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PURPOSE: The purpose of this study is to describe and assess the impact of multi-domain biopsychosocial (BPS) recovery on outcomes following lumbar spine fusion. We hypothesized that discrete patterns of BPS recovery (e.g., clusters) would be identified, and then associated with postoperative outcomes and preoperative patient data. METHODS: Patient-reported outcomes for pain, disability, depression, anxiety, fatigue, and social roles were collected at multiple timepoints for patients undergoing lumbar fusion between baseline and one year. Multivariable latent class mixed models assessed composite recovery as a function of (1) pain, (2) pain and disability, and (3) pain, disability, and additional BPS factors. Patients were assigned to clusters based on their composite recovery trajectories over time. RESULTS: Using all BPS outcomes from 510 patients undergoing lumbar fusion, three multi-domain postoperative recovery clusters were identified: Gradual BPS Responders (11%), Rapid BPS Responders (36%), and Rebound Responders (53%). Modeling recovery from pain alone or pain and disability alone failed to generate meaningful or distinct recovery clusters. BPS recovery clusters were associated with number of levels fused and preoperative opioid use. Postoperative opioid use (p < 0.01) and hospital length of stay (p < 0.01) were associated with BPS recovery clusters even after adjusting for confounding factors. CONCLUSION: This study describes distinct clusters of recovery following lumbar spine fusion derived from multiple BPS factors, which are related to patient-specific preoperative factors and postoperative outcomes. Understanding postoperative recovery trajectories across multiple health domains will advance our understanding of how BPS factors interact with surgical outcomes and could inform personalized care plans.
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Vértebras Lumbares , Fusión Vertebral , Humanos , Vértebras Lumbares/cirugía , Analgésicos Opioides , Región Lumbosacra/cirugía , Dolor/etiología , Fusión Vertebral/efectos adversos , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
OBJECTIVE: Venous thromboembolism (VTE) following traumatic spinal cord injury (SCI) is a significant clinical concern. This study sought to determine the incidence of VTE and hemorrhagic complications among patients with SCI who received low-molecular-weight heparin (LMWH) within 24 hours of injury or surgery and identify variables that predict VTE using the prospective Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database. METHODS: The TRACK-SCI database was queried for individuals with traumatic SCI from 2015 to 2022. Primary outcomes of interest included rates of VTE (including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and in-hospital hemorrhagic complications that occurred after LWMH administration. Secondary outcomes included intensive care unit and hospital length of stay, discharge location type, and in-hospital mortality. RESULTS: The study cohort consisted of 162 patients with SCI. Fifteen of the 162 patients withdrew from the study, leading to loss of data for certain variables for these patients. One hundred thirty patients (87.8%) underwent decompression and/or fusion surgery for SCI. DVT occurred in 11 (7.4%) of 148 patients, PE in 9 (6.1%) of 148, and any VTE in 18 (12.2%) of 148 patients. The analysis showed that admission lower-extremity motor score (p = 0.0408), injury at the thoracic level (p = 0.0086), admission American Spinal Injury Association grade (p = 0.0070), and younger age (p = 0.0372) were significantly associated with VTE. There were 3 instances of postoperative spine surgery-related bleeding (2.4%) in the 127 patients who had spine surgery with bleeding complication data available, with one requiring return to surgery (0.8%). Thirteen (8.8%) of 147 patients had a bleeding complication not related to spine surgery. There were 2 gastrointestinal bleeds associated with nasogastric tube placement, 3 cases of postoperative non-spine-related surgery bleeding, and 8 cases of other bleeding complications (5.4%) not related to any surgery. CONCLUSIONS: Initiation of LMWH within 24 hours was associated with a low rate of spine surgery-related bleeding. Bleeding complications unrelated to SCI surgery still occur with LMWH administration. Because neurosurgical intervention is typically the limiting factor in initializing chemical DVT prophylaxis, many of these bleeding complications would have likely occurred regardless of the protocol.
