bluuebunny/crossref_metadata_2025 huggingface dataset:
A Broadly Applicable Method for Characterizing the Slope of the Electrically Evoked Compound Action Potential Amplitude Growth Function
Authors: Skidmore Jeffrey , Ramekers Dyan , Colesa Deborah J. , Schvartz-Leyzac Kara C. , Pfingst Bryan E. , He Shuman
Published: June 2021

Objectives:

Amplitudes of electrically evoked compound action potentials (eCAPs) as a function of the stimulation level constitute the eCAP amplitude growth function (AGF). The slope of the eCAP AGF (i.e., rate of growth of eCAP amplitude as a function of stimulation level), recorded from subjects with cochlear implants (CIs), has been widely used as an indicator of survival of cochlear nerve fibers. However, substantial variation in the approach used to calculate the slope of the eCAP AGF makes it difficult to compare results across studies. In this study, we developed an improved slope-fitting method by addressing the limitations of previously used approaches and ensuring its application for the estimation of the maximum slopes of the eCAP AGFs recorded in both animal models and human listeners with various etiologies.

Design:

The new eCAP AGF fitting method was designed based on sliding window linear regression. Slopes of the eCAP AGF estimated using this new fitting method were calculated and compared with those estimated using four other fitting methods reported in the literature. These four methods were nonlinear regression with a sigmoid function, linear regression, gradient calculation, and boxcar smoothing. The comparison was based on the fitting results of 72 eCAP AGFs recorded from 18 acutely implanted guinea pigs, 46 eCAP AGFs recorded from 23 chronically implanted guinea pigs, and 2094 eCAP AGFs recorded from 200 human CI users from 4 patient populations. The effect of the choice of input units of the eCAP AGF (linear versus logarithmic) on fitting results was also evaluated.

Results:

The slope of the eCAP AGF was significantly influenced by the slope-fitting method and by the choice of input units. Overall, slopes estimated using all five fitting methods reflected known patterns of neural survival in human patient populations and were significantly correlated with speech perception scores. However, slopes estimated using the newly developed method showed the highest correlation with spiral ganglion neuron density among all five fitting methods for animal models. In addition, this new method could reliably and accurately estimate the slope for 4 human patient populations, while the performance of the other methods was highly influenced by the morphology of the eCAP AGF.

Conclusions:

The novel slope-fitting method presented in this study addressed the limitations of the other methods reported in the literature and successfully characterized the slope of the eCAP AGF for various animal models and CI patient populations. This method may be useful for researchers in conducting scientific studies and for clinicians in providing clinical care for CI users.
Association of Nutritional Status with New-Onset Delirium in Elderly, Acute Care, Orthopaedic Trauma Patients: A Single-Center Observational Study
Authors: Maher Susan S. , Franco-Garcia Esteban , Zhou Carmen , Heng Marilyn , van Pelt Maria , Akeju Oluwaseun , Quraishi Sadeq A.
Published: June 2021

Objective:

To determine whether nutritional status at hospital admission is independently associated with new-onset delirium (NOD) in elderly, orthopaedic trauma patients.

Design:

Single-center, retrospective, cross-sectional study.

Setting:

Data from patients at a large teaching hospital in Boston, MA, were analyzed.

Patients:

All patients were ≥65 years and hospitalized for acute surgical management of their major fractures after trauma.

Intervention:

None.

Main Outcome Measurement:

Nutritional status was assessed at admission using the Mini Nutritional Assessment-Short Form (MNA-SF). Delirium was assessed using the Confusion Assessment Method within 24 hours of admission and daily throughout hospitalization.

Results:

The incidence of delirium was 20% (94/471). Each unit decrement in MNA-SF was associated with a 14% higher risk of NOD (adjusted OR 1.14; 95% CI 1.05–1.28). Moreover, malnourished patients (MNA-SF score 0–7) were twice as likely to develop NOD (adjusted OR 2.07; 95% CI 1.01–4.35) compared with patients who were not malnourished (MNA-SF score 8–14).

Conclusions:

In hospitalized, elderly, orthopaedic trauma patients, poor nutritional status may be a modifiable risk factor for NOD. Future studies are needed to determine whether aggressive nutritional interventions can reduce the incidence of NOD and improve outcomes in this cohort of patients.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Superficial Deltoid Ligament and Deep Deltoid Ligament Play Equally Important Roles in the Stability of Isolated Lateral Malleolus (OTA/AO 44-B1) Fractures: A Biomechanical Study
Authors: Hempen Eric C. , Butler Bennet A. , Barbosa Mauricio , Muriuki Muturi , Havey Robert M. , Kadakia Anish R.
Published: June 2021

Objective:

To evaluate the individual contributions to stability of the superficial and deep deltoid ligaments in the setting of SER IV ankle fractures.

Methods:

Nineteen total cadaveric specimens were used. SER IV injuries were created with the rupture of either the superficial (SER IV-S) (n = 9) or deep deltoid (SER IV-D) (n = 10). These were tested by applying an external rotation force (1 Nm, 2 Nm, 3 Nm, and 4 Nm). Changes in the position of the talus were recorded with a 3D motion tracker. Injury conditions were compared with a 4-step general linear model with repeated measures. Injury condition was also compared with the intact state and to each other using 2-tailed t tests.

