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STUDY DESIGN: Preclinical pilot study. OBJECTIVES: To explore peripheral and central nociceptive mechanisms that contribute to muscle stretch-induced locomotor deficits following spinal cord injury. SETTING: Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA. METHODS: Ten female Sprague-Dawley rats received moderate, 25 g/cm T10 contusion injuries and recovered for 4 weeks. Rats were divided into three groups: Morphine/Ibuprofen-treated, Acetaminophen/Baclofen-treated, and saline control. Each group received daily hindlimb muscle stretching during weeks 4, 5, 9, and 10 post-injury and drugs were administered with stretching during weeks 4 and 9 only. Locomotor function was assessed throughout the experiment using the BBB Open Field Locomotor Scale. Hindlimb responses including spasticity, writhing, and clonic-like vibrations during muscle stretching were classified and scored. RESULTS: Consistent with our previous studies, hindlimb muscle stretching caused significant deficits in locomotor recovery following spinal cord injury. Baclofen and Ibuprofen partially mitigated the stretching effect, but none of the drugs significantly prevented the drop in locomotor function during stretching. Interestingly, treatment with Baclofen or Ibuprofen significantly reduced hindlimb responses such as spasticity and writhing during stretching, while Morphine exacerbated clonic-like vibrations in response to stretching maneuvers. CONCLUSIONS: These findings suggest that stretching may inhibit locomotor recovery through combined mechanisms of peripheral inflammation and sensitization of nociceptive afferents. When combined with central sprouting and loss of descending controls after SCI, this results in exaggerated nociceptive input during stretching. The inability of the applied clinical drugs to mitigate the detrimental effects of stretching highlights the complexity of the stretching phenomenon and emphasizes the need for further investigation.
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This paper provides an overview of the history, composition, organization, responsibilities, and regulatory requirements of Data Safety Monitoring Boards (DSMB), with particular reference to the context of clinical trials in spinal cord injury. It is intended to help potential members of such boards and those undertaking the design of new clinical trials to understand the important role of the DSMB in safeguarding the integrity of complex trials, promoting safety, and countering potential bias. An independent DSMB helps to protect research subjects by providing study oversight and serves as an additional step to assure that clinical trials are performed to existing and appropriate standards. The DSMB must meet on a regular schedule, diligently evaluate all the information it receives, and report in a timely and decisive manner. Members must be free of significant conflicts of interest throughout the study and be adequately trained and experienced to serve their roles within the group. DSMB service can be a valuable learning experience and a gratifying opportunity to participate in advancing medicine and helping to maintain and improve the standards of research.
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Comitês de Monitoramento de Dados de Ensaios Clínicos , Traumatismos da Medula Espinal , Humanos , Ensaios Clínicos como AssuntoRESUMO
BACKGROUND: To monitor the use of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and related medicines for pre-exposure prophylaxis (PrEP) as HIV prevention using commercial pharmacy data, it is necessary to determine whether TDF/FTC prescriptions are used for PrEP, or for some other clinical indication. OBJECTIVE: To validate an algorithm to distinguish the use of TDF/FTC for HIV prevention or infectious disease treatment. METHODS: An algorithm was developed to identify whether TDF/FTC prescriptions were for PrEP or for other indications from large-scale administrative databases. The algorithm identifies TDF/FTC prescriptions, and then excludes patients with International Classification of Diseases (ICD)-9 diagnostic codes, medications or procedures that suggest indications other than for PrEP (e.g., documentation of HIV infection, chronic hepatitis B (CHB), or use of TDF/FTC for post-exposure prophylaxis (PEP)). For evaluation, we collected data by clinician assessment of medical records for patients with TDF/FTC, and compared the assessed indication identified by the clinician review with the assessed indication identified by the algorithm. The algorithm was then applied and evaluated in a large urban community-based sexual health clinic. RESULTS: The PrEP algorithm demonstrated high sensitivity and moderate specificity (99.6%, 49.6%) in the electronic medical record database, and high sensitivity and specificity (99%, 87%) in data from the urban community health clinic. CONCLUSIONS: The PrEP algorithm classified the indication for PrEP in most subjects treated with TDF/FTC with sufficient accuracy to be useful for surveillance purposes. The methods described can serve as a basis for developing a robust and evolving case definition for antiretroviral prescriptions for HIV prevention purposes. CLINICALTRIAL: None required.
