TLR2 agonist prevents the progression of periapical lesions in mice by reducing osteoclast activity and regulating the frequency of Tregs.

AIM: To evaluate the role of regulatory T lymphocytes (Tregs) in the presence or absence of the synthetic ligand Pam3Cys during the progression of periapical lesion in wild-type (WT) and toll-like receptor 2 knockout (TLR2KO) mice. METHODOLOGY: A total of 130 C57BL/6 male WT and TLR2KO mice were allocated into control (n = 5) and experimental (periapical lesion induction) (n = 10) groups. In specific groups (WT+Pam3cys and TLR2KO+Pam3cys), the synthetic ligand Pam3cys was administered intraperitoneally every 7 days, according to the experimental period (14, 21 and 42 days). At the end of those periods, the animals were euthanized, and the mandible and the spleen were submitted to histotechnical processing. Mandible histological sections were analysed by haematoxylin and eosin, TRAP histoenzymology and immunohistochemistry (FOXP3, RANK, RANKL and OPG). Spleen sections were analysed by immunohistochemistry (FOXP3). RESULTS: The inflammatory infiltrate and bone resorption were more intense in the TLR2KO group compared to the WT group. The animals that received the Pam3cys had smaller periapical lesions when compared to the animals that did not receive the ligand (p < .05). TLR2KO animals showed a significant increase in the number of osteoclasts when compared to TLR2KO+Pam3cys group (p < .05). At 21 days, the WT+Pam3cys group had a lower number of osteoclasts when compared to the WT animals (p = .02). FOXP3 expression was more intense in the WT+Pam3cys groups when compared to the WT animals in the 42 days (p = .03). In the spleen analysis, the WT+Pam3cys group also had a higher expression of FOXP3 when compared to the WT animals at 14 and 42 days (p = .02). Concerning RANKL, there was a reduction in staining in the KOTLR2+Pam3cys groups at 21 and 42 days (p = .03) and a higher binding ratio between RANK/RANKL in animals that did not receive the ligand. CONCLUSION: Administration of the Pam3cys increased the proliferation of Tregs, showed by FOXP3 expression and prevented the progression of the periapical lesion in WT mice. On the other hand, in the TLR2KO animals, Treg expression was lower with larger areas of periapical lesions. Finally, systemic administration of the Pam3cys in KO animals was able to limit the deleterious effects of the absence of the TLR2 receptor.

Factors Associated With Regular Dental Care in People With Spinal Cord Injury: A Secondary Analysis of Data From the FRASCI Study.

Background: Oral health and regular dental care are critical to overall health. Research has found associations between oral health and infections, respiratory disease, and poor quality of life in the general population. While risks for all are increased in people with spinal cord injury (SCI), there is limited information on dental care after SCI. Objectives: The purpose of this analysis was to examine factors associated with regular dental care in people with SCI. Methods: We analyzed data from 348 individuals with traumatic and nontraumatic SCI who were enrolled in the Fracture Risk after SCI (FRASCI) study. The dataset included two variables on dental care, as well as demographics, injury-related characteristics, and secondary conditions. Bivariate relationships were determined using two-sided t tests and chi-square tests. Results: Over 60% of the sample received regular dental care twice per year, and 71% reported seeing a dentist within the past year. Those participants receiving regular dental care twice a year were more likely to be female, be working, have more than a high school diploma, have private insurance, and need a caregiver compared to those who do not receive regular dental care. In addition, these participants were more likely to have had pneumonia since their SCI and have had a urinary tract infection in the past year and since injury. Conclusion: More data on oral health are needed to make conclusions about the impact of oral health on secondary conditions and quality of life in people with SCI.

Feasibility of using remotely delivered Spring Forest Qigong to reduce neuropathic pain in adults with spinal cord injury: a pilot study.

Introduction: Approximately 69% of 299,000 Americans with spinal cord injury (SCI) suffer debilitating chronic neuropathic pain, which is intractable to treatment. The aim of this study is to determine feasibility, as the primary objective, and estimates of efficacy of a remotely delivered Qigong intervention in adults with SCI-related neuropathic pain, as the secondary objective. Methods: We recruited adults with SCI-related neuropathic pain, with SCI ≥3 months, with complete or incomplete SCI, and highest neuropathic pain level of >3 on the Numeric Pain Rating Scale (NPRS), using nationwide volunteer sampling. Using a non-randomized controlled trial design, participants practiced Spring Forest Qigong's "Five Element Qigong Healing Movements" (online video) by combining movement to the best of their ability with kinesthetic imagery, at least 3x/week for 12 weeks. Adherence was automatically tracked through the Spring Forest Qigong website. Outcomes of neuropathic pain intensity (NPRS) were assessed weekly, and SCI-related symptoms were assessed at baseline, 6, and 12 weeks of Qigong practice and at 6-week and 1-year follow-ups. Results: We recruited 23 adults with chronic SCI (7/2021-2/2023). In total, 18 participants started the study and completed all study components, including the 6-week follow-up. Twelve participants completed the 1-year follow-up assessment. Feasibility was demonstrated through participants' willingness to participate, adherence, and acceptability of the study. Mean age of the 18 participants was 60 ± 12 years, and they were 15 ± 11 years post-SCI with the highest baseline neuropathic pain of 7.94 ± 2.33, which was reduced to 4.17 ± 3.07 after 12 weeks of Qigong practice (Cohen's d = 1.75). This pain relief remained at 6-week and 1-year follow-ups. Participants reported reduced spasm frequency (change score 1.17 ± 1.20, d = 0.98) and severity (0.72 ± 1.02, d = 0.71), reduced interference of neuropathic pain on mood (3.44 ± 2.53, d = 1.36), sleep (3.39 ± 2.40, d = 1.41), daily activities (3.17 ± 2.77, d = 1.14), greater ability to perform functional activities (6.68 ± 3.07, d = 2.18), and improved mood (2.33 ± 3.31, d = 0.70) after Qigong. Discussion: Remote Spring Forest Qigong's "Five Element Qigong Healing Movements" practice is feasible in adults with SCI-related neuropathic pain, with promising prolonged results of neuropathic pain relief and improvement in SCI-related symptoms after Qigong practice. Clinical trial registration: https://www.clinicaltrials.gov/ct2/show/NCT04917107, identifier NCT04917107.

