Fibre-rich diet attenuates chemotherapy-related neuroinflammation in mice.

The gastrointestinal microbiota has received increasing recognition as a key mediator of neurological conditions with neuroinflammatory features, through its production of the bioactive metabolites, short-chain fatty acids (SCFAs). Although neuroinflammation is a hallmark shared by the neuropsychological complications of chemotherapy (including cognitive impairment, fatigue and depression), the use of microbial-based therapeutics has not previously been studied in this setting. Therefore, we aimed to investigate the effect of a high fibre diet known to modulate the microbiota, and its associated metabolome, on neuroinflammation caused by the common chemotherapeutic agent 5-fluorouracil (5-FU). Twenty-four female C57Bl/6 mice were treated with 5-FU (400 mg/kg, intraperitoneal, i.p.) or vehicle control, with or without a high fibre diet (constituting amylose starch; 4.7 % crude fibre content), given one week prior to 5-FU and until study completion (16 days after 5-FU). Faecal pellets were collected longitudinally for 16S rRNA gene sequencing and terminal SCFA concentrations of the caecal contents were quantified using gas chromatography-mass spectrometry (GC-MS). Neuroinflammation was determined by immunofluorescent analysis of astrocyte density (GFAP). The high fibre diet significantly altered gut microbiota composition, increasing the abundance of Bacteroidaceae and Akkermansiaceae (p < 0.0001 and p = 0.0179) whilst increasing the production of propionate (p = 0.0097). In the context of 5-FU, the diet reduced GFAP expression in the CA1 region of the hippocampus (p < 0.0001) as well as the midbrain (p = 0.0216). Astrocyte density negatively correlated with propionate concentrations and the abundance of Bacteroidaceae and Akkermansiaceae, suggesting a relationship between neuroinflammatory and gastrointestinal markers in this model. This study provides the first evidence of the neuroprotective effects of fibre via dietary intake in alleviating the neuroimmune changes seen in response to systemically administered 5-FU, indicating that the microbiota-gut-brain axis is a targetable mediator to reduce the neurotoxic effects of chemotherapy treatment.

Musculoskeletal mimics of lumbosacral radiculopathy.

Electrodiagnostic evaluations are commonly requested for patients with suspected radiculopathy. Understanding lower extremity musculoskeletal conditions is essential for electrodiagnostic medicine specialists, as musculoskeletal disorders often mimic or coexist with radiculopathy. This review delineates radicular pain from other types originating from the lumbosacral spine and describes musculoskeletal conditions frequently mimicking radiculopathy, such as those that cause radiating pain and sensorimotor dysfunction. In clinical evaluation, a history of pain radiating along a specific dermatomal territory with associated sensory disturbance suggests radiculopathy. Physical examination findings consistent with radiculopathy include myotomal weakness, depressed or absent muscle stretch reflexes, focal atrophy along a discrete nerve root territory, and potentially positive dural tension maneuvers like the straight leg raise. However, electrodiagnostic medicine specialists must be knowledgeable of musculoskeletal mimics, which may manifest as incomplete radiation within or beyond a dermatomal territory, non-radiating pain, tenderness, and give-way weakness, in the context of a normal neurological examination. A systematic approach to musculoskeletal examination is vital, and this review focuses on high-yield physical examination maneuvers and diagnostic investigations to differentiate between musculoskeletal conditions and radiculopathy. This approach ensures accurate diagnoses, promotes resource stewardship, enhances patient satisfaction, and optimizes care delivery. Musculoskeletal conditions resembling L1 to S4 radiculopathy are reviewed, emphasizing their distinctive features in history, physical examination, and diagnostic investigation. Among the more than 30 musculoskeletal disorders reviewed are hip and knee osteoarthritis, lumbar facet syndrome, myofascial pain syndrome, greater trochanteric pain syndrome, and plantar fasciitis.

Assessment, management, and rehabilitation of traumatic peripheral nerve injuries for non-surgeons.

