Optimal Design of Clinical Trials Involving Persons with Disorders of Consciousness.

BACKGROUND: Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC. METHODS: The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC. RESULTS: There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC. CONCLUSIONS: Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care.

Biomarkers Assessing the Role of Cumulus Cells on IVF Outcomes: A Systematic Review.

PURPOSE: Although significant improvements in assisted reproductive technology (ART) outcomes have been accomplished, a critical question remains: which embryo is most likely to result in a pregnancy? Embryo selection is currently based on morphological and genetic criteria; however, these criteria do not fully predict good-quality embryos and additional objective criteria are needed. The cumulus cells are critical for oocyte and embryo development. This systematic review assessed biomarkers in cumulus-oocyte complexes and their association with successful IVF outcomes. METHODS: A comprehensive search was conducted using PubMed, Embase, Scopus, and Web of Science from inception until November 2022. Only English-language publications were included. Inclusion criteria consisted of papers that evaluated genetic biomarkers associated with the cumulus cells (CCs) in humans and the following three outcomes of interest: oocyte quality, embryo quality, and clinical outcomes, including fertilization, implantation, pregnancy, and live birth rates. RESULTS: The search revealed 446 studies of which 42 met eligibility criteria. Nineteen studies correlated genetic and biochemical biomarkers in CCs with oocyte quality. A positive correlation was reported between oocyte quality and increased mRNA expression in CCs of genes encoding for calcium homeostasis (CAMK1D), glucose metabolism (PFKP), extracellular matrix (HAS2, VCAN), TGF-ß family (GDF9, BMP15), and prostaglandin synthesis (PTGS2). Nineteen studies correlated genetic and biochemical biomarkers in CCs with embryo quality. A positive correlation was reported between embryo quality and increased mRNA expression in CCs of genes encoding for extracellular matrix (HAS2), prostaglandin synthesis (PTGS2), steroidogenesis (GREM1), and decreased expression of gene encoding for hormone receptor (AMHR2). Twenty-two studies assessed genetic and biochemical biomarkers in CCs with clinical outcomes. Increased expression of genes encoding for extracellular matrix (VCAN), and TGF-ß family (GDF9, BMP15) were positively correlated with pregnancy rate. CONCLUSION: Genetic biomarkers from cumulus cells were associated with oocyte quality (CAMK1D, PFKP, HAS2, VCAN, GDF-9, BMP-15, PTGS2), embryo quality (GREM1, PTGS2, HAS2), and pregnancy rate (GDF9, BMP15, VCAN). These results might help guide future studies directed at tests of cumulus cells to devise objective criteria to predict IVF outcomes.

Predictive ability of pancreatic cyst fluid biomarkers: A systematic review and meta-analysis.

BACKGROUND: Mucinous pancreatic cysts harbor the potential to progress to highly lethal pancreatic ductal adenocarcinoma (PDAC). Since these precursor cysts require cancer surveillance or surgical resection, they need to be reliably distinguished from harmless pancreatic cysts. Current clinical and radiographic assessment is imperfect and the value of cyst fluid analysis for differential diagnosis is unclear. Therefore, we set out to investigate the value of cyst fluid biomarkers in distinguishing pancreatic cysts. METHODS: We performed a systematic review of the current literature to identify articles that evaluated the diagnostic performance of clinically relevant and promising candidate cyst fluid biomarkers, with a particular emphasis on DNA-based biomarkers. Meta-analysis was performed for biomarkers targeted at identifying cyst type and presence of high-grade dysplasia or PDAC. RESULTS: Data from a total of 42 studies was analyzed. Mutations in KRAS and/or GNAS allowed identification of mucinous cysts with a sensitivity of 79% and specificity of 98%. This exceeded the performance of the traditional biomarker carcinoembryonic antigen (CEA; sensitivity 58%, specificity 87%). Mutations in VHL were specific for serous cystadenomas (SCAs; sensitivity 56%, specificity 99%) and help to exclude mucinous cysts. Mutations in CDKN2A, PIK3CA, SMAD4, and TP53 each had high specificities of 97%, 97%, 98%, and 95%, respectively, to identify high-grade dysplasia or PDAC in mucinous cysts. CONCLUSIONS: Cyst fluid analysis can be a valuable tool in the characterization of pancreatic cysts, with relevant clinical implications. Our results support the use of DNA-based cyst fluid biomarkers in the multidisciplinary diagnostic work-up of pancreatic cysts.