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Embolia Pulmonar , Traumatismos de la Médula Espinal , Traumatismos Vertebrales , Tromboembolia Venosa , Humanos , Heparina de Bajo-Peso-Molecular/efectos adversos , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/prevención & control , Tromboembolia Venosa/epidemiología , Estudios Prospectivos , Anticoagulantes/efectos adversos , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/cirugía , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/epidemiología , Embolia Pulmonar/prevención & control , Hemorragia Posoperatoria/epidemiología , Sistema de Registros , HeparinaRESUMEN
PURPOSE: The paraspinal muscles (PSM) are a key feature potentially related to low back pain (LBP), and their structure and composition can be quantified using MRI. Most commonly, quantifying PSM measures across individual muscles and individual spinal levels renders numerous separate metrics that are analyzed in isolation. However, comprehensive multivariate approaches would be more appropriate for analyzing the PSM within an individual. To establish and test these methods, we hypothesized that multivariate summaries of PSM MRI measures would associate with the presence of LBP symptoms (i.e., pain intensity). METHODS: We applied hierarchical multiple factor analysis (hMFA), an unsupervised integrative method, to clinical PSM MRI data from unique cohort datasets including a longitudinal cohort of astronauts with pre- and post-spaceflight data and a cohort of chronic LBP subjects and asymptomatic controls. Three specific use cases were investigated: (1) predicting longitudinal changes in pain using combinations of baseline PSM measures; (2) integrating baseline and post-spaceflight MRI to assess longitudinal change in PSM and how it relates to pain; and (3) integrating PSM quality and adjacent spinal pathology between LBP patients and controls. RESULTS: Overall, we found distinct complex relationships with pain intensity between particular muscles and spinal levels. Subjects with high asymmetry between left and right lean muscle composition and differences between spinal segments PSM quality and structure are more likely to increase in pain reported outcome after prolonged time in microgravity. Moreover, changes in PSM quality and structure between pre and post-spaceflight relate to increase in pain after prolonged microgravity. Finally, we show how unsupervised hMFA recapitulates previous research on the association of CEP damage and LBP diagnostic. CONCLUSION: Our analysis considers the spine as a multi-segmental unit as opposed to a series of discrete and isolated spine segments. Integrative and multivariate approaches can be used to distill large and complex imaging datasets thereby improving the clinical utility of MRI-based biomarkers, and providing metrics for further analytical goals, including phenotyping.
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Dolor de la Región Lumbar , Ingravidez , Humanos , Dolor de la Región Lumbar/diagnóstico , Imagen por Resonancia Magnética/métodos , Músculos Paraespinales/patología , Aprendizaje Automático no SupervisadoRESUMEN
OBJECTIVE: Previous work has shown that maintaining mean arterial pressures (MAPs) between 76 and 104 mm Hg intraoperatively is associated with improved neurological function at discharge in patients with acute spinal cord injury (SCI). However, whether temporary fluctuations in MAPs outside of this range can be tolerated without impairment of recovery is unknown. This retrospective study builds on previous work by implementing machine learning to derive clinically actionable thresholds for intraoperative MAP management guided by neurological outcomes. METHODS: Seventy-four surgically treated patients were retrospectively analyzed as part of a longitudinal study assessing outcomes following SCI. Each patient underwent intraoperative hemodynamic monitoring with recordings at 5-minute intervals for a cumulative 28,594 minutes, resulting in 5718 unique data points for each parameter. The type of vasopressor used, dose, drug-related complications, average intraoperative MAP, and time spent in an extreme MAP range (< 76 mm Hg or > 104 mm Hg) were collected. Outcomes were evaluated by measuring the change in American Spinal Injury Association Impairment Scale (AIS) grade over the course of acute hospitalization. Features most predictive of an improvement in AIS grade were determined statistically by generating random forests with 10,000 iterations. Recursive partitioning was used to establish clinically intuitive thresholds for the top features. RESULTS: At discharge, a significant improvement in AIS grade was noted by an average of 0.71 levels (p = 0.002). The hemodynamic parameters most important in predicting improvement were the amount of time intraoperative MAPs were in extreme ranges and the average intraoperative MAP. Patients with average intraoperative MAPs between 80 and 96 mm Hg throughout surgery had improved AIS grades at discharge. All patients with average intraoperative MAP > 96.3 mm Hg had no improvement. A threshold of 93 minutes spent in an extreme MAP range was identified after which the chance of neurological improvement significantly declined. Finally, the use of dopamine as compared to norepinephrine was associated with higher rates of significant cardiovascular complications (50% vs 25%, p < 0.001). CONCLUSIONS: An average intraoperative MAP value between 80 and 96 mm Hg was associated with improved outcome, corroborating previous results and supporting the clinical verifiability of the model. Additionally, an accumulated time of 93 minutes or longer outside of the MAP range of 76-104 mm Hg is associated with worse neurological function at discharge among patients undergoing emergency surgical intervention for acute SCI.