Results:

The general linear model showed that increased loading had a significant effect with axial rotation (P = 0.02) and sagittal translation (P = 0.003). SER IV-S and SER IV-D showed significantly greater instability compared with the intact state in axial rotation (1 Nm, 2 Nm, and 3 Nm). SER IV-S and SER IV-D did not significantly differ from each other.

Conclusions:

SER IV fracture patterns can be unstable with isolated injury to either the superficial or deep deltoid. This challenges the notion that deep deltoid rupture is necessary. Further clinical studies would help quantify the consequences of this instability.
Treatment of refractory diffuse large B-cell lymphoma by chidamide combined with autologous stem cell transplantation: a case report
Authors: Wu Pengqiang , Ma Tao , Chen Yan , Wang Fujue , Chen Yingying , Gao Jie , Zhou Zhencang , Jia Yongqian
Published: June 2021

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin’s lymphoma, with certain DLBCLs affecting specific anatomic sites, such as primary cutaneous DLBCL, leg type and intravascular large B-cell lymphoma. However, the occurrence of secondary cutaneous involvement in DLBCL while patients are undergoing regular chemotherapy is rare. In this study, we reported a case of refractory diffuse large B-cell lymphoma with cutaneous involvement that achieved complete remission for more than 4 years with epigenetic regulation of chidamide in combination with chemotherapy and autologous hematopoietic stem cell transplantation including a pretreatment regimen containing chidamide.
Therapeutic options in inoperable ROS1-rearranged inflammatory myofibroblastic tumor of the tongue in a child: a case report and literature review
Authors: Styczewska Malgorzata , Patel Agastya , Jaskulowska Joanna , Godzinski Jan , Swieton Dominik , Wasag Bartosz , Dass Juliea , Bien Ewa , Krawczyk Malgorzata A.
Published: June 2021

Inflammatory myofibroblastic tumor (IMT) is a rare borderline malignancy, usually treated with surgery only. Exceedingly rare cases of inoperable, recurrent, or metastatic IMTs pose a therapeutic challenge. We report successful treatment of a 7-year-old girl with an inoperable anaplastic lymphoma kinase (ALK)-negative IMT of the tongue. The patient underwent various anti-inflammatory (steroids, nonsteroidal anti-inflammatory drugs, clarithromycin) and antiproliferative (chemotherapy) therapies to enable tumor regression and complete resection. Ultimately, next-generation sequencing of the tumor revealed a TFG-ROS-1 translocation, allowing for an off-label targeted therapy with crizotinib. Crizotinib treatment caused slight tumor regression but evident change of its structure, allowing for complete non-mutilating resection. Two histopathology examinations revealed complete disappearance of neoplastic cells following therapy. The patient remains disease-free 22 months after the delayed surgery. In children with inoperable ALK-negative IMTs, molecular testing must be performed to identify other targetable oncogenic fusions, including TFG-ROS1.
Chronic propranolol treatment moderately attenuated development of N-methyl-N-nitrosourea-induced mammary carcinoma in female rats
Authors: Tibensky Miroslav , Cernackova Alena , Horvathova Lubica , Macejova Dana , Tillinger Andrej , Mravec Boris
Published: June 2021

The sympathetic nervous system participates in the development and progression of several cancer types and this effect is mediated mainly via β-adrenergic signaling. However, the potential of β-adrenergic signaling blockade to prevent cancer development after exposure to carcinogens has not been investigated, yet. Therefore, in our study, we determined the effect of the β-blocker propranolol on the development and progression of mammary cancer induced in female rats by administration of the chemical carcinogen N-methyl-N-nitrosourea (MNU). The propranolol treatment (20 mg/kg body weight) started 12 days after MNU administration and lasted 10 weeks. We found that both saline and propranolol treatment significantly increased gene expression of the catecholamine-synthesizing enzyme tyrosine hydroxylase, indicating that repeated injection of saline or propranolol-induced stress in these two groups. However, compared to the vehicle-treated group, propranolol slightly delayed the development and moderately reduced the incidence of mammary carcinoma in animals. To evaluate the mechanisms mediating the effect of propranolol on the development of MNU-induced cancer, we investigated several parameters of the tumor microenvironment and found that propranolol increased gene expression of Casp3. Our data indicate that propranolol treatment that starts after exposure to carcinogens might represent a new, useful approach for preventing the development of cancer, especially in stressed individuals. However, the potential efficiency of propranolol treatment for preventing cancer development and progression in individuals exposed to carcinogens needs further investigation.
Nurses' Strategies to Prevent and/or Decrease Work-Related Technostress
Authors: Lucena Joana Côrte-Real , Carvalho Carla , Santos-Costa Paulo , Mónico Lisete , Parreira Pedro
Published: June 2021

Although there is evidence of the impact of technostress on nurses' physical and psychological well-being, there is no clear understanding of what strategies are used by nurses to prevent/decrease work-related technostress. Thus, we aim to map existing literature that describe the strategies used by nurses to prevent or decrease work-related technostress. This review followed the methodology proposed by the Joanna Briggs Institute for scoping reviews. Data analysis, extraction, and synthesis were performed by two independent reviewers. After contrasting the found literature with the inclusion criteria outlined, no studies were found that address our review question. Overall, we found that technostress is a broad concept, thus becoming difficult to define. Given the complexity and demands of the clinical settings where nurses work, it may be that other stressors are more commonly identified and reported in the literature.
Nursing Praxis for Reducing Documentation Burden Within Nursing Admission Assessments
Authors: Phillips Toni , Baur Karen
Published: June 2021

