Protocol for the Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study: a prospective, observational, multicentre cohort study of acute spinal cord injury.

INTRODUCTION: Spinal cord injury (SCI) is a catastrophic event with devastating physical, social and occupational consequences for patients and their families. The number of patients with acute SCI in China continues to grow rapidly, but there have been no large prospective cohort studies of patients with acute SCI. This proposed study aims to establish a multicentre, extensive sample cohort of clinical data and biological samples of patients in China, which would aid the systematisation and standardisation of clinical research and treatment of acute SCI, thus reducing the heavy burden of acute SCI on patients and society. METHODS AND ANALYSIS: The Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study is an observational, multicentre cohort study of patients with acute SCI admitted to the Qilu Hospital of Shandong University and other participating centres with prospective collection of their clinical data and biological samples. We aim to recruit 2097 patients in this study. Demographics, disease history, emergency intervention information, motor and sensory examinations, surgical information, medication information and rehabilitation evaluation will be recorded. This will facilitate the development of a prediction model for complications and prognosis of patients with acute SCI and an evaluation of the current management of acute SCI. Among these variables, detailed information on surgical treatment will also be used to assess procedures for acute SCI treatment. Outcome measurements, including the International Standard for Neurological Classification of Spinal Cord Injury examinations, the occurrence of complications and death, will be performed repeatedly during follow-up. We will analyse imaging data and blood samples to develop SCI imaging markers and biomarkers. ETHICS AND DISSEMINATION: This study protocol has been approved by the Medical Ethics Committee of the Qilu Hospital of Shandong University and all other participating centres. The findings will be disseminated in peer-reviewed journals and academic conferences.

Traumatic spinal injury-related hospitalizations in the United States, 2016-2019: a retrospective study.

BACKGROUND: Traumatic spinal injury (TSI) is associated with significant fatality and social burden; however, the epidemiology and treatment of patients with TSI in the US remain unclear. MATERIALS AND METHODS: An adult population was selected from the National Inpatient Sample database from 2016 to 2019. TSI incidence was calculated and TSI-related hospitalizations were divided into operative and nonoperative groups according to the treatments received. TSIs were classified as fracture, dislocation, internal organ injury, nerve root injury, or sprain injuries based on their nature. The annual percentage change (APC) was calculated to identify trends. In-hospital deaths were utilized to evaluate the prognosis of different TSIs. RESULTS: Overall, 95 047 adult patients were hospitalized with TSI in the US from 2016 to 2019, with an incidence rate of 48.4 per 100 000 persons in 2019 (95% CI: 46.2-50.6). The total incidence increased with an APC of 1.5% (95% CI: 0.1-3%) from 2016 to 2019. Operative TSI treatment was more common than nonoperative (32.8 vs. 3.8; 95% CI: 32.3-33.2 vs. 3.6-4%). The number of operations increased from 37 555 (95% CI: 34 674-40 436) to 40 460 (95% CI: 37 372-43 548); however, the operative rate only increased for internal organ injury (i.e. spinal cord injury [SCI])-related hospitalizations (APC, 3.6%; 95% CI: 2.8-4.4%). In-hospital mortality was highest among SCI-related hospitalizations, recorded at 3.9% (95% CI: 2.9-5%) and 28% (95% CI: 17.9-38.2%) in the operative and nonoperative groups, respectively. CONCLUSIONS: The estimated incidence of TSI in US adults increased from 2016 to 2019. The number of operations increased; however, the proportion of operations performed on TSI-related hospitalizations did not significantly change. In 2019, SCI was the highest associated mortality TSI, regardless of operative or nonoperative treatment.

A critical appraisal of clinical practice guidelines on surgical treatments for spinal cord injury.