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Traumatismos de la Médula Espinal , Árboles de Decisión , Humanos , Estudios Longitudinales , Aprendizaje Automático , Recuperación de la Función , Estudios Retrospectivos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/cirugíaRESUMEN
BACKGROUND: Minocycline is a clinically available synthetic tetracycline derivative with anti-inflammatory and antibiotic properties. The majority of studies show that minocycline can reduce tissue damage and improve functional recovery following central nervous system injuries, mainly attributed to the drug's direct anti-inflammatory, anti-oxidative, and neuroprotective properties. Surprisingly the consequences of minocycline's antibiotic (i.e., antibacterial) effects on the gut microbiota and systemic immune response after spinal cord injury have largely been ignored despite their links to changes in mental health and immune suppression. METHODS: Here, we sought to determine minocycline's effect on spinal cord injury-induced changes in the microbiota-immune axis using a cervical contusion injury in female Lewis rats. We investigated a group that received minocycline following spinal cord injury (immediately after injury for 7 days), an untreated spinal cord injury group, an untreated uninjured group, and an uninjured group that received minocycline. Plasma levels of cytokines/chemokines and fecal microbiota composition (using 16s rRNA sequencing) were monitored for 4 weeks following spinal cord injury as measures of the microbiota-immune axis. Additionally, motor recovery and anxiety-like behavior were assessed throughout the study, and microglial activation was analyzed immediately rostral to, caudal to, and at the lesion epicenter. RESULTS: We found that minocycline had a profound acute effect on the microbiota diversity and composition, which was paralleled by the subsequent normalization of spinal cord injury-induced suppression of cytokines/chemokines. Importantly, gut dysbiosis following spinal cord injury has been linked to the development of anxiety-like behavior, which was also decreased by minocycline. Furthermore, although minocycline attenuated spinal cord injury-induced microglial activation, it did not affect the lesion size or promote measurable motor recovery. CONCLUSION: We show that minocycline's microbiota effects precede its long-term effects on systemic cytokines and chemokines following spinal cord injury. These results provide an exciting new target of minocycline as a therapeutic for central nervous system diseases and injuries.
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Ansiedad/etiología , Microbioma Gastrointestinal/efectos de los fármacos , Inflamación/etiología , Minociclina/efectos adversos , Minociclina/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Ansiedad/inducido químicamente , Citocinas/sangre , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Disbiosis/etiología , Femenino , Inflamación/inducido químicamente , Inflamación/patología , Microglía/efectos de los fármacos , Microglía/patología , Ratas , Ratas Endogámicas Lew , Recuperación de la Función/efectos de los fármacos , Traumatismos de la Médula Espinal/patologíaRESUMEN
OBJECTIVE: Traumatic spinal cord injury (SCI) is a dreaded condition that can lead to paralysis and severe disability. With few treatment options available for patients who have suffered from SCI, it is important to develop prospective databases to standardize data collection in order to develop new therapeutic approaches and guidelines. Here, the authors present an overview of their multicenter, prospective, observational patient registry, Transforming Research and Clinical Knowledge in SCI (TRACK-SCI). METHODS: Data were collected using the National Institute of Neurological Disorders and Stroke (NINDS) common data elements (CDEs). Highly granular clinical information, in addition to standardized imaging, biospecimen, and follow-up data, were included in the registry. Surgical approaches were determined by the surgeon treating each patient; however, they were carefully documented and compared within and across study sites. Follow-up visits were scheduled for 6 and 12 months after injury. RESULTS: One hundred sixty patients were enrolled in the TRACK-SCI study. In this overview, basic clinical, imaging, neurological severity, and follow-up data on these patients are presented. Overall, 78.8% of the patients were determined to be surgical candidates and underwent spinal decompression and/or stabilization. Follow-up rates to date at 6 and 12 months are 45% and 36.3%, respectively. Overall resources required for clinical research coordination are also discussed. CONCLUSIONS: The authors established the feasibility of SCI CDE implementation in a multicenter, prospective observational study. Through the application of standardized SCI CDEs and expansion of future multicenter collaborations, they hope to advance SCI research and improve treatment.
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Elementos de Datos Comunes , Traumatismos de la Médula Espinal , Adulto , Bases de Datos Factuales , Femenino , Humanos , Masculino , National Institute of Neurological Disorders and Stroke (U.S.) , Gravedad del Paciente , Estudios Prospectivos , Sistema de Registros , Traumatismos de la Médula Espinal/clasificación , Traumatismos de la Médula Espinal/cirugía , Estados UnidosRESUMEN
Rehabilitative training is one of the most successful therapies to promote motor recovery after spinal cord injury, especially when applied early after injury. Polytrauma and management of other medical complications in the acute post-injury setting often preclude or complicate early rehabilitation. Therefore, interventions that reopen a window of opportunity for effective motor training after chronic injury would have significant therapeutic value. Here, we tested whether this could be achieved in rats with chronic (8 weeks) dorsolateral quadrant sections of the cervical spinal cord (C4) by inducing mild neuroinflammation. We found that systemic injection of a low dose of lipopolysaccharide improved the efficacy of rehabilitative training on forelimb function, as assessed using a single pellet reaching and grasping task. This enhanced recovery was found to be dependent on the training intensity, where a high-intensity paradigm induced the biggest improvements. Importantly, in contrast to training alone, the combination of systemic lipopolysaccharide and high-intensity training restored original function (reparative plasticity) rather than enhancing new motor strategies (compensatory plasticity). Accordingly, electrophysiological and tract-tracing studies demonstrated a recovery in the cortical drive to the affected forelimb muscles and a restructuration of the corticospinal innervation of the cervical spinal cord. Thus, we propose that techniques that can elicit mild neuroinflammation may be used to enhance the efficacy of rehabilitative training after chronic spinal cord injury.