The purpose of this quality improvement project was to conduct a scholarly assessment of the information collected within the nursing admission encounter and implement content revisions across three pilot medical surgical units. The guiding principles were to preserve regulatory information, identify nurse-sensitive data, and eliminate nonessential information. The goal was to decrease the number of clicks and time expended to document electronically an acute admission encounter by 20% and to project the number of hours returned to patient care as a result of decreasing computer clicks. A second goal was to quantify the projected costs of completing a nursing admission encounter. This quality improvement project leveraged nurse executive competencies to intersect the nursing process to develop a nursing documentation praxis. This author's praxis reduced nursing documentation burden in clicks by 29% and reduced time to document on an admission encounter by 34%. This restored the focus on nurse-patient interactions by returning 1016 hours per year to patient care activities, across three pilot units, as well as quantified the costs of completing a nursing admission assessment to utilize in future cost analysis of nursing tasks.
Implementation of Vancomycin Therapeutic Monitoring Guidelines: Focus on Bayesian Estimation Tools in Neonatal and Pediatric Patients
Authors: Han Jihye , Sauberan Jason , Tran Martin Tuan , Adler-Shohet Felice C. , Michalik David E. , Tien Tran Hoang , Tran Lan , DO Dylan Huy , Bradley John S. , Le Jennifer
Published: June 2021

Background:

The 2020 consensus guidelines for vancomycin therapeutic monitoring recommend using Bayesian estimation targeting the ratio of the area under the curve over 24 hours to minimum inhibitory concentration as an optimal approach to individualize therapy in pediatric patients. To support institutional guideline implementation in children, the objective of this study was to comprehensively assess and compare published population-based pharmacokinetic (PK) vancomycin models and available Bayesian estimation tools, specific to neonatal and pediatric patients.

Methods:

PubMed and Embase databases were searched from January 1994 to December 2020 for studies in which a vancomycin population PK model was developed to determine clearance and volume of distribution in neonatal and pediatric populations. Available Bayesian software programs were identified and assessed from published articles, software program websites, and direct communication with the software company. In the present review, 14 neonatal and 20 pediatric models were included. Six programs (Adult and Pediatric Kinetics, BestDose, DoseMeRx, InsightRx, MwPharm++, and PrecisePK) were evaluated.

Results:

Among neonatal models, Frymoyer et al and Capparelli et al used the largest PK samples to generate their models, which were externally validated. Among the pediatric models, Le et al used the largest sample size, with multiple external validations. Of the Bayesian programs, DoseMeRx, InsightRx, and PrecisePK used clinically validated neonatal and pediatric models.

Conclusions:

To optimize vancomycin use in neonatal and pediatric patients, clinicians should focus on selecting a model that best fits their patient population and use Bayesian estimation tools for therapeutic area under the –curve–targeted dosing and monitoring.
Using a Prism Paradigm to Identify Sensorimotor Impairment in Youth Following Concussion
Authors: Little C. Elaine , Dukelow Sean P. , Schneider Kathryn J. , Emery Carolyn A.
Published: June 2021

Objective:

The study assesses the intrarater reliability and utility of a prism paradigm to identify sensorimotor impairment following sports-related concussion in youth, (recent and history of concussion) compared with youth with no concussion.

Setting:

University of Calgary.

Participants:

Three groups of 40 ice hockey players ranging in age from 11 to 17 years were included: (1) no concussion; (2) recent concussion, mean number of days since last concussion 5 (95% CI, 4-6); and (3) history of concussion, mean number of days since last concussion 631 (95% CI, 505-730).

Design:

Cross-sectional study.

Main Measures:

The vestibulo-ocular reflex is a fundamental reflex of the central nervous system that stabilizes the position of the eyes during head movement and adapts when sensory input is altered (the bend of the light on the retina by prism glasses). The prism adaptation measure was the number of throws taken to adapt to wearing prism glasses while throwing balls at a central target.

Results:

The intraclass correlation coefficient (0.73; 95% CI, 0.55-0.84) and the Bland-Altman 95% levels of agreement (lower limit −18.5; 95% CI, −22.4 to −14.6); and upper limit 16.6; 95% CI, 12.7-20.5) reflected good intrarater reliability. Prism adaptation measures were significantly different across groups (F
2,119 = 51.9, P < .001, r = 0.52, power of 90%), with the mean number of throws for youth (aged 11-17 years) in each group as follows: 10 (95% CI, 8-12) no concussion history; 25 (95% CI, 23-27) recent concussion (1-11 days); and 17 (95% CI, 15-20) history of concussion (90-1560 days).

Conclusion:

Use of a prism paradigm as a clinical measurement tool has the potential to alter concussion management in youth. The prism paradigm is objective, is readily translatable to the clinical arena, has minimal associated costs, and is easily administered, reliable, and portable.
Progressive Neurodegeneration Across Chronic Stages of Severe Traumatic Brain Injury
Authors: Belchev Zorry , Gilboa Asaf , Binns Malcolm , Colella Brenda , Glazer Joanna , Mikulis David J. , Green Robin E.
Published: June 2021

Objective:

To examine the trajectory of structural gray matter changes across 2 chronic periods of recovery in individuals who have sustained severe traumatic brain injury (TBI), adding to the growing literature indicating that neurodegenerative processes occur in the months to years postinjury.