BACKGROUND CONTEXT: Spinal cord injury (SCI) is a global health problem with a heavy economic burden. Surgery is considered as the cornerstone of SCI treatment. Although various organizations have formulated different guidelines on surgical treatment for SCI, the methodological quality of these guidelines has still not been critically appraised. PURPOSE: We aim to systematically review and appraise the current guidelines on surgical treatments of SCI and summarize the related recommendations with the quality evaluation of supporting evidence. STUDY DESIGN: Systematic review. METHODS: Medline, Cochrane library, Web of Science, Embase, Google Scholar, and online guideline databases were searched from January 2000 to January 2022. The most updated and recent guidelines containing evidence-based or consensus-based recommendations and established by authoritative associations were included. The Appraisal of Guidelines for Research and Evaluation, 2nd edition instrument containing 6 domains (eg, applicability) was used to appraise the included guidelines. An evidence-grading scale (ie, level of evidence, LOE) was utilized to evaluate the quality of supporting evidence. The supporting evidence was categorized as A (the best quality), B, C, and D (the worst quality). RESULTS: Ten guidelines from 2008 to 2020 were included, however, all of them acquired the lowest scores in the domain of applicability among all the six domains. Fourteen recommendations (eight evidence-based recommendations and six consensus-based recommendations) were totally involved. The SCI types of the population and timing of surgery were studied. Regarding the SCI types of the population, eight guidelines (8/10, 80%), two guidelines (2/10, 20%), and three guidelines (3/10, 30%) recommended surgical treatment for patients with SCI without further clarification of characteristics, incomplete SCI, and traumatic central cord syndrome (TCCS), respectively. Besides, one guideline (1/10, 10%) recommended against surgery for patients with SCI without radiographic abnormality. Regarding the timing of surgery, there were eight guidelines (8/10, 80%), two guidelines (2/10, 20%), and two guidelines (2/10, 20%) with recommendations for patients with SCI without further clarification of characteristics, incomplete SCI, and TCCS, respectively. For patients with SCI without further clarification of characteristics, all eight guidelines (8/8, 100%) recommended for early surgery and five guidelines (5/8, 62.5%) recommended for the specific timing, which ranged from within 8 hours to within 48 hours. For patients with incomplete SCI, two guidelines (2/2, 100%) recommended for early surgery, without specific time thresholds. For patients with TCCS, one guideline (1/2, 50%) recommended for surgery within 24 hours, and another guideline (1/2, 50%) simply recommended for early surgery. The LOE was B in eight recommendations, C in three recommendations, and D in three recommendations. CONCLUSIONS: We remind the reader that even the highest quality guidelines often have significant flaws (eg, poor applicability), and some of the conclusions are based on consensus recommendations which is certainly less than ideal. With these caveats, we found most included guidelines (8/10, 80%) recommended early surgical treatment for patients after SCI, which was consistent between evidence-based recommendations and consensus-based recommendations. Regarding the specific timing of surgery, the recommended time threshold did vary, but it was usually within 8 to 48 hours, where the LOE was B to D.

A critical appraisal of clinical practice guidelines for management of four common complications after spinal cord injury.

BACKGROUND CONTEXT: Complications such as pressure sores, pulmonary infection, urinary tract infection (UTI), and venous thromboembolism (VTE) are common after spinal cord injury (SCI). These have serious consequences for patients' physical, social, and vocational well-being. Several authoritative organizations have developed guidelines for managing these complications after SCI. PURPOSE: We aim to systematically review and appraise guidelines on the management of four common complications (pressure sores, pulmonary infection, UTI, and VTE) after SCI as well as to summarize relevant recommendations and assess the quality of their supporting evidence. DESIGN: Systematic review. METHODS: We searched Medline, Embase, Cochrane, and Web of Science, as well as guideline-specific databases (eg, National Guideline Clearinghouse) and Google Scholar, from January 2000 to January 2022. We included the most updated guidelines developed by specific authoritative organizations. We evaluated the included guidelines using the Appraisal of Guidelines for Research and Evaluation 2nd edition instrument, which measures six domains (eg, applicability). Recommendations extracted from guidelines were categorized as for, against, or neither for nor against. An evidence assessment was adopted to classify the quality of supporting evidence as poor, fair, or good. RESULTS: Eleven guidelines from 2005 to 2020 were included, all of which, among the six domains, scored lowest in the domain of applicability. For pressure sores, guidelines recommended for skin inspection, repositioning, and the use of pressure reduction equipment as preventive measures and dressings, debridement, and surgery as treatment measures. For pulmonary infection, guidelines recommended for physical (eg, the use of an insufflation-exsufflation device) and pharmacological measures (eg, the use of bronchodilators). For UTI, guidelines recommended for antibiotics as a treatment measure but recommended against cranberries, methenamine salts, and acidification or alkalinization agents as preventive measures. For VTE prophylaxis, five guidelines recommended for low molecular weight heparin (LMWH). Three guidelines recommended against unfractionated heparin, whereas one guideline recommended for it. Most of the supporting evidence was of poor quality (130/139), and the rest was of fair quality (9/139). CONCLUSIONS: For pressure sores, pulmonary infection, and UTI, evidence of poor to fair quality indicated consistent recommendations for prevention and treatment measures. For VTE, LMWH was consistently recommended, whereas recommendations on the use of unfractionated heparin were controversial.