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Mielitis/rehabilitación , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/terapia , Animales , Médula Cervical/lesiones , Femenino , Miembro Anterior/inervación , Inflamación , Lipopolisacáridos/uso terapéutico , Mielitis/terapia , Regeneración Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Tractos Piramidales/fisiopatología , Ratas , Ratas Endogámicas Lew , Recuperación de la Función/fisiología , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
IL-37, a member of the IL-1 family, broadly reduces innate inflammation as well as acquired immunity. Whether the antiinflammatory properties of IL-37 extend to the central nervous system remains unknown, however. In the present study, we subjected mice transgenic for human IL-37 (hIL-37tg) and wild-type (WT) mice to spinal cord contusion injury and then treated them with recombinant human IL-37 (rIL-37). In the hIL-37tg mice, the expression of IL-37 was barely detectable in the uninjured cords, but was strongly induced at 24 h and 72 h after the spinal cord injury (SCI). Compared with WT mice, hIL-37tg mice exhibited increased myelin and neuronal sparing and protection against locomotor deficits, including 2.5-fold greater speed in a forced treadmill challenge. Reduced levels of cytokines (e.g., an 80% reduction in IL-6) were observed in the injured cords of hIL-37tg mice, along with lower numbers of blood-borne neutrophils, macrophages, and activated microglia. We treated WT mice with a single intraspinal injection of either full-length or processed rIL-37 after the injury and found that the IL-37-treated mice had significantly enhanced locomotor skills in an open field using the Basso Mouse Scale, as well as supported faster speed on a mechanical treadmill. Treatment with both forms of rIL-37 led to similar beneficial effects on locomotor recovery after SCI. This study presents novel data indicating that IL-37 suppresses inflammation in a clinically relevant model of SCI, and suggests that rIL-37 may have therapeutic potential for the treatment of acute SCI.
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Interleucina-1/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Quimiocinas/antagonistas & inhibidores , Quimiocinas/metabolismo , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Interleucina-1/genética , Ratones , ARN Mensajero/genética , Traumatismos de la Médula Espinal/metabolismoRESUMEN
The reticulospinal tract (RtST) descends from the reticular formation and terminates in the spinal cord. The RtST drives the initiation of locomotion and postural control. RtST axons form new contacts with propriospinal interneurons (PrINs) after incomplete spinal cord injury (SCI); however, it is unclear if injured or uninjured axons make these connections. We completely transected all traced RtST axons in rats using a staggered model, where a hemisection SCI at vertebra T10 is followed by a contralateral hemisection at vertebra T7. In one group of the animals, the T7 SCI was performed 2 weeks after the T10 SCI (delayed; dSTAG), and in another group, the T10 and T7 SCIs were concomitant (cSTAG). dSTAG animals had significantly more RtST-PrIN contacts in the grey matter compared to cSTAG animals (p < 0.05). These results were accompanied by enhanced locomotor recovery with dSTAG animals significantly outperforming cSTAG animals (BBB test; p < 0.05). This difference suggests that activity in neuronal networks below the first SCI may contribute to enhanced recovery, because dSTAG rats recovered locomotor ability before the second hemisection. In conclusion, our findings support the hypothesis that the injured RtST forms new connections and is a key player in the recovery of locomotion post-SCI.