Using remotely delivered Spring Forest Qigong™ to reduce neuropathic pain in adults with spinal cord injury: protocol of a quasi-experimental feasibility clinical trial.

BACKGROUND: About 69% of Americans living with spinal cord injury (SCI) suffer from long-term debilitating neuropathic pain, interfering with the quality of daily life. Neuropathic pain is refractory to many available treatments-some carrying a risk for opioid addiction-highlighting an urgent need for new treatments. In this study, we will test our hypothesis that Spring Forest Qigong™ will reduce SCI-related neuropathic pain by improving body awareness. We will determine whether remotely delivered Qigong is feasible and we will collect data on neuropathic pain, and other reported associations with pain such as spasms frequency and/or severity, functional performance, mood, and body awareness. METHODS: In this quasi-experimental pilot clinical trial study, adults with SCI will practice Qigong at home with a 45-min video, at least 3 × /week for 12 weeks. The Qigong practice includes movements with guided breathing and is individualized based on functional abilities, i.e., the participants follow along with the Qigong movements to the level of their ability, with guided breathing, and perform kinesthetic imagery by focusing on the feeling in the whole body as if doing the whole-body Qigong movement while standing. The highest, average, and lowest neuropathic pain ratings perceived in the prior week will be recorded weekly until the 6-week follow-up. The other outcomes will be collected at 5 time points: at baseline, midway during the Qigong intervention (6 weeks), after the Qigong intervention (12 weeks), after a 6-week and 1-year follow-up. Rate parameters for the feasibility markers will be estimated based on the participants who achieved each benchmark. DISCUSSION: The University of Minnesota (UMN)'s Institutional Review Board (IRB) approved the study (IRB #STUDY00011997). All participants will sign electronic informed consent on the secure UMN REDCap platform. The results will be presented at academic conferences and published in peer-reviewed publications. TRIAL REGISTRATION: ClinicalTrial.gov registration number: NCT04917107 , (this protocol paper refers to the substudy), first registered 6/8/2021.

Unveiling the role of osteoblastic micro RNAs in the skeleton: from biological functions to therapeutic potential / Rol de los micro-ARN osteoblásticos en el esqueleto: desde las funciones biológicas al potencial terapéutico

MicroRNAs (miRNAs) are small non-coding RNA molecules that play critical roles in post-transcriptional gene regulation. They function by binding to target messenger RNA (mRNA) molecules, leading to their degradation or inhibiting their translation into proteins. In the context of skeletal diseases, such as osteoporosis, osteoarthritis, and bone metastasis, there is growing evidence osteoblastic miRNAs, are involved in the regulation of bone formation and maintenance.Osteoblasts are bone-forming cells responsible for synthesizing and depositing the extracellular matrix, which ultimately mineralizes to form bone tissue. Osteoblastic miRNAs modulate various aspects of osteoblast function, including proliferation, differentiation, mineralization, and apoptosis. Dysregulation of these miRNAs can disrupt the balance between bone formation and resorption, leading to skeletal diseases.The therapeutic implications of targeting osteoblastic miRNAs in skeletal diseases are significant. Modulating the expression levels of specific miRNAs holds promise for developing novel therapeutic strategies to enhance bone formation, prevent bone loss, and promote bone regeneration. Potential therapeutic approaches include the use of synthetic miRNA mimics to restore miRNA expression in diseases associated with miRNA downregulation or the use of anti-miRNA oligonucleotides to inhibit miRNA function in diseases associated with miRNA upregulation.miRNA-based therapies are still in the early stages of development, and further research is needed to fully understand the complexity of miRNA networks. Additionally, the delivery of miRNAs to specific target tissues and cells remains a challenge that needs to be addressed for effective clinical translation. Nonetheless, targeting osteoblastic miRNAs represents a promising avenue for future therapeutic interventions in skeletal diseases. (AU)

