Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model.

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

Dual Inhibition of Human Parainfluenza Type 3 and Respiratory Syncytial Virus Infectivity with a Single Agent.

Human parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) cause lower respiratory infection in infants and young children. There are no vaccines for these pathogens, and existing treatments have limited or questionable efficacy. Infection by HPIV3 or RSV requires fusion of the viral and cell membranes, a process mediated by a trimeric fusion glycoprotein (F) displayed on the viral envelope. Once triggered, the pre-fusion form of F undergoes a series of conformational changes that first extend the molecule to allow for insertion of the hydrophobic fusion peptide into the target cell membrane and then refold the trimeric assembly into an energetically stable post-fusion state, a process that drives the merger of the viral and host cell membranes. Peptides derived from defined regions of HPIV3 F inhibit infection by HPIV3 by interfering with the structural transitions of the trimeric F assembly. Here we describe lipopeptides derived from the C-terminal heptad repeat (HRC) domain of HPIV3 F that potently inhibit infection by both HPIV3 and RSV. The lead peptide inhibits RSV infection as effectively as does a peptide corresponding to the RSV HRC domain itself. We show that the inhibitors bind to the N-terminal heptad repeat (HRN) domains of both HPIV3 and RSV F with high affinity. Co-crystal structures of inhibitors bound to the HRN domains of HPIV3 or RSV F reveal remarkably different modes of binding in the N-terminal segment of the inhibitor.

Longitudinal study evaluating post-ICU syndrome differences between acute care surgery and trauma SICU survivors.

BACKGROUND: Post-intensive care unit (ICU) syndrome (PICS) occurs at an exorbitant rate in surgical ICU (SICU) survivors. It remains unknown if critical illness due to trauma versus acute care surgery (ACS) may represent different pathophysiologic entities. In this longitudinal study, we determined if admission criteria in a cohort of trauma and ACS patients were associated with differences in the occurrence of PICS. METHODS: Patients were 18 years or older, admitted to a Level I trauma center to the trauma or ACS services, remained in the SICU for ≥72 hours, and were seen in an ICU Recovery Center at 2 weeks, 12 weeks, and 24 weeks after hospital discharge. Post-ICU syndrome sequelae were diagnosed by dedicated specialist staffing using clinical criteria and screening questionnaires. The PICS symptoms were distilled into physical, cognitive, and psychiatric categories. Preadmission histories, hospital courses, and recovery data were collected via retrospective chart review. RESULTS: One hundred twenty-six patients were included: 74 (57.3%) trauma patients and 55 (42.6%) ACS patients. Prehospital psychosocial histories were similar between groups. Acute care surgery patients had a significantly longer hospital course, higher APACHE II and III scores, were intubated for longer, and had higher rates of sepsis, acute renal failure, open abdomen, and hospital readmissions. At the 2-week follow-up visit, ACS patients had higher rates of PICS sequelae (ACS, 97.8% vs. trauma 85.3%; p = 0.03), particularly in the physical (ACS, 95.6% vs. trauma 82.0%, p = 0.04), and psychiatric domains (ACS, 55.6% vs. trauma 35.0%, p = 0.04). At the 12-week and 24-week visits, rates of PICS symptoms were comparable between groups. CONCLUSION: The occurrence of PICS is extraordinarily high in both trauma and ACS SICU survivors. Despite entering the SICU with similar psychosocial histories, the two cohorts have different pathophysiologic experiences, which are associated with a higher rate of impairment in the ACS patients during early follow-up. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

High occurrence of postintensive care syndrome identified in surgical ICU survivors after implementation of a multidisciplinary clinic.

BACKGROUND: Postintensive care syndrome (PICS) has been identified in a large proportion of medical intensive care unit survivors; however, the occurrence surgical intensive care unit (SICU) survivors is unknown. We implemented a multidisciplinary critical care outpatient clinic (CCOC) to identify the occurrence of PICS in SICU survivors. METHODS: Seventy acute care surgery and trauma patients, 18 years or older, who remained in the SICU for 72 hours or longer at a Level I trauma center were seen in CCOC at 2 weeks, 12 weeks, and 24 weeks after hospital discharge. The CCOC staffing included a nurse coordinator, social worker, critical care pharmacist, physical therapist, and acute care surgeon who identified PICS sequelae in their respective specialties by clinical criteria and screening questionnaires. RESULTS: Of 82 eligible patients, 70 (85.4%) were seen at least once for 116 total visits. Forty-three (61.4%) patients suffered traumatic injuries and 27 (38.6%) underwent emergent general surgery. Sixty-seven (95.7%) demonstrated at least one PICS criterion. Over all visits, 26 (37.1%) patients presented with one PICS criterion, 24 (34.3%) patients with two, and 17 (24.3%) with three. Cognitive impairment was observed in 29 (41.4%) patients, psychiatric in 30 (42.9%), and physical symptoms in 65 (92.9%). Activity Measure for Post-Acute Care scores improved from severe impairment at admission to full function by 12 weeks postdischarge, yet 6 Minute Walk Test scores remained below age-matched references through all visits. Patients expressed mild to moderate depression based on Patient Health Questionnaire-9 scores. A medication reconciliation was completed at 96.5% (112/116) of the visits with 116 total medication recommendations. By 24 weeks following discharge, only 26.4% (14/53) of previously employed patients had resumed work. CONCLUSION: Through the successful implementation of a multidisciplinary CCOC, this study identifies an exorbitant rate of PICS among SICU survivors. LEVEL OF EVIDENCE: Therapeutic/epidemiological, level III.