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Axones/patología , Interneuronas/patología , Locomoción , Regeneración Nerviosa , Traumatismos de la Médula Espinal/fisiopatología , Animales , Femenino , Técnicas de Trazados de Vías Neuroanatómicas , Ratas Endogámicas Lew , Recuperación de la Función , Traumatismos de la Médula Espinal/patología , Vértebras TorácicasRESUMEN
Olfactory ensheathing cell (OEC) transplantation emerged some years ago as a promising therapeutic strategy to repair injured spinal cord. However, inhibitory molecules are present for long periods of time in lesioned spinal cord, inhibiting both OEC migration and axonal regrowth. Two families of these molecules, chondroitin sulphate proteoglycans (CSPG) and myelin-derived inhibitors (MAIs), are able to trigger inhibitory responses in lesioned axons. Mounting evidence suggests that OEC migration is inhibited by myelin. Here we demonstrate that OEC migration is largely inhibited by CSPGs and that inhibition can be overcome by the bacterial enzyme Chondroitinase ABC. In parallel, we have generated a stable OEC cell line overexpressing the Nogo receptor (NgR) ectodomain to reduce MAI-associated inhibition in vitro and in vivo. Results indicate that engineered cells migrate longer distances than unmodified OECs over myelin or oligodendrocyte-myelin glycoprotein (OMgp)-coated substrates. In addition, they also show improved migration in lesioned spinal cord. Our results provide new insights toward the improvement of the mechanisms of action and optimization of OEC-based cell therapy for spinal cord lesion.
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Proteínas de la Mielina/metabolismo , Vaina de Mielina/metabolismo , Regeneración Nerviosa/fisiología , Neuroglía/fisiología , Animales , Axones/metabolismo , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Células Cultivadas , Proteoglicanos Tipo Condroitín Sulfato/farmacología , Clonación Molecular , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Técnicas Analíticas Microfluídicas , Proteínas de la Mielina/genética , Neuroglía/metabolismo , Receptor Nogo 1 , Bulbo Olfatorio/citología , Glicoproteína Oligodendrócito-Mielina/farmacología , Estructura Terciaria de Proteína , Ratas , Receptores de Superficie Celular/genética , Traumatismos de la Médula Espinal/terapia , Imagen de Lapso de TiempoRESUMEN
Cell therapy for spinal cord injury (SCI) is a promising strategy for clinical application. Both bone marrow mesenchymal stromal cells (MSCs; also known as bone marrow-derived 'mesenchymal stem cells') and olfactory ensheathing cells (OECs) have demonstrated beneficial effects following transplantation in animal models of SCI. However, due to the large number of affecting parameters that determine the therapy success and the lack of methodological consensus, the comparison of different works is difficult. Therefore, we compared the effects of MSC and OEC transplants at early or delayed time after a spinal cord contusion injury in the rat. Functional outcomes for locomotion, sensory perception and electrophysiological responses were assessed. Moreover, the grafted cells survival and the amount of cavity and spared tissue were studied. The findings indicate that grafted cells survived until 7 days post-injection, but markedly disappeared in the following 2 weeks. Despite the low survival of the cells, MSC and OEC grafts provided tissue protection after early and delayed transplantation. Nevertheless, only acute MSC grafts improved locomotion recovery in treadmill condition and electrophysiological outcomes with respect to the other injured groups. These results, together with previous works, indicate that the MSC seem a better option than OEC for treatment of contusion injuries.
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Células Ependimogliales/trasplante , Trasplante de Células Madre Mesenquimatosas , Traumatismos de la Médula Espinal/terapia , Médula Espinal/patología , Médula Espinal/fisiopatología , Animales , Supervivencia Celular/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Células Ependimogliales/fisiología , Potenciales Evocados Motores/fisiología , Femenino , Masculino , Actividad Motora/fisiología , Músculo Esquelético/fisiopatología , Conducción Nerviosa/fisiología , Bulbo Olfatorio/citología , Ratas Sprague-Dawley , Recuperación de la Función/fisiología , Reflejo/fisiología , Corteza Sensoriomotora/fisiopatología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Sensación Térmica/fisiología , Tacto/fisiologíaRESUMEN
AIMS: Dithiocarb (diethyldithiocarbamate, DEDTC) belongs to the group of dithiocarbamates and is the main metabolite of disulphiram, a drug of choice for the treatment of alcohol dependence. Its therapeutic potential relays on its ability to create an unpleasant aversive reaction following the ingestion of alcohol, and this effect is usually accompanied by neurobehavioural symptoms. Most of these can be attributed to the impaired metabolism of brain biogenic amines. METHODS: To gain new insights into the dithiocarbamates and their effects on neurotransmitter systems, an in vivo experimental model based on daily injections of DEDTC in adult mice for 7 days was established. To this end, the concentrations of the three major brain monoamines, dopamine (DA), noradrenaline (NA) and serotonin (5-HT) were measured in whole brain extracts with high-performance liquid chromatography (HPLC). The levels of D2 dopamine receptor (D2R) were evaluated by Western blot and by immunohistochemical techniques the cell pattern of tyrosine hydroxylase (TH), dopa beta hydroxylase (DBH) and choline acetyltransferase ChAT) were analysed. RESULTS: A significant reduction in DA and 5-HT levels was observed, whereas NA was not affected. Moreover, decreases in D2R levels, as well as in enzymes such as TH, DBH and ChAT, were found. CONCLUSIONS: Our data suggest that DEDTC provokes alterations in biogenic amines and in different substrates of neurotransmitter systems, which could explain some of the neurobehavioural effects observed in patients treated with disulphiram.