Electrodiagnostic evaluation is often requested for persons with peripheral nerve injuries and plays an important role in their diagnosis, prognosis, and management. Peripheral nerve injuries are common and can have devastating effects on patients' physical, psychological, and socioeconomic well-being; alongside surgeons, electrodiagnostic medicine specialists serve a central function in ensuring patients receive optimal treatment for these injuries. Surgical intervention-nerve grafting, nerve transfers, and tendon transfers-often plays a critical role in the management of these injuries and the restoration of patients' function. Increasingly, nerve transfers are becoming the standard of care for some types of peripheral nerve injury due to two significant advantages: first, they shorten the time to reinnervation of denervated muscles; and second, they confer greater specificity in directing motor and sensory axons toward their respective targets. As the indications for, and use of, nerve transfers expand, so too does the role of the electrodiagnostic medicine specialist in establishing or confirming the diagnosis, determining the injury's prognosis, recommending treatment, aiding in surgical planning, and supporting rehabilitation. Having a working knowledge of nerve and/or tendon transfer options allows the electrodiagnostic medicine specialist to not only arrive at the diagnosis and prognosticate, but also to clarify which nerves and/or muscles might be suitable donors, such as confirming whether the branch to supinator could be a nerve transfer donor to restore distal posterior interosseous nerve function. Moreover, post-operative testing can determine if nerve transfer reinnervation is occurring and progress patients' rehabilitation and/or direct surgeons to consider tendon transfers.

Experiences and Challenges Updating a Living Evidence-Based Review of Randomized Controlled Trials on Mental Health and Behavioral Disorders in Individuals With Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To describe experiences and challenges when updating a living evidence-based review database of randomized controlled trials (RCTs) on mental health and behavioral disorders in moderate to severe traumatic brain injury (MSTBI). METHOD: This commentary derives from our experience developing an extensive database of RCTs on MSTBI that has been conceptualized as a living evidence-based review. Our working group focused on mental health and behavior RCTs and reflected upon their experiences and challenges using the living systematic approach. We discuss challenges associated with metrics of study quality, injury etiology and severity, time post-injury, country of origin, and variability in outcome measures. RESULTS: RCTs were conducted almost solely in high income countries, with smaller sample sizes, and most conducted in the chronic phase post-TBI. Issues related to lack of transparency, unclear and incomplete reporting of injury severity, etiology, and time post-injury remain a concern and can lead to challenges associated with interpretation of results, validity, and reliability of the data. There was significant heterogeneity regarding the use of outcome measures and constructs, underscoring the need for standardization. CONCLUSION: Lack of standardization and incomplete reporting of injury characteristics makes it difficult to compare data between RCTs of MSTBI, perform meta-analyses, and generate evidence-based clinical recommendations.

Evidence-Based Review of Randomized Controlled Trials of Interventions for Mental Health Management Post-Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To present an evidence-based review of randomized controlled trials (RCTs) evaluating interventions for mental health post-moderate to severe traumatic brain injury (post-MSTBI), as part of an extensive database that has been conceptualized as a living systematic review. METHODS: Systematic searches were conducted for RCTs published in the English language in MEDLINE, PubMed, Scopus, CINAHL, EMBASE, and PsycINFO, up to and including December 2022, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodological quality of RCTs was assessed using the Physiotherapy Evidence Database scale, and the level of evidence was assigned using a modified Sackett scale. RESULTS: Eighty-seven RCTs examining mental health interventions and outcome measures post-MSTBI were included. These studies collectively enrolled 6471 participants. A total of 41 RCTs (47.1%) were conducted in the United States and 56 studies (64.4%) were published after 2010. A total of 62 RCTs (71.3%) examined nonpharmacological interventions and 25 RCTs (28.7%) examined pharmacological interventions. Effective pharmacological treatments included desipramine and cerebrolysin; methylphenidate and rivastigmine showed conflicting evidence. Cognitive behavioral therapy (CBT) was found to be effective for hopelessness, stress, and anxiety, compared to usual care; however, it may be as effective as supportive psychotherapy for depression. CBT combined with motivational interviewing may be as effective as CBT combined with nondirective counseling for depression, stress, and anxiety. Acceptance and commitment therapy was effective for anxiety, stress, and depression. Tai Chi, dance, and walking appeared to be effective for depression and stress, while other nonpharmacological treatments such as peer mentoring showed limited effectiveness. CONCLUSION: This evidence-based review provides a comprehensive overview of the research landscape of RCTs addressing mental health post-MSTBI. The findings from these RCTs may be valuable for health care professionals, researchers, and policymakers involved in the field of mental health and neurorehabilitation.