Participants:

Patients who experienced posttraumatic amnesia of 1 hour or more, and/or scored 12 or less on the Glasgow Coma Scale at the emergency department or the scene of the accident, and/or had positive brain imaging findings were recruited while receiving inpatient care, resulting in 51 patients with severe TBI.

Methods:

Secondary analyses of gray matter changes across approximately 5 months, 1 year, and 2.5 years postinjury were undertaken, using an automated segmentation protocol with improved accuracy in populations with morphological anomalies. We compared patients and matched controls on regions implicated in poorer long-term clinical outcome (accumbens, amygdala, brainstem, hippocampus, thalamus). To model brain-wide patterns of change, we then conducted an exploratory principal component analysis (PCA) on the linear slopes of all regional volumes across the 3 time points. Finally, we assessed nonlinear trends across earlier (5 months-1 year) versus later (1-2.5 years) time-windows with PCA to compare degeneration rates across time. Chronic degeneration was predicted cortically and subcortically brain-wide, and within specific regions of interest.

Results:

(1) From 5 months to 1 year, patients showed significant degeneration in the accumbens, and marginal degeneration in the amygdala, brainstem, thalamus, and the left hippocampus when examined unilaterally, compared with controls. (2) PCA components representing subcortical and temporal regions, and regions from the basal ganglia, significantly differed from controls in the first time-window. (3) Progression occurred at the same rate across both time-windows, suggesting neither escalation nor attenuation of degeneration across time.

Conclusion:

Localized yet progressive decline emphasizes the necessity of developing interventions to offset degeneration and improve long-term functioning.
Perceived Injustice After Mild Traumatic Brain Injury
Authors: Mäki Kaisa , Nybo Taina , Hietanen Marja , Huovinen Antti , Marinkovic Ivan , Isokuortti Harri , Melkas Susanna
Published: June 2021

Objective:

To examine perceived injustice and its associations with self-reported symptoms and return to work at 3 months after injury in a prospectively recruited sample of patients with mild traumatic brain injury (mTBI).

Design:

Observational study.

Setting:

TBI outpatient unit.

Participants:

Adult patients aged 18 to 68 years with mTBI (n = 100) or orthopedic injury ([OI]; n = 34).

Main Measures:

The Injustice Experience Questionnaire (IEQ) and its associations with the Rivermead Post Concussion Questionnaire (RPQ), Beck Depression Inventory–Second Edition (BDI-II), PTSD Checklist–Civilian Version (PCL-C), and Pain Visual Analog Scale (PVAS). Information on injury-related characteristics, compensation seeking and litigation, and return-to-work status was also collected.

Results:

Median IEQ total score was 3 (range, 0-23) in the mTBI group and 2.5 (range, 0-25) in the OI group. In the mTBI group, IEQ was significantly correlated with RPQ (r
s = 0.638, P < .01), BDI-II (r
s = 0.612, P < .01), PCL-C (r
s = 0.679, P < .01), and PVAS (r
s = 0.232, P < .05). The association between IEQ and PCL-C (r
s =0.797, P < .01) and BDI-II (r
s = 0.395, P < .05) was also found in the OI group. In both groups, patients who were still on sick leave at 3 months after injury tended to report higher perceived injustice (IEQ total score) than patients who had returned to work or studies. However, this difference did not reach statistical significance.

Conclusions:

Perceived injustice is associated with self-reported symptoms in patients with mTBI. Our results suggest that perceived injustice could be a relevant construct to consider in clinical management of patients with mTBI. Also, perceived injustice could be a potential target for psychological interventions promoting recovery after mTBI.
Contributions of PCSS, BESS, Tandem Gait, and Romberg Test for Identifying Balance Deficits in Pediatric Concussions
Authors: Patel Rishi D. , LaBella Cynthia R.
Published: June 2021

Objective:

Balance deficits are common after concussions in pediatric patients. This study evaluates 3 clinical tools for identifying postconcussion balance deficits in a pediatric population: (1) Post-Concussion Symptom Scale (PCSS); (2) Balance Error Scoring System (BESS); and (3) physical examination measures of balance: tandem gait (TG) and Romberg test.

Setting:

Data were collected in a tertiary care outpatient pediatric sports medicine clinic.

Participants:

English-speaking patients aged 8 to 17 years who presented to a tertiary care hospital-based pediatric sports medicine clinic and diagnosed with concussion between August 2014 and February 2018 were invited to participate. A total of 614 patients were screened and/or approached during the inclusion period and 500 were enrolled. Of those enrolled, 423 patients had complete data collected and analyzed.

Design:

This is a cross-sectional, observational data set from a longitudinal, prospective study.

Main Measures:

Data extracted from patients' electronic medical records included physical examination, PCSS, and BESS scores from their initial visit. Descriptive statistics were calculated for the outcome measures. A logistic regression was performed to evaluate significant contributors to abnormal BESS score (≥25).

