Brimonidine eye drops reveal diminished sympathetic pupillary tone in comatose patients with brain injury.

BACKGROUND: There is an urgent need for easy-to-perform bedside measures to detect residual consciousness in clinically unresponsive patients with acute brain injury. Interestingly, the sympathetic control of pupil size is thought to be lost in states of unconsciousness. We therefore hypothesized that administration of brimonidine (an alpha-2-adrenergic agonist) eye drops into one eye should produce a pharmacologic Horner's syndrome if the clinically unresponsive patient is conscious, but not if the patient is unconscious. Here, in a first step to explore this hypothesis, we investigated the potential of brimonidine eye drops to distinguish preserved sympathetic pupillary function in awake volunteers from impairment of sympathetic tone in patients in a coma. METHODS: We enrolled comatose patients admitted for acute brain injury to one of the intensive care units (ICU) of a tertiary referral center, in whom EEG and/or neuroimaging for all practical purposes had ruled out residual consciousness. Exclusion criteria were deep sedation, medications with known drug interactions with brimonidine, and a history of eye disease. Age- and sex-matched healthy and awake volunteers served as controls. We measured pupils of both eyes, under scotopic conditions, at baseline and five times 5-120 min after administering brimonidine into the right eye, using automated pupillometry. Primary outcomes were miosis and anisocoria at the individual and group levels. RESULTS: We included 15 comatose ICU patients (seven women, mean age 59 ± 13.8 years) and 15 controls (seven women, mean age 55 ± 16.3 years). At 30 min, miosis and anisocoria were seen in all 15 controls (mean difference between the brimonidine-treated pupil and the control pupil: - 1.31 mm, 95% CI [- 1.51; - 1.11], p < 0.001), but in none (p < 0.001) of the 15 ICU patients (mean difference: 0.09 mm, 95% CI [- 0.12;0.30], p > 0.99). This effect was unchanged after 120 min and remained robust in sensitivity analyses correcting for baseline pupil size, age, and room illuminance. CONCLUSION: In this proof-of-principle study, brimonidine eye drops produced anisocoria in awake volunteers but not in comatose patients with brain injury. This suggests that automated pupillometry after administration of brimonidine can distinguish between the extremes of the spectrum of consciousness (i.e., fully conscious vs. deeply comatose). A larger study testing the "intermediate zone" of disorders of consciousness in the ICU seems warranted.

Understanding, detecting, and stimulating consciousness recovery in the ICU.

Coma is a medical and socioeconomic emergency. Although underfunded, research on coma and disorders of consciousness has made impressive progress. Lesion-network-mapping studies have delineated the precise brainstem regions that consistently produce coma when damaged. Functional neuroimaging has revealed how mechanisms like "communication through coherence" and "inhibition by gating" work in synergy to enable cortico-cortical processing and how this information transfer is disrupted in brain injury. On the cellular level, break-down of intracellular communication between the layer 5 pyramidal cell soma and the apical dendritic part impairs dendritic information integration, with up-stream effects on microcircuits in local neuronal populations and on large-scale fronto-parietal networks, which correlates with loss of consciousness. A breakthrough in clinical concepts occurred when fMRI, and later EEG, studies revealed that 15% of clinically unresponsive patients in acute and chronic settings are in fact awake and aware, as shown by their command following abilities revealed by brain activation during motor and locomotion imagery tasks. This condition is now termed "cognitive motor dissociation." Furthermore, epidemiological data on coma were literally non-existent until recently because of difficulties related to case ascertainment with traditional methods, but crowdsourcing of family observations enabled the first estimates of how frequent coma is in the general population (pooled annual incidence of 201 coma cases per 100,000 population in the UK and the USA). Diagnostic guidelines on coma and disorders of consciousness by the American Academy of Neurology and the European Academy of Neurology provide ambitious clinical frameworks to accommodate these achievements. As for therapy, a broad range of medical and non-medical treatment options is now being tested in increasingly larger trials; in particular, amantadine and transcranial direct current stimulation appear promising in this regard. Major international initiatives like the Curing Coma Campaign aim to raise awareness for coma and disorders of consciousness in the public, with the ultimate goal to make more brain-injured patients recover consciousness after a coma. To highlight all these accomplishments, this paper provides a comprehensive overview of recent progress and future challenges related to understanding, detecting, and stimulating consciousness recovery in the ICU.

Multimodal prediction of residual consciousness in the intensive care unit: the CONNECT-ME study.