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Long ascending propriospinal neurons (LAPNs) are a subset of spinal interneurons that provide direct connectivity between distant spinal segments. Here, we focus specifically on an anatomically defined population of "inter-enlargement" LAPNs with cell bodies at L2/3 and terminals at C5/6. Previous studies showed that silencing LAPNs in awake and freely moving animals disrupted interlimb coordination of the hindlimbs, forelimbs, and heterolateral limb pairs. Surprisingly, despite a proportion of LAPNs being anatomically intact post- spinal cord injury (SCI), silencing them improved locomotor function but only influenced coordination of the hindlimb pair. Given the functional significance of LAPNs pre- and post-SCI, we characterized their anatomy and SCI-induced anatomical plasticity. This detailed anatomical characterization revealed three morphologically distinct subsets of LAPNs that differ in soma size, neurite complexity and/or neurite orientation. Following a mild thoracic contusive SCI there was a marked shift in neurite orientation in two of the LAPN subsets to a more dorsoventral orientation, and collateral densities decreased in the cervical enlargement but increased just caudal to the injury epicenter. These post-SCI anatomical changes potentially reflect maladaptive plasticity and an effort to establish new functional inputs from sensory afferents that sprout post-SCI to achieve circuitry homeostasis.
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Neurônios , Traumatismos da Medula Espinal , Animais , Medula Espinal , Interneurônios/fisiologia , Membro Posterior , Plasticidade NeuronalRESUMO
Spinal locomotor circuitry is comprised of rhythm generating centers, one for each limb, that are interconnected by local and long-distance propriospinal neurons thought to carry temporal information necessary for interlimb coordination and gait control. We showed previously that conditional silencing of the long ascending propriospinal neurons (LAPNs) that project from the lumbar to the cervical rhythmogenic centers (L1/L2 to C6), disrupts right-left alternation of both the forelimbs and hindlimbs without significantly disrupting other fundamental aspects of interlimb and speed-dependent coordination (Pocratsky et al., 2020). Subsequently, we showed that silencing the LAPNs after a moderate thoracic contusive spinal cord injury (SCI) resulted in better recovered locomotor function (Shepard et al., 2021). In this research advance, we focus on the descending equivalent to the LAPNs, the long descending propriospinal neurons (LDPNs) that have cell bodies at C6 and terminals at L2. We found that conditional silencing of the LDPNs in the intact adult rat resulted in a disrupted alternation of each limb pair (forelimbs and hindlimbs) and after a thoracic contusion SCI significantly improved locomotor function. These observations lead us to speculate that the LAPNs and LDPNs have similar roles in the exchange of temporal information between the cervical and lumbar rhythm generating centers, but that the partial disruption of the pathway after SCI limits the independent function of the lumbar circuitry. Silencing the LAPNs or LDPNs effectively permits or frees-up the lumbar circuitry to function independently.
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Contusões , Traumatismos da Medula Espinal , Ratos , Animais , Medula Espinal/fisiologia , Neurônios/fisiologia , Traumatismos da Medula Espinal/genética , Membro Posterior/fisiologia , Extremidade Inferior , Locomoção/fisiologiaRESUMO
Spinal cord injury (SCI) is a debilitating condition with an estimated 18,000 new cases annually in the United States. The field has accepted and adopted standardized databases such as the Open Data Commons for Spinal Cord Injury (ODC-SCI) to aid in broader analyses, but these currently lack high-throughput data despite the availability of nearly 6000 samples from over 90 studies available in the Sequence Read Archive. This limits the potential for large datasets to enhance our understanding of SCI-related mechanisms at the molecular and cellular level. Therefore, we have developed a protocol for processing RNA-Seq samples from high-throughput sequencing experiments related to SCI resulting in both raw and normalized data that can be efficiently mined for comparisons across studies, as well as homologous discovery across species. We have processed 1196 publicly available RNA-Seq samples from 50 bulk RNA-Seq studies across nine different species, resulting in an SQLite database that can be used by the SCI research community for further discovery. We provide both the database as well as a web-based front-end that can be used to query the database for genes of interest, differential gene expression, genes with high variance, and gene set enrichments.