Evidence-Based Review of Randomized Controlled Trials of Interventions for the Management of Behavioral Issues in Individuals With Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To present an evidence-based review of randomized controlled trials (RCTs) evaluating interventions for the management of behavioral issues post moderate to severe traumatic brain injury (MSTBI), as part of an extensive database that has been conceptualized as a living systematic review. METHODS: Systematic searches were conducted in MEDLINE, PubMed, Scopus, CINAHL, EMBASE and PsycINFO, up to and including December 2022, for articles published in the English language, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of RCT was assessed using the Physiotherapy Evidence Database (PEDro) scale, and level of evidence was assigned using a modified Sackett scale. RESULTS: Forty-six RCTs examining interventions and outcome measures related to behavioral issues post-MSTBI were included. These studies collectively enrolled 3,267 participants. The majority of RCTs were conducted in the United States (n = 27; 58.7%) and 28 (60.9%) were conducted after 2010. Of these, 27 RCTs examined non-pharmacological interventions and 19 examined pharmacological interventions. Effective pharmacological treatments included amantadine and dexmedetomidine. Effective non-pharmacological interventions included sensory stimulation in the acute phase, anger self-management programs, peer mentoring, problem-solving, and emotional regulation. Psychotherapy showed conflicting evidence. CONCLUSION: This evidence-based review provides a comprehensive overview of the research landscape of RCTs addressing behavior post-MSTBI. The findings from these RCTs may be valuable for health care professionals, researchers, and policymakers involved in the field of TBI and behavior.

Machine learning method for predicting pacemaker implantation following transcatheter aortic valve replacement.

BACKGROUND: An accurate assessment of permanent pacemaker implantation (PPI) risk following transcatheter aortic valve replacement (TAVR) is important for clinical decision making. The aims of this study were to investigate the significance and utility of pre- and post-TAVR ECG data and compare machine learning approaches with traditional logistic regression in predicting pacemaker risk following TAVR. METHODS: Five hundred fifity seven patients in sinus rhythm undergoing TAVR for severe aortic stenosis (AS) were included in the analysis. Baseline demographics, clinical, pre-TAVR ECG, post-TAVR data, post-TAVR ECGs (24 h following TAVR and before PPI), and echocardiographic data were recorded. A Random Forest (RF) algorithm and logistic regression were used to train models for assessing the likelihood of PPI following TAVR. RESULTS: Average age was 80 ± 9 years, with 52% male. PPI after TAVR occurred in 95 patients (17.1%). The optimal cutoff of delta PR (difference between post and pre TAVR PR intervals) to predict PPI was 20 ms with a sensitivity of 0.82, a specificity of 0.66. With regard to delta QRS, the optimal cutoff was 13 ms with a sensitivity of 0.68 and a specificity of 0.59. The RF model that incorporated post-TAVR ECG data (AUC 0.81) more accurately predicted PPI risk compared to the RF model without post-TAVR ECG data (AUC 0.72). Moreover, the RF model performed better than logistic regression model in predicting PPI risk (AUC: 0.81 vs. 0.69). CONCLUSIONS: Machine learning using RF methodology is significantly more powerful than traditional logistic regression in predicting PPI risk following TAVR.

