PLUS-IS-LESS project: Procalcitonin and Lung UltraSonography-based antibiotherapy in patients with Lower rESpiratory tract infection in Swiss Emergency Departments: study protocol for a pragmatic stepped-wedge cluster-randomized trial.

BACKGROUND: Lower respiratory tract infections (LRTIs) are among the most frequent infections and a significant contributor to inappropriate antibiotic prescription. Currently, no single diagnostic tool can reliably identify bacterial pneumonia. We thus evaluate a multimodal approach based on a clinical score, lung ultrasound (LUS), and the inflammatory biomarker, procalcitonin (PCT) to guide prescription of antibiotics. LUS outperforms chest X-ray in the identification of pneumonia, while PCT is known to be elevated in bacterial and/or severe infections. We propose a trial to test their synergistic potential in reducing antibiotic prescription while preserving patient safety in emergency departments (ED). METHODS: The PLUS-IS-LESS study is a pragmatic, stepped-wedge cluster-randomized, clinical trial conducted in 10 Swiss EDs. It assesses the PLUS algorithm, which combines a clinical prediction score, LUS, PCT, and a clinical severity score to guide antibiotics among adults with LRTIs, compared with usual care. The co-primary endpoints are the proportion of patients prescribed antibiotics and the proportion of patients with clinical failure by day 28. Secondary endpoints include measurement of change in quality of life, length of hospital stay, antibiotic-related side effects, barriers and facilitators to the implementation of the algorithm, cost-effectiveness of the intervention, and identification of patterns of pneumonia in LUS using machine learning. DISCUSSION: The PLUS algorithm aims to optimize prescription of antibiotics through improved diagnostic performance and maximization of physician adherence, while ensuring safety. It is based on previously validated tests and does therefore not expose participants to unforeseeable risks. Cluster randomization prevents cross-contamination between study groups, as physicians are not exposed to the intervention during or before the control period. The stepped-wedge implementation of the intervention allows effect calculation from both between- and within-cluster comparisons, which enhances statistical power and allows smaller sample size than a parallel cluster design. Moreover, it enables the training of all centers for the intervention, simplifying implementation if the results prove successful. The PLUS algorithm has the potential to improve the identification of LRTIs that would benefit from antibiotics. When scaled, the expected reduction in the proportion of antibiotics prescribed has the potential to not only decrease side effects and costs but also mitigate antibiotic resistance. TRIAL REGISTRATION: This study was registered on July 19, 2022, on the ClinicalTrials.gov registry using reference number: NCT05463406. TRIAL STATUS: Recruitment started on December 5, 2022, and will be completed on November 3, 2024. Current protocol version is version 3.0, dated April 3, 2023.

Unilateral orolingual angioedema in a patient with sarcoidosis after intravenous thrombolysis due to acute stroke without improvement after treatment with icatibant.

A potential complication after intravenous administration of recombinant tissue plasminogen activators (rtPAs) for thrombolysis in acute ischaemic stroke is orolingual angioedema, with an incidence of 0.4%-7.9%. In the herewith reported case, we discuss potential links between a history of sarcoidosis and the occurrence of orolingual angioedema after rtPA administration. Sarcoidosis is often accompanied by an elevated ACE level. In contrast, low ACE levels appear to play a role in the pathomechanism currently assumed to trigger angioedema, that is, the activation of the bradykinin and complement pathways. Medication with ACE inhibitors is considered a risk factor for angioedema. Based on these considerations, the patient was also treated with icatibant, a bradykinin B2-receptor antagonist, which has been found useful in recent publications on treating orolingual angioedema after intravenous lysis in ischaemic stroke.

Longitudinal study of a NoGo-P3 event-related potential component following mild traumatic brain injury in adults.