Results:

There were 423 patients (56.7% female; 14.7 ± 2.01 years old) included in the study. Overall, we identified 336 patients (79.4%) with balance difficulties. Of the 336 with balance difficulties, 284 (84.5%) reported “balance problems” and/or “dizziness” on PCSS, 153 (45.5%) had abnormal BESS scores (≥25), and 100 (29.8%) had an abnormality on either TG or Romberg test.

Conclusion:

Balance difficulties were identified in close to 80% of children with concussions. Using PCSS and BESS along with physical examination measures, TG and Romberg test, identified more patients with balance deficits than using TG and Romberg test alone.
Piezo2 mechanosensitive ion channel is located to sensory neurons and nonneuronal cells in rat peripheral sensory pathway: implications in pain
Authors: Shin Seung Min , Moehring Francie , Itson-Zoske Brandon , Fan Fan , Stucky Cheryl L. , Hogan Quinn H. , Yu Hongwei
Published: June 2021

Piezo2 mechanotransduction channel is a crucial mediator of sensory neurons for sensing and transducing touch, vibration, and proprioception. We here characterized Piezo2 expression and cell specificity in rat peripheral sensory pathway using a validated Piezo2 antibody. Immunohistochemistry using this antibody revealed Piezo2 expression in pan primary sensory neurons of dorsal root ganglia in naïve rats, which was actively transported along afferent axons to both central presynaptic terminals innervating the spinal dorsal horn (DH) and peripheral afferent terminals in the skin. Piezo2 immunoreactivity (IR) was also detected in the postsynaptic neurons of the DH and in the motor neurons of the ventral horn, but not in spinal glial fibrillary acidic protein–positive and Iba1-positive glia. Notably, Piezo2-IR was clearly identified in peripheral nonneuronal cells, including perineuronal glia, Schwann cells in the sciatic nerve and surrounding cutaneous afferent endings, as well as in skin epidermal Merkel cells and melanocytes. Immunoblots showed increased Piezo2 in dorsal root ganglia ipsilateral to plantar injection of complete Freund's adjuvant, and immunostaining revealed increased Piezo2-IR intensity in the DH ipsilateral to complete Freund's adjuvant injection. This elevation of DH Piezo2-IR was also evident in various neuropathic pain models and monosodium iodoacetate knee osteoarthritis pain model, compared with controls. We conclude that (1) the pan neuronal profile of Piezo2 expression suggests that Piezo2 may function extend beyond simply touch or proprioception mediated by large-sized low-threshold mechanosensitive primary sensory neurons; (2) Piezo2 may have functional roles involving sensory processing in the spinal cord, Schwann cells, and skin melanocytes; and (3) aberrant Piezo2 expression may contribute pain pathogenesis.
Postinjury stimulation triggers a transition to nociplastic pain in mice
Authors: Hankerd Kali , McDonough Kathleen E. , Wang Jigong , Tang Shao-Jun , Chung Jin Mo , La Jun-Ho
Published: June 2021

Acute injury–induced pain can transition to chronic nociplastic pain, which predominantly affects women. To facilitate studies on the underlying mechanisms of nociplastic pain, we developed a mouse model in which postinjury thermal stimulation (intermittent 40°C water immersion for 10 minutes at 2 hours postcapsaicin) prolongs capsaicin (ie, experimental injury)-induced transient mechanical hypersensitivity outside of the injury area. Although capsaicin injection alone induced mechanical and thermal hypersensitivity that resolved in ∼7 days (slower recovery in females), the postinjury stimulation prolonged capsaicin-induced mechanical, but not thermal, hypersensitivity up to 3 weeks in both sexes. When postinjury stimulation was given at a lower intensity (30°C) or at later time points (40°C at 1-3 days postcapsaicin), chronification of mechanical hypersensitivity occurred only in females. Similar chronification could be induced by a different postinjury stimulation modality (vibration of paw) or with a different injury model (plantar incision). Notably, the 40°C postinjury stimulation did not prolong capsaicin-induced inflammation in the hind paw, indicating that the prolonged mechanical hypersensitivity in these mice arises without clear evidence of ongoing injury, reflecting nociplastic pain. Although morphine and gabapentin effectively alleviated this persistent mechanical hypersensitivity in both sexes, sexually dimorphic mechanisms mediated the hypersensitivity. Specifically, ongoing afferent activity at the previously capsaicin-injected area was critical in females, whereas activated spinal microglia were crucial in males. These results demonstrate that postinjury stimulation of the injured area can trigger the transition from transient pain to nociplastic pain more readily in females, and sex-dependent mechanisms maintain the nociplastic pain state.
Evaluation of the effect of analgesic treatment on signs of nociception-related behaviors during physiotherapy in patients with disorders of consciousness: a pilot crossover randomized controlled trial
Authors: Bonin Estelle A.C. , Binda Fossati Mariachiara L. , Filippini Maria M. , Bornheim Stephen , Lejeune Nicolas , O'Brien Anthony T. , Bodart Olivier , Laureys Steven , Thibaut Aurore , Chatelle Camille
Published: June 2021