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CONTEXT: Activity-based therapy initiated within days of the accident could prevent complications and improve neurofunctional outcomes in patients with traumatic spinal cord injury (TSCI). However, it has never been attempted in humans with TSCI because of practical obstacles and potential safety concerns. The PROMPT-SCI trial is the first attempt at implementing ABT within the first days following a TSCI (i.e. very early ABT; VE-ABT). The objective is to determine if VE-ABT can be initiated safely in the intensive care unit (ICU) within 48 h of early decompressive surgery. DESIGN: As part of the PROMPT-SCI trial, 15 adult patients with severe TSCI were enrolled between April and November of 2021. The intervention consisted of 30-minute sessions of motor-assisted in-bed leg cycling starting within 48 h of early spinal surgery. Safety was assessed through continuous monitoring of vital signs and recording of adverse events during and after sessions. The main outcome measure was the achievement (yes or no) of a full and safe session within 48 h of early surgery. FINDINGS: Out of the 15 participants, 10 (66.6%) achieved this outcome. Out of the remaining 5, 2 were not cleared to engage in cycling within 48 h of surgery and 3 initiated cycling within 48 h but stopped prematurely. All 5 eventually completed a full and safe session within the next 1-2 days. In all 15 participants, there were no neurological deteriorations after the first completed session. CONCLUSION: Our results suggest that it is safe and feasible to perform a first session of VE-ABT within days of a severe TSCI with no serious adverse events and excellent completion rates.
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Traumatismos da Medula Espinal , Adulto , Humanos , Procedimentos Neurocirúrgicos/métodos , Avaliação de Resultados em Cuidados de Saúde , Traumatismos da Medula Espinal/complicações , Fatores de TempoRESUMO
Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore-hind coupling together with appropriate control of left-right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.
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Contusões , Traumatismos da Medula Espinal , Ratos , Animais , Locomoção , Medula Espinal , Marcha/fisiologia , Membro PosteriorRESUMO
Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore-hind coupling together with appropriate control of left-right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.
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It is well established that both positive and negative housing conditions of laboratory animals can affect behavioral, biochemical, and physiological responses. Housing enhancements have been shown to have beneficial effects on locomotor outcomes in rodents with spinal cord injury (SCI). Subsequent to an unplanned housing enhancement of the addition of a balcony to home cages by animal care personnel at a research facility, a retrospective analysis of multiple SCI studies was performed to determine whether outcomes differed before (four studies, N = 28) and after (four studies, N = 23) the addition of the balcony. Locomotor and morphological differences were compared after a mild-moderate T9 spinal cord contusion injury in wild-type mice. Post-injury assessments of locomotor function for 6 weeks included Basso Mouse Scale (BMS) and treadmill kinematic assessments (week 6). Balcony-housed mice showed greater improvements not only in basic locomotor functions (weight-supported stepping, balance) compared to those in standard housing, but also surpassed mice in standard housing without the balcony in higher-order locomotor recovery outcomes, including BMS late-stage recovery measures (paw, tail, and trunk indices). Additionally, balcony-housed mice had overall higher BMS scores, consistently attained more BMS subscores, and had better treadmill track width and stride length compared to those with no balcony. The housing enhancement of a balcony led to unforeseen consequences and unexpected higher recovery outcomes compared to mice in standard housing. This retrospective study highlights the importance of housing conditions in the key outcomes of locomotor recovery after incomplete contusive SCIs in mice.