A critical appraisal of clinical practice guidelines on pharmacological treatments for spinal cord injury.

BACKGROUND CONTEXT: Spinal cord injury brings devastating consequences and huge economic burden. Different authoritative organizations have developed different guidelines for pharmacological treatments of spinal cord injury, but there is a lack of a critical appraisal of them. PURPOSE: To systematically review and appraise guidelines regarding their recommendations for pharmacological treatments for spinal cord injury. STUDY DESIGN: Systematic review. METHODS: We searched Medline, Embase, Cochrane, and Web of Science from January 2000 to January 2022 as well as guideline-specific databases (eg, Congress of Neurological Surgeons) and Google Scholar. We included the most updated guideline containing evidence-based recommendations or consensus-based recommendations developed by specific authoritative organizations if multiple versions were available. We appraised guidelines through the Appraisal of Guidelines for Research and Evaluation, 2nd edition instrument consisting of six domains (eg, applicability). With supporting evidence, recommendations were classified as: for, against, neither for nor against. We utilized an evidence assessment system to categorize the quality of supporting evidence as poor, fair, or good. RESULTS: Eight guidelines developed from 2008 to 2020 were included, but all of them scored lowest in the domain of applicability among all six domains. Twelve pharmacological agents (eg, methylprednisolone) were studied. For methylprednisolone, three guidelines (3/8=37.5%) recommended for (one evidence-based and two consensus-based), three (3/8=37.5%) recommended against (all evidence-based), and two (2/8=25%) recommended neither for nor against. For monosialotetrahexosylganglioside (GM-1), one guideline (1/4=25%) recommended for (consensus-based), one (1/4=25%) recommended against (evidence-based), and two (2/4=50%) recommended neither for nor against. For other agents (eg, minocycline), most guidelines (3/5=60%) recommended neither for nor against, one (1/5=20%) recommended against naloxone (evidence-based) and nimodipine (evidence-based), and one (1/5=20%) recommended for neural growth factor (consensus-based). The quality of most of the supporting evidence was poor, and the rest was fair. CONCLUSIONS: There were inconsistencies among recommendations for methylprednisolone and GM-1. Evidence-based recommendations tended to recommend against, whereas consensus-based recommendations tended to recommend for.

Clinical features and burden of osteoporotic fractures among the elderly in the USA from 2016 to 2018.

This study provides a national estimate of the incidence of hospitalizations and assesses the clinical features and outcomes during inpatient admission due to osteoporotic fractures diagnosed by ICD-10-CM/PCS among the elderly in the USA, using the US Nationwide Inpatient Sample, 2016-2018. PURPOSE: To provide a national estimate of the incidence of hospitalizations and assess the clinical features and outcomes during inpatient admission due to osteoporotic fractures (OFs) among the elderly in the USA. METHODS: The study included all inpatients aged 65 years and older who participated in the US Nationwide Inpatient Sample (NIS). We conducted a retrospective analysis of hospitalizations with OFs diagnosed by the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS), using the US NIS, 2016-2018. Trends in epidemiological characteristics and outcomes were calculated by annual percentage change (APC). RESULTS: From 2016 to 2018, there were an estimated 0.16 million hospitalizations for OFs, and the estimated annual incidence rate changed from 995 cases per 1 million persons in 2016 to 1114 cases per 1 million persons in 2018 (APC, 5.8% [95% CI, 0.0 to 12.0]; P > 0.05). Over two-thirds of the patients (68.2%) were age-related osteoporosis with current pathological fracture, and OFs were more likely to occur in vertebra (51.7%) and femur (34.7%). During the hospitalization, the average length of stay (LOS) was 5.83 days, the average cost reached $60,901.04, and the overall mortality was 2.3%. All outcomes including LOS, average cost and mortality did not change significantly in 2016-2018 (all P values for trend were over 0.05). CONCLUSION: Between 2016 and 2018, the incidence rate of OFs remained relatively stable, but the total number of cases was huge. OFs was predominantly age-related, mostly in vertebrae and femurs, with relatively stable cost and mortality during hospitalization.

m6 A demethylase ALKBH5 drives denervation-induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling.