Neuro-orthopedic disorders are common in patients with disorders of consciousness (DOC) and can lead to potential pain. However, the patients' inability to communicate makes pain detection and management very challenging for clinicians. In this crossover randomized double-blind placebo-controlled study, we investigated the effects of an analgesic treatment on the presence of nociception-related behaviors. At baseline, the Nociception Coma Scale-Revised (NCS-R) was performed in 3 conditions: a non-noxious stimulation, a noxious stimulation, and during a physiotherapy session. Patients with a NCS-R total score during physiotherapy equal or above the score observed after the noxious stimulation could participate to the clinical trial, as well as patients with a score above 5. They received an analgesic treatment and a placebo on 2 consecutive days in a randomized order followed by an assessment with the NCS-R. Of the 18 patients, 15 displayed signs of potential pain during physiotherapy. Patients showed higher NCS-R scores during physiotherapy compared with the other conditions, suggesting that mobilizations were potentially painful. Of these 15 patients, 10 met the criteria to participate in the placebo-controlled trial. We did not find any effect of analgesic treatment on the NCS-R scores. This study highlights that physiotherapy may be potentially painful for patients with DOC, while analgesic treatments did not reduced NCS-R scores. Therefore, careful monitoring with appropriate assessment and treatment before and during mobilization should become a priority in clinical settings. Future studies should focus on the development of assessment tools sensitive to analgesic dosage to manage pain in DOC.
Within-day rhythms of pain and cognitive function in people with and without fibromyalgia: synchronous or syncopated?
Authors: Whibley Daniel , Williams David A. , Clauw Daniel J. , Sliwinski Martin J. , Kratz Anna L.
Published: June 2021

Cognitive dysfunction is a common fibromyalgia (FM) symptom and can impact on the daily lives of those affected. We investigated whether within-day pain intensity ratings were associated with contemporaneous objective and subjective measures of cognitive function and whether within-day increases in pain intensity preceded increases in cognitive dysfunction or vice versa. Inclusion of a non-FM group allowed us to examine whether effects were specific to FM. Fifty people with FM and 50 non-FM controls provided 7 days of data. Cognitive tests (processing speed and working memory) and ecological momentary assessments (pain intensity and self-reported cognitive functioning) were conducted ×5/day. Three-level multilevel models examined contemporaneous and within-day 1-lag pain intensity–cognitive functioning associations. Interaction terms assessed possible moderating effects of FM status. Momentary increase in pain was associated with increased self-reported cognitive dysfunction, more strongly so for those with FM (B = 0.27, 95% confidence interval 0.22–0.32; non-FM B = 0.17, 95% confidence interval 0.10–0.23). For the FM group, higher pain was associated with longer processing speed; for the non-FM group, higher pain was associated with shorter processing speed. Pain increase did not precede change in subjective or objective cognitive function in the FM group, but reduction in working memory preceded increase in pain intensity. This finding warrants further research attention and, if replicated, could hold prognostic and/or therapeutic potential.
Impact of variability in baseline pain on the placebo response in randomized, placebo-controlled, crossover trials in peripheral neuropathic pain
Authors: Gillving Mimmi , Demant Dyveke , Holbech Jakob V. , Vase Lene , Bach Flemming W. , Jensen Troels S. , Finnerup Nanna B. , Sindrup Søren H.
Published: June 2021

Large placebo responses often negatively affect randomized controlled trials within the pain area. Understanding different possible factors that influence the placebo response is therefore important. In this retrospective analysis, we hypothesized that a large variability in baseline pain score would predict a greater placebo response and analyzed the impact of the coefficient of variation, SD, and difference between the highest and lowest numeric rating scale (NRS) score at baseline on the placebo response. A total of 160 observations on placebo response from 3 controlled clinical trials with a crossover design were included in this study. In general, the placebo response was low with a mean reduction in pain intensity of 0.5 points (range −5 to 7) measured on a 0 to 10 point NRS, and only 15% were placebo responders as defined by more than 30% reduction in NRS pain score from baseline to the end of the placebo treatment period. We found no significant impact of baseline pain coefficient of variation, SD, or the difference between lowest and highest baseline pain score on the placebo response. Placebo response in one trial did not predict placebo response in another trial. A large placebo response was not associated with a large treatment response. In conclusion, in this retrospective data analysis, there was no impact of baseline pain variability on the placebo response in controlled clinical trials with a crossover design in patients with peripheral neuropathic pain.
Using wearable technology to detect prescription opioid self-administration
Authors: Salgado García Francisco I. , Indic Premananda , Stapp Joshua , Chintha Keerthi K. , He Zhaomin , Brooks Jeffrey H. , Carreiro Stephanie , Derefinko Karen J.
Published: June 2021

Appropriate monitoring of opioid use in patients with pain conditions is paramount, yet it remains a very challenging task. The current work examined the use of a wearable sensor to detect self-administration of opioids after dental surgery using machine learning. Participants were recruited from an oral and maxillofacial surgery clinic. Participants were 46 adult patients (26 female) receiving opioids after dental surgery. Participants wore Empatica E4 sensors during the period they self-administered opioids. The E4 collected physiological parameters including accelerometer x-, y-, and z-axes, heart rate, and electrodermal activity. Four machine learning models provided validation accuracies greater than 80%, but the bagged-tree model provided the highest combination of validation accuracy (83.7%) and area under the receiver operating characteristic curve (0.92). The trained model had a validation sensitivity of 82%, a specificity of 85%, a positive predictive value of 85%, and a negative predictive value of 83%. A subsequent test of the trained model on withheld data had a sensitivity of 81%, a specificity of 88%, a positive predictive value of 87%, and a negative predictive value of 82%. Results from training and testing model of machine learning indicated that opioid self-administration could be identified with reasonable accuracy, leading to considerable possibilities of the use of wearable technology to advance prevention and treatment.
Microglial ablation does not affect opioid-induced hyperalgesia in rodents
Authors: Liu Xin , Liu Bo-Long , Yang Qing , Zhou Xiangfu , Tang Shao-Jun
Published: June 2021