Los micro-ARNs (miARNss) son pequeños ARN no codificantes que desempeñan un papel fundamental en la regulación génica postranscripcional. Ejercen su función al unir-se a moléculas de ARN mensajero (ARNm), promoviendo su degradación e inhibiendo su traducción en proteínas. En el contexto de las enfermedades esqueléticas, como la osteoporosis, la osteoartritis y la metástasis ósea existe evidencia de que los miARNs osteoblásticos están involucrados en la regulación de la formación y del mantenimiento óseo. Los osteoblastos son células formadoras de hueso responsables de sintetizar y depositar la matriz extracelular, que finalmente se mineraliza para formar el hueso. Los miARNs derivados de osteoblastos modulan varios aspectos de la función de estas células, incluida la proliferación, diferenciación, mineralización y la apoptosis. La desregulación de estos miARNs puede alterar el equilibrio entre la formación y la resorción ósea, lo que lleva a enfermedades óseas. Las implicaciones terapéuticas de los miARNs osteoblásticos en enfermedades esqueléticas son significativas. La modulación de los niveles de expresión de miARNs específicos es prometedora para desarrollar nuevas estrate-gias terapéuticas a fin de mejorar la formación, prevenir la pérdida y promover la regeneración ósea. Los enfoques terapéuticos potenciales incluyen el uso de miméticos de miARNs para restaurar la expresión de miARNs o el uso de oligonucleótidos anti-miARNs para inhibir su función. Las terapias basadas en miARNs aún se encuentran en las primeras etapas de desarrollo. La administración de miARNs a las células y los tejidos específicos sigue siendo un desafío para lograr una aplicación clínica eficaz. (AU)

Diagnosis and Management of Cardiovascular Risk in Individuals With Spinal Cord Injury: A Narrative Review.

More than 16 000 Americans experience spinal cord injury (SCI), resulting in chronic disability and other secondary sequelae, each year. Improvements in acute medical management have increased life expectancy. Cardiovascular disease is a leading cause of death in this population, and seems to occur earlier in individuals with SCI compared with the general population. People with SCI experience a high burden of traditional cardiovascular disease risk factors, including dyslipidemia and diabetes, and demonstrate anatomic, metabolic, and physiologic changes alongside stark reductions in physical activity after injury. They also experience multiple, complex barriers to care relating to disability and, in many cases, compounding effects of intersecting racial and socioeconomic health inequities. Given this combination of risk factors, some investigators have proposed that people with SCI are at increased risk for cardiovascular disease, beyond that associated with traditional risk factors, and SCI could be considered a risk-enhancing factor, analogous to other risk-enhancing factors defined by the 2019 American Heart Association/American College of Cardiology Primary Prevention Guidelines. However, more research is needed in this population to clarify the role of traditional risk factors, novel risk factors, health care access, social determinants of health, and intersectionality of disability, race, and socioeconomic status. There is an urgent need for primary care physicians and cardiologists to have awareness of the importance of timely diagnosis and management of cardiac risk factors for people with SCI.

Exploring perspectives on assistive technology use: barriers, facilitators, and access.

PURPOSE: This qualitative study explored perceived barriers and facilitators to access and utilization of assistive technology (AT) among Veterans and civilians living with tetraplegia. We also explored differences in access to and utilization of AT between civilians and Veterans. MATERIALS AND METHODS: Semi-structured focus groups were conducted with 32 adults (15 Veterans, 17 non-Veterans) living with tetraplegia between the ages of 18 and 65 and who were at least one-year post-injury. Focus groups were conducted at two rehabilitation sites: Craig Hospital and the Louis Stokes Cleveland VA Medical Center. Participants were asked to discuss what they perceive as (1) the facilitators and barriers of AT access and utilization, and (2) the value of AT use in everyday living. Data were analyzed using thematic analysis of verbatim transcripts. RESULTS AND CONCLUSIONS: Facilitators of AT utilization and access included being connected to resources, trial-and-error, and knowledge gained from peers. Barriers to AT use included cost of devices, a general lack of awareness of resources, and requirements for eligibility; the latter two themes were endorsed solely by Veteran participants. Benefits of AT included increased independence, participation, productivity, quality of life, and safety. Findings highlight key facilitators of AT procurement and use, barriers that contribute to underutilization of AT, and important benefits experienced as a result of using AT that underscore the importance of AT for individuals with SCI.

The need to maintain connections with rehabilitation resources (e.g., the Department of Vocational Rehabilitation, occupational and physical therapists, the VA, inpatient facilities) is vital to learning about and procuring AT.There is a need for a tailored approach to address AT underutilization in civilian and Veteran populations.Despite the barriers to AT use and the challenges associated with discovery of AT, utilization of AT may lead to increased independence, participation, productivity, quality of life, and safety.

The Pathophysiology, Identification and Management of Fracture Risk, Sublesional Osteoporosis and Fracture among Adults with Spinal Cord Injury.

