Combined Cardiothoracic Surgery and Liver Transplantation Versus Isolated Liver Transplantation.

OBJECTIVE: Combined cardiothoracic surgery and liver transplantation (cCSLT) recently increasingly has been used. Despite that, liver transplant immediately after cardiothoracic surgery has not been well-characterized. The authors aimed to compare perioperative management and postoperative outcomes between patients undergoing cCSLT and isolated liver transplantation (iLT). DESIGN: A retrospective study. SETTING: University tertiary medical center. PARTICIPANTS: Twenty-five cCSLT patients and 1091 iLT patients at a single institution from 2010 to 2017. INTERVENTIONS: Twenty-five cCSLT patients were compared with 100 randomly selected and 100 propensity-matched iLT patients. MEASUREMENTS AND MAIN RESULTS: All cCSLT patients underwent comprehensive preoperative evaluation by a multidisciplinary team. Of 25 cardiothoracic surgeries, heart transplant (n = 9) was most common, followed by coronary artery bypass grafting (n = 5) and lung transplant (n = 3). Intraoperative management of cCSLT was provided by 2 separate teams, one for cardiothoracic surgery and one for liver transplantation. Patients undergoing cCSLT often required cardiopulmonary bypass, an intra-aortic balloon pump, extracorporeal membrane oxygenation, or cardiac pharmacologic therapies and, additionally, needed more interventions including antifibrinolytic administration, venovenous bypass, massive blood transfusion, and platelet transfusions compared with iLT patients. Ninety-day survival rates were similar in the cCSLT (100%) and iLT groups (random iLT 87% and matched iLT 93%, log-rank test p = 0.089). CONCLUSIONS: Despite having end-stage liver disease and advanced cardiothoracic disorders and experiencing a complex intraoperative course, cCSLT patients had comparable 90-day survival to iLT patients. Comprehensive planning before transplant, optimal patient/donor selection, the multiple-team model, and meticulous intraoperative management are critical to the success of cCSLT.

Regional Versus Global Measurements of Right Ventricular Strain Performed in the Operating Room With Transesophageal Echocardiography.

OBJECTIVE: To compare regional and global measures of right ventricular (RV) strain in patients undergoing intraoperative transesophageal echocardiography (TEE). DESIGN: Prospective, nonrandomized, observational study. SETTING: Single tertiary-level, university hospital. PARTICIPANTS: The study comprised 48 patients undergoing intraoperative TEE. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A global RV strain measurement (termed RV 5-wall strain [RV 5WS]) was calculated by averaging the longitudinal strain calculated from multiple TEE views. This global strain measurement was compared with the more standard regional strain measurements obtained in a single 4-chamber view (RV free-wall strain [RV FWS] and RV global longitudinal strain [RV GLS]) and with traditional measures of RV function. Regional and global strain measurements were feasible in the operating room. RV FWS and RV GLS strongly correlated with RV 5WS (r = 0.86 and 0.87, respectively) with no significant bias and limits of agreement of approximately -5% to 5%. RV FWS and RV GLS were even more closely correlated with each other (r = 0.99) with no significant bias and limits of agreement less than -2% to 2%. Both regional and global RV strain measurements showed a high sensitivity (RV FWS 94%; RV GLS 94%; RV 5WS 89%) and moderate specificity (RV FWS 70%; RV GLS 67%; RV 5WS 63%) for RV dysfunction based on a reference standard of 3-dimensional RV ejection fraction. CONCLUSIONS: Both regional and global RV strain measurements are feasible in the operating room with TEE. Regional and global measures of RV function correlate well and are sensitive indicators of RV dysfunction.

A Comparison of Left- and Right-Sided Strain Software for the Assessment of Intraoperative Right Ventricular Function.

