Coronary Artery Calcium Scores and Atherosclerotic Cardiovascular Disease Risk Stratification in Smokers

ObjectivesThis study assessed the utility of the pooled cohort equation (PCE) and/or coronary artery calcium (CAC) for atherosclerotic cardiovascular disease (ASCVD) risk assessment in smokers, especially those who were lung cancer screening eligible (LCSE).BackgroundThe U.S. Preventive Services Task Force recommended and the Centers for Medicare & Medicaid Services currently pays for annual screening for lung cancer with low-dose computed tomography scans in a specified group of cigarette smokers. CAC can be obtained from these low-dose scans. The incremental utility of CAC for ASCVD risk stratification remains unclear in this high-risk group.MethodsOf 6,814 MESA (Multi-Ethnic Study of Atherosclerosis) participants, 3,356 (49.2% of total cohort) were smokers (2,476 former and 880 current), and 14.3% were LCSE. Kaplan-Meier, Cox proportional hazards, area under the curve, and net reclassification improvement (NRI) analyses were used to assess the association between PCE and/or CAC and incident ASCVD. Incident ASCVD was defined as coronary death, nonfatal myocardial infarction, or fatal or nonfatal stroke.ResultsSmokers had a mean age of 62.1 years, 43.5% were female, and all had a mean of 23.0 pack-years of smoking. The LCSE sample had a mean age of 65.3 years, 39.1% were female, and all had a mean of 56.7 pack-years of smoking. After a mean of 11.1 years of follow-up 13.4% of all smokers and 20.8% of LCSE smokers had ASCVD events; 6.7% of all smokers and 14.2% of LCSE smokers with CAC = 0 had an ASCVD event during the follow-up. One SD increase in the PCE 10-year risk was associated with a 68% increase risk for ASCVD events in all smokers (hazard ratio: 1.68; 95% confidence interval: 1.57 to 1.80) and a 22% increase in risk for ASCVD events in the LCSE smokers (hazard ratio: 1.22; 95% confidence interval: 1.00 to 1.47). CAC was associated with increased ASCVD risk in all smokers and in LCSE smokers in all the Cox models. The C-statistic of the PCE for ASCVD was higher in all smokers compared with LCSE smokers (0.693 vs. 0.545). CAC significantly improved the C-statistics of the PCE in all smokers but not in LCSE smokers. The event and nonevent net reclassification improvements for all smokers and LCSE smokers were 0.018 and ?0.126 versus 0.16 and ?0.196, respectively.ConclusionsIn this well-characterized, multiethnic U.S. cohort, CAC was predictive of ASCVD in all smokers and in LCSE smokers but modestly improved discrimination over and beyond the PCE. However, 6.7% of all smokers and 14.2% of LCSE smokers with CAC = 0 had an ASCVD event during follow-up.     

Physical examination, central venous pressure, and chest radiography for the prediction of transpulmonary thermodilution-derived hemodynamic parameters in critically ill patients: a prospective trial

Purpose

Physical examination, assessment of central venous pressure (CVP) and chest radiography are diagnostic tools for estimation of volume status in intensive care unit (ICU) patients. Passive leg raising (PLR) is a test to estimate fluid responsiveness. Transpulmonary thermodilution (TPTD) is established for measurement of cardiac index (CI), global end-diastolic volume index (GEDVI), and extravascular lung water index (EVLWI). This study compares the estimation of volume status using physical examination, CVP, chest radiography, PLR, and TPTD.

Materials and Methods

This study was a prospective trial. Seventy-one patients in a medical ICU were studied. Interventions were as follows: physical examination by 2 independent examiners. CVP was measured. TPTD was performed. In 2 patient subgroups PLR and chest radiography was performed. Comparison of clinical and x-ray-based estimation of volume status, CVP, PLR, and TPTD variables was performed.

Results

Estimation of volume status based on physical examination showed a poor interobserver agreement between the examiners. There was no significant correlation between physical examination–based estimation of volume status and CVP or TPTD-derived GEDVI. There was no significant correlation between CVP and GEDVI, EVLWI or CI. PLR did not indicate fluid responsiveness. Radiographically estimated and TPTD-GEDVI/EVLWI values were significantly different.

Conclusions

In ICU patients, assessment of volume status remains difficult. Physical examination, CVP, and portable radiography do not correlate with TPTD assessment of volume status, preload, or pulmonary hydration.     