Use of CGRP receptor blocker erenumab in the management of post-traumatic headache: a case series of 5 women.

CONTEXT: Post-traumatic headache (PTH) is a disabling headache disorder and the most common sequela of mild traumatic brain injury. The pathophysiology of PTH is poorly understood and there is limited available evidence to guide prophylactic medication selection. Emerging understanding of the pathophysiology of migraine headaches has led to the development of monoclonal antibodies, including erenumab. Erenumab has shown promise for the prevention of primary migraine headache; however, it has not yet been studied in PTH. CASE SERIES: five women (average age 43.0 ± 17.9y) received treatment with erenumab for PTH secondary to mTBI. The average duration of PTH prior to starting erenumab was 32.0 ± 18.2 months. All patients were taking at least one daily headache prophylactic therapy prior to erenumab. The average pre-erenumab headache intensity was 86/100. On erenumab, the average reported reduction in headache intensity was 51.1%. After starting erenumab, all five patients were able to discontinue one or more medication(s). The most common side effect was constipation (three patients). There were no serious adverse events after an average follow-up of 3.4 ± 1.5 months. One patient discontinued erenumab during this period of follow-up after the resolution of her headaches. CONCLUSION: Erenumab appears to be safe and effective for the management of PTH.

Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines.

PURPOSE: The aim of this study was to update the clinical practice guidelines for the use of agents for the prevention and/or treatment of gastrointestinal mucositis (GIM). METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, and No Guideline Possible. RESULTS: A total of 78 papers across 13 interventions were examined of which 25 were included in the final review. No new guidelines were possible for any agent due to inadequate and/or conflicting evidence. Existing guidelines for probiotics and hyperbaric oxygen were unchanged. CONCLUSIONS: Of the agents studied for the prevention and treatment of GIM, the evidence continues to support use of probiotics containing Lactobacillus spp. for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy, and hyperbaric oxygen therapy to treat radiation-induced proctitis. Additional well-designed research is encouraged to enable a decision regarding palifermin, glutamine, sodium butyrate, and dietary interventions, for the prevention or treatment of GIM.

Matrix metalloproteinase expression is altered in the small and large intestine following fractionated radiation in vivo.

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is associated with significant diarrhoea, pain and rectal bleeding. Matrix metalloproteinases (MMPs) have been reported to be involved in chemotherapy-induced gut toxicity and RIGT following single-dose irradiation in vivo. We therefore proposed MMPs would be involved in the pathobiology of RIGT following fractionated irradiation. METHODS: Dark Agouti rats were treated with fractionated radiation (3 × 2.5 Gy/week for 6 weeks). Rats were killed at 3, 6 and 15 weeks to represent acute and chronic toxicities. Sections of jejunum and colon were immunostained for MMP-1, MMP-2, MMP-9 and MMP-14. Relative mRNA expression in jejunum and colon was quantified by RT-PCR for MMP-1, MMP-2, MMP-9 and MMP-14. Western blotting was also conducted on jejunum and colon tissue collected at week 6 to determine protein levels of pro- and active MMP-2. RESULTS: MMP-2 total protein levels, determined by western blotting, significantly increased in both the jejunum (p = 0.0359) and the colon (p = 0.0134) 6 weeks into the fractionated radiation schedule. MMP-1, MMP-2, and MMP-14 mRNA expression significantly increased in the jejunum. MMP-2 mRNA expression was also significantly increased in the colon. Immunostaining of MMP-2 was observed to be increased in both crypt enterocytes and the lamina propria. CONCLUSIONS: MMP-2 plays a role in the pathobiology of gastrointestinal toxicities following fractionated irradiation. Whilst MMP-1 and MMP-14 mRNA expression was increased, this occurred only in the jejunum, suggesting MMPs are differentially involved in RIGT depending on the intestinal region. Further studies are needed to elucidate the role these mediators play in the development and potentiation of RIGT.