BACKGROUND: The prevention of lower extremity fractures and fracture-related morbidity and mortality is a critical component of health services for adults living with chronic spinal cord injury (SCI). METHODS: Established best practices and guideline recommendations are articulated in recent international consensus documents from the International Society of Clinical Densitometry, the Paralyzed Veterans of America Consortium for Spinal Cord Medicine and the Orthopedic Trauma Association. RESULTS: This review is a synthesis of the aforementioned consensus documents, which highlight the pathophysiology of lower extremity bone mineral density (BMD) decline after acute SCI. The role and actions treating clinicians should take to screen, diagnose and initiate the appropriate treatment of established low bone mass/osteoporosis of the hip, distal femur or proximal tibia regions associated with moderate or high fracture risk or diagnose and manage a lower extremity fracture among adults with chronic SCI are articulated. Guidance regarding the prescription of dietary calcium, vitamin D supplements, rehabilitation interventions (passive standing, functional electrical stimulation (FES) or neuromuscular electrical stimulation (NMES)) to modify bone mass and/or anti-resorptive drug therapy (Alendronate, Denosumab, or Zoledronic Acid) is provided. In the event of lower extremity fracture, the need for timely orthopedic consultation for fracture diagnosis and interprofessional care following definitive fracture management to prevent health complications (venous thromboembolism, pressure injury, and autonomic dysreflexia) and rehabilitation interventions to return the individual to his/her pre-fracture functional abilities is emphasized. CONCLUSIONS: Interprofessional care teams should use recent consensus publications to drive sustained practice change to mitigate fracture incidence and fracture-related morbidity and mortality among adults with chronic SCI.

Bone Mineral Loss at the Distal Femur and Proximal Tibia Following Spinal Cord Injury in Men and Women.

PURPOSE: Spinal cord injury (SCI) causes rapid bone loss and increases risk of fragility fractures in the lower extremities. The majority of individuals with SCI are men, and few studies have investigated sex as a biological variable in SCI-induced osteoporosis. This cross-sectional study aimed to quantify sex-specific differences in bone mineral following SCI. METHODS: Quantitative computed tomography (QCT) scans of the distal femur and proximal tibia were obtained at baseline of one of four clinical trials enrolling people who sustained SCI 1 month to 50 years prior to recruitment. Bone volume (BV), bone mineral content (BMC), bone mineral density (BMD), and bending strength index (BSI) were quantified in the integral, trabecular, and cortical bone in the epiphysis, metaphysis and diaphysis. Scans from 106 men and 31 women were analyzed to measure sex-specific effects on bone loss over time post-SCI. RESULTS: BMC and BSI declined exponentially as a function of time post-SCI and were best described by separate decay curves for men and women. Women had BV, BMC, and BSI at 58-77% that of men in the acute and plateau phases, with both sexes showing similar rates of loss as a function of time post-SCI. Trabecular BMD was best described as an exponential decay versus time post-SCI, with no sex-specific differences. CONCLUSIONS: Due to consistently lower BV, BMC, and BSI, women may be more susceptible to fractures after SCI than men.

Resting state functional connectivity differentiation of neuropathic and nociceptive pain in individuals with chronic spinal cord injury.

Many individuals with spinal cord injury live with debilitating chronic pain that may be neuropathic, nociceptive, or a combination of both in nature. Identification of brain regions demonstrating altered connectivity associated with the type and severity of pain experience may elucidate underlying mechanisms, as well as treatment targets. Resting state and sensorimotor task-based magnetic resonance imaging data were collected in 37 individuals with chronic spinal cord injury. Seed-based correlations were utilized to identify resting state functional connectivity of regions with established roles in pain processing: the primary motor and somatosensory cortices, cingulate, insula, hippocampus, parahippocampal gyri, thalamus, amygdala, caudate, putamen, and periaqueductal gray matter. Resting state functional connectivity alterations and task-based activation associated with individuals' pain type and intensity ratings on the International Spinal Cord Injury Basic Pain Dataset (0-10 scale) were evaluated. We found that intralimbic and limbostriatal resting state connectivity alterations are uniquely associated with neuropathic pain severity, whereas thalamocortical and thalamolimbic connectivity alterations are associated specifically with nociceptive pain severity. The joint effect and contrast of both pain types were associated with altered limbocortical connectivity. No significant differences in task-based activation were identified. These findings suggest that the experience of pain in individuals with spinal cord injury may be associated with unique alterations in resting state functional connectivity dependent upon pain type.

Predictors of discharge disposition and mortality following hospitalization with SARS-CoV-2 infection.

