Research into TBI biomarkers has accelerated rapidly in the past decade owing to the heterogeneous nature of TBI pathologies and management, which pose challenges to TBI evaluation, management, and prognosis. TBI biomarker proteins resulting from axonal, neuronal, or glial cell injuries are widely used and have been extensively studied. However, they might not pass the blood-brain barrier with sufficient amounts to be detected in peripheral blood specimens, and further might not be detectable in the cerebrospinal fluid owing to flow limitations triggered by the injury itself. Despite the advances in TBI research, there is an unmet clinical need to develop and identify novel TBI biomarkers that entirely correlate with TBI pathologies on the molecular level, including mild TBI, and further enable physicians to predict patient outcomes and allow researchers to test neuroprotective agents to limit the extents of injury. Although the extracellular vesicles have been identified and studied long ago, they have recently been revisited and repurposed as potential TBI biomarkers that overcome the many limitations of the traditional blood and CSF assays. Animal and human experiments demonstrated the accuracy of several types of exosomes and miRNAs in detecting mild, moderate, and severe TBI. In this paper, we provide a comprehensive review of the traditional TBI biomarkers that are helpful in clinical practice. Also, we highlight the emerging roles of exosomes and miRNA being the promising candidates under investigation of current research.

Clinical research usually involves patients with a certain disease or a condition. The generalizability of clinical research findings is based on multiple factors related to the internal and external validity of the research methods. The main methodological issue that influences the generalizability of clinical research findings is the sampling method. In this educational article, we are explaining the different sampling methods in clinical research.

Context: Caffeine is the most commonly used psychoactive legal drug in the world. Caffeine’s role in controlling pain has received less attention in the past, yet is being increasingly considered. This article briefly reviewed the literature to clarify the role of caffeine as a drug for pain control and attract investigators to this topic. Evidence Acquisition: The data on Caffeine as an adjuvant therapy or as a main component for pain modulation has been narratively reviewed. Results: Caffeine plays an important role in pain modulation through their action on adenosine receptors which are involved in nociception. The use of caffeine as adjuvant treatment was well-established in the literature and caffeine is currently available in some over the counter medications. Studies showed controversial results about the interaction between caffeine and morphine for pain relief in patients with terminal stage cancer. As a main component for pain modulation, Caffeine can be used for hypnic headache and postdural puncture headache. Conclusions: Caffeine has a potential role for pain modulation. Current evidence on caffeine use for migraine and terminal stage cancer is not well-established. Future studies should address the use of caffeine alone for different types of pain with dose escalation and standardization of outcome measurement. Keywords: Caffeine; Adenosine; Role; Pain Management