OBJECTIVE: To compare intraoperative right ventricular (RV) strain measurements made with left ventricular (LV) strain software commonly found on the echocardiography machine (Philips QLAB chamber motion quantification, version 10.7, Philips, Amsterdam, The Netherlands), with offline analysis using the dedicated RV strain software (EchoInsight, version 2.2.6.2230, Epsilon Imaging, Ann Arbor, MI). DESIGN: Prospective, nonrandomized, observational study. SETTING: Single tertiary level, university-affiliated hospital. PARTICIPANTS: The study comprised 48 patients undergoing transesophageal echocardiography for cardiac or noncardiac surgery. INTERVENTIONS: Two-dimensional (2D) and 3-dimensional (3D) images of the right ventricle were obtained. Intraoperative 2D images were analyzed in real time for RV free wall strain (FWS) and global longitudinal strain (GLS) using QLAB chamber motion quantification (CMQ) LV strain software on the echocardiography machine. Two dimensional images were then analyzed offline to determine the RV FWS and GLS using EchoInsight RV-specific strain software. Three-dimensional images were then analyzed offline to detemine the 3D RV ejection fraction (3D RV EF) using TomTec 4D RV function (Unterschleissheim, Germany). Spearman's correlation and Bland-Altman analyses were used to characterize the relationship between RV strain measurements. Both types of strain measurements were compared to a reference standard of 3D RV EF. MEASUREMENTS AND MAIN RESULTS: Intraoperative RV strain measurements using LV-specific strain software correlated with offline RV strain measurements using the RV-specific strain software (FWS rho = 0.85; GLS rho = 0.81). The bias and limits of agreement were 0.75% (- 6.66 to 8.17) for FWS and -4.53% (-11.55 to 2.50) for GLS. The sensitivity and specificity for RV dysfunction for the intraoperative LV-specific software were 94% (95% confidence interval [CI] 73-100) and 70% (95% CI 51-85), respectively, for RV FWS and 94% (95% CI 73-100) and 67% (95% CI 47-83), respectively, for RV GLS. The sensitivity and specificity for RV dysfunction for the offline RV-specific software were 89% (95% CI 65-99) and 73% (95% CI 54-88), respectively, for RV FWS and 94% (95% CI 73-100) and 30% (95% CI 15-49), respectively, for RV GLS. CONCLUSION: Intraoperative RV strain measurements using LV-specific strain software commonly available on the echocardiography machine (QLAB CMQ) correlate with offline RV strain measurements using RV-specific strain software (EchoInsight). The bias and limits of agreement for these left- and right-sided strain software suggest that these 2 measures of RV function cannot be used interchangeably. Both, however, were sensitive measures of RV dysfunction and therefore are likely clinically relevant.

A Sensory-Driven Trade-Off between Coordinated Motion in Social Prey and a Predator's Visual Confusion.

Social animals are capable of enhancing their awareness by paying attention to their neighbors, and prey found in groups can also confuse their predators. Both sides of these sensory benefits have long been appreciated, yet less is known of how the perception of events from the perspectives of both prey and predator can interact to influence their encounters. Here we examined how a visual sensory mechanism impacts the collective motion of prey and, subsequently, how their resulting movements influenced predator confusion and capture ability. We presented virtual prey to human players in a targeting game and measured the speed and accuracy with which participants caught designated prey. As prey paid more attention to neighbor movements their collective coordination increased, yet increases in prey coordination were positively associated with increases in the speed and accuracy of attacks. However, while attack speed was unaffected by the initial state of the prey, accuracy dropped significantly if the prey were already organized at the start of the attack, rather than in the process of self-organizing. By repeating attack scenarios and masking the targeted prey's neighbors we were able to visually isolate them and conclusively demonstrate how visual confusion impacted capture ability. Delays in capture caused by decreased coordination amongst the prey depended upon the collection motion of neighboring prey, while it was primarily the motion of the targets themselves that determined capture accuracy. Interestingly, while a complete loss of coordination in the prey (e.g., a flash expansion) caused the greatest delay in capture, such behavior had little effect on capture accuracy. Lastly, while increases in collective coordination in prey enhanced personal risk, traveling in coordinated groups was still better than appearing alone. These findings demonstrate a trade-off between the sensory mechanisms that can enhance the collective properties that emerge in social animals and the individual group member's predation risk during an attack.

Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1.

LKB1 and its downstream targets of the AMP-activated protein kinase family are important regulators of many aspects of skeletal muscle cell function, including control of mitochondrial content and capillarity. LKB1 deficiency in skeletal and cardiac muscle (mLKB1-KO) greatly impairs exercise capacity. However, cardiac dysfunction in that genetic model prevents a clear assessment of the role of skeletal muscle LKB1 in the observed effects. Our purposes here were to determine whether skeletal muscle-specific knockout of LKB1 (skmLKB1-KO) decreases exercise capacity and mitochondrial protein content, impairs accretion of mitochondrial proteins after exercise training, and attenuates improvement in running performance after exercise training. We found that treadmill and voluntary wheel running capacity was reduced in skmLKB1-KO vs. control (CON) mice. Citrate synthase activity, succinate dehydrogenase activity, and pyruvate dehydrogenase kinase content were lower in KO vs. CON muscles. Three weeks of treadmill training resulted in significantly increased treadmill running performance in both CON and skmLKB1-KO mice. Citrate synthase activity increased significantly with training in both genotypes, but protein content and activity for components of the mitochondrial electron transport chain increased only in CON mice. Capillarity and VEGF protein was lower in skmLKB1-KO vs. CON muscles, but VEGF increased with training only in skmLKB1-KO. Three hours after an acute bout of muscle contractions, PGC-1α, cytochrome c, and VEGF gene expression all increased in CON but not skmLKB1-KO muscles. Our findings indicate that skeletal muscle LKB1 is required for accretion of some mitochondrial proteins but not for early exercise capacity improvements with exercise training.