IMPORTANCE: The SARS-CoV-2 pandemic has overwhelmed hospital capacity, prioritizing the need to understand factors associated with type of discharge disposition. OBJECTIVE: Characterization of disposition associated factors following SARS-CoV-2. DESIGN: Retrospective study of SARS-CoV-2 positive patients from March 7th, 2020, to May 4th, 2022, requiring hospitalization. SETTING: Midwest academic health-system. PARTICIPANTS: Patients above the age 18 years admitted with PCR + SARS-CoV-2. INTERVENTION: None. MAIN OUTCOMES: Discharge to home versus PAC (inpatient rehabilitation facility (IRF), skilled-nursing facility (SNF), long-term acute care (LTACH)), or died/hospice while hospitalized (DH). RESULTS: We identified 62,279 SARS-CoV-2 PCR+ patients; 6,248 required hospitalizations, of whom 4611(73.8%) were discharged home, 985 (15.8%) to PAC and 652 (10.4%) died in hospital (DH). Patients discharged to PAC had a higher median age (75.7 years, IQR: 65.6-85.1) compared to those discharged home (57.0 years, IQR: 38.2-69.9), and had longer mean length of stay (LOS) 14.7 days, SD: 14.0) compared to discharge home (5.8 days, SD: 5.9). Older age (RRR:1.04, 95% CI:1.041-1.055), and higher Elixhauser comorbidity index [EI] (RRR:1.19, 95% CI:1.168-1.218) were associated with higher rate of discharge to PAC versus home. Older age (RRR:1.069, 95% CI:1.060-1.077) and higher EI (RRR:1.09, 95% CI:1.071-1.126) were associated with more frequent DH versus home. Blacks, Asians, and Hispanics were less likely to be discharged to PAC (RRR, 0.64 CI 0.47-0.88), (RRR 0.48 CI 0.34-0.67) and (RRR 0.586 CI 0.352-0.975). Having alpha variant was associated with less frequent PAC discharge versus home (RRR 0.589 CI 0.444-780). The relative risks for DH were lower with a higher platelet count 0.998 (CI 0.99-0.99) and albumin levels 0.342 (CI 0.26-0.45), and higher with increased CRP (RRR 1.006 CI 1.004-1.007) and D-Dimer (RRR 1.070 CI 1.039-1.101). Increased albumin had lower risk to PAC discharge (RRR 0.630 CI 0.497-0.798. An increase in D-Dimer (RRR1.033 CI 1.002-1.064) and CRP (RRR1.002 CI1.001-1.004) was associated with higher risk of PAC discharge. A breakthrough (BT) infection was associated with lower likelihood of DH and PAC. CONCLUSION: Older age, higher EI, CRP and D-Dimer are associated with PAC and DH discharges following hospitalization with COVID-19 infection. BT infection reduces the likelihood of being discharged to PAC and DH.

Pharmacologic and Nonpharmacologic Treatment Modalities for Bone Loss in SCI - Proposal for Combined Approach.

Increased risk of bone fracture due to bone mineral density (BMD) loss is a serious consequence of spinal cord injury (SCI). Traditionally, pharmaceutical approaches, such as bisphosphonates, have been prescribed to prevent bone loss. However, there is controversy in the literature regarding efficacy of these medications to mitigate the drastic bone loss following SCI. Individuals with SCI are particularly at risk of osteoporosis because of the lack of ambulation and weight bearing activities. In the past two decades, functional electric stimulation (FES) has allowed for another approach to treat bone loss. FES approaches are expanding into various modalities such as cycling and rowing exercises and show promising outcomes with minimal consequences. In addition, these non-pharmacological treatments can elevate overall physical and mental health. This article provides an overview of efficacy of different treatment options for BMD loss for SCI and advocates for a combined approach be pursued in standard of care.

Using remotely delivered Spring Forest Qigong™ to reduce neuropathic pain in adults with spinal cord injury: A non-randomized controlled trial.

Importance: The manuscript proposes the feasibility and potential of a remote Qigong intervention to reduce neuropathic pain in adults with spinal cord injury (SCI)-related neuropathic pain. Objective: We determined the feasibility and estimates of efficacy of a remotely delivered Qigong intervention in adults with SCI-related neuropathic pain. Design: This is a non-randomized controlled trial with outcomes assessed at baseline-, 6- and 12-weeks of Qigong practice, and at 6-weeks and 1-year follow-up. Setting: Completely remote clinical trial. Participants: Adults with SCI-related neuropathic pain, with SCI ≥3 months, with complete or incomplete SCI, and highest neuropathic pain level of >3 on the Numeric Pain Rating Scale (NPRS). We used nationwide volunteer sampling.We recruited 23 adults with chronic SCI (7/2021-2/2022). Eighteen participants started the study and completed all study components, including the 6-week follow-up. Twelve participants completed the 1-year follow-up assessment. Intervention: Participants practiced the Spring Forest Qigong™ "Five Element Healing Movements" with an online video by combining movement with kinesthetic imagery, at least 3x/week for 12 weeks. Main Outcomes and Measures: To address the feasibility outcome and track adherence, the website automatically monitored the days and duration that the Qigong video was played. Self-report neuropathic pain intensity and SCI-related symptoms such as spasms, functional performance, mood, and body appreciation were also collected. Results: Eighteen participants, 60±12 years of age, 15±11 years post-SCI had a highest baseline neuropathic pain of 7.94±2.33 on the NPRS, which was reduced to 4.17±3.07 after 12 weeks of Qigong practice (Cohen's d =1.75). This pain relief remained at 6-week and 1-year follow-ups. Participants reported reduced spasm frequency (change score 1.17±1.20, d =0.98) and severity (0.72±1.02, d =0.71), and reduced interference of neuropathic pain on mood (3.44±2.53, d =1.36), sleep (3.39±2.40, d =1.41), and daily activities (3.17±2.77, d =1.14). They had a greater ability to perform functional activities (Patient Specific Functional Scale, 6.68±3.07, d =2.18) and had improved mood (Patient Health Questionnaire-9, 2.33±3.31, d =0.70). Conclusions and Relevance: Our preliminary data demonstrate the feasibility of Qigong practice in adults with SCI-related neuropathic pain and promising results of neuropathic pain relief and improvement in SCI-related symptoms after Qigong practice. Trial Registration this manuscript refers to the quasi-experimental substudy: CREATION: A Clinical Trial of Qigong for Neuropathic Pain Relief in Adults with Spinal Cord Injury, NCT04917107 , https://www.clinicaltrials.gov/ct2/show/NCT04917107 .

