Interspecies comparison of the early transcriptomic changes associated with hepatitis B virus exposure in human and macaque immune cell populations.

Background and aims: Hepatitis B virus (HBV) infection affects 300 million individuals worldwide, representing a major factor for the development of hepatic complications. Although existing antivirals are effective in suppressing replication, eradication of HBV is not achieved. Therefore, a multi-faceted approach involving antivirals and immunomodulatory agents is required. Non-human primates are widely used in pre-clinical studies due to their close evolutionary relationship to humans. Nonetheless, it is fundamental to identify the differences in immune response between humans and these models. Thus, we performed a transcriptomic characterization and interspecies comparison of the early immune responses to HBV in human and cynomolgus macaques. Methods: We characterized early transcriptomic changes in human and cynomolgus B cells, T cells, myeloid and plasmacytoid dendritic cells (pDC) exposed to HBV ex vivo for 2 hours. Differentially-expressed genes were further compared to the profiles of HBV-infected patients using publicly-available single-cell data. Results: HBV induced a wide variety of transcriptional changes in all cell types, with common genes between species representing only a small proportion. In particular, interferon gamma signaling was repressed in human pDCs. At the gene level, interferon gamma inducible protein 16 (IFI16) was upregulated in macaque pDCs, while downregulated in humans. Moreover, IFI16 expression in pDCs from chronic HBV-infected patients anti-paralleled serum HBsAg levels. Conclusion: Our characterization of early transcriptomic changes induced by HBV in humans and cynomolgus macaques represents a useful resource for the identification of shared and divergent host responses, as well as potential immune targets against HBV.

A standardized gnotobiotic mouse model harboring a minimal 15-member mouse gut microbiota recapitulates SOPF/SPF phenotypes.

Mus musculus is the classic mammalian model for biomedical research. Despite global efforts to standardize breeding and experimental procedures, the undefined composition and interindividual diversity of the microbiota of laboratory mice remains a limitation. In an attempt to standardize the gut microbiome in preclinical mouse studies, here we report the development of a simplified mouse microbiota composed of 15 strains from 7 of the 20 most prevalent bacterial families representative of the fecal microbiota of C57BL/6J Specific (and Opportunistic) Pathogen-Free (SPF/SOPF) animals and the derivation of a standardized gnotobiotic mouse model called GM15. GM15 recapitulates extensively the functionalities found in the C57BL/6J SOPF microbiota metagenome, and GM15 animals are phenotypically similar to SOPF or SPF animals in two different facilities. They are also less sensitive to the deleterious effects of post-weaning malnutrition. In this work, we show that the GM15 model provides increased reproducibility and robustness of preclinical studies by limiting the confounding effect of fluctuation in microbiota composition, and offers opportunities for research focused on how the microbiota shapes host physiology in health and disease.

Characterization and analytical validation of a new antigenic rapid diagnostic test for Ebola virus disease detection.

Hemorrhagic fever outbreaks are difficult to diagnose and control in part because of a lack of low-cost and easily accessible diagnostic structures in countries where etiologic agents are present. Furthermore, initial clinical symptoms are common and shared with other endemic diseases such as malaria or typhoid fever. Current molecular diagnostic methods such as polymerase chain reaction require trained personnel and laboratory infrastructure, hindering diagnostics at the point of need, particularly in outbreak settings. Therefore, rapid diagnostic tests such as lateral flow can be broadly deployed and are typically well-suited to rapidly diagnose hemorrhagic fever viruses, such as Ebola virus. Early detection and control of Ebola outbreaks require simple, easy-to-use assays that can detect very low amount of virus in blood. Here, we developed and characterized an immunoassay test based on immunochromatography coupled to silver amplification technology to detect the secreted glycoprotein of EBOV. The glycoprotein is among the first viral proteins to be detected in blood. This strategy aims at identifying infected patients early following onset of symptoms by detecting low amount of sGP protein in blood samples. The limit of detection achieved by this sGP-targeted kit is 2.2 x 104 genome copies/ml in plasma as assayed in a monkey analytical cohort. Clinical performance evaluation showed a specificity of 100% and a sensitivity of 85.7% when evaluated with plasma samples from healthy controls and patients infected with Zaire Ebola virus from Macenta, Guinea. This rapid and accurate diagnostic test could therefore be used in endemic countries for early detection of infected individuals in point of care settings. Moreover, it could also support efficient clinical triage in hospitals or clinical centers and thus reducing transmission rates to prevent and better manage future severe outbreaks.

The Montreal Cognitive Assessment in persons with traumatic brain injury.