Opioids are the frontline analgesics in pain management. However, chronic use of opioid analgesics causes paradoxical pain that contributes to the decrease of their efficacy in pain control and the escalation of dose in long-term management of pain. The underling pathogenic mechanism is not well understood. Microglia have been commonly believed to play a critical role in the expression of opioid-induced hyperalgesia in animal models. We performed microglial ablation experiments using either genetic (CD11b-diphtheria toxin receptor transgenic mouse) or pharmacological (colony-stimulating factor-1 receptor inhibitor PLX5622) approaches. Surprisingly, ablating microglia using these specific and effective approaches did not cause detectable impairment in the expression of hyperalgesia induced by morphine. We confirmed this conclusion with a behavioral test of mechanical and thermal hyperalgesia, in male and female mice, and with different species (mouse and rat). These findings raise caution about the widely assumed contribution of microglia to the development of opioid-induced hyperalgesia.
Reliability and clinical utility of the chronic pain classification in the 11th Revision of the International Classification of Diseases from a global perspective: results from India, Cuba, and New Zealand
Authors: Korwisi Beatrice , Garrido Suárez Bárbara Beatriz , Goswami Subrata , Gunapati Nischala Reddy , Hay Ginea , Hernández Arteaga Manuel Angel , Hill Charlotte , Jones David , Joshi Muralidhar , Kleinstäuber Maria , López Mantecón Ana Marta , Nandi Gargi , Papagari Chandra Shekhar Reddy , Rabí Martínez María del Carmen , Sarkar Biplab , Swain Nicola , Templer Paul , Tulp Maartje , White Naomi , Treede Rolf-Detlef , Rief Winfried , Barke Antonia
Published: June 2021

Chronic pain affects 1 in 5 persons and contributes substantially to the global burden of disease. The 11th Revision of the International Classification of Diseases (ICD-11) includes a comprehensive classification of chronic pain. The aim of this ecological implementation field study was to evaluate the classification's interrater reliability and clinical utility in countries with different income levels. The study was conducted in 4 pain clinics in Cuba, India, and New Zealand. Twenty-one clinicians used the ICD-11 to diagnose and code n = 353 patients with chronic pain. Of these, 111 were assessed by 2 clinicians, and Fleiss' kappa was calculated to establish interrater reliability for any diagnosis assigned to ≥15 patients. The clinicians rated the clinical utility of all diagnoses. The interrater reliability could be calculated for 11 diagnoses. It was substantial for 10 diagnoses and moderate for 1 (kappa: 0.596-0.783). The mean clinical utility of the ICD-11 chronic pain diagnoses was rated as 8.45 ± 1.69/10. Clinical utility was rated higher for ICD-11 than for the commonly used classification systems (P < 0.001, η2 = 0.25) and differed between all centers (P < 0.001, η2 = 0.60). The utility of the ICD-11 diagnoses was rated higher than the commonly used diagnoses in Dunedin and Havana, and no difference was found in Kolkata and Hyderabad. The study showed the high interrater reliability of the new chronic pain diagnoses. The perceived clinical utility of the diagnoses indicates their superiority or equality compared with the classification systems currently used in pain clinics. These results suggest the global applicability of the classification in specialized pain treatment settings.
Frontier review of the roles of exosomes in osteoarthritis
Authors: Liu Ding-Hao , Jheng Ying-Chun , Chen Po-Yin , Yarmishyn Aliaksandr A. , Huang Shih-En , Chien Chian-Shiu , Tsai Pin-Hsing , Chien Yueh , Yang Yi-Ping , Kao Chung-Lan
Published: June 2021

Osteoarthritis (OA) is a common degenerative disease; however, its exact pathophysiology and early diagnosis are still a challenge. Growing attention to the exosomes may inspire innovations that would make the current management of OA more effective. The exosomes in synovial fluid are relatively stable, and they can be easily isolated by the relatively noninvasive procedure of liquid biopsy to provide diagnostic and monitoring value. Some miRNAs (miR-504, miR-146a, miR-26a, miR-200c, and miR-210) have been known to be secreted in exosomes of OA patients. On the other hand, intraarticular injection of platelet-rich plasma (PRP) is becoming a popular therapy for OA patients. PRP is also a source of exosomes and their numerous contents. It is evident from the literature that PRP-derived exosomes can induce chondrogenic gene expression in OA chondrocytes. Here, we review the latest findings on the roles of exosomes in OA with the emphasis on PRP-derived exosomes and their potential applications for treating OA.
Factors Associated With Frailty in Patients Undergoing Cardiac Surgery
Authors: Chen Wei-Yi , Liu Chieh-Yu , Shih Chun-Che , Chen Yih-Sharng , Cheng Hsiao-Wei , Chiou Ai-Fu
Published: June 2021

Background

Frailty may increase the risk of complications and mortality in patients undergoing cardiac surgery. Few studies on frailty and its associated factors have been conducted in these patients.

