Multimodal Prediction of 3- and 12-Month Outcomes in ICU Patients with Acute Disorders of Consciousness.

BACKGROUND: In intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC), outcome prediction is key to decision-making regarding prognostication, neurorehabilitation, and management of family expectations. Current prediction algorithms are largely based on chronic DoC, whereas multimodal data from acute DoC are scarce. Therefore, the Consciousness in Neurocritical Care Cohort Study Using Electroencephalography and Functional Magnetic Resonance Imaging (i.e. CONNECT-ME; ClinicalTrials.gov identifier: NCT02644265) investigates ICU patients with acute DoC due to traumatic and nontraumatic brain injuries, using electroencephalography (EEG) (resting-state and passive paradigms), functional magnetic resonance imaging (fMRI) (resting-state) and systematic clinical examinations. METHODS: We previously presented results for a subset of patients (n = 87) concerning prediction of consciousness levels in the ICU. Now we report 3- and 12-month outcomes in an extended cohort (n = 123). Favorable outcome was defined as a modified Rankin Scale score ≤ 3, a cerebral performance category score ≤ 2, and a Glasgow Outcome Scale Extended score ≥ 4. EEG features included visual grading, automated spectral categorization, and support vector machine consciousness classifier. fMRI features included functional connectivity measures from six resting-state networks. Random forest and support vector machine were applied to EEG and fMRI features to predict outcomes. Here, random forest results are presented as areas under the curve (AUC) of receiver operating characteristic curves or accuracy. Cox proportional regression with in-hospital death as a competing risk was used to assess independent clinical predictors of time to favorable outcome. RESULTS: Between April 2016 and July 2021, we enrolled 123 patients (mean age 51 years, 42% women). Of 82 (66%) ICU survivors, 3- and 12-month outcomes were available for 79 (96%) and 77 (94%), respectively. EEG features predicted both 3-month (AUC 0.79 [95% confidence interval (CI) 0.77-0.82]) and 12-month (AUC 0.74 [95% CI 0.71-0.77]) outcomes. fMRI features appeared to predict 3-month outcome (accuracy 0.69-0.78) both alone and when combined with some EEG features (accuracies 0.73-0.84) but not 12-month outcome (larger sample sizes needed). Independent clinical predictors of time to favorable outcome were younger age (hazard ratio [HR] 1.04 [95% CI 1.02-1.06]), traumatic brain injury (HR 1.94 [95% CI 1.04-3.61]), command-following abilities at admission (HR 2.70 [95% CI 1.40-5.23]), initial brain imaging without severe pathological findings (HR 2.42 [95% CI 1.12-5.22]), improving consciousness in the ICU (HR 5.76 [95% CI 2.41-15.51]), and favorable visual-graded EEG (HR 2.47 [95% CI 1.46-4.19]). CONCLUSIONS: Our results indicate that EEG and fMRI features and readily available clinical data predict short-term outcome of patients with acute DoC and that EEG also predicts 12-month outcome after ICU discharge.

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.

Analysis of expression profiling data suggests explanation for difficulties in finding biomarkers for nasal polyps.

BACKGROUND: Identification of clinically useful biomarkers for Nasal Polyposis in chronic rhinosinusitis (CRSwNP) has proven dif-ficult. We analyzed gene expression profiling data to find explanations for this. METHODS: We analyzed mRNA expression profiling data, GSE36830, of six uncinate tissues from healthy controls and six NP from CRSwNP patients. We performed Ingenuity Pathway Analysis (IPA) of differentially expressed genes to identify pathways and predicted upstream regulators. RESULTS: We identified 1,608 differentially expressed genes and 177 significant pathways, of which Th1 and Th2 activation pathway and leukocyte extravasation signaling were most significant. We identified 75 upstream regulators whose activity was predicted to be upregulated. These included regulators of known pathogenic and therapeutic relevance, like IL-4. However, only seven of the 75 regulators were actually differentially expressed in NP, namely CSF1, TYROBP, CCL2, CCL11, SELP, ADORA3, ICAM1. Interes-tingly, these did not include IL-4, and four of the seven were receptors. This suggested a potential explanation for the discrepancy between the predicted and observed expression levels of the regulators, namely that the receptors, and not their ligands, were upregulated. Indeed, we found that 10 receptors of key predicted upstream regulators were upregulated, including IL4R. CONCLUSION: Our findings indicate that the difficulties in finding specific biomarkers for CRSwNP depend on the complex underly-ing mechanisms, which include multiple pathways and regulators, each of which may be subdivided into multiple components such as ligands, soluble and membrane-bound receptors. This suggests that combinations of biomarkers may be needed for CRSwNP diagnostics.