The objective of this study was to examine the performance of patients with traumatic brain injury (TBI) on the Montreal Cognitive Assessment (MoCA). The MoCA was administered to 214 patients with TBI during their acute care hospitalization in a Level 1 trauma center. The results showed that patients with severe TBI had lower scores on the MoCA compared with patients with mild and moderate TBI, F(2, 211) = 10.35, p = .0001. This difference was found for visuospatial/executive, attention, and orientation subtests (p < .05). Linear regression demonstrated that age, education, TBI severity, and the presence of neurological antecedents were the best predictors of cognitive impairments explaining 42% of the total variability of the MoCA. This information can enable clinicians to predict early cognitive impairments and plan cognitive rehabilitation earlier in the recovery process.

Early conversational discourse abilities following traumatic brain injury: an acute predictive study.

PRIMARY OBJECTIVE: To date, little information is available regarding communication and conversational discourse proficiency post-traumatic brain injury (TBI) in the acute care phase. The main goal of this study was to examine how conversational discourse impairment following TBI predicts early outcome. Factors which influence conversational discourse performance were also explored. METHODS: The conversational discourse checklist of the Protocole Montréal d'évaluation de la communication (D-MEC) was administered in an acute tertiary care trauma centre to 195 adults within 3 weeks post-TBI. Outcome was measured with the Disability Rating Scale (DRS), the extended Glasgow Outcome Scale (GOS-E) and included discharge destinations from acute care. MAIN OUTCOMES AND RESULTS: Linear regression results showed that the D-MEC total score, age and initial GCS score accounted for 50% of the variation of the DRS scores. The DRS score was lower, signifying better outcome, when the total D-MEC score was higher, the subject was younger and when the initial GCS score was higher. Moreover, D-MEC performance significantly predicted the moderate and severe disability categories of the GOS-E and the probability of requiring rehabilitation (p < 0.05). CONCLUSION: These results provide additional information to guide healthcare professionals in predicting overall outcome acutely post-TBI.

Acute evaluation of conversational discourse skills in traumatic brain injury.

This study looked at performance on the conversational discourse checklist of the Protocole Montréal d'évaluation de la communication (D-MEC) in 195 adults with TBI of all severity hospitalized in a Level 1 Trauma Centre. To explore validity, results were compared to findings on tests of memory, mental flexibility, confrontation naming, semantic and letter category naming, verbal reasoning, and to scores on the Montreal Cognitive Assessment. The relationship to outcome as measured with the Disability Rating Scale (DRS), the Extended Glasgow Outcome Scale (GOS-E), length of stay, and discharge destinations was also determined. Patients with severe TBI performed significantly worse than mild and moderate groups (χ(2)(KW2df) = 24.435, p = .0001). The total D-MEC score correlated significantly with all cognitive and language measures (p < .05). It also had a significant moderate correlation with the DRS total score (r = -.6090, p < .0001) and the GOS-E score (r = .539, p < .0001), indicating that better performance on conversational discourse was associated with a lower disability rating and better global outcome. Finally, the total D-MEC score was significantly different between the discharge destination groups (F(3,90) = 20.19, p < .0001). Thus, early identification of conversational discourse impairment in acute care post-TBI was possible with the D-MEC and could allow for early intervention in speech-language pathology.

The mini-mental state examination and the Montreal Cognitive Assessment after traumatic brain injury: an early predictive study.

PRIMARY OBJECTIVE: To compare results on the Montreal Cognitive Assessment (MoCA) to those on the Mini-Mental State Examination (MMSE) in patients with traumatic brain injury (TBI) and to predict the outcome at discharge from the acute care setting. RESEARCH DESIGN: A retrospective study. METHODS AND PROCEDURES: The MoCA and the MMSE were administered to 214 patients with TBI during their acute care hospitalization in a Level I trauma centre. Outcome was measured with the Disability Rating Scale (DRS). MAIN OUTCOMES AND RESULTS: A linear regression determined that the MoCA, the MMSE, TBI severity, education level and presence of diffuse injuries predicted 57% of the total variability of the DRS scores. The model without the MMSE had a R2 of 53.7% and the model without the MoCA had a R2 of 55.0%. The models without the MMSE or the MoCA had a R2 of 24.9%. CONCLUSIONS: These results indicated that the MoCA and the MMSE function as similar predictors of the DRS at discharge.

Criterion validity of a functional cognitive task in patients with severe traumatic brain injury.

PRIMARY OBJECTIVE: To verify criterion validity of measures from a functional cognitive task (FCT) carried out with patients with severe traumatic brain injury (sTBI) at 2-5 years post-injury. METHODS AND PROCEDURES: Forty-six patients with sTBI took part in a long-term outcome study where the FCT and the Neurobehavioural Rating Scale-Revised (NBRS-R) were administered and the FIM™ instrument was rated. The FCT is a telephone information gathering task for evaluating functional cognitive skills. RESULTS: Ten of 16 measures of the FCT were significantly correlated with similar or related concepts from the NBRS-R. The FIM™ cognitive score and the individual items of this score were significantly correlated with 13 of the FCT measures and with the percentage of amount of information gathered. Internal consistency was good for 13 of 16 measures. Overall, patients generally had mild difficulty on the FCT concepts. CONCLUSION: The FCT can be used with patients with sTBI to evaluate certain aspects of functional cognition. It has good criterion validity and internal consistency, but additional research is required to further measure reliability and its applicability to other severity of TBI and to other phases of recovery.