Objective

The aim of this study was to explore frailty and related factors in patients undergoing cardiac surgery.

Methods

A total of 154 patients undergoing cardiac surgery in northern Taiwan were recruited using a longitudinal study design and interviewed using structured questionnaires assessing physical activity, anxiety and depression, and social support before surgery and at 1 month and 3 months after surgery.

Results

The prevalence of frailty in patients undergoing cardiac surgery was 16.2%, 20.5%, and 16.6% before surgery and at 1 month and 3 months after surgery, respectively. Frail and prefrail patients undergoing cardiac surgery were more likely to be unemployed, have gout, have a higher New York Heart Association class, have preoperative dysrhythmia, undergo cardiopulmonary bypass, have a lower functional ability, have a higher European System for Cardiac Operative Risk Evaluation score, have a longer anesthesia time, have longer endotracheal tube and extracorporeal circulation times, have longer intensive care unit and hospital stays, have lower hemoglobin and albumin levels, have higher anxiety and depression levels, and have lower Mini-Mental State Examination scores. The significant predictors of prefrailty and frailty included unemployment, the presence of gout, higher New York Heart Association classes, less independence in activities of daily living, lower hemoglobin levels, and higher levels of depression.

Conclusions

Frailty was associated with patients' functional status, perioperative conditions and psychosocial factors. Preoperative assessments of frailty and appropriate interventions are needed to improve frailty in patients undergoing cardiac surgery.
Effects of Bedtime Dosing With Suvorexant and Zolpidem on Balance and Psychomotor Performance in Healthy Elderly Participants During the Night and in the Morning
Authors: Bland Hubert , Li Xiaodong , Mangin Eric , Yee Ka Lai , Lines Christopher , Herring W. Joseph , Gillespie Gillian
Published: June 2021

Purpose/Background

This study was designed as an early assessment of the safety of the orexin receptor antagonist suvorexant, but also included exploratory assessments of balance and psychomotor performance that are the focus of this report.

Methods/Procedures

This was a double-blind, randomized, 3-period, crossover, phase 1 study. Balance and psychomotor performance were evaluated during the night in 12 healthy elderly participants after bedtime administration of suvorexant 30 mg (a supratherapeutic dose), the GABAergic agonist zolpidem 5 mg (the recommended dose in the elderly), or placebo. Balance (body sway measured by platform stability) and psychomotor performance (measured by choice reaction time) were assessed predose and at 1.5, 4, and 8 hours postdose in each period. Memory (measured by word recall) was assessed predose and at 4 hours postdose.

Findings/Results

At 1.5 hours after nighttime administration of each drug (the approximate time of their anticipated maximal plasma concentrations), both zolpidem and suvorexant increased body sway versus placebo, with a greater increase for zolpidem than suvorexant. Suvorexant increased choice reaction time compared with placebo or zolpidem at 1.5 hours. There were no treatment differences on body sway or choice reaction time at 4 or 8 hours, or on word recall at 4 hours.

Implications/Conclusions

These exploratory data suggest that a 30-mg dose of suvorexant (supratherapeutic) and a 5-mg dose of zolpidem (recommended dose in the elderly) impaired balance at 1.5 hours in healthy elderly people, with potentially less impairment for suvorexant relative to zolpidem, but no treatment differences on body sway or psychomotor performance at 4 and 8 hours. Because of their exploratory nature, these findings and their clinical relevance, if any, require confirmation in a prospective study.
Six Month Mortality in Patients with COVID-19 and Non-COVID-19 Viral Pneumonitis Managed with Veno-Venous Extracorporeal Membrane Oxygenation
Authors: Garfield Benjamin , Bianchi Paolo , Arachchillage Deepa , Hartley Philip , Naruka Vinci , Shroff Diana , Law Alexander , Passariello Maurizio , Patel Brijesh , Price Susanna , Rosenberg Alexander , Singh Suveer , Trimlett Richard , Xu Tina , Doyle James , Ledot Stephane
Published: June 2021

A significant proportion of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) with high risk of death. The efficacy of veno-venous extracorporeal membrane oxygenation (VV-ECMO) for COVID-19 on longer-term outcomes, unlike in other viral pneumonias, is unknown. In this study, we aimed to compare the 6 month mortality of patients receiving VV-ECMO support for COVID-19 with a historical viral ARDS cohort. Fifty-three consecutive patients with COVID-19 ARDS admitted for VV-ECMO to the Royal Brompton Hospital between March 17, 2020 and May 30, 2020 were identified. Mortality, patient characteristics, complications, and ECMO parameters were then compared to a historical cohort of patients with non-COVID-19 viral pneumonia. At 6 months survival was significantly higher in the COVID-19 than in the non-COVID-19 viral pneumonia cohort (84.9% vs. 66.0%, p = 0.040). Patients with COVID-19 had an increased Murray score (3.50 vs. 3.25, p = 0.005), a decreased burden of organ dysfunction (sequential organ failure score score [8.76 vs. 10.42, p = 0.004]), an increased incidence of pulmonary embolism (69.8% vs. 24.5%, p < 0.001) and in those who survived to decannulation longer ECMO runs (19 vs. 11 days, p = 0.001). Our results suggest that survival in patients supported with EMCO for COVID-19 are at least as good as those treated for non-COVID-19 viral ARDS.