BACKGROUND: Skeletal muscle atrophy is a common clinical manifestation of various neurotrauma and neurological diseases. In addition to the treatment of primary neuropathies, it is a clinical condition that should be investigated. FoxO3 activation is an indispensable mechanism in denervation-induced muscle atrophy; however, upstream factors that control FoxO3 expression and activity have not been fully elucidated. N6 -methyladenosine (m6 A) methylation is a novel mode of epitranscriptional gene regulation that affects several cellular processes. However, the biological significance of m6 A modification in FoxO3-dependent atrophy is unknown. METHODS: We performed gain-of-function and loss-of-function experiments and used denervation-induced muscle atrophy mouse model to evaluate the effects of m6 A modification on muscle mass control and FoxO3 activation. m6 A-sequencing and mass spectrometry analyses were used to establish whether histone deacetylase 4 (HDAC4) is a mediator of m6 A demethylase ALKBH5 regulation of FoxO3. A series of cellular and molecular biological experiments (western blot, immunoprecipitation, half-life assay, m6 A-MeRIP-qPCR, and luciferase reporter assays among others) were performed to investigate regulatory relationships among ALKBH5, HDAC4, and FoxO3. RESULTS: In skeletal muscles, denervation was associated with a 20.7-31.9% decrease in m6 A levels (P < 0.01) and a 35.6-115.2% increase in demethylase ALKBH5 protein levels (P < 0.05). Overexpressed ALKBH5 reduced m6 A levels, activated FoxO3 signalling, and induced excess loss in muscle wet weight (-10.3% for innervation and -11.4% for denervation, P < 0.05) as well as a decrease in myofibre cross-sectional areas (-35.8% for innervation and -33.3% for denervation, P < 0.05) during innervation and denervation. Specific deletion of Alkbh5 in the skeletal muscles prevented FoxO3 activation and protected mice from denervation-induced muscle atrophy, as evidenced by increased muscle mass (+16.0%, P < 0.05), size (+50.0%, P < 0.05) and MyHC expression (+32.6%, P < 0.05). Mechanistically, HDAC4 was established to be a crucial central mediator for ALKBH5 in enhancing FoxO3 signalling in denervated muscles. ALKBH5 demethylates and stabilizes Hdac4 mRNA. HDAC4 interacts with and deacetylates FoxO3, resulting in a significant increase in FoxO3 expression (+61.3-82.5%, P < 0.01) and activity (+51.6-122.0%, P < 0.001). CONCLUSIONS: Our findings elucidate on the roles and mechanisms of ALKBH5-mediated m6 A demethylation in the control of muscle mass during denervation and activation of FoxO3 signalling by targeting HDAC4. These results suggest that ALKBH5 is a potential therapeutic target for neurogenic muscle atrophy.

Magnesium supplementation enhances mTOR signalling to facilitate myogenic differentiation and improve aged muscle performance.

Magnesium (Mg2+), as an essential mineral, supports and sustains the health and activity of the organs of the human body. Despite some clinical evidence on the association of Mg2+ deficiency with muscle regeneration dysfunction and sarcopenia in older-aged individuals, there is no consensus on the action mode and molecular mechanism by which Mg2+ influences aged muscle size and function. Here, we identified the appropriate Mg2+ environment that promotes the myogenic differentiation and myotube hypertrophy in both C2C12 myoblast and primary aged muscle stem cell (MuSC). Through animal experiments, we demonstrated that Mg2+ supplementation in aged mice significantly promotes muscle regeneration and conserves muscle mass and strength. Mechanistically, Mg2+ stimulation activated the mammalian target of rapamycin (mTOR) signalling, inducing the myogenic differentiation and protein synthesis, which consequently offers protections against the age-related decline in muscle regenerative potential and muscle mass. These findings collectively provide a promising therapeutic strategy for MuSC dysfunction and sarcopenia through Mg2+ supplementation in the elderly.