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Monoaminas Biogénicas/análisis , Química Encefálica/efectos de los fármacos , Ditiocarba/farmacología , Animales , Encéfalo/enzimología , Colina O-Acetiltransferasa/metabolismo , Ditiocarba/administración & dosificación , Dopamina/análisis , Masculino , Ratones , Norepinefrina/análisis , Receptores de Dopamina D2/análisis , Serotonina/análisis , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The field of neurotrauma is grappling with the effects of the recently identified replication crisis. As such, care must be taken to identify and perform the most appropriate statistical analyses. This will prevent misuse of research resources and ensure that conclusions are reasonable and within the scope of the data. We anticipate that Bayesian statistical methods will see increasing use in the coming years. Bayesian methods integrate prior beliefs (or prior data) into a statistical model to merge historical information and current experimental data. These methods may improve the ability to detect differences between experimental groups (i.e., statistical power) when used appropriately. However, researchers need to be aware of the strengths and limitations of such approaches if they are to implement or evaluate these analyses. Ultimately, an approach using Bayesian methodologies may have substantial benefits to statistical power, but caution needs to be taken when identifying and defining prior beliefs.
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Background: Recovery following total joint arthroplasty is patient-specific, yet groups of patients tend to fall into certain similar patterns of recovery. The purpose of this study was to identify and characterize recovery patterns following total hip arthroplasty (THA) and total knee arthroplasty (TKA) using patient-reported outcomes that represent distinct health domains. We hypothesized that recovery patterns could be defined and predicted using preoperative data. Methods: Adult patients were recruited from a large, urban academic center. To model postoperative responses to THA and TKA across domains such as physical health, mental health, and joint-specific measures, we employed a longitudinal clustering algorithm that incorporates each of these health domains. The clustering algorithm from multiple health domains allows the ability to define distinct recovery trajectories, which could then be predicted from preoperative and perioperative factors using a multinomial regression. Results: Four hundred forty-one of 1134 patients undergoing THA and 346 of 921 undergoing TKA met eligibility criteria and were used to define distinct patterns of recovery. The clustering algorithm was optimized for 3 distinct patterns of recovery that were observed in THA and TKA patients. Patients recovering from THA were divided into 3 groups: standard responders (50.8%), late mental responders (13.2%), and substandard responders (36.1%). Multivariable, multinomial regression suggested that these 3 groups had defined characteristics. Late mental responders tended to be obese (P = .05) and use more opioids (P = .01). Substandard responders had a larger number of comorbidities (P = .02) and used more opioids (P = .001). Patients recovering from TKA were divided among standard responders (55.8%), poor mental responders (24%), and poor physical responders (20.2%). Poor mental responders were more likely to be female (P = .04) and American Society of Anesthesiologists class III/IV (P = .004). Poor physical responders were more likely to be female (P = .03), younger (P = .04), American Society of Anesthesiologists III/IV (P = .04), use more opioids (P = .02), and be discharged to a nursing facility (P = .001). The THA and TKA models demonstrated areas under the curve of 0.67 and 0.72. Conclusions: This multidomain, longitudinal clustering analysis defines 3 distinct patterns in the recovery of THA and TKA patients, with most patients in both cohorts experiencing robust improvement, while others had equally well defined yet less optimal recovery trajectories that were either delayed in recovery or failed to achieve a desired outcome. Patients in the delayed recovery and poor outcome groups were slightly different between THA and TKA. These groups of patients with similar recovery patterns were defined by patient characteristics that include potentially modifiable comorbid factors. This research suggests that there are multiple defined recovery trajectories after THA and TKA, which provides a new perspective on THA and TKA recovery. Level of Evidence: III.