Identifying Body Awareness-Related Brain Network Changes after Cognitive Multisensory Rehabilitation for Neuropathic Pain Relief in Adults with Spinal Cord Injury: Delayed Treatment arm Phase I Randomized Controlled Trial.

Background: Neuropathic pain after spinal cord injury (SCI) is notoriously hard to treat. Mechanisms of neuropathic pain are unclear, which makes finding effective treatments challenging. Prior studies have shown that adults with SCI have body awareness deficits. Recent imaging studies, including ours, point to the parietal operculum and insula as key areas for both pain perception and body awareness. Cognitive multisensory rehabilitation (CMR) is a physical therapy approach that helps improve body awareness for pain reduction and sensorimotor recovery. Based on our prior brain imaging work in CMR in stroke, we hypothesized that improving body awareness through restoring parietal operculum network connectivity leads to neuropathic pain relief and improved sensorimotor and daily life function in adults with SCI. Thus, the objectives of this study were to (1) determine baseline differences in resting-state and task-based functional magnetic resonance imaging (fMRI) brain function in adults with SCI compared to healthy controls and (2) identify changes in brain function and behavioral pain and pain-associated outcomes in adults with SCI after CMR. Methods: Healthy adults underwent a one-time MRI scan and completed questionnaires. We recruited community-dwelling adults with SCI-related neuropathic pain, with complete or incomplete SCI >3 months, and highest neuropathic pain intensity level of >3 on the Numeric Pain Rating Scale (NPRS). Participants with SCI were randomized into two groups, according to a delayed treatment arm phase I randomized controlled trial (RCT): Group A immediately received CMR intervention, 3x/week, 45 min/session, followed by a 6-week and 1-year follow-up. Group B started with a 6-week observation period, then 6 weeks of CMR, and a 1-year follow-up. Highest, average, and lowest neuropathic pain intensity levels were assessed weekly with the NPRS as primary outcome. Other primary outcomes (fMRI resting-state and functional tasks; sensory and motor function with the INSCI AIS exam), as well as secondary outcomes (mood, function, spasms, and other SCI secondary conditions), were assessed at baseline, after the first and second 6-week period. The INSCI AIS exam and questionnaires were repeated at the 1-year follow-up. Findings: Thirty-six healthy adults and 28 adults with SCI were recruited between September 2020 and August 2021, and of those, 31 healthy adults and 26 adults with SCI were enrolled in the study. All 26 participants with SCI completed the intervention and pre-post assessments. There were no study-related adverse events. Participants were 52±15 years of age, and 1-56 years post-SCI. During the observation period, group B did not show any reductions in neuropathic pain and did not have any changes in sensation or motor function (INSCI ASIA exam). However, both groups experienced a significant reduction in neuropathic pain after the 6-week CMR intervention. Their highest level of neuropathic pain of 7.81±1.33 on the NPRS at baseline was reduced to 2.88±2.92 after 6 weeks of CMR. Their change scores were 4.92±2.92 (large effect size Cohen's d =1.68) for highest neuropathic pain, 4.12±2.23 ( d =1.85) for average neuropathic pain, and 2.31±2.07 ( d =1.00) for lowest neuropathic pain. Nine participants out of 26 were pain-free after the intervention (34.62%). The results of the INSCI AIS testing also showed significant improvements in sensation, muscle strength, and function after 6 weeks of CMR. Their INSCI AIS exam increased by 8.81±5.37 points ( d =1.64) for touch sensation, 7.50±4.89 points ( d =1.53) for pin prick sensation, and 3.87±2.81 ( d =1.38) for lower limb muscle strength. Functional improvements after the intervention included improvements in balance for 17 out of 18 participants with balance problems at baseline; improved transfers for all of them and a returned ability to stand upright with minimal assistance in 12 out of 20 participants who were unable to stand at baseline. Those improvements were maintained at the 1-year follow-up. With regard to brain imaging, we confirmed that the resting-state parietal operculum and insula networks had weaker connections in adults with SCI-related neuropathic pain (n=20) compared to healthy adults (n=28). After CMR, stronger resting-state parietal operculum network connectivity was found in adults with SCI. Also, at baseline, as expected, right toe sensory stimulation elicited less brain activation in adults with SCI (n=22) compared to healthy adults (n=26). However, after CMR, there was increased brain activation in relevant sensorimotor and parietal areas related to pain and mental body representations (i.e., body awareness and visuospatial body maps) during the toe stimulation fMRI task. These brain function improvements aligned with the AIS results of improved touch sensation, including in the feet. Interpretation: Adults with chronic SCI had significant neuropathic pain relief and functional improvements, attributed to the recovery of sensation and movement after CMR. The results indicate the preliminary efficacy of CMR for restoring function in adults with chronic SCI. CMR is easily implementable in current physical therapy practice. These encouraging impressive results pave the way for larger randomized clinical trials aimed at testing the efficacy of CMR to alleviate neuropathic pain in adults with SCI. Clinical Trial registration: ClinicalTrials.gov Identifier: NCT04706208. Funding: AIRP2-IND-30: Academic Investment Research Program (AIRP) University of Minnesota School of Medicine. National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR002494; the Biotechnology Research Center: P41EB015894, the National Institute of Neurological Disorders & Stroke Institutional Center Core Grants to Support Neuroscience Research: P30 NS076408; and theHigh-Performancee Connectome Upgrade for Human 3T MR Scanner: 1S10OD017974.

