The Association Among Clinical Profiles, Modifiers, and Prolonged Recovery in Adolescents With Sport-Related Concussion.

OBJECTIVE: The purposes were to (1) describe the prevalence of clinical profiles and modifiers, (2) examine the association between clinical profiles and prolonged recovery, and (3) examine the interaction between clinical profiles and modifiers and prolonged recovery in adolescents with sport-related concussion (SRC). DESIGN: Retrospective, cross-sectional. SETTING: Interdisciplinary specialty sports concussion clinic. PATIENTS: Patients (n = 299) aged 12 to 19 years who were diagnosed with SRC within 30 days of injury. INDEPENDENT VARIABLES: Clinical profiles and modifiers were decided by the clinical judgment of the clinical neuropsychologist and sports medicine physician, using data from the Clinical Profile Screen and information gathered from the clinical interview, neurocognitive, and vestibular and ocular motor testing. MAIN OUTCOME MEASURES: Prolonged recovery was defined as ≥28 days from the date of injury to the date of clearance. RESULTS: The most common clinical profiles were migraine (34.8%) and cognitive-fatigue (23.4%). There were no significant relationships between clinical profiles and prolonged recovery (Wald = 5.89, df = 4, P = 0.21). The presence of a modifier did not significantly affect the relationship between clinical profiles and prolonged recovery ( = 6.5, df = 5, P = 0.26). The presence of any modifier yielded a 10-day increase in median recovery time within the cognitive/fatigue clinical profile (Wilcoxon rank-sum = 268.5, P = 0.01). CONCLUSIONS: Although patients with a clinical profile and modifier may not experience prolonged recovery, they may experience longer recovery time than patients with a clinical profile and no modifier.

Effects of cloth face masks on physical and cognitive performance during maximal exercise testing.

Wearing a cloth face mask has been shown to impair exercise performance; it is essential to understand the impact wearing a cloth face mask may have on cognitive performance. Participants completed two maximal cardiopulmonary exercise tests on a cycle ergometer (with and without a cloth face mask) with a concurrent cognitive task. Blood pressure, heart rate, oxygen saturation, perceived exertion, shortness of breath, accuracy, and reaction time were measured at rest, during each exercise stage, and following a 4-minute recovery period. The final sample included 35 adults (age = 26.1 ± 5.8 years; 12 female/23 male). Wearing a cloth face mask was associated with significant decreases in exercise duration (-2:00 ± 3:40 min, P = 0.003), peak measures of maximal oxygen uptake (-818.9 ± 473.3 mL/min, -19.0 ± 48 mL·min-1·kg-1, P < 0.001), respiratory exchange ratio (-0.04 ± 0.08, P = 0.005), minute ventilation (-36.9 ± 18 L/min), oxygen pulse (-3.9 ± 2.3, P < 0.001), heart rate (-7.9 ± 12.6 bpm, P < 0.001), oxygen saturation (-1.5 ± 2.8%, P = 0.004), and blood lactate (-1.7 ± 2.5 mmol/L, P < 0.001). While wearing a cloth face mask significantly impaired exercise performance during maximal exercise testing, cognitive performance was unaffected in this selected group of young, active adults.

Reduction in cardiopulmonary and cognitive performance after COVID-19 in a competitive athlete.

A 23-year-old male competitive athlete performed a maximal cardiopulmonary exercise test on a cycle ergometer with a concurrent cognitive test on an iPad 6 days before and 19 weeks after a nonhospitalized COVID-19 illness. Results indicated reductions in time to exhaustion (-3.25 min), peak oxygen consumption (-1.68 mL/kg/min), and accuracy (-8%) during peak exertion despite his return to prior levels of activity. Reductions in functional or cognitive performance in competitive athletes may elicit noticeable differences in athletic performance; therefore, fitness specialists should consider the assessment of both cognitive function as well as aerobic capacity in athletes following COVID-19, regardless of severity, to facilitate safe and effective return to activity.

Natural Killer Cell-Mediated Immunotherapy for Leukemia.

Leukemia is a malignancy of the bone marrow and blood resulting from the abnormal differentiation of hematopoietic stem cells (HSCs). There are four main types of leukemia including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). While chemotherapy and radiation have been conventional forms of treatment for leukemia, these therapies increase infection susceptibility, adverse side effects and immune cell inactivation. Immunotherapies are becoming promising treatment options for leukemia, with natural killer (NK) cell-mediated therapy providing a specific direction of interest. The role of NK cells is critical for cancer cell elimination as these immune cells are the first line of defense against cancer proliferation and are involved in both recognition and cytolysis of rapidly dividing and abnormal cell populations. NK cells possess various activating and inhibitory receptors, which regulate NK cell function, signaling either inhibition and continued surveillance, or activation and subsequent cytotoxic activity. In this review, we describe NK cells and NK cell receptors, functional impairment of NK cells in leukemia, NK cell immunotherapies currently under investigation, including monoclonal antibodies (mAbs), adoptive transfer, chimeric antigen receptor-NKs (CAR-NKs), bi-specific/tri-specific killer engagers (BiKEs/TriKEs) and future potential targets of NK cell-based immunotherapy for leukemia.