Consciousness in Neurocritical Care Cohort Study Using fMRI and EEG (CONNECT-ME): Protocol for a Longitudinal Prospective Study and a Tertiary Clinical Care Service.

Aims and Objectives: To facilitate individualized assessment of unresponsive patients in the intensive care unit for signs of preserved consciousness after acute brain injury. Background: Physicians and neuroscientists are increasingly recognizing a disturbing dilemma: Brain-injured patients who appear entirely unresponsive at the bedside may show signs of covert consciousness when examined by functional MRI (fMRI) or electroencephalography (EEG). According to a recent meta-analysis, roughly 15% of behaviorally unresponsive brain-injured patients can participate in mental tasks by modifying their brain activity during EEG- or fMRI-based paradigms, suggesting that they are conscious and misdiagnosed. This has major ethical and practical implications, including prognosis, treatment, resource allocation, and end-of-life decisions. However, EEG- or fMRI-based paradigms have so far typically been tested in chronic brain injury. Hence, as a novel approach, CONNECT-ME will import the full range of consciousness paradigms into neurocritical care. Methods: We will assess intensive care patients with acute brain injury for preserved consciousness by serial and multimodal evaluation using active, passive and resting state fMRI and EEG paradigms, as well as state-of-the-art clinical techniques including pupillometry and sophisticated clinical rating scales such as the Coma Recovery Scale-Revised. In addition, we are establishing a biobank (blood, cerebrospinal fluid and brain tissue, where available) to facilitate future genomic and microbiomic research to search for signatures of consciousness recovery. Discussion: We anticipate that this multimodal approach will add vital clinical information, including detection of preserved consciousness in patients previously thought of as unconscious, and improved (i.e., personalized) prognostication of individual patients. Our aim is two-fold: We wish to establish a cutting-edge tertiary care clinical service for unresponsive patients in the intensive care unit and lay the foundation for a fruitful multidisciplinary research environment for the study of consciousness in acute brain injury. Of note, CONNECT-ME will not only enhance our understanding of consciousness disorders in acute brain injury but it will also raise awareness for these patients who, for obvious reasons, have lacked a voice so far. Trial registration: The study is registered with clinicaltrials.org (ClinicalTrials.gov Identifier: NCT02644265).

MOBILE-izing Adolescent Sexual and Reproductive Health Care: A Pilot Study Using a Mobile Health Unit in Chicago.

BACKGROUND: Adolescents experience numerous barriers to obtaining sexual and reproductive health care (SRHC). Mobile Health Units (MHUs) can remove some barriers by traveling to the community. This pilot study developed Mobile SRHC through an iterative process on an existing MHU and evaluated it among adolescents and providers. METHODS: Mobile SRHC was developed through a mixed-method, multiphase study. Three key informant interviews with MHU providers, an adolescent needs assessment survey, and a Youth Model Development Session informed model development. Emergency contraception (EC), oral contraceptive pills (OCPs), and depot-medroxyprogesterone acetate (DMPA) were sequentially incorporated into MHU services. Administrative data assessed method distribution and surveys assessed patient satisfaction. RESULTS: Key informants held positive attitudes toward implementing Mobile SRHC into their practice. Needs assessment surveys (N = 103) indicated a majority was interested in learning about sexual health (66.0%) and obtaining birth control (54.4%) on an MHU. Over 3 months, 123 adolescents participated in Mobile SRHC. Seven packs and 9 prescriptions of EC, 8 3-month packs and 10 prescriptions of OCPs, and 5 injections and 5 prescriptions of DMPA were distributed. Ninety-two percent of adolescent participants reported they would recommend Mobile SRHC to friends. CONCLUSIONS: Mobile SRHC is a feasible approach for reproductive health care among adolescents.