Social structure emerges via the interaction between local ecology and individual behaviour.

1. The formation of groups is a fundamental aspect of social organization, but there are still many questions regarding how social structure emerges from individuals making non-random associations. 2. Although food distribution and individual phenotypic traits are known to separately influence social organization, this is the first study, to our knowledge, experimentally linking them to demonstrate the importance of their interaction in the emergence of social structure. 3. Using an experimental design in which food distribution was either clumped or dispersed, in combination with individuals that varied in exploratory behaviour, our results show that social structure can be induced in the otherwise non-social European shore crab (Carcinus maenas). 4. Regardless of food distribution, individuals with relatively high exploratory behaviour played an important role in connecting otherwise poorly connected individuals. In comparison, low exploratory individuals aggregated into cohesive, stable subgroups (moving together even when not foraging), but only in tanks where resources were clumped. No such non-foraging subgroups formed in environments where food was evenly dispersed. 5. Body size did not accurately explain an individual's role within the network for either type of food distribution. 6. Because of their synchronized movements and potential to gain social information, groups of low exploratory crabs were more effective than singletons at finding food. 7. Because social structure affects selection, and social structure is shown to be sensitive to the interaction between ecological and behavioural differences among individuals, local selective pressures are likely to reflect this interaction.

The ghost of social environments past: dominance relationships include current interactions and experience carried over from previous groups.

Dominance hierarchies pervade animal societies. Within a static social environment, in which group size and composition are unchanged, an individual's hierarchy rank results from intrinsic (e.g. body size) and extrinsic (e.g. previous experiences) factors. Little is known, however, about how dominance relationships are formed and maintained when group size and composition are dynamic. Using a fusion-fission protocol, we fused groups of previously isolated shore crabs (Carcinus maenas) into larger groups, and then restored groups to their original size and composition. Pre-fusion hierarchies formed independently of individuals' sizes, and were maintained within a static group via winner/loser effects. Post-fusion hierarchies differed from pre-fusion ones; losing fights during fusion led to a decline in an individual's rank between pre- and post-fusion conditions, while spending time being aggressive during fusion led to an improvement in rank. In post-fusion tanks, larger individuals achieved better ranks than smaller individuals. In conclusion, dominance hierarchies in crabs represent a complex combination of intrinsic and extrinsic factors, in which experiences from previous groups can carry over to affect current competitive interactions.

Motion cues tune social influence in shoaling fish.

Social interactions have important consequences for individual fitness. Collective actions, however, are notoriously context-dependent and identifying how animals rapidly weigh the actions of others despite environmental uncertainty remains a fundamental challenge in biology. By exposing zebrafish (Danio rerio) to virtual fish silhouettes in a maze we isolated how the relative strength of a visual feature guides individual directional decisions and, subsequently, tunes social influence. We varied the relative speed and coherency with which a portion of silhouettes adopted a direction (leader/distractor ratio) and established that solitary zebrafish display a robust optomotor response to follow leader silhouettes that moved much faster than their distractors, regardless of stimulus coherency. Although recruitment time decreased as a power law of zebrafish group size, individual decision times retained a speed-accuracy trade-off, suggesting a benefit to smaller group sizes in collective decision-making. Directional accuracy improved regardless of group size in the presence of the faster moving leader silhouettes, but without these stimuli zebrafish directional decisions followed a democratic majority rule. Our results show that a large difference in movement speeds can guide directional decisions within groups, thereby providing individuals with a rapid and adaptive means of evaluating social information in the face of uncertainty.

Finding Some Good in an Invasive Species: Introduction and Assessment of a Novel CURE to Improve Experimental Design in Undergraduate Biology Classrooms.

Reports such as Vision and Change in Undergraduate Biology Education call for integration of course-based undergraduate research experiences (CUREs) into biology curricula and less emphasis on "cookbook" laboratories. CUREs, often characterized by a single open-ended research question, allow students to develop hypotheses, design experiments, and collaborate with peers. Conversely, "cookbook" labs incentivize task completion and have pre-determined experimental outcomes. While research comparing CUREs and "cookbook" labs is growing, there are fewer comparisons among CUREs. Here, we present a novel CURE built around an invasive grass, Bromus inermis. We evaluated this CURE's effectiveness in improving students' understanding of the Vision and Change competency relating to the application of the scientific process through development and testing of hypotheses. We did so by comparing changes in pre- and posttest scores on the Experimental Design Ability Test (EDAT) between Brome CURE students and students in a concurrent CURE, SEA-PHAGES. While students in both CUREs showed improvements at the end of the semester, Brome CURE students showed a greater increase in EDAT scores than did SEA-PHAGES CURE students. Additionally, Brome CURE students had significantly higher gains in 6 of the 10 EDAT criteria. We conclude that the Brome CURE is an effective ecological parallel to the SEA-PHAGES CURE and can help students gain a meaningful understanding of Vision and Change competencies. Journal of Microbiology & Biology Education.