Neuromodulation Through Spinal Cord Stimulation Restores Ability to Voluntarily Cycle After Motor Complete Paraplegia.

Abstract Epidural spinal cord stimulation (eSCS) of the lower thoracic spinal cord has been shown to partially restore volitional movement in patients with complete chronic spinal cord injury (cSCI). Combining eSCS with intensive locomotor training improves motor function, including standing and stepping, but many patients with cSCI suffer from long-standing muscle atrophy and loss of bone mineral density, which may prohibit safe implementation. Safe, accessible, and effective avenues for pairing neuromodulation with activity-based therapy remain unexplored. Cycling is one such option that can be utilized as an eSCS therapy given its low-risk and low-weight-bearing requirement. We investigated the feasibility and kinematics of motor-assisted and passive cycle-based therapy for cSCI patients with epidural spinal cord stimulation. Seven participants who underwent spinal cord stimulation surgery in the Epidural Stimulation After Neurologic Damage (E-STAND) trial (NCT03026816) participated in a cycling task using the motor assist MOTOmed Muvi 300. A factorial design was used such that participants were asked to cycle with and without conscious effort with and without stimulation. We used mixed effects models assessing maximum power output and time pedaling unassisted to evaluate the interaction between stimulation and conscious effort. Cycling was well-tolerated and we observed no adverse events, including in participants up to 17 years post-initial injury and up to 58 years old. All participants were found to be able to pedal without motor assist, which primarily occurred when stimulation and effort were applied together (p = 0.001). Additionally, the combination of stimulation and intention was significantly associated with higher maximum power production (p < 0.0001) and distance pedaled (p = 0.0001). No association was found between volitional movement and participant factors: age, time since injury, and spinal cord atrophy. With stimulation and conscious effort, all participants were able to achieve active cycling without motor assistance. Thus, our stationary cycling factorial study design demonstrated volitional movement restoration with eSCS in a diverse study population of cSCI participants. Further, motor-assist cycling was well-tolerated without any adverse events. Cycling has the potential to be a safe research assessment and physical therapy modality for cSCI patients utilizing eSCS who have a high risk of injury with weight bearing exercise. The cycling modality in this study was demonstrated to be a straightforward assessment of motor function and safe for all participants regardless of age or time since initial injury.

Changes in essential care in individuals with spinal cord injury during the COVID-19 pandemic.

STUDY DESIGN: Cross-sectional, observational study. OBJECTIVES: To determine whether changes in essential care during the COVID-19 pandemic impacted satisfaction with activities, participation, and relationships among individuals with spinal cord injury (SCI). SETTING: Data were collected online between December 31, 2020 and February 14, 2021 among community dwelling adults with SCI (N = 123). METHODS: The primary outcome variables were satisfaction with the ability to complete activities of daily living (ADLs) (mobility, dressing, feeding, and toileting), as well as satisfaction with participation in household and recreational activities, and satisfaction with relationships among friends, family, and with the status of one's relationship measured with the International Spinal Cord Injury Data Sets Activities and Participation Basic Data Set. Primary predictors were age, gender, time since injury, completeness of injury, injury level, access to mental health, access to medications, access to medical supplies, and access to personal care assistants (PCAs). RESULTS: Impact on access to mental health and impact on access to supplies were the most common factors affecting satisfaction with activities, participation, and relationships for individuals with SCI during the COVID-19 pandemic. Impact on access to PCAs/homecare was also found to impact certain outcomes including feeding and participation in household activities. CONCLUSIONS: Future supply chain disruptions from pandemics or natural disasters could have wide-reaching effects for individuals with SCIs. Thus, further research and advocacy is needed to improve mental health care planning and supply chain access during subsequent natural disasters.

Comparison of DXA-based versus CT-based indices to predict prevalent fracture history in men with spinal cord injury.

Fracture risk prediction remains challenging in adults with spinal cord injury. Here, we compare the ability of CT- and DXA-derived indices to discriminate between those with and without prevalent osteoporotic fracture. Novel CT-derived indices may offer improved assessment of fragility fracture risk as well as improved monitoring of response to therapies. INTRODUCTION: Individuals with spinal cord injury are particularly susceptible to osteoporosis. As advanced imaging techniques become more readily available clinically, there is limited information on the relative strength of various outcomes for fracture risk prediction. The purpose of this study was to compare the ability of DXA-based versus CT-based indices to predict prevalent fracture history in adults with spinal cord injury. METHODS: Thirty-six men with known SCI underwent dual energy X-ray absorptiometry and computed tomography assessments of the lower extremities. We used age-adjusted area under the curve models to compare the predictive value for each bone parameter to identify prevalent fracture history. RESULTS: CT-based indices outperformed DXA-based indices at all sites. The site with the highest AUC was the trabecular BMD at the proximal tibial epiphysis. CONCLUSIONS: CT imaging may have clinical utility to improve fracture risk prediction in adults with SCI. More work is needed to confirm these findings and to assess the value of CT-based indices to predict incident fracture, monitor longitudinal bone loss, and monitor response to various therapies, both pharmacological and rehabilitation.