The Mediator Complex Subunit 12 (MED-12) Gene and Uterine Fibroids: a Systematic Review.

Uterine leiomyomas are the most common tumor of reproductive-age women worldwide. Although benign, uterine fibroids cause significant morbidity and adversely impact the quality of life for affected women. Somatic mutations in the exon 2 of the mediator complex subunit 12 (MED-12) gene represent the most common single gene mutation associated with uterine leiomyomas. The objective of this review was to evaluate the current role of MED-12 mutation in the pathophysiology of uterine fibroids, to assess the prevalence of MED-12 mutation among different populations, and to identify the most common subtypes of MED-12 mutations found in uterine fibroids. A comprehensive search was conducted using Pubmed, Embase, Scopus, and the Web of Science. English-language publications that evaluated MED-12 mutation and uterine fibroids in humans, whether experimental or clinical, were considered. We identified 380 studies, of which 23 were included, comprising 1353 patients and 1872 fibroid tumors. Of the total number of tumors analyzed, 1045 (55.8%) harbored a MED-12 mutation. Among the 23 studies included, the frequency of MED-12 mutation varied from 31.1 to 80% in fibroid samples. The most common type of MED-12 mutation was a heterozygous missense mutation affecting codon 44 of exon 2, specifically the nucleotide 131. Studies reported that MED-12 mutation acts by increasing levels of AKT and disrupting the cyclin C-CDK8/19 kinase activity. The overall average prevalence of MED-12 mutation in uterine fibroids was found to be 55.8% across the global population, though the frequency varied greatly among different countries.

Remote Delivery of Vestibular Rehabilitation for Vestibular Dysfunction: A Systematic Review.

BACKGROUND: People with vestibular dysfunction encounter many obstacles when seeking vestibular rehabilitation treatment. Remote delivery of vestibular rehabilitation may offer a promising avenue for overcoming these barriers, ensuring uninterrupted and cost-effective care. OBJECTIVE: To evaluate clinical trials studying telerehabilitation and virtual reality devices as therapeutic interventions for individuals with vestibular dysfunction. METHODS: A PRISMA systematic review of PubMed, EMBASE, Cochrane, Web of Science, and SCOPUS was conducted for randomized controlled trials describing the use of remote care delivery for vestibular rehabilitation. Bias of studies was assessed with the revised Cochrane risk-of-bias tool (RoB2). RESULTS: The search identified 1,358 unique articles and 14 articles matched the search criteria. Study samples size ranged from 20 to 337, with mean ages ranging from 29.3 to 77.7 years. Interventions included telephone and online communication, exergaming devices, web-based applications, and head-mounted devices to deliver vestibular rehabilitation. Outcomes included validated questionnaires, objective clinical tests, and physical examinations. CONCLUSIONS: The studies reviewed in this article reported greater or equivalent outcomes when incorporating remote care options as supplements or alternatives to standard care for patients with vestibular dysfunction. Further research is required to address limitations in these studies such as heterogeneity of control groups and cost-effectiveness of these interventions.

Comparative Scoping Review of Prenatal Care Resources for Families of Children With Spinal Dysraphism and Hydrocephalus in High-Income Countries and Low- and Middle-Income Countries.