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The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) model is a widely recognized prognostic model applied after traumatic brain injury (TBI). However, it was developed with patient cohorts that may not reflect modern practice patterns in North America. We analyzed data from two sources: the placebo arm of the phase II double-blinded, multicenter, randomized controlled trial Prehospital Tranexamic Acid for TBI (TXA) cohort and an observational cohort with similar inclusion/exclusion criteria (Predictors of Low-risk Phenotypes after Traumatic Brain Injury Incorporating Proteomic Biomarker Signatures [PROTIPS] cohort). All three versions of the IMPACT model-core, extended, and laboratory-were evaluated for 6-month mortality (Glasgow Outcome Scale Extended [GOSE] = 1) and unfavorable outcomes (GOSE = 1-4). Calibration (intercept and slope) and discrimination (area under the receiver operating characteristic curve [ROC-AUC]) were used to assess model performance. We then compared three model updating methods-recalibration in the large, logistic recalibration, and coefficient update-with the best update method determined by likelihood ratio tests. In our calibration analysis, recalibration improved both intercepts and slopes, indicating more accurate predicted probabilities when recalibration was done. Discriminative performance of the IMPACT models, measured by AUC, showed mortality prediction ROCs between 0.61 and 0.82 for the TXA cohort, with the coefficient updated Lab model achieving the highest at 0.84. Unfavorable outcomes had lower AUCs, ranging from 0.60 to 0.79. Similarly, in the PROTIPS cohort, AUCs for mortality ranged from 0.75 to 0.82, with the coefficient updated Lab model also showing superior performance (AUC 0.84). Unfavorable outcomes in this cohort presented AUCs from 0.67 to 0.73, consistently lower than mortality predictions. The closed testing procedure using likelihood ratio tests consistently identified the coefficient update model as superior, outperforming the original and recalibrated models across all cohorts. In our comprehensive evaluation of the IMPACT model, the coefficient updated models were the best performing across all cohorts through a structured closed testing procedure. Thus, standardization of model updating procedures is needed to reproducibly determine the best performing versions of IMPACT that reflect the specific characteristics of a dataset.
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Translation of spinal cord injury (SCI) therapeutics from pre-clinical animal studies into human studies is challenged by effect size variability, irreproducibility, and misalignment of evidence used by pre-clinical versus clinical literature. Clinical literature values reproducibility, with the highest grade evidence (class 1) consisting of meta-analysis demonstrating large therapeutic efficacy replicating across multiple studies. Conversely, pre-clinical literature values novelty over replication and lacks rigorous meta-analyses to assess reproducibility of effect sizes across multiple articles. Here, we applied modified clinical meta-analysis methods to pre-clinical studies, comparing effect sizes extracted from published literature to raw data on individual animals from these same studies. Literature-extracted data (LED) from numerical and graphical outcomes reported in publications were compared with individual animal data (IAD) deposited in a federally supported repository of SCI data. The animal groups from the IAD were matched with the same cohorts in the LED for a direct comparison. We applied random-effects meta-analysis to evaluate predictors of neuroconversion in LED versus IAD. We included publications with common injury models (contusive injuries) and standardized end-points (open field assessments). The extraction of data from 25 published articles yielded n = 1841 subjects, whereas IAD from these same articles included n = 2441 subjects. We observed differences in the number of experimental groups and animals per group, insufficient reporting of dropout animals, and missing information on experimental details. Meta-analysis revealed differences in effect sizes across LED versus IAD stratifications, for instance, severe injuries had the largest effect size in LED (standardized mean difference [SMD = 4.92]), but mild injuries had the largest effect size in IAD (SMD = 6.06). Publications with smaller sample sizes yielded larger effect sizes, while studies with larger sample sizes had smaller effects. The results demonstrate the feasibility of combining IAD analysis with traditional LED meta-analysis to assess effect size reproducibility in SCI.
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BACKGROUND: Tools, such as the STarTBack Screening Tool (SBT), have been developed to identify risks of progressing to chronic disability in low back pain (LBP) patients in the primary care population. However, less is known about predictors of change in function after treatment in the specialty care population. OBJECTIVE: We pursued a retrospective observational cohort study involving LBP patients seen in a multidisciplinary specialty clinic to assess which features can predict change in function at follow-up. METHODS: The SBT was administered at initial visit, and a variety of patient characteristics were available in the chart including the presence of chronic overlapping pain conditions (COPCs). Patient Reported Outcomes Measurement Information System-10 (PROMIS-10) global physical health (PH) and global mental health (MH) were measured at baseline and at pragmatic time points during follow-up. Linear regression was used to estimate adjusted associations between available features and changes in PROMIS scores. RESULTS: 241 patients were followed for a mean of 17.0 ± 7.5 months. Mean baseline pain was 6.7 (SD 2.1), PROMIS-10 global MH score was 44.8 (SD 9.3), and PH score was 39.4 (SD 8.6). 29.7% were low-risk on the SBT, 41.8% were medium-risk, and 28.5% were high-risk. Mean change in MH and PH scores from baseline to the follow-up questionnaire were 0.86 (SD 8.11) and 2.39 (SD 7.52), respectively. Compared to low-risk patients, high-risk patients had a mean 4.35 points greater improvement in their MH score (p= 0.004) and a mean 3.54 points greater improvement in PH score (p= 0.006). Fewer COPCs also predicted greater improvement in MH and PH. CONCLUSIONS: SBT and the presence of COPC, which can be assessed at initial presentation to a specialty clinic, can predict change in PROMIS following treatment. Effort is needed to identify other factors that can help predict change in function after treatment in the specialty care setting.