Neural mechanisms of brain-computer interface control

Brain-computer interfaces (BCIs) enable people with paralysis to communicate with their environment. Motor imagery can be used to generate distinct patterns of cortical activation in the electroencephalogram (EEG) and thus control a BCI. To elucidate the cortical correlates of BCI control, users of a sensory motor rhythm (SMR)-BCI were classified according to their BCI control performance. In a second session these participants performed a motor imagery, motor observation and motor execution task in a functional magnetic resonance imaging (fMRI) scanner. Group difference analysis between high and low aptitude BCI users revealed significantly higher activation of the supplementary motor areas (SMA) for the motor imagery and the motor observation tasks in high aptitude users. Low aptitude users showed no activation when observing movement. The number of activated voxels during motor observation was significantly correlated with accuracy in the EEG-BCI task (r=0.53). Furthermore, the number of activated voxels in the right middle frontal gyrus, an area responsible for processing of movement observation, correlated (r=0.72) with BCI-performance. This strong correlation highlights the importance of these areas for task monitoring and working memory as task goals have to be activated throughout the BCI session. The ability to regulate behavior and the brain through learning mechanisms involving imagery such as required to control a BCI constitutes the consequence of ideo-motor co-activation of motor brain systems during observation of movements. The results demonstrate that acquisition of a sensorimotor program reflected in SMR-BCI-control is tightly related to the recall of such sensorimotor programs during observation of movements and unrelated to the actual execution of these movement sequences.     

TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity

The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and β-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT(1A) receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1(-/-) mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.     

Experiences in the management of brainstem hematomas

The purpose of this study was to present our experience in the management of spontaneous brainstem hematomas (BSH). Records of 58 consecutive patients were reviewed, including demographic data, symptoms, Glasgow Coma Scale, treatment, intraoperative findings (in surgical cases), and outcome according to the Glasgow Outcome Scale. Fifteen patients were comatose (GCS 4 or less): 11/15 patients were treated conservatively. Four patients with accompanying acute occlusive hydrocephalus were treated by placement of an external ventricular drainage. None survived. In nine patients (60%), arteriosclerosis and/or long-standing arterial hypertension were known and arteriopathic BSH was suspected. Forty-three patients were not comatose: 37 patients showed no impairment of consciousness (GCS 15), 6 patients presented with mild disturbance of conscious state (GCS 13), progressing to coma (GCS 8) in 1. In the majority (36/43) of the non-comatose patients (83.7%) cavernoma could be revealed and removed surgically. In six patients (14%), an atypically located arteriopathic BSH was assumed and treated medically. One patient had an underlying brainstem arteriovenous malformation and was treated radiosurgically. Many arteriopathic BSH cause immediate coma indicating direct and irreversible damage of midpontine structures. Thus, we suggest not to proceed to surgery, even if the bleeding is accompanied by acute hydrocephalus. The majority of BSH not resulting in immediate coma are caused by underlying cavernomas. In these cases surgery should be considered.     

Cell adhesion-mediated radioresistance revisited

PURPOSE: Integrin-mediated adhesion of cells to proteins of the extracellular matrix modulates the cellular response to ionizing radiation in vitro. This mechanism might be in part causative for radiation and chemoresistance phenotypes in tumor cells. MATERIALS AND METHODS: A PubMed database search was performed and the data were summarized with a focus on cell adhesion-mediated radioresistance (CAM-RR). RESULTS: Integrins and their associated downstream signaling pathways as well as cooperative interactions of integrins with receptor tyrosine kinases mediate defensive mechanisms that aggravate the therapeutic eradication of tumor cells by radiotherapy. CONCLUSIONS: A better knowledge of the molecular composition and function of the multiprotein, multifunctional cell-matrix interactions mediating complexes termed focal adhesions may point at significant differences between normal and tumor cells, which could foster the development of novel targeted therapies in radiotherapy.     

Executive control of countermanding saccades by the supplementary eye field

The supplementary eye field registers the occurrence of conflict, errors and reward in macaque monkeys performing a saccade-countermanding task. Using intracortical microstimulation, we determined whether the supplementary eye field only monitors or can actually influence performance. Weak microstimulation of many sites in the supplementary eye field improved monkeys' performance on a 'stop signal' task by delaying saccade initiation. This effect depended on the context of the task because simple visually guided saccades were not delayed by the same stimulation. These results demonstrate that the supplementary eye field can exert contextual executive control over saccade generation.