Fractionated abdominal irradiation induces intestinal microvascular changes in an in vivo model of radiotherapy-induced gut toxicity.

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is associated with diarrhoea, pain and rectal bleeding and can occur as an acute or chronic toxicity. The microvasculature has been shown to be altered in the development of RIGT; however, the features are not yet characterized. We hypothesized that apoptosis of microvascular cells would occur early in the gastrointestinal tract following fractionated irradiation, followed by late microvascular changes, including sclerosis and telangiectasis. METHODS: Female Dark Agouti rats were treated with a 6-week fractionated radiation schedule of 3 × 2.5 Gy doses per week localized to the abdomen. At 3, 6 and 15 weeks, the intestines were assessed for markers of acute and chronic injury including morphological changes, collagen deposition, apoptosis and proliferation. RESULTS: Apoptosis of microvascular cells significantly increased at 6 and 15 weeks in the jejunum (p = 0.0026 and p = 0.0062, respectively) and at 6 and 15 weeks in the colon (p < 0.0001 and p = 0.0005, respectively) in rats receiving fractionated radiation to the abdomen. Histopathological changes of the colon microvasculature were also seen from week 3, including thickening of the lamina propria and dilated, thickened, telangiectatic vessels. CONCLUSIONS: Findings of this study provide evidence of regional and timing-specific changes in the intestinal microvasculature in response to fractionated radiotherapy which may play a role in development of both acute and chronic RIGT.

Enabling Oral SN38-Based Chemotherapy with a Combined Lipophilic Prodrug and Self-Microemulsifying Drug Delivery System.

Oral chemotherapy with SN38 is restricted by its poor solubility in gastrointestinal (GI) fluids and low permeability. Here we report the oral delivery of SN38 by a combined lipophilic prodrug and lipid-based formulation strategy. A lead lipophilic prodrug of SN38, SN38-undecanoate (SN38-unde20), was incorporated into a self-microemulsifying drug delivery system (SMEDDS) for improved in vitro and in vivo performance. The formulation was purposefully designed and optimized with long chain lipids and lipid-based nonionic surfactants to maximize drug solubilization in GI conditions, facilitate trans-membrane permeation, and hence improve oral absorption. SN38-unde20-SMEDDS significantly increased (>7 fold) drug solubilization in the aqueous phase compared to unformulated drug during in vitro lipolysis and drug solubilization studies. In an orally dosed in vivo pharmacokinetics study in a Dark Agouti rat model, the SN38-unde20-SMEDDS formulation confirmed oral absorption of SN38-unde20 and subsequent reconversion to SN38. Importantly, the overall plasma exposure of SN38 (AUC0→∞) was equivalent for orally dosed SN38-unde20-SMEDDS in comparison with a parenteral dose of SN38-unde20-SMEDDS and SN38 at an identical dose (10 mg/kg). The combination of lipophilic prodrug along with an optimal delivery carrier is demonstrated to enable effective oral delivery of challenging chemotherapeutic compounds that are conventionally dosed by injection.

Assessment of work limitations and disability in systemic vasculitis.

