+/K+-ATPase. Thus, 3 was found to inhibit Na+/K+-ATPase, but 1 did not. In addition, the cytotoxic and Na+/K+-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters.

Structurally Modified Cyclopenta[b]benzofuran Analogues Isolated from Aglaia perviridis.

Four new cyclopenta[b]benzofuran derivatives based on an unprecedented carbon skeleton (1-4), with a dihydrofuran ring fused to dioxanyl and aryl rings, along with a new structural analogue (5) of 5‴-episilvestrol (episilvestrol, 7), were isolated from an aqueous extract of a large-scale re-collection of the roots of Aglaia perviridis collected in Vietnam. Compound 5 demonstrated mutarotation in solution due to the presence of a hydroxy group at C-2‴, leading to the isolation of a racemic mixture, despite being purified on a chiral-phase HPLC column. Silvestrol (6) and episilvestrol (7) were isolated from the most potently cytotoxic chloroform subfraction of the roots. All new structures were elucidated using 1D and 2D NMR, HRESIMS, IR, UV, and ECD spectroscopic data. Of the five newly isolated compounds, only compound 5 exhibited cytotoxic activity against a human colon cancer (HT-29) and human prostate cancer cell line (PC-3), with IC50 values of 2.3 µM in both cases. The isolated compounds (1-5) double the number of dioxanyl ring-containing rocaglate analogues reported to date from Aglaia species and present additional information on the structural requirements for cancer cell line cytotoxicity within this compound class.

Probabilistic sensitivity analysis on Markov models with uncertain transition probabilities: an application in evaluating treatment decisions for type 2 diabetes.

Markov models are commonly used for decision-making studies in many application domains; however, there are no widely adopted methods for performing sensitivity analysis on such models with uncertain transition probability matrices (TPMs). This article describes two simulation-based approaches for conducting probabilistic sensitivity analysis on a given discrete-time, finite-horizon, finite-state Markov model using TPMs that are sampled over a specified uncertainty set according to a relevant probability distribution. The first approach assumes no prior knowledge of the probability distribution, and each row of a TPM is independently sampled from the uniform distribution on the row's uncertainty set. The second approach involves random sampling from the (truncated) multivariate normal distribution of the TPM's maximum likelihood estimators for its rows subject to the condition that each row has nonnegative elements and sums to one. The two sampling methods are easily implemented and have reasonable computation times. A case study illustrates the application of these methods to a medical decision-making problem involving the evaluation of treatment guidelines for glycemic control of patients with type 2 diabetes, where natural variation in a patient's glycated hemoglobin (HbA1c) is modeled as a Markov chain, and the associated TPMs are subject to uncertainty.

Simulation model of the relationship between cesarean section rates and labor duration.

Cesarean delivery is the most common major abdominal surgery in many parts of the world, and it accounts for nearly one-third of births in the United States. For a patient who requires a C-section, allowing prolonged labor is not recommended because of the increased risk of infection. However, for a patient who is capable of a successful vaginal delivery, performing an unnecessary C-section can have a substantial adverse impact on the patient's future health. We develop two stochastic simulation models of the delivery process for women in labor; and our objectives are (i) to represent the natural progression of labor and thereby gain insights concerning the duration of labor as it depends on the dilation state for induced, augmented, and spontaneous labors; and (ii) to evaluate the Friedman curve and other labor-progression rules, including their impact on the C-section rate and on the rates of maternal and fetal complications. To use a shifted lognormal distribution for modeling the duration of labor in each dilation state and for each type of labor, we formulate a percentile-matching procedure that requires three estimated quantiles of each distribution as reported in the literature. Based on results generated by both simulation models, we concluded that for singleton births by nulliparous women with no prior complications, labor duration longer than two hours (i.e., the time limit for labor arrest based on the Friedman curve) should be allowed in each dilation state; furthermore, the allowed labor duration should be a function of dilation state.

A stochastic model of acute-care decisions based on patient and provider heterogeneity.