Functional MRI (fMRI) and EEG may reveal residual consciousness in patients with disorders of consciousness (DoC), as reflected by a rapidly expanding literature on chronic DoC. However, acute DoC is rarely investigated, although identifying residual consciousness is key to clinical decision-making in the intensive care unit (ICU). Therefore, the objective of the prospective, observational, tertiary centre cohort, diagnostic phase IIb study 'Consciousness in neurocritical care cohort study using EEG and fMRI' (CONNECT-ME, NCT02644265) was to assess the accuracy of fMRI and EEG to identify residual consciousness in acute DoC in the ICU. Between April 2016 and November 2020, 87 acute DoC patients with traumatic or non-traumatic brain injury were examined with repeated clinical assessments, fMRI and EEG. Resting-state EEG and EEG with external stimulations were evaluated by visual analysis, spectral band analysis and a Support Vector Machine (SVM) consciousness classifier. In addition, within- and between-network resting-state connectivity for canonical resting-state fMRI networks was assessed. Next, we used EEG and fMRI data at study enrolment in two different machine-learning algorithms (Random Forest and SVM with a linear kernel) to distinguish patients in a minimally conscious state or better (≥MCS) from those in coma or unresponsive wakefulness state (≤UWS) at time of study enrolment and at ICU discharge (or before death). Prediction performances were assessed with area under the curve (AUC). Of 87 DoC patients (mean age, 50.0 ± 18 years, 43% female), 51 (59%) were ≤UWS and 36 (41%) were ≥ MCS at study enrolment. Thirty-one (36%) patients died in the ICU, including 28 who had life-sustaining therapy withdrawn. EEG and fMRI predicted consciousness levels at study enrolment and ICU discharge, with maximum AUCs of 0.79 (95% CI 0.77-0.80) and 0.71 (95% CI 0.77-0.80), respectively. Models based on combined EEG and fMRI features predicted consciousness levels at study enrolment and ICU discharge with maximum AUCs of 0.78 (95% CI 0.71-0.86) and 0.83 (95% CI 0.75-0.89), respectively, with improved positive predictive value and sensitivity. Overall, both machine-learning algorithms (SVM and Random Forest) performed equally well. In conclusion, we suggest that acute DoC prediction models in the ICU be based on a combination of fMRI and EEG features, regardless of the machine-learning algorithm used.

The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas.

Glioblastoma multiforme is the most common primary brain tumor and among the most lethal types of cancer. Several mono-target small molecule-inhibitors have been investigated as novel therapeutics, thus far with poor success. In this study we investigated the anticancer effects of SB747651A, a multi-target small-molecule inhibitor, in three well characterized patient-derived glioblastoma spheroid cultures and a murine orthotopic xenograft model. Concentrations of 5-10 µM SB747651A reduced cell proliferation, spheroid formation, migration and chemoresistance, while apoptotic cell death increased. Investigation of oncogenic kinase signaling showed decreased phosphorylation levels of mTOR, CREB, GSK3 and GYS1 leading to altered glycogen metabolism and formation of intracellular reactive oxygen species. Expression levels of cancer stemness marker SOX2 were reduced in treated tumor cells and SB747651A treatment significantly prolonged survival of mice with intracranial glioblastoma xenografts, while no adverse effects were observed in vivo at doses of 25 mg/kg administered 5 days/week for 8 weeks. These findings suggest that SB747651A has anticancer effects in glioblastoma. The cancer-related pathophysiological mechanisms targeted by SB747651A are shared among many types of cancer; however, an in-depth clarification of the mechanisms of action in cancer cells is important before further potential application of SB747651A as an anticancer agent can be considered.

FightHPV: Design and Evaluation of a Mobile Game to Raise Awareness About Human Papillomavirus and Nudge People to Take Action Against Cervical Cancer.

BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted infection globally. High-risk HPV types can cause cervical cancer, other anogenital cancer, and oropharyngeal cancer; low-risk HPV types can cause genital warts. Cervical cancer is highly preventable through HPV vaccination and screening; however, a lack of awareness and knowledge of HPV and these preventive strategies represents an important barrier to reducing the burden of the disease. The rapid development and widespread use of mobile technologies in the last few years present an opportunity to overcome this lack of knowledge and create new, effective, and modern health communication strategies. OBJECTIVE: This study aimed to describe the development of a mobile app called FightHPV, a game-based learning tool that educates mobile technology users about HPV, the disease risks associated with HPV infection, and existing preventive methods. METHODS: The first version of FightHPV was improved in a design-development-evaluation loop, which incorporated feedback from a beta testing study of 40 participants, a first focus group of 6 participants aged between 40 and 50 years and a second focus group of 23 participants aged between 16 and 18 years. Gameplay data from the beta testing study were collected using Google Analytics (Google), whereas feedback from focus groups was evaluated qualitatively. Of the 29 focus group participants, 26 returned self-administered questionnaires. HPV knowledge before and after playing the game was evaluated in the 22 participants from the second focus group who returned a questionnaire. RESULTS: FightHPV communicates concepts about HPV, associated diseases and their prevention by representing relationships among 14 characters in 6 episodes of 10 levels each, with each level being represented by a puzzle. Main concepts were reinforced with text explanations. Beta testing revealed that many players either failed or had to retry several times before succeeding at the more difficult levels in the game. It also revealed that players gave up at around level 47 of 60, which prompted the redesign of FightHPV to increase accessibility to all episodes. Focus group discussions led to several improvements in the user experience and dissemination of health information in the game, such as making all episodes available from the beginning of the game and rewriting the information in a more appealing way. Among the 26 focus group participants who returned a questionnaire, all stated that FightHPV is an appealing educational tool, 69% (18/26) reported that they liked the game, and 81% (21/26) stated that the game was challenging. We observed an increase in HPV knowledge after playing the game (P=.001). CONCLUSIONS: FightHPV was easy to access, use, and it increased awareness about HPV infection, its consequences, and preventive measures. FightHPV can be used to educate people to take action against HPV and cervical cancer.