Effects of wearing a cloth face mask on performance, physiological and perceptual responses during a graded treadmill running exercise test.

OBJECTIVES: To (1) determine if wearing a cloth face mask significantly affected exercise performance and associated physiological responses, and (2) describe perceptual measures of effort and participants' experiences while wearing a face mask during a maximal treadmill test. METHODS: Randomised controlled trial of healthy adults aged 18-29 years. Participants completed two (with and without a cloth face mask) maximal cardiopulmonary exercise tests (CPETs) on a treadmill following the Bruce protocol. Blood pressure, heart rate, oxygen saturation, exertion and shortness of breath were measured. Descriptive data and physical activity history were collected pretrial; perceptions of wearing face masks and experiential data were gathered immediately following the masked trial. RESULTS: The final sample included 31 adults (age=23.2±3.1 years; 14 women/17 men). Data indicated that wearing a cloth face mask led to a significant reduction in exercise time (-01:39±01:19 min/sec, p<0.001), maximal oxygen consumption (VO2max) (-818±552 mL/min, p<0.001), minute ventilation (-45.2±20.3 L/min), maximal heart rate (-8.4±17.0 beats per minute, p<0.01) and increased dyspnoea (1.7±2.9, p<0.001). Our data also suggest that differences in SpO2 and rating of perceived exertion existed between the different stages of the CPET as participant's exercise intensity increased. No significant differences were found between conditions after the 7-minute recovery period. CONCLUSION: Cloth face masks led to a 14% reduction in exercise time and 29% decrease in VO2max, attributed to perceived discomfort associated with mask-wearing. Compared with no mask, participants reported feeling increasingly short of breath and claustrophobic at higher exercise intensities while wearing a cloth face mask. Coaches, trainers and athletes should consider modifying the frequency, intensity, time and type of exercise when wearing a cloth face mask.

Outcomes Using a Postoperative Protocol in Pediatric Single-Stage Laryngotracheal Reconstruction.

OBJECTIVES: The aim of this study was to evaluate single-stage laryngotracheal reconstruction (ssLTR) outcomes before and after the implementation of a postoperative care protocol in pediatric patients. METHODS: A case-control study with chart review was conducted at 2 tertiary academic centers from 2010 to 2016. Pediatric patients who underwent ssLTR with a postoperative care protocol were compared with those who did not receive care under this protocol. Data regarding perioperative management were collected and compared using χ2 and Wilcoxon rank tests. Planned extubation, length of intubation in the intensive care unit, and complications were examined. RESULTS: Nineteen patients completed ssLTR after the protocol was initiated, and 26 prior patients were used as control subjects. Planned extubation failed in 9 patients (35%) in the control group compared with 1 patient (5%) in the protocol group (P < .05). Using a structured protocol demonstrated a decrease in delayed extubation and intensive care unit stay (P < .05). Despite more postprotocol patients' requiring posterior graft placement, preprotocol patients were less likely to be extubated within 7 days (P < .05). CONCLUSIONS: The authors propose an intensive care unit protocol that uses a combination of pharmacologic agents to optimally reduce the risk for adverse events that delay time to extubation and thus decannulation. Timely extubation was more likely with the use of this postoperative care protocol using a multidisciplinary approach involving otolaryngologists, pharmacists, intensivists, and anesthesiologists.

Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection.

Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3) enteral nutrition (EN) should be preferred as a nutritional intervention over total parenteral nutrition (TPN) postoperatively; and, (4) a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life.

Early afferent activity from the facet joint after painful trauma to its capsule potentiates neuronal excitability and glutamate signaling in the spinal cord.