Prevalence and influencing factors of spinal cord injury-related osteoporosis and fragility fractures in Thai people with chronic spinal cord injury: A cross-sectional, observational study.

Objective: To investigate the prevalence and influencing factors of spinal cord injury (SCI)-related osteoporosis and fragility fractures in Thai people with chronic spinal cord injury.Design: A cross-sectional, observational study.Setting: Outpatient clinic, Department of Rehabilitation Medicine, Maharaj Nakorn Chiang Mai Hospital.Participants: Thais with chronic spinal cord injury (SCI) (duration of injury at least one year).Intervention: Not applicable.Outcome measures: Dual-energy X-ray absorptiometry (DXA) was performed to measure bone mineral density (BMD) at the hip. Analyses were performed to identify risk factors for SCI-related osteoporosis or fragility fracture development. Thai FRAX® score was calculated with and without BMD and compared for each participant.Results: Among 64 Thais with chronic SCI, the prevalence of SCI-related osteoporosis was 43.8%. Female sex, non-ambulatory status, and at least 10 years duration of spinal cord injury increased the risk of having SCI-related osteoporosis. The prevalence of fragility fracture was 9.4%. Female sex, duration of SCI, and being diagnosed with SCI-related osteoporosis increased the risk of having a fragility fracture. Thai FRAX® score without BMD value underestimated the risk of prevalent fracture in 7.8% of participants.Conclusions: SCI-related osteoporosis and fragility fractures are common in Thais with chronic SCI. Our findings emphasize the importance of SCI-related osteoporosis and fragility fracture surveillance in people with chronic SCI regardless of their ethnicity. FRAX® without BMD calculations could underestimate the risk of fragility fracture in people with chronic SCI. Therefore, further studies are needed to develop an SCI-specific fracture-risk assessment tool using risk factors proposed in previous studies and in this study.

Identifying Body Awareness-Related Brain Network Changes After Cognitive Multisensory Rehabilitation for Neuropathic Pain Relief in Adults With Spinal Cord Injury: Protocol of a Phase I Randomized Controlled Trial.

Background: About 69% of the 299,000 Americans living with spinal cord injury (SCI) experience long-term debilitating neuropathic pain. New treatments are needed because current treatments do not provide enough pain relief. We have found that insular-opercular brain network alterations may contribute to neuropathic pain and that restoring this network could reduce neuropathic pain. Here, we outline a study protocol using a physical therapy approach, cognitive multisensory rehabilitation (CMR), which has been shown to restore OP1/OP4 connections in adults post stroke, to test our hypothesis that CMR can normalize pain perception through restoring OP1/OP4 connectivity in adults with SCI and relieve neuropathic pain. Objectives: To compare baseline brain function via resting-state and task-based functional magnetic resonance imaging in adults with SCI versus uninjured controls, and to identify changes in brain function and behavioral pain outcomes after CMR in adults with SCI. Methods: In this phase I randomized controlled trial, adults with SCI will be randomized into two groups: Group A will receive 6 weeks of CMR followed by 6 weeks of standard of care (no therapy) at home. Group B will start with 6 weeks of standard of care (no therapy) at home and then receive 6 weeks of CMR. Neuroimaging and behavioral measures are collected at baseline, after the first 6 weeks (A: post therapy, B: post waitlist), and after the second 6 weeks (A: post-therapy follow-up, B: post therapy), with follow-up of both groups up to 12 months. Conclusion: The successful outcome of our study will be a critical next step toward implementing CMR in clinical care to improve health in adults with SCI.

MicroRNA-148a-3p is a candidate mediator of increased bone marrow adiposity and bone loss following spinal cord injury.

Spinal cord injury is often followed by osteoporosis characterized by rapid and severe bone loss. This leads to an increased risk of osteoporotic fracture in people with spinal cord injury, resulting in increased healthcare costs, morbidity, and mortality. Though it is common, the mechanisms underlying this osteoporosis are not completely understood and treatment options are limited. No biomarkers have been identified for predicting fracture risk. In this study, we sought to investigate microRNA mediated mechanisms relating to osteoporosis following spinal cord injury. We studied subjects with acute SCI (n=12), chronic SCI (n=18), and controls with no SCI (n=23). Plasma samples from all subjects underwent transcriptomic analysis to quantify microRNA expression, after which miR-148a-3p was selected for further study. We performed CT scans of the knee on all subjects with SCI and analyzed these scans to quantify bone marrow adipose tissue volume. MiR-148a-3p was upregulated in subjects with acute SCI vs chronic SCI, as well as in acute SCI vs no SCI. Subjects with chronic SCI had greater levels of marrow adiposity in the distal femoral diaphysis compared to subjects with acute SCI. MiR-148a-3p levels were negatively associated with distal femoral diaphysis marrow adiposity. A multivariable model showed that miR-148a-3p and BMI explained 24% of variation in marrow adiposity. A literature search revealed that miR-148a-3p has multiple bone and fat metabolism related targets. Our findings suggest that miR-148a-3p is a mediator of osteoporosis following spinal cord injury and a potential future therapeutic target.