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Spinal cord injury (SCI) is a debilitating disease resulting in an estimated 18,000 new cases in the United States on an annual basis. Significant behavioral research on animal models has led to a large amount of data, some of which has been catalogued in the Open Data Commons for Spinal Cord Injury (ODC-SCI). More recently, high throughput sequencing experiments have been utilized to understand molecular mechanisms associated with SCI, with nearly 6,000 samples from over 90 studies available in the Sequence Read Archive. However, to date, no resource is available for efficiently mining high throughput sequencing data from SCI experiments. Therefore, we have developed a protocol for processing RNA-Seq samples from high-throughput sequencing experiments related to SCI resulting in both raw and normalized data that can be efficiently mined for comparisons across studies as well as homologous discovery across species. We have processed 1,196 publicly available RNA-seq samples from 50 bulk RNA-Seq studies across nine different species, resulting in an SQLite database that can be used by the SCI research community for further discovery. We provide both the database as well as a web-based front-end that can be used to query the database for genes of interest, differential gene expression, genes with high variance, and gene set enrichments.
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BACKGROUND: Serum alkaline phosphatase (ALP) is measured as an indicator of bone or liver disease. Bone-specific alkaline phosphatase (B-ALP) is an isoform of ALP found in the bone tissue which can predict fractures and heterotopic ossification. OBJECTIVE: The aim of this scoping review was to explore the current use of ALP and B-ALP in studies using humans or animal models of SCI, and to identify ways to advance future research using ALP and B-ALP as a bone marker after SCI. RESULTS: HUMAN STUDIES: 42 studies were included. The evidence regarding changes or differences in ALP levels in individuals with SCI compared to controls is conflicting. For example, a negative correlation between B-ALP and total femur BMD was observed in only one of three studies examining the association. B-ALP seemed to increase after administration of teriparatide, and to decrease after treatment with denosumab. The effects of exercise on ALP and B-ALP levels are heterogeneous and depend on the type of exercise performed. ANIMAL STUDIES: 11 studies were included. There is uncertainty regarding the response of ALP or B-ALP levels after SCI; levels increased after some interventions, including vibration protocols, curcumin supplementation, cycles in electromagnetic field or hyperbaric chamber. Calcitonin or bisphosphonate administration did not affect ALP levels. CONCLUSION: Researchers are encouraged to measure the bone-specific isoform of ALP rather than total ALP in future studies in humans of animal models of SCI.
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Conservadores da Densidade Óssea , Traumatismos da Medula Espinal , Humanos , Animais , Fosfatase Alcalina/farmacologia , Osso e Ossos , Remodelação Óssea/fisiologia , Densidade Óssea/fisiologia , BiomarcadoresRESUMO
Neuronal ryanodine receptors (RyR) release calcium from internal stores and play a key role in synaptic plasticity, learning, and memory. Dysregulation of RyR function contributes to neurodegeneration and negatively impacts neurological recovery after spinal cord injury (SCI). However, the individual role of RyR isoforms and the underlying mechanisms remain poorly understood. To determine whether RyR2 plays a direct role in axonal fate and functional recovery after SCI, we bred Advillin-Cre: tdTomato (Ai9) reporter mice with "floxed" RyR2 mice to directly knock out (KO) RyR2 function in dorsal root ganglion neurons and their spinal projections. Adult 6- to 8-week-old RyR2KO and littermate controls were subjected to a contusive SCI and their dorsal column axons were imaged in vivo using two-photon excitation microscopy. We found that direct RyR2KO in dorsal column primary afferents did not significantly alter secondary axonal degeneration after SCI. We next assessed behavioral recovery after SCI and found that direct RyR2KO in primary afferents worsened open-field locomotor scores (Basso Mouse Scale subscore) compared to littermate controls. However, both TreadScan™ gait analysis and overground kinematic gait analysis tests revealed subtle, but no fundamental, differences in gait patterns between the two groups after SCI. Subsequent removal of spared afferent fibers using a dorsal column crush revealed similar outcomes in both groups. Analysis of primary afferents at the lumbar (L3-L5) level similarly revealed no noticeable differences between groups. Together, our results support a modest contribution of dorsal column primary afferent RyR2 in neurological recovery after SCI.