BACKGROUND: Event-related potentials have repeatedly revealed electrophysiological markers of cognitive dysfunction associated with Mild Traumatic Brain Injury (MTBI) and may represent a sensitive tool to guide cognitive rehabilitative interventions. We previously found patients with symptomatic MTBI characterized by smaller P300 (or P3) wave amplitudes in a NoGo-P3 subcomponent in the acute phase of the injury. The goal of this longitudinal study was to investigate whether this early NoGo-P3 subcomponent differs over time in symptomatic MTBI patients and healthy controls. METHODS: We included adults with a diagnosis of MTBI and individually matched healthy controls tested at 1 week, 3 months, and 1 year after the MTBI. Symptoms were assessed by the Rivermead Post-Concussion Symptoms Questionnaire. NoGo-P3 was collected by using a cued Go/NoGo task and the relevant subcomponent was extracted by independent component analysis. RESULTS: Among 53 adults with a diagnosis of MTBI and 53 controls, we included 35 with symptomatic MTBI and 35 matched healthy controls (18 females each group; mean age 34.06±13.15 and 34.26±12.98 years). Amplitudes for the early NoGo-P3 subcomponent were lower for symptomatic MTBI patients than controls (P<0.05) at 1 week post-injury. Furthermore, mixed ANOVA revealed a significant time by group interaction (P<0.05), so the effect of time differed for symptomatic MTBI patients and healthy controls. The amplitudes for MTBI patients normalized from 1 week to 3 months post-injury and were comparable to those of controls from 3 months to 1 year post-injury. However, amplitudes for 3 MTBI patients with particularly severe complaints 1 year post-injury did not normalize and were lower than those for the remaining MTBI sample (P<0.05). CONCLUSIONS: Selected event-related potentials can be used as a sensitive and objective tool to illustrate the cognitive consequences of and recovery after MTBI.

Prefrontal Cortical Thickening after Mild Traumatic Brain Injury: A One-Year Magnetic Resonance Imaging Study.

The objective of this study was to evaluate group-by-time interactions between gray matter morphology of healthy controls and that of patients with mild traumatic brain injury (mTBI) as they transitioned from acute to chronic stages, and to relate these findings to long-term cognitive alterations to identify distinct recovery trajectories between good outcome (GO) and poor outcome (PO). High-resolution T1-weighted magnetic resonance images were acquired in 49 mTBI patients within 7 days and 1 year post-injury and at equivalent times in 49 healthy controls. Using linear mixed-effects models, we performed mass-univariate analyses and associated the results of the interaction with changes in cognitive performance. Morphological alterations indexed by increased or decreased cortical thickness have been expected mainly in frontal, parietal, and temporal brain regions. A significant interaction was found in cortical thickness, spatially restricted to bilateral structures of the prefrontal cortex, showing thickening in mTBI and normal developmental thinning in controls. A discrete thickness increase that can interpreted as the absence of cortical thinning typically seen in the healthy population was associated with cognitive recovery in the GO subgroup, while the exaggerated cortical thickening in the PO patients was linked to worsening cognitive performance. Thickness of the prefrontal cortex is subject to structural alterations during the first year after mTBI. Beside beneficial neuroplasticity, a prolonged state of neuroinflammation for symptomatic patients (maladaptive neuroplasticity) cannot be excluded. If the underlying cellular processes responsible for cortical thickening following mTBI have been determined, brain stimulation or even pharmacological intervention targeting the prefrontal cortex might promote endogenous neural restoration.

Functional and Structural Network Recovery after Mild Traumatic Brain Injury: A 1-Year Longitudinal Study.