Cardiovascular death in women who had hypertension in pregnancy: a case-control study.

OBJECTIVE: To determine whether an association exists between hypertension in pregnancy and later development of cardiovascular disease. DESIGN: Case-control study of women who delivered with and without hypertensive complications during the same period. SETTING: University Hospital in Reykjavik, Iceland. POPULATION: Three hundred and twenty-five women with hypertension in pregnancy (blood pressure > or =140/90 mmHg after 20 weeks of gestation) in the years 1931-1947, graded by severity. For each case, two normotensive control women, delivering before or after the case and matched for parity and age were selected, giving a total of 629 women. METHODS: Causes of death were evaluated for the presence of ischaemic heart disease, cerebrovascular events and cancer, up until the end of 1996. MAIN OUTCOME MEASURES: Survival curves, median survival times, risk of death by age group and severity of disease. RESULTS: Death with evidence of ischaemic heart disease was more common in cases (24.3%) than in control women (14.6%) (RR 1.66; 95% CI 1.27-2.17). Cerebrovascular event deaths occurred in 9.5% of cases and in 6.5% of controls (RR 1.46; 95% CI 0.94-2.28). Cancer death rates were not different (RR 1.22; 95% CI 0.91-1.63). Survival times were shorter on average by three to nine years as a consequence of cardiovascular disease. This varied by age group in the index pregnancy for women with a history of hypertension in pregnancy. The effect was smaller if the case pregnancy occurred at a young age. There was a linear trend with increasing severity of hypertensive disease in pregnancy in death rates from ischaemic heart disease (chi(2) (1)= 5.8, P= 0.02). CONCLUSIONS: Long term follow up suggests an increased risk of death from ischaemic heart disease and cerebrovascular events among women who suffered hypertension in pregnancy.

Do lipids, blood pressure, diabetes, and smoking confer equal risk of myocardial infarction in women as in men? The Reykjavik Study.

BACKGROUND: Studies on coronary risk factors in men and women are mainly based on mortality data and few compare results of both sexes with consistent study design and diagnostic criteria. This study assesses the major risk factors for coronary events in men and women from the Reykjavik Study. DESIGN: Within a prospective, population-based cohort study individuals without history of myocardial infarction were identified and the relative risk of baseline variables was assessed in relation to verified myocardial infarction or coronary death during follow-up. METHODS: Of the 9681 women and 8888 men who attended risk assessment from 1967-1991, with follow-up period of up to 28 years, 706 women and 1700 men suffered a non-fatal myocardial infarction or coronary death. RESULTS: Serum cholesterol was a significant risk factor for both sexes, with hazard ratios (HR) decreasing with age. Systolic blood pressure was a stronger risk factor for women as was ECG-confirmed left ventricular hypertrophy (women HR 2.89, 95% confidence interval [CI] 1.67-5.01; men HR 1.11 [CI 0.86-1.43]). Fasting blood glucose > or =6.7 mmol/L identified significantly higher risk for women (HR 2.65) than men (HR 2.08) as did self-reported diabetes. Triglyceride risk was significantly higher for women and decreased significantly with age. Smoking increased risk two- to five-fold, increasing with dose, for women, which was significantly higher than the doubling in risk for men. CONCLUSIONS: This large study of the major risk factors compared between the sexes demonstrates similar relative risk of myocardial infarction associated with cholesterol for both sexes, however, the relative risk is higher in women for many other risk factors such as smoking, diabetes, elevated triglycerides and left ventricular hypertrophy.