OBJECTIVES: Despite advances in the management of systemic vasculitis (SV), direct consequences of the disease, leading to impairments in physical and mental function can cause disability. The objective of this study was to assess work limitations in SV. METHODS: SV patients were recruited from a tertiary care clinic. Work disabled (WD) was defined as not working, early retirement, or reduced hours at work. Participants who were working at the time of enrolment completed the Work Limitations Questionnaire (WLQ). Other work-related measures were self-reported by questionnaire. Disease outcome measures (Vasculitis Damage Index (VDI), Health Assessment Questionnaire-Disability Index (HAQ) and pain visual analogue score (VAS)) were obtained at time of WLQ. RESULTS: 103 participants were enrolled with mean age 58 (SD17), 60% females, 48% with anti-neutrophilic cytoplasmic antibody-associated vasculitis (AAV), 26% with large vessel vasculitis (LVV) and 26% with other types of SV. 22 (21%) were WD secondary to SV, 29 (28%) were working and 52 (51%) subjects were not working for reasons other than SV. SV-related WD subjects were more likely to have a lower level of education (p=0.003) than non-WD subjects. The VDI was higher in SV-related WD vs. non-WD subjects: 1.9 (SD 2.7) vs. 2.9 (SD 1.4); p=0.015. 38 subjects were working in some capacity and completed the WLQ; their productivity loss was 8.2% and this was highly correlated with HAQ and pain VAS (rho=0.585 and rho=0.458, respectively). CONCLUSIONS: SV-related work disability occurred in 21% and was associated with lower levels of education, higher disease severity and worse functional outcomes.

Serum-derived bovine immunoglobulin/protein isolate in the alleviation of chemotherapy-induced mucositis.

BACKGROUND: Gastrointestinal (GI) mucositis caused by chemotherapy is associated with diarrhoea and intestinal barrier disruption caused by apoptosis, immune dysfunction and microbiome alterations. Serum-derived bovine immunoglobulin/protein isolate (SBI) has been shown to manage HIV-associated enteropathy and irritable bowel syndrome with diarrhoea (IBS-D). We investigated in a rat model whether SBI was effective in alleviating symptoms of irinotecan-induced GI mucositis. METHODS: Animals were gavaged with 250 or 500 mg/kg of SBI twice daily for 4 days, before intraperitoneal administration of 200 mg/kg irinotecan. Twice daily gavaging of SBI continued for 6 days post-irinotecan. Animals were monitored for bodyweight changes and incidence of diarrhoea and clinical symptoms of stress. Tissues and blood samples were collected at necropsy 6 h, and 2, 4 and 6 days post-irinotecan. H&E-stained colon and jejunum were analysed for histological damage. RESULTS: The overall incidence, severity and duration of diarrhoea, and clinical symptoms of mucositis were decreased in irinotecan-treated animals that had received SBI. Animals receiving 500 mg/kg SBI also tended to lose less bodyweight than animals treated only with irinotecan (P > 0.10). SBI-gavaged animals had less pronounced irinotecan-induced changes in neutrophil (P = 0.04959) and lymphocyte (P = 0.0035) levels, and lower tissue damage scores than those receiving irinotecan alone (P < 0.0001). CONCLUSIONS: Twice daily oral gavage of SBI was well-tolerated and reduced the incidence, severity and duration of irinotecan-induced mucositis. SBI was associated with less pronounced changes in inflammatory cell levels and tissue damage to colon and jejunum. Ongoing experiments aim to investigate the mechanisms of SBI-associated gastrointestinal protection.

Management of Mucositis During Chemotherapy: From Pathophysiology to Pragmatic Therapeutics.

Chemotherapy-induced mucositis is a common condition caused by the breakdown of the mucosal barrier. Symptoms can include pain, vomiting and diarrhoea, which can often necessitate chemotherapy treatment breaks or dose reductions, thus compromising survival outcomes. Despite the significant impact of mucositis, there are currently limited clinically effective pharmacological therapies for the pathology. New emerging areas of research have been proposed to play key roles in the development of mucositis, providing rationale for potential new therapeutics for the prevention, treatment or management of chemotherapy-induced mucositis. This review aims to address these new areas of research and to comment on the therapeutics arising from them.

Mortality and discharge disposition among older adults with moderate to severe traumatic brain injury.