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STUDY DESIGN: Preclinical pilot study. OBJECTIVES: To test the hypothesis that spinal opioidergic circuitry contributes to muscle stretch-induced locomotor deficits. SETTING: Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA. METHODS: A pilot study with eight female Sprague-Dawley rats that received 25 g-cm T10 contusion injuries and recovered for 5 weeks. Rats were divided into two groups with one group receiving subcutaneous injections of naltrexone dissolved in saline (15 mg/kg) or an equal volume of saline. Each group received a daily 24-minute stretching protocol during weeks 6, 8, and 11 post-injury. Locomotor function was assessed throughout using the BBB Open Field Locomotor Scale. RESULTS: Consistent with previous findings, stretching reduced locomotor function in both naltrexone and saline groups. However, the loss of locomotor function appeared earlier in the naltrexone group. Animals in both groups had a similar rate of recovery following the termination of stretching. Interestingly, the administration of naltrexone did not influence acute thermal cutaneous nociceptive responses as measured by a tail-flick assay but caused a significant increase in spasticity following stretch. CONCLUSIONS: The results of this study suggest that the endogenous opioid system plays a role in modulating the negative impact of muscle stretch on spinal cord motor circuitry that is vulnerable due to loss of descending input. The observed actions of the broad-spectrum opioid antagonist naltrexone imply that pharmaceuticals targeting the endogenous opioid system post-SCI may have unintended consequences.
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Antagonistas de Entorpecentes , Traumatismos da Medula Espinal , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Membro Posterior , Humanos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Projetos Piloto , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Medula Espinal , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológicoRESUMO
Long ascending propriospinal neurons (LAPNs) are a subpopulation of spinal cord interneurons that directly connect the lumbar and cervical enlargements. Previously we showed, in uninjured animals, that conditionally silencing LAPNs disrupted left-right coordination of the hindlimbs and forelimbs in a context-dependent manner, demonstrating that LAPNs secure alternation of the fore- and hindlimb pairs during overground stepping. Given the ventrolateral location of LAPN axons in the spinal cord white matter, many likely remain intact following incomplete, contusive, thoracic spinal cord injury (SCI), suggesting a potential role in the recovery of stepping. Thus, we hypothesized that silencing LAPNs after SCI would disrupt recovered locomotion. Instead, we found that silencing spared LAPNs post-SCI improved locomotor function, including paw placement order and timing, and a decrease in the number of dorsal steps. Silencing also restored left-right hindlimb coordination and normalized spatiotemporal features of gait such as stance and swing time. However, hindlimb-forelimb coordination was not restored. These data indicate that the temporal information carried between the spinal enlargements by the spared LAPNs post-SCI is detrimental to recovered hindlimb locomotor function. These findings are an illustration of a post-SCI neuroanatomical-functional paradox and have implications for the development of neuronal- and axonal-protective therapeutic strategies and the clinical study/implementation of neuromodulation strategies.
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Extremidades/fisiopatologia , Interneurônios/fisiologia , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/reabilitação , Animais , Modelos Animais de Doenças , Extremidades/inervação , Feminino , Marcha , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Activity-based therapy (ABT) is an important aspect of rehabilitation following traumatic spinal cord injury (SCI). Unfortunately, it has never been adapted to acute care despite compelling preclinical evidence showing that it is safe and effective for promoting neurological recovery when started within days after SCI. This article provides the protocol for a study that will determine the feasibility and explore potential benefits of early ABT in the form of in-bed leg cycling initiated within 48 hours after the end of spinal surgery for SCI. METHODS AND ANALYSIS: PROMPT-SCI (protocol for rapid onset of mobilisation in patients with traumatic SCI) is a single-site single-arm proof-of-concept trial. Forty-five patients aged 18 years or older with a severe traumatic SCI (American Spinal Injury Association Impairment Scale grade A, B or C) from C0 to L2 undergoing spinal surgery within 48 hours of the injury will be included. Participants will receive daily 30 min continuous sessions of in-bed leg cycling for 14 consecutive days, initiated within 48 hours of the end of spinal surgery. The feasibility outcomes are: (1) absence of serious adverse events associated with cycling, (2) completion of 1 full session within 48 hours of spinal surgery for 90% of participants and (3) completion of 11 sessions for 80% of participants. Patient outcomes 6 weeks and 6 months after the injury will be measured using neurofunctional assessments, quality of life questionnaires and inpatient length of stay. Feasibility and patient outcomes will be analysed with descriptive statistics. Patient outcomes will also be compared with a matched historical cohort that has not undergone in-bed cycling using McNemar and Student's t-tests for binary and continuous outcomes, respectively. ETHICS AND DISSEMINATION: PROMPT-SCI is approved by the Research Ethics Board of the CIUSSS NIM. Recruitment began in April 2021. Dissemination strategies include publications in scientific journals and presentations at conferences. TRIAL REGISTRATION NUMBER: NCT04699474.