The influence of matrix components on the morphological differentiation of a proliferating hepatocyte line from liver of newborn mice.

The differentiation behaviour of a liver epithelial cell line of the newborn mouse cultured on various matrix components (Thermanox pure, Thermanox coated with ECM, dried collagen type I and type II, wet collagen type I and type III and on floating collagen) was investigated by electron microscopy. Only during the last few days of pregnancy and up to day 9 p.p. could these cells be isolated using a very delicate method. The cells were smaller than differentiated hepatocytes and proliferated spontaneously. They resembled the so-called oval liver cells. On Thermanox pure or Thermanox coated with ECM, dried collagen type I or type II a confluent monolayer developed after about 6 days that consisted of rather flat extended cells which were characterized by short contacts and the absence of any morphological indications of differentiation. On wet collagen the extension area was smaller and the cells were taller. The length of the contact area and the number and size of gap junctions and cell organelles increased. On floating collagen multi-layered aggregates of polygonal cells developed that were characterized by extended cell contacts, bile capillary-like structures and highly developed cell organelles, especially rough endoplasmic reticulum. Since differentiation processes can be demonstrated ultrastructurally only on wet collagen, especially on floating collagen, the chemical composition of the substrate and a specific matrix-cell interaction cannot be the only triggering factor. It is assumed that mechanical properties of the substrate, e.g. plasticity, are involved. The change in the shape of the cell, the prolongation or intensification of the cell contact and the adaptation of the cytoskeleton might play a decisive role in this connection.

Normally sulphated and highly sulphated glycosaminoglycans (GAG) affecting fibrillogenesis of type I and type II collagen in vitro.

Proteoglycans (PG) and glycosaminoglycans (GAG) influence the aggregation of collagen molecules during fibrillogenesis and the ultimate fibril width. The current in vitro experiments suggest that collagen type II may interact more strongly with highly sulphated GAG than type I collagen. Electron microscopic investigations indicate that, after addition of highly sulphated GAG, the fibrils of type II collagen become significantly (p less than 0.001) thicker than fibrils of a control experiment.

An electron microscopical study of the influence of different glycosaminoglycans on the fibrillogenesis of collagen type I and II in vitro.

Proteoglycans (PG) and glycosaminoglycans (GAG) bind to collagen, and thus influence fibril formation. Polysaccharides interfere with the aggregation of collagen molecules and affect pattern formation. The morphological structure of type I and type II collagen was studied after adding different GAG to collagen solutions in test tubes in vitro. Electron microscopical investigations suggest that sulfated GAG change the aggregation behaviour of collagen molecules. Thus, the cross-striation pattern is changed. This effect seems to be based on the degree of sulfatation and not on the molecular weight of the GAG. Furthermore, GAG appear to have a stabilizing influence on the in vitro fibril formation.

Formation of an atypical collagen and cartilage pattern in limb bud cultures by highly sulfated GAG.

Addition of 1 mg/ml or higher doses of the highly sulfated pentosanpolysulfoester SP54 or the mucopolysaccharidepolysulfoester Arteparon to limb bud cultures from 11-day-old mouse embryos caused a marked reduction in the growth of the distal parts of the cartilage anlagen. The most striking effect, however, was the change in the collagen structure of the cartilaginous intercellular substance. After more than 0.05 mg/ml SP54 or Arteparon no collagen filaments were seen but collagen aggregates with an altered cross-striation occurred. They were produced by an antiparallel arrangement of collagen molecules caused by the highly sulfated substances. By immunofluorescence microscopy it was shown that SP54 and Arteparon did not influence the distribution of the collagen types but only affected the aggregation of collagen type II. From the morphological point of view the production of endogenous PG seemed to be uneffected by SP54 and Arteparon. The effect of SP54 and Arteparon was reversible. After removal of these substances characteristic collagen filaments re-formed. The collagen aggregates were decomposed extracellularly or phagocytosed by chondroblasts and decomposed intracellularly.