The primary cause of preventable death in many hospitals is the failure to recognize and/or rescue patients from acute physiologic deterioration (APD). APD affects all hospitalized patients, potentially causing cardiac arrest and death. Identifying APD is difficult, and response timing is critical - delays in response represent a significant and modifiable patient safety issue. Hospitals have instituted rapid response systems or teams (RRT) to provide timely critical care for APD, with thresholds that trigger the involvement of critical care expertise. The National Early Warning Score (NEWS) was developed to define these thresholds. However, current triggers are inconsistent and ignore patient-specific factors. Further, acute care is delivered by providers with different clinical experience, resulting in quality-of-care variation. This article documents a semi-Markov decision process model of APD that incorporates patient and provider heterogeneity. The model allows for stochastically changing health states, while determining patient subpopulation-specific RRT-activation thresholds. The objective function minimizes the total time associated with patient deterioration and stabilization; and the relative values of nursing and RRT times can be modified. A case study from January 2011 to December 2012 identified six subpopulations. RRT activation was optimal for patients in "slightly concerning" health states (NEWS > 0) for all subpopulations, except surgical patients with low risk of deterioration for whom RRT was activated in "concerning" states (NEWS > 4). Clustering methods identified provider clusters considering RRT-activation preferences and estimation of stabilization-related resource needs. Providers with conservative resource estimates preferred waiting over activating RRT. This study provides simple practical rules for personalized acute care delivery.

Competing risks analysis in mortality estimation for breast cancer patients from independent risk groups.

This study quantifies breast cancer mortality in the presence of competing risks for complex patients. Breast cancer behaves differently in different patient populations, which can have significant implications for patient survival; hence these differences must be considered when making screening and treatment decisions. Mortality estimation for breast cancer patients has been a significant research question. Accurate estimation is critical for clinical decision making, including recommendations. In this study, a competing risks framework is built to analyze the effect of patient risk factors and cancer characteristics on breast cancer and other cause mortality. To estimate mortality probabilities from breast cancer and other causes as a function of not only the patient's age or race but also biomarkers for estrogen and progesterone receptor status, a nonparametric cumulative incidence function is formulated using data from the community-based Carolina Mammography Registry. Based on the log(-log) transformation, confidence intervals are constructed for mortality estimates over time. To compare mortality probabilities in two independent risk groups at a given time, a method with improved power is formulated using the log(-log) transformation.

Multifunctional Polymer-Coated Carbon Nanotubes for Safe Drug Delivery.

Though progress in the use carbon nanotubes in medicine has been most encouraging for therapeutic and diagnostic applications, any translational success must involve overcoming the toxicological and surface functionalization challenges inherent in the use of such nanotubes. Ideally, a carbon nanotube-based drug delivery system would exhibit low toxicity, sustained drug release, and persist in circulation without aggregation. We report a carbon nanotube (CNT) coated with a biocompatible block-co-polymer composed of poly(lactide)-poly(ethylene glycol) (PLA-PEG) to reduce short-term and long-term toxicity, sustain drug release of paclitaxel (PTX), and prevent aggregation. The copolymer coating on the surface of CNTs significantly reduces in vitro toxicity in human umbilical vein endothelial cells (HUVEC) and U-87 glioblastoma cells. Moreover, coating reduces in vitro inflammatory response in rat lung epithelial cells. Compared to non-coated CNTs, in vivo studies show no long-term inflammatory response with CNT coated with PLA-PEG (CLP) and the surface coating significantly decreases acute toxicity by doubling the maximum tolerated dose in mice. Using polymer coatings, we can encapsulate PTX and release over one week to increase the therapeutic efficacy compared to free drugs. In vivo biodistribution and histology studies suggests a lower degree of aggregation in tissues in that CLP accumulate more in the brain and less in the spleen than the CNT-PLA (CL) formulation.

Measurement of the membrane potential in small cells using patch clamp methods.