BACKGROUND AND OBJECTIVES: Low- and middle-income countries (LMICs) face higher incidences and burdens of care for neural tube defects (NTDs) and hydrocephalus compared with high-income countries (HICs), in part due to limited access to neurosurgical intervention. In this scoping review, we aim to integrate studies on prenatal care, counseling, and surgical management for families of children with spinal dysraphism and hydrocephalus in LMICs and HICs. METHODS: PubMed, Embase, Global Index Medicus, and Web of Science electronic databases were searched for English language articles pertaining to prenatal care, counseling, and surgical management for families of children with spinal dysraphism and hydrocephalus in HICs and LMICs. Identified abstracts were screened for full-text review. Studies meeting inclusion criteria were reviewed in full and analyzed. RESULTS: Seventy studies met the inclusion criteria. Twelve studies (16.9%) were conducted in HICs only, 50 studies (70.4%) were conducted in LMICs only, and 9 studies (12.7%) encompassed both. On thematic analysis, seven underlying topics were identified: epidemiology, folate deficiency and supplementation/fortification, risk factors other than folate deficiency, prenatal screening, attitudes and perceptions about NTDs and their care, surgical management, and recommendations for guideline implementation. CONCLUSION: NTDs have become a widely acknowledged public health problem in many LMICs. Prenatal counseling and care and folate fortification are critical in the prevention of spinal dysraphism. However, high-quality, standardized studies reporting their epidemiology, prevention, and management remain scarce. Compared with NTDs, research on the prevention and screening of hydrocephalus is even further limited. Future studies are necessary to quantify the burden of disease and identify strategies for improving global outcomes in treating and reducing the prevalence of NTDs and hydrocephalus. Surgical management of NTDs in LMICs is currently limited, but pediatric neurosurgeons may be uniquely equipped to address disparities in the care and counseling of families of children with spinal dysraphism and hydrocephalus.

Long-Term Neuropsychiatric, Neurocognitive, and Functional Outcomes of Patients Receiving ECMO: A Systematic Review and Meta-Analysis

BACKGROUND AND OBJECTIVES: Despite the common occurrence of neurologic complications during extracorporeal membrane oxygenation (ECMO) support, data on long-term neuropsychiatric, neurocognitive, and functional outcomes are sparse. We aimed to determine the prevalence of long-term neuropsychiatric symptoms, neurocognitive and functional impairment, and favorable neurologic outcomes in adult patients who receive ECMO. METHODS: PubMed, Embase, Cochrane, Web of Science, and Scopus were searched for text related to ECMO and neuropsychiatric, neurocognitive, and functional outcomes from inception to May 3, 2023. Our primary outcome was the prevalence of neuropsychiatric symptoms (pain/discomfort, anxiety, depression, posttraumatic stress disorder [PTSD], and sleep disturbance) at long-term (≥6 months) follow-up. Our secondary outcomes were the prevalence of neurocognitive impairment (memory, attention, and reasoning), functional impairment (daily activities, physical activity/mobility, and personal/self-care), and favorable neurologic outcomes (Cerebral Performance Category ≤2, modified Rankin scale ≤3, or Glasgow Outcome Scale ≥4). This study was registered in PROSPERO (CRD42023420565). RESULTS: We included 59 studies with 3,280 patients (median age 54 years, 69% male). The cohort consisted of 86% venoarterial (VA)-ECMO (n = 2,819) and 14% venovenous (VV)-ECMO (n = 461) patients. More than 10 tools were used to assess neuropsychiatric and neurocognitive outcomes, indicating a lack of standardization in assessment methodologies. The overall prevalence of neuropsychiatric symptoms was 41% (95% CI 33%-49%): pain/discomfort (52%, 95% CI 42%-63%), sleep disturbance (37%, 95% CI 0%-98%), anxiety (36%, 95% CI 27%-46%), depression (31%, 95% CI 22%-40%), and PTSD (18%, 95% CI 9%-29%). The prevalence of neurocognitive impairment was 38% (95% CI 13%-65%). The prevalence of functional impairment was 52% (95% CI 40%-64%): daily activities (54%, 95% CI 41%-66%), mobility (41%, 95% CI 28%-54%), and self-care (21%, 95% CI 13%-31%). The prevalence of neuropsychiatric symptoms in VV-ECMO patients was higher than that in VA-ECMO patients (55% [95% CI 34%-75%] vs 32% [95% CI 23%-41%], p = 0.01), though the prevalence of neurocognitive and functional impairment was not different between the groups. The prevalence of favorable neurologic outcomes was not different at various follow-ups: 3 months (23%, 95% CI 12%-36%), 6 months (25%, 95% CI 16%-35%), and ≥1 year (28%, 95% CI 21%-36%, p = 0.68). DISCUSSION: A substantial proportion of ECMO patients seemed to experience neuropsychiatric symptoms and neurocognitive and functional impairments at long-term follow-up. Considerable heterogeneity in methodology for gauging these outcomes exists, warranting the need for standardization. Multicenter prospective observational studies are indicated to further investigate risk factors for these outcomes in ECMO-supported patients.