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Traumatismos da Medula Espinal , Traumatismos da Coluna Vertebral , Cuidados Críticos , Humanos , Perna (Membro) , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: Appendicitis is the most common cause of an acute surgical abdomen in children. Diagnosis is often challenging as few pediatric patients present with classic symptoms. Clinicians are thus dependent on imaging to reach an accurate diagnosis. Although computerized tomography (CT) has high sensitivity and specificity, it has the disadvantage of imparting ionizing radiation. Ultrasound (US) is readily available and has comparable accuracy to CT when performed by experienced sonographers. We sought to examine the impact of a system-wide process improvement plan on CT use and other metrics in pediatric patients who presented to the Emergency Department (ED) with suspected appendicitis. METHODS: This is a retrospective study of the impact of a Pediatric Appendicitis Pathway (PAP) within a large integrated hospital system with 12 EDs including 3 designated hub EDs. Patients were placed in an initial risk category utilizing the Pediatric Appendicitis Score (PAS), and received US of the appendix at a hub ED if indicated by the PAS. Patients presenting to community EDs who required US appendix were transferred to hub EDs for imaging. Patients presenting in the 6-month pre-implementation period were compared to patients presenting in a 14-month post-implementation period on CT and US utilization, negative and missed appendectomy rates, and ED length of stay (LOS). RESULTS: 1874 patients (401 pre-PAP and 1473 post-PAP) were included in the study. At the hub EDs the rate of CT imaging for suspected appendicitis was reduced from 31% to 17% with a resultant increase in US utilization from 83% (333/401) to 90% (1331/1473) (p < 0.001). At community general EDs (404 pre-PAP and 449 post-PAP), the rate of CT was decreased from 45% (181/404) to 32%(144/449) (p < 0.001)) There was no significant change in the negative appendectomy rate pre-PAP (1/59 = 1.7%) and post-PAP (4/168 = 2.4%) (p = 0.99) at the hub EDs. There were no missed appendicitis cases after PAP implementation compared to 1 case in the pre-PAP period. Overall LOS was similar pre and post-PAP, however LOS was longer in patients that required transfer from community general EDs to hub EDs (median 264 vs 342 min, p < 0.001). CONCLUSIONS: A PAP that stratified patients into risk groups using the PAS and encouraged the use of US as a first line imaging modality, reduced the number of CT performed in a large integrated health system without significant changes to clinical outcomes. Furthermore, transferring select patients for an US as opposed to obtaining an initial CT in community general EDs was feasible and reduced CT use in the pediatric population.
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Apendicite/diagnóstico por imagem , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitais Pediátricos/estatística & dados numéricos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Abdome Agudo/diagnóstico por imagem , Criança , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Injury to descending autonomic (sympathetic) pathways is common after high-level spinal cord injury (SCI) and associated with abnormal blood pressure and heart rate regulation. In individuals with high-level SCI, abnormal sympathovagal balance (such as during autonomic dysreflexia; paroxysmal hypertension provoked by sensory stimuli below the injury) is proarrhythmogenic. Exercise training is a key component of SCI rehabilitation and management of cardiovascular disease risk, but it is unclear whether exercise training influences susceptibility to cardiac arrhythmia. We aimed to evaluate: (i) whether susceptibility to arrhythmia increases in a rodent-model of SCI; (ii) the impact of the sympathomimetic drug dobutamine (DOB) on arrhythmia risk; (iii) whether exercise training ameliorates arrhythmia risk. Twenty-one Wistar rats were divided into 3 subgroups: T2-contusive SCI (T2, nâ¯=â¯7), T2-contusive SCI completing passive hindlimb cycling training (PHLC, nâ¯=â¯7), and T10-contusive SCI (T10, nâ¯=â¯7). Known electrocardiographic arrhythmia markers and heart rate variability parameters were evaluated before (PRE), 1-week (POST) and 5-weeks post-SCI (TERM) at baseline and during DOB infusion (30⯵g/kg/min). Baseline markers of arrhythmia risk were increased in both T2 and T10 animals. DOB decreased R-R interval (pâ¯<â¯0.001), and increased markers of risk for ventricular arrhythmia, particularly in high-level (T2) animals (pâ¯<â¯0.05). Exercise training blunted the exacerbation of markers of arrhythmia risk in the presence of DOB. Markers of risk for cardiac arrhythmia are increased in experimental SCI, and DOB further increases arrhythmia risk in high-level SCI. Exercise training did not improve markers of arrhythmia risk at rest, but did ameliorate markers of arrhythmia risk during sympathetic stimulation.