The resting membrane potential, E(m), of mammalian cells is a fundamental physiological parameter. Even small changes in E(m) can modulate excitability, contractility and rates of cell migration. At present accurate, reproducible measurements of E(m) and determination of its ionic basis remain significant challenges when patch clamp methods are applied to small cells. In this study, a mathematical model has been developed which incorporates many of the main biophysical principles which govern recordings of the resting potential of 'small cells'. Such a prototypical cell (approx. capacitance, 6 pF; input resistance 5 GΩ) is representative of neonatal cardiac myocytes, and other cells in the cardiovascular system (endothelium, fibroblasts) and small cells in other tissues, e.g. bone (osteoclasts) articular joints (chondrocytes) and the pancreas (ß cells). Two common experimental conditions have been examined: (1) when the background K(+) conductance is linear; and (2) when this K(+) conductance is highly nonlinear and shows pronounced inward rectification. In the case of a linear K(+) conductance, the presence of a "leakage" current through the seal resistance between the cell membrane and the patch pipette always depolarizes E(m). Our calculations confirm that accurate characterization of E(m) is possible when the seal resistance is at least 5 times larger than the input resistance of the targeted cell. Measurement of E(m) under conditions in which the main background current includes a markedly nonlinear K(+) conductance (due to inward rectification) yields complex and somewhat counter-intuitive findings. In fact, there are at least two possible stable values of resting membrane potential for a cell when the nonlinear, inwardly rectifying K(+) conductance interacts with the seal current. This type of bistable behavior has been reported in a variety of small mammalian cells, including those from the heart, endothelium, smooth muscle and bone. Our theoretical treatment of these two common experimental situations provides useful mechanistic insights, and suggests practical methods by which these significant limitations, and their impact, can be minimized.

Three-dimensional analysis of solid oxide fuel cell Ni-YSZ anode interconnectivity.

A method is described for quantitatively analyzing the level of interconnectivity of solid-oxide fuel cell electrode phases. The method was applied to the three-dimensional microstructure of a Ni-Y2O3-stabilized ZrO2 (Ni-YSZ) anode active layer measured by focused ion beam scanning electron microscopy. Each individual contiguous network of Ni, YSZ, and porosity was identified and labeled according to whether it was contiguous with the rest of the electrode. It was determined that the YSZ phase was 100% connected, whereas at least 86% of the Ni and 96% of the pores were connected. Triple-phase boundary (TPB) segments were identified and evaluated with respect to the contiguity of each of the three phases at their locations. It was found that 11.6% of the TPB length was on one or more isolated phases and hence was not electrochemically active.

Clinical judgment analysis of the parameters used by consultant urologists in the management of prostate cancer.

PURPOSE: We assessed which clinical parameters consultant urologists use to recommend treatment for early prostate cancer. MATERIALS AND METHODS: A total of 30 consultant urologists reviewed 70 paper representations of patients with prostate cancer. Each contained 7 commonly available cues, including prostate specific antigen, Gleason grade, rectal examination, magnetic resonance imaging/laparoscopic stage, medical history, patient choice and age, in addition to 2 cues not yet routinely available, that is predicted life expectancy and 10-year survival probability, as calculated using actuarial formulas based on noncancer comorbidity. Consultants indicated how strongly they would recommend radical prostatectomy, radiotherapy with or without hormones, or active surveillance/hormones. Judgment analysis was performed using multiple regression analysis with significance considered at p

Three-dimensional reconstruction of a solid-oxide fuel-cell anode.

The drive towards increased energy efficiency and reduced air pollution has led to accelerated worldwide development of fuel cells. As the performance and cost of fuel cells have improved, the materials comprising them have become increasingly sophisticated, both in composition and microstructure. In particular, state-of-the-art fuel-cell electrodes typically have a complex micro/nano-structure involving interconnected electronically and ionically conducting phases, gas-phase porosity, and catalytically active surfaces. Determining this microstructure is a critical, yet usually missing, link between materials properties/processing and electrode performance. Current methods of microstructural analysis, such as scanning electron microscopy, only provide two-dimensional anecdotes of the microstructure, and thus limited information about how regions are interconnected in three-dimensional space. Here we demonstrate the use of dual-beam focused ion beam-scanning electron microscopy to make a complete three-dimensional reconstruction of a solid-oxide fuel-cell electrode. We use this data to calculate critical microstructural features such as volume fractions and surface areas of specific phases, three-phase boundary length, and the connectivity and tortuosity of specific subphases.