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Dolor Crónico , Dolor de la Región Lumbar , Medición de Resultados Informados por el Paciente , Humanos , Dolor de la Región Lumbar/terapia , Dolor de la Región Lumbar/fisiopatología , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Dolor Crónico/terapia , Adulto , Dimensión del Dolor , Evaluación de la DiscapacidadRESUMEN
Background: Paraspinal muscle fat infiltration is associated with spinal degeneration and low back pain, however, quantifying muscle fat using clinical magnetic resonance imaging (MRI) techniques continues to be a challenge. Advanced MRI techniques, including chemical-shift encoding (CSE) based water-fat MRI, enable accurate measurement of muscle fat, but such techniques are not widely available in routine clinical practice. Methods: To facilitate assessment of paraspinal muscle fat using clinical imaging, we compared four thresholding approaches for estimating muscle fat fraction (FF) using T1- and T2-weighted images, with measurements from water-fat MRI as the ground truth: Gaussian thresholding, Otsu's method, K-mean clustering, and quadratic discriminant analysis. Pearson's correlation coefficients (r), mean absolute errors, and mean bias errors were calculated for FF estimates from T1- and T2-weighted MRI with water-fat MRI for the lumbar multifidus (MF), erector spinae (ES), quadratus lumborum (QL), and psoas (PS), and for all muscles combined. Results: We found that for all muscles combined, FF measurements from T1- and T2-weighted images were strongly positively correlated with measurements from the water-fat images for all thresholding techniques (r = 0.70-0.86, p < 0.0001) and that variations in inter-muscle correlation strength were much greater than variations in inter-method correlation strength. Conclusion: We conclude that muscle FF can be quantified using thresholded T1- and T2-weighted MRI images with relatively low bias and absolute error in relation to water-fat MRI, particularly in the MF and ES, and the choice of thresholding technique should depend on the muscle and clinical MRI sequence of interest.
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BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.
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Factor de Transcripción Activador 3 , Biomarcadores , Accidente Cerebrovascular Isquémico , Neuronas , Traumatismos de la Médula Espinal , Animales , Femenino , Humanos , Masculino , Ratones , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Biomarcadores/metabolismo , Biomarcadores/sangre , Modelos Animales de Enfermedad , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/sangre , Ratones Noqueados , Neuronas/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/complicacionesRESUMEN
Background #OrthoTwitter has evolved to disseminate findings and engage the public. However, the academic impact of Twitter utilization in orthopaedic surgery is unknown. Questions/purposes The purpose of the study was to evaluate relationships between the author and manuscript Twitter activity and citations. Methods Manuscripts in 17 orthopaedic journals from 2018 were identified. Citations, online mentions, impact factors, and subspecialties were obtained. H-index and Twitter account details for authors were obtained for a subset of manuscripts. Relationships between Twitter activity and citations were evaluated. Results 2,473/4,224 (58.5%) manuscripts were mentioned on Twitter (n=29,958 mentions), with Twitter manuscripts cited more frequently (median 10 vs. 7, p<0.0001). Twitter mentions, impact factors, non-open-access status, and subspecialties were associated with citation counts. Articles mentioned in 10, 100, and 1,000 Tweets were observed to have a 1.1-fold, 1.7-fold, and 245-fold increase in citations. In author-level analyses, 156 (20.0%) first and 216 (27.7%) senior authors had Twitter accounts. Citation count was associated with increasing senior author H-index (ß est=0.13, p<0.05), Twitter mentions (ß est=0.0043, p<0.0001), impact factors (ß est=0.13, p<0.0001), and having a first (ß est=0.20, p<0.05) or senior author (ß est=0.17, p<0.05) on Twitter. Articles published in arthroplasty (ß est=0.49, p<0.05), general interest (ß est=0.55, p<0.01), sports (ß est=0.63, p<0.01), and non-open access journals (ß est=0.41, p<0.001) were cited more. H-index correlated with followers for first (rho=0.31, p<0.0001) and senior authors (rho=0.44, p<0.0001). Conclusion Author Twitter utilization is independently associated with manuscript citations. Authors should be aware of the potential association between social media utilization and traditional academic impact. Understanding the relationship between social media utilization and academic impact is necessary to effectively disseminate research.