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Disreflexia Autonômica , Traumatismos da Medula Espinal , Animais , Arritmias Cardíacas/etiologia , Sistema Nervoso Autônomo , Ratos , Ratos Wistar , Medula Espinal , Traumatismos da Medula Espinal/terapiaRESUMO
Hemodynamic instability and cardiovascular (CV) dysfunction are hallmarks of patients living with cervical and high thoracic spinal cord injuries (SCI). Individuals experience bouts of autonomic dysreflexia (AD) and persistent hypotension which hamper the activities of daily living. Despite the widespread use of exercise training to improve health and CV function after SCI, little is known about how different training modalities impact hemodynamic stability and severity of AD in a model of incomplete SCI. In this study, we used implantable telemetry devices to assess animals with T2 contusions following 3.5 weeks of exercise training initiated 8 days post-injury: passive hindlimb cycling (T2-CYC, n = 5) or active forelimb swimming (T2-SW, n = 6). Uninjured and non-exercised SCI control groups were also included (CON, n = 6; T2-CON, n = 7; T10-CON, n = 6). Five weeks post-injury, both T2-CON and T2-CYC presented with resting hypotension compared to uninjured CON and T10-CON groups; no differences were noted in resting blood pressure in T2-SW versus CON and T10-CON. Furthermore, pressor responses to colorectal distention (AD) were larger in all T2-injured groups compared to T10-CON, and were not attenuated by either form of exercise training. Interestingly, when T2-injured animals were re-stratified based on terminal BBB scores (regardless of training group), animals with limited hindlimb recovery (T2-LOW, n = 7) had more severe AD responses. Our results suggest that the spontaneous recovery of locomotor and autonomic function after severe but incomplete T2 SCI also influences the severity of AD, and that short periods (3.5 weeks) of passive hindlimb cycling or active forelimb swimming are ineffective in this model.
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Disreflexia Autonômica/prevenção & controle , Membro Posterior/irrigação sanguínea , Condicionamento Físico Animal , Traumatismos da Medula Espinal/complicações , Natação , Animais , Disreflexia Autonômica/etiologia , Disreflexia Autonômica/patologia , Pressão Sanguínea , Frequência Cardíaca , Masculino , Ratos , Ratos WistarRESUMO
The nervous system coordinates pathways and circuits to process sensory information and govern motor behaviors. Mapping these pathways is important to further understand the connectivity throughout the nervous system and is vital for developing treatments for neuronal diseases and disorders. We targeted long ascending propriospinal neurons (LAPNs) in the rat spinal cord utilizing Fluoro-Ruby (FR) [10kD rhodamine dextran amine (RDA)], and two dual-viral systems. Dual-viral tracing utilizing a retrograde adeno-associated virus (retroAAV), which confers robust labeling in the brain, resulted in a small number of LAPNs being labeled, but dual-viral tracing using a highly efficient retrograde (HiRet) lentivirus provided robust labeling similar to FR. Additionally, dual-viral tracing with HiRet lentivirus and tracing with FR may preferentially label different subpopulations of LAPNs. These data demonstrate that dual-viral tracing in the spinal cord employing a HiRet lentivirus provides robust and specific labeling of LAPNs and emphasizes the need to empirically optimize viral systems to target specific neuronal population(s).