Brain connectivity after mild traumatic brain injury (mTBI) has not been investigated longitudinally with respect to both functional and structural networks together within the same patients, crucial to capture the multifaceted neuropathology of the injury and to comprehensively monitor the course of recovery and compensatory reorganizations at macro-level. We performed a prospective study with 49 mTBI patients at an average of 5 days and 1 year post-injury and 49 healthy controls. Neuropsychological assessments as well as resting-state functional and diffusion-weighted magnetic resonance imaging were obtained. Functional and structural connectome analyses were performed using network-based statistics. They included a cross-sectional group comparison and a longitudinal analysis with the factors group and time. The latter tracked the subnetworks altered at the early phase and, in addition, included a whole-brain group × time interaction analysis. Finally, we explored associations between the evolution of connectivity and changes in cognitive performance. The early phase of mTBI was characterized by a functional hypoconnectivity in a subnetwork with a large overlap of regions involved within the classical default mode network. In addition, structural hyperconnectivity in a subnetwork including central hub areas such as the cingulate cortex was found. The impaired functional and structural subnetworks were strongly correlated and revealed a large anatomical overlap. One year after trauma and compared to healthy controls we observed a partial normalization of both subnetworks along with a considerable compensation of functional and structural connectivity subsequent to the acute phase. Connectivity changes over time were correlated with improvements in working memory, divided attention, and verbal recall. Neuroplasticity-induced recovery or compensatory processes following mTBI differ between brain regions with respect to their time course and are not fully completed 1 year after trauma.

Connectomic and Surface-Based Morphometric Correlates of Acute Mild Traumatic Brain Injury.

Reduced integrity of white matter (WM) pathways and subtle anomalies in gray matter (GM) morphology have been hypothesized as mechanisms in mild traumatic brain injury (mTBI). However, findings on structural brain changes in early stages after mTBI are inconsistent and findings related to early symptoms severity are rare. Fifty-one patients were assessed with multimodal neuroimaging and clinical methods exclusively within 7 days following mTBI and compared to 53 controls. Whole-brain connectivity based on diffusion tensor imaging was subjected to network-based statistics, whereas cortical surface area, thickness, and volume based on T1-weighted MRI scans were investigated using surface-based morphometric analysis. Reduced connectivity strength within a subnetwork of 59 edges located predominantly in bilateral frontal lobes was significantly associated with higher levels of self-reported symptoms. In addition, cortical surface area decreases were associated with stronger complaints in five clusters located in bilateral frontal and postcentral cortices, and in the right inferior temporal region. Alterations in WM and GM were localized in similar brain regions and moderately-to-strongly related to each other. Furthermore, the reduction of cortical surface area in the frontal regions was correlated with poorer attentive-executive performance in the mTBI group. Finally, group differences were detected in both the WM and GM, especially when focusing on a subgroup of patients with greater complaints, indicating the importance of classifying mTBI patients according to severity of symptoms. This study provides evidence that mTBI affects not only the integrity of WM networks by means of axonal damage but also the morphology of the cortex during the initial post-injury period. These anomalies might be greater in the acute period than previously believed and the involvement of frontal brain regions was consistently pronounced in both findings. The dysconnected subnetwork suggests that mTBI can be conceptualized as a dysconnection syndrome. It remains unclear whether reduced WM integrity is the trigger for changes in cortical surface area or whether tissue deformations are the direct result of mechanical forces acting on the brain. The findings suggest that rapid identification of high-risk patients with the use of clinical scales should be assessed acutely as part of the mTBI protocol.

Altered cognitive processes in the acute phase of mTBI: an analysis of independent components of event-related potentials.

Mild traumatic brain injuries (mTBI) generate acute disruptions of brain function and a subset of patients shows persisting cognitive, affective, and somatic symptoms. Deficits in the executive function domain are among the more frequent cognitive impairments reported by mTBI patients. By means of independent component analysis, event-related potential components from a visual cued go/nogo task, namely contingent negative variation (CNV) and NoGo-P3, were decomposed into distinct independent components that have been shown to be associated with the executive processes of energization, monitoring, and task setting. A group of symptomatic mTBI patients was compared with a group of controls matched for sex, age, and education. Patients showed reduced amplitudes in the late CNV as well as in the early NoGo-P3 subcomponents. Whereas the decreased CNVlate component indicates an impaired ability to generate representations of stimulus-response associations and to energize the maintenance of response patterns, the reduced P3NOGOearly component suggests a deficient ability to invest attentional effort in the initiation of response patterns in mTBI patients. Besides indicating the effects of mTBI on cognitive brain processing, the results may open up the possibility for assessing individual mTBI profiles and facilitate personalized rehabilitative measures.