Cervical facet joint injury induces persistent pain and central sensitization. Preventing the peripheral neuronal signals that initiate sensitization attenuates neuropathic pain. Yet, there is no clear relationship among facet joint afferent activity, development of central sensitization, and pain, which may be hindering effective treatments for this pain syndrome. This study investigates how afferent activity from the injured cervical facet joint affects induction of behavioral sensitivity and central sensitization. Intra-articular bupivacaine was administered to transiently suppress afferent activity immediately or 4 days after facet injury. Mechanical hyperalgesia was monitored after injury, and spinal neuronal hyperexcitability and spinal expression of proteins that promote neuronal excitability were measured on day 7. Facet injury with saline vehicle treatment induced significant mechanical hyperalgesia (P<.027), dorsal horn neuronal hyperexcitability (P<.026), upregulation of pERK1/2, pNR1, mGluR5, GLAST, and GFAP, and downregulation of GLT1 (P<.032). However, intra-articular bupivacaine immediately after injury significantly attenuated hyperalgesia (P<.0001), neuronal hyperexcitability (P<.004), and dysregulation of excitatory signaling proteins (P<.049). In contrast, intra-articular bupivacaine at day 4 had no effect on these outcomes. Silencing afferent activity during the development of neuronal hyperexcitability (4 hours, 8 hours, 1 day) attenuated hyperalgesia and neuronal hyperexcitability (P<.045) only for the treatment given 4 hours after injury. This study suggests that early afferent activity from the injured facet induces development of spinal sensitization via spinal excitatory glutamatergic signaling. Peripheral intervention blocking afferent activity is effective only over a short period of time early after injury and before spinal modifications develop, and is independent of modulating spinal glial activation.

Riluzole effects on behavioral sensitivity and the development of axonal damage and spinal modifications that occur after painful nerve root compression.

OBJECT: Cervical radiculopathy is often attributed to cervical nerve root injury, which induces extensive degeneration and reduced axonal flow in primary afferents. Riluzole inhibits neuro-excitotoxicity in animal models of neural injury. The authors undertook this study to evaluate the antinociceptive and neuroprotective properties of riluzole in a rat model of painful nerve root compression. METHODS: A single dose of riluzole (3 mg/kg) was administered intraperitoneally at Day 1 after a painful nerve root injury. Mechanical allodynia and thermal hyperalgesia were evaluated for 7 days after injury. At Day 7, the spinal cord at the C-7 level and the adjacent nerve roots were harvested from a subgroup of rats for immunohistochemical evaluation. Nerve roots were labeled for NF200, CGRP, and IB4 to assess the morphology of myelinated, peptidergic, and nonpeptidergic axons, respectively. Spinal cord sections were labeled for the neuropeptide CGRP and the glutamate transporter GLT-1 to evaluate their expression in the dorsal horn. In a separate group of rats, electrophysiological recordings were made in the dorsal horn. Evoked action potentials were identified by recording extracellular potentials while applying mechanical stimuli to the forepaw. RESULTS: Even though riluzole was administered after the onset of behavioral sensitivity at Day 1, its administration resulted in immediate resolution of mechanical allodynia and thermal hyperalgesia (p < 0.045), and these effects were maintained for the study duration. At Day 7, axons labeled for NF200, CGRP, and IB4 in the compressed roots of animals that received riluzole treatment exhibited fewer axonal swellings than those from untreated animals. Riluzole also mitigated changes in the spinal distribution of CGRP and GLT-1 expression that is induced by a painful root compression, returning the spinal expression of both to sham levels. Riluzole also reduced neuronal excitability in the dorsal horn that normally develops by Day 7. The frequency of neuronal firing significantly increased (p < 0.045) after painful root compression, but riluzole treatment maintained neuronal firing at sham levels. CONCLUSIONS: These findings suggest that early administration of riluzole is sufficient to mitigate nerve root-mediated pain by preventing development of neuronal dysfunction in the nerve root and the spinal cord.

Nanoparticles functionalized with collagenase exhibit improved tumor accumulation in a murine xenograft model.

Nanoparticles have garnered widespread interest for both the imaging and treatment of cancer due to their unique and tunable pharmacokinetics and their ability to carry a high payload of diverse compounds. However, despite these favorable attributes, the extent of tumor accumulation can be severely restricted due to the dense stroma surrounding the often-permeable blood vessel wall and high intratumoral pressure. In this study, we investigated whether modifying the surface of pegylated gold nanoparticles (AuNPs) with collagenase could improve the accumulation of nanoparticles within a murine tumor xenograft. It was determined that collagenase remains active after surface conjugation and the presence of collagenase has no measureable effect on cell proliferation in vitro. Following intravenous injection, the largest fractions of collagenase-labeled AuNPs were found in the liver and spleen. Histological analysis revealed no signs of toxicity in either of these organs. Blood chemistry revealed normal levels of liver enzymes, but a slightly elevated level of total bilirubin. Within the tumor, AuNPs labeled with collagenase exhibited a 35% increase in accumulation compared with unlabeled AuNPs. Therefore, these studies provide preliminary evidence that the functionalization of nanoparticles with collagenase represent an effective and safe approach to improve tumor accumulation.