Understanding the Ghanaian Neurosurgical Literature: A Scoping Review and Bibliometric Analysis.

BACKGROUND: Research serves to bolster clinical neurosurgery by critically assessing various disease pathologies, while identifying important challenges and opportunities. However, there is limited information on the landscape of the Ghanaian neurosurgical literature. METHODS: A scoping review and bibliometric analysis was conducted in accordance with PRISMA guidelines. PubMed, Embase, Global Index Medicus, and Web of Science electronic databases were searched from inception until December 21, 2021 for English language articles about neurosurgery in Ghana. RESULTS: 927 articles were identified and 66 were ultimately included in the analysis. A majority of them, 42.4%, were retrospective cohort studies, with 62.1% published after 2010. There were no randomized controlled or basic science studies. Most articles were published in the West African Journal of Medicine (24.2%) and non-infectious/non-traumatic spinal pathology was the most commonly discussed topic (22.7%); 66.7% of articles included only authors affiliated with Ghanaian institutions, and international collaborators frequently originated from the United States (15.9%). Only 22.7% of the manuscripts reported a funding source. Commonly reported challenges included limited sample sizes, delays in diagnosis and treatment, and lack of proper diagnostic tools and specialized care. CONCLUSIONS: This review revealed that while the Ghanaian academic neurosurgery output has been increasing over time, these have been limited to cohort studies largely assessing spine pathology. The Ghanaian neurosurgical research environment may be bolstered by an increase in research funding, the establishment of longitudinal clinical databases, training in research methodology, increased incentives for researchers, strengthening of research collaborative networks, and increased engagement of neurosurgical trainees in research.

A recommended preclinical extracorporeal cardiopulmonary resuscitation model for neurological outcomes: A scoping review.

Background: Despite the high prevalence of neurological complications and mortality associated with extracorporeal cardiopulmonary resuscitation (ECPR), neurologically-focused animal models are scarce. Our objective is to review current ECPR models investigating neurological outcomes and identify key elements for a recommended model. Methods: We searched PubMed and four other engines for animal ECPR studies examining neurological outcomes. Inclusion criteria were: animals experiencing cardiac arrest, ECPR/ECMO interventions, comparisons of short versus long cardiac arrest times, and neurological outcomes. Results: Among 20 identified ECPR animal studies (n = 442), 13 pigs, 4 dogs, and 3 rats were used. Only 10% (2/20) included both sexes. Significant heterogeneity was observed in experimental protocols. 90% (18/20) employed peripheral VA-ECMO cannulation and 55% (11/20) were survival models (median survival = 168 hours; ECMO duration = 60 minutes). Ventricular fibrillation (18/20, 90%) was the most common method for inducing cardiac arrest with a median duration of 15 minutes (IQR = 6-20). In two studies, cardiac arrests exceeding 15 minutes led to considerable mortality and neurological impairment. Among seven studies utilizing neuromonitoring tools, only four employed multimodal devices to evaluate cerebral blood flow using Transcranial Doppler ultrasound and near-infrared spectroscopy, brain tissue oxygenation, and intracranial pressure. None examined cerebral autoregulation or neurovascular coupling. Conclusions: The substantial heterogeneity in ECPR preclinical model protocols leads to limited reproducibility and multiple challenges. The recommended model includes large animals with both sexes, standardized pre-operative protocols, a cardiac arrest time between 10-15 minutes, use of multimodal methods to evaluate neurological outcomes, and the ability to survive animals after conducting experiments.