Clock drawing and mini-mental state examination in patients with traumatic brain injury.

The aim of this study was to compare the performances of patients with mild, moderate, and severe traumatic brain injury (TBI) on the Clock Drawing Test (CDT), the Mini-Mental State Examination (MMSE), and neuropsychological measures as well as to correlate these measures with outcome assessed by the Extended Glasgow Outcome Score. This study was conducted in an acute care early rehabilitation setting on 102 patients with mild, 30 with moderate, and 30 with severe TBI. Patients with moderate and severe TBI showed more impairment on the CDT compared with those with mild TBI. Similar results were obtained for the MMSE, F ((2,159df)) = 3.789, p = .025. Finally, a receiver-operating characteristic analysis showed that the CDT and the Trail-Making Test-Part B (TMT-B) in combination have the potential for prediction of outcome in a TBI population. In conclusion, this combination of the CDT and the TMT-B seems to be useful for early assessment of TBI patients.

Neuroanatomical correlates of the clock drawing test in patients with traumatic brain injury.

OBJECTIVE: The clock drawing test (CDT) is a quick and easy to administer test that has traditionally shown parietal lobe dysfunction. The aim of this study was to correlate performance on the CDT with the presence of acute traumatic cerebral injuries sustained after traumatic brain injury (TBI). METHODS: A retrospective study was conducted on 170 patients with TBI of all severity admitted to an acute care setting. These patients sustained different types of injuries (epidural haematoma, subdural haematoma, subarachnoid haemorrhage, intraparenchymal haematoma and brain oedema) in different sites (frontal, temporal, parietal, occipital lobes, bilateral and right or left hemisphere). RESULTS: The CDT total score was significantly lower for subjects presenting subarachnoid haemorrhage (4.80 ± 3.34 vs 7.04 ± 3.14, t(168df) = 4.477, p < 0.001) and for those presenting brain oedema (4.50 ± 3.06 vs 6.69 ± 3.38, t(168df) = 4.214, p < 0.001), parietal injury (5.15 ± 3.17 vs 6.42 ± 3.52, t(168df) = 2.416, p = 0.017) or bilateral injuries (5.28 ± 3.31 vs 6.62 ± 3.44, t(168df) = 2.569, p = 0.011) compared to those who did not. CONCLUSION: This study provides empirical evidence of the relationship between TBIs and results on the CDT, supporting previous studies done with other populations.

Long-term outcome after severe traumatic brain injury: the McGill interdisciplinary prospective study.

OBJECTIVE: To obtain a comprehensive understanding of long-term outcome after severe traumatic brain injury (sTBI). PARTICIPANTS: Forty-six patients with sTBI. DESIGN: Comparison of interdisciplinary evaluation results at discharge from acute care and at 2 to 5 year follow-up. MAIN MEASURES: Extended Glasgow Outcome Scale, the FIM instrument, and the Neurobehavioral Rating Scale-Revised. RESULTS: Significant improvement was observed on the FIM instrument, the Extended Glasgow Outcome Scale, and on 3 factors of the Neurobehavioral Rating Scale-Revised. These measures at discharge were significant predictors of outcome. CONCLUSION: Patients with sTBI 2 to 5 years postinjury showed relatively good physical and functional outcome but poorer cognitive and emotional outcome.

Meeting the nutritional needs of patients with severe dysphagia following a stroke: an interdisciplinary approach.

Dysphagia is a common problem with individuals who have experienced a stroke. The interdisciplinary stroke team noted delays in clinical decision-making, or in implementing plans for patients with severe dysphagia requiring an alternative method to oral feeding, such as enteral feeding via Dobhoff (naso-jejunum) or PEG (percutaneous endoscopic gastrostomy) tubes, occurred because protocols had not been established. This resulted in undernourishment, which in turn contributed to clinical problems, such as infections and confusion, which delayed rehabilitation and contributed to excess disability. The goal of the project was to improve quality of care and quality of life for stroke patients experiencing swallowing problems by creating a dysphagia management decision-making process. The project began with a retrospective chart review of 91 cases over a period of six months to describe the population characteristics, dysphagia frequency, stroke and dysphagia severity, and delays encountered with decision-making regarding dysphagia management. A literature search was conducted, and experts in the field were consulted to provide current knowledge prior to beginning the project. Using descriptive statistics, dysphagia was present in 44% of the stroke population and 69% had mild to moderate stroke severity deficit. Delays were found in the decision to insert a PEG (mean 10 days) and the time between decision and PEG insertion (mean 12 days). Critical periods were examined in order to speed up the process of decision-making and intervention. This resulted in the creation of a decision-making algorithm based on stroke and dysphagia severity that will be tested during winter 2002.