PURPOSE: This study examined the research on older adults with a moderate to severe traumatic brain injury (TBI), with a focus on mortality and discharge disposition. METHOD: Systematic searches were conducted in MEDLINE, CINAHL, EMBASE and PsycINFO for studies up to April 2022 in accordance with PRISMA guidelines. RESULTS: 64 studies, published from 1992 to 2022, met the inclusion criteria. Mortality was higher for older adults ≥60 years old than for their younger counterparts; with a dramatic increase for those ≥80 yr, with rates as high as 93 %. Similar findings were reported regarding mortality in intensive care, surgical mortality, and mortality post-hospital discharge; with an 80 % rate at 1-year post-discharge. Up to 68.4 % of older adults were discharged home; when compared to younger adults, those ≥65 years were less likely to be discharged home (50-51 %), compared to those <64 years (77 %). Older adults were also more likely to be discharged to long-term care (up to 31.6 %), skilled nursing facilities (up to 46.1 %), inpatient rehabilitation (up to 26.9 %), and palliative or hospice care (up to 58 %). CONCLUSION: Given their vulnerability, optimizing outcomes for older adults with moderate-severe TBI across the healthcare continuum is critical.

Overview of randomized controlled trials of moderate to severe traumatic brain injury: A systematic review.

BACKGROUND: Given the complexity of post-TBI medical, surgical, and rehabilitative care, research is critical to optimize interventions across the continuum of care and improve outcomes for persons with moderate to severe TBI. OBJECTIVE: To characterize randomized controlled trials (RCTs) of moderate to severe traumatic brain injury (TBI) in the literature. METHOD: Systematic searches of MEDLINE, PubMed, Scopus, CINAHL, EMBASE and PsycINFO for RCTs up to December 2022 inclusive were conducted in accordance with PRISMA guidelines. RESULTS: 662 RCTs of 91,946 participants published from 1978 to 2022 met inclusion criteria. The number of RCTs published annually has increased steadily. The most reported indicator of TBI severity was the Glasgow Coma Scale (545 RCTs, 82.3%). 432 (65.3%) RCTs focused on medical/surgical interventions while 230 (34.7%) addressed rehabilitation. Medical/surgical RCTs had larger sample sizes compared to rehabilitation RCTs. Rehabilitation RCTs accounted for only one third of moderate to severe TBI RCTs and were primarily conducted in the chronic phase post-injury relying on smaller sample sizes. CONCLUSION: Further research in the subacute and chronic phases as well as increasing rehabilitation focused TBI RCTs will be important to optimizing the long-term outcomes and quality of life for persons living with TBI.

Comparing Randomized Controlled Trials of Moderate to Severe Traumatic Brain Injury in Lower to Middle Income Countries Versus High Income Countries.

Outcomes from traumatic brain injury (TBI) including death differ significantly between high-, middle-, and low-income countries. Little is known, however, about differences in TBI research across the globe. The objective of this article was to examine randomized controlled trials (RCTs) of moderate-to-severe TBI in high-income countries (HICs) compared with low- and middle-income countries (LMICs), as defined by the World Bank income per capita cutoff of $13,205 US dollars. A systematic review was conducted for articles published in the English language to December 2022 inclusive using MEDLINE, PubMed, Scopus, CINAHL, EMBASE, and PsycINFO in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Inclusion criteria: (1) human participants with a mean age of ≥18 years; (2) ≥50% of the sample had moderate to severe TBI; and (3) the study design was a RCT. Data extracted included author, year, country, sample size, primary focus (medical/surgical management or rehabilitation), injury etiology, time post-injury, and indicator(s) used to define TBI severity. There were 662 RCTs (published 1978-2022) that met inclusion criteria comprising 91,946 participants. There were 48 countries represented: 30 HICs accounting for 451 RCTs (68.1%) and 18 LMICs accounting for 211 RCTs (31.9%). The 62.6% of RCTs from LMICs were conducted in the acute phase post-injury (≤1 month) compared with 42.1% of RCTs from HICs. Of RCTs from LMICs, 92.4% focused on medical/surgical management compared with 52.5% from HICs. Since 2016, more RCTs have been conducted in LMICs than in HICs, indicating the importance of better understanding this pattern of research output.