An anatomical and immunohistochemical characterization of afferents innervating the C6-C7 facet joint after painful joint loading in the rat.

STUDY DESIGN: This study used retrograde neuronal tracing and immunohistochemistry to identify neurons innervating the C6-C7 facet joint and those expressing calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG) of rats after painful cervical facet joint injury. OBJECTIVE: The objective of this study was to characterize the innervation of the C6-C7 facet joint after painful joint injury in the rat. SUMMARY OF BACKGROUND DATA: The cervical facet joint is a source of neck pain, and its loading can initiate persistent pain. CGRP is a nociceptive neurotransmitter; peptidergic afferents have been identified in the facet joint's capsule. Although studies suggest that facet joint injury alters CGRP expression in joint afferents, the distribution of neurons innervating the C6-C7 facet joint and their expression of CGRP after a painful joint injury have not been investigated. METHODS: Holtzman rats (Harlan Sprague-Dawley, Indianapolis, IN) received an intra-articular injection of cholera toxin subunit B in the C6-C7 facet joints. After injection, subgroups underwent either a painful joint distraction or sham procedure. Mechanical sensitivity was assessed, and immunohistochemical techniques were used to quantify CGRP expression and cholera toxin subunit B labeling in the C5-C8 DRGs. RESULTS: Facet joint distraction-induced (P ≤ 0.0002) hypersensitivity. Neurons labeled by the joint injection were identified in the C5-C8 DRGs. Significantly, more (P ≤ 0.0001) cholera toxin subunit B-positive neurons were identified in the C7 DRG than any other level. At C7, 54.4% ± 15.3% of those neurons were also CGRP-positive, whereas only 41.5% ± 5.4% of all neurons were CGRP-positive; this difference was significant (P = 0.0084). CONCLUSION: The greatest number of afferents from the C6-C7 facet joint has cell bodies in the C7 DRG, implicating this level as the most relevant for pain from this joint. In addition, peptidergic afferents seem to have an important role in facet joint-mediated pain.

The roles of mechanical compression and chemical irritation in regulating spinal neuronal signaling in painful cervical nerve root injury.

Both traumatic and slow-onset disc herniation can directly compress and/or chemically irritate cervical nerve roots, and both types of root injury elicit pain in animal models of radiculopathy. This study investigated the relative contributions of mechanical compression and chemical irritation of the nerve root to spinal regulation of neuronal activity using several outcomes. Modifications of two proteins known to regulate neurotransmission in the spinal cord, the neuropeptide calcitonin gene-related peptide (CGRP) and glutamate transporter 1 (GLT-1), were assessed in a rat model after painful cervical nerve root injuries using a mechanical compression, chemical irritation or their combination of injury. Only injuries with compression induced sustained behavioral hypersensitivity (p≤0.05) for two weeks and significant decreases (p<0.037) in CGRP and GLT-1 immunoreactivity to nearly half that of sham levels in the superficial dorsal horn. Because modification of spinal CGRP and GLT-1 is associated with enhanced excitatory signaling in the spinal cord, a second study evaluated the electrophysiological properties of neurons in the superficial and deeper dorsal horn at day 7 after a painful root compression. The evoked firing rate was significantly increased (p=0.045) after compression and only in the deeper lamina. The painful compression also induced a significant (p=0.002) shift in the percentage of neurons in the superficial lamina classified as low- threshold mechanoreceptive (sham 38%; compression 10%) to those classified as wide dynamic range neurons (sham 43%; compression 74%). Together, these studies highlight mechanical compression as a key modulator of spinal neuronal signaling in the context of radicular injury and pain.

Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention.

The 14 kDa homodimeric N1L protein is a potent vaccinia and variola (smallpox) virulence factor. It is not essential for viral replication, but it causes a strong attenuation of viral production in culture when deleted. The N1L protein is predicted to contain the BH3-like binding domain characteristic of Bcl-2 family proteins, and it is able to bind the BH3 peptides. Its overexpression has been reported to prevent infected cells from committing apoptosis. Therefore, interfering with the N1L apoptotic blockade may be a legitimate therapeutic strategy affecting the viral growth. By using in silico ligand docking and an array of in vitro assays, we have identified submicromolar (600 nM) N1L antagonists belonging to the family of polyphenols. Their affinity is comparable to that of the BH3 peptides (70-1000 nM). We have also identified the natural polyphenol resveratrol as a moderate N1L inhibitor. Finally, we show that our ligands efficiently inhibit growth of vaccinia virus.