Numerical assessment affects aggression and competitive ability: a team-fighting strategy for the ant Formica xerophila.

The relationship between numerical advantage and competitive ability is a fundamental component in contests between groups of social animals. An individual's ability to correctly assess the numerical state of its group is of vital importance. In addition to numerical dominance, the group's fighting ability also plays an important role in competitive interactions. By staging experimental fights between two Formica ant species, I show that Formica xerophila are able to assess their own group's strength prior to any competitive encounter. Ants that perceive themselves as part of a large group act more aggressively toward a competitor than ants that perceive themselves as isolated individuals. This increase in aggression improves F. xerophila's competitive ability. Furthermore, the number of individuals in a contest was found to affect competitive ability. In contests with equal number of competitors, groups of F. xerophila were more successful than individual F. xerophila. Contrary to previous predictions using Lanchester's laws of fighting, F. xerophila's ability to kill competitors increased nonlinearly with group size. This nonlinearity was due to the collective fighting strategy of an F. xerophila group isolating and engaging a single Formica integroides competitors.

Application of a weight of evidence approach utilising biological effects, histopathology and contaminant levels to assess the health and pollution status of Irish blue mussels (Mytilus edulis).

A weight of evidence (WOE) approach, integrating biological effects, mussel histopathology and tissue contaminant levels is proposed to evaluate mussel health and pollution status. Contaminant levels, histopathology and several biological effects (BEs) including Lysosomal membrane stability (LMS), acetylcholinesterase (AChe), metallothionein proteins (MT) and alkali labile phosphate (ALP), in Mytilus edulis are presented, improving the current knowledge base for these data. Potential links between histopathology, BEs and contaminants and ranking of sites are investigated with an integrated response (IR) indexing technique. Histopathological condition indices (Ih) in mussel digestive gland are used to calculate health indices. A spatial and temporal assessment is conducted at Irish coastal locations. Linear mixed effects modelling revealed effects of confounding factors such as reproductive condition on NRRT (gonad stage (p < 0.001)). Higher prevalence of inflammation, brown cells and epithelial thinning of the digestive gland was evident at Dublin and Wexford and this linked well with the Ih. Levels of contaminants were generally found to be low with few exceptions as were BE responses. Using the IR approach, Dublin was ranked as being most impacted while Shannon ranked the least impacted, this being consistent with the BE ranking.

Decreased Left Caudate Volume Is Associated with Increased Severity of Autistic-Like Symptoms in a Cohort of ADHD Patients and Their Unaffected Siblings.

Autism spectrum disorder (ASD) symptoms frequently occur in individuals with attention-deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural brain correlates, knowledge of the structural brain profile of individuals with ADHD with raised ASD symptoms is limited. The presence of ASD-like symptoms was measured by the Children's Social Behavior Questionnaire (CSBQ) in a sample of typically developing controls (n = 154), participants with ADHD (n = 239), and their unaffected siblings (n = 144) between the ages of 8 and 29. Structural magnetic resonance imaging (MRI) correlates of ASD ratings were analysed by studying the relationship between ASD ratings and grey matter volumes using mixed effects models which controlled for ADHD symptom count and total brain volume. ASD ratings were significantly elevated in participants with ADHD relative to controls and unaffected siblings. For the entire group (participants with ADHD, unaffected siblings and TD controls), mixed effect models revealed that the left caudate nucleus volume was negatively correlated with ASD ratings (t = 2.83; P = 0.005). The current findings are consistent with the role of the caudate nucleus in executive function, including the selection of goals based on the evaluation of action outcomes and the use of social reward to update reward representations. There is a specific volumetric profile associated with subclinical ASD-like symptoms in participants with ADHD, unaffected siblings and controls with the caudate nucleus and globus pallidus being of critical importance in predicting the level of ASD-like symptoms in all three groups.

Rapid genotypic change and plasticity in arbuscular mycorrhizal fungi is caused by a host shift and enhanced by segregation.

Arbuscular mycorrhizal fungi (AMF) are among the most abundant symbionts of plants, improving plant productivity and diversity. They are thought to mostly grow vegetatively, a trait assumed to limit adaptability. However, AMF can also harbor genetically different nuclei (nucleotypes). It has been shown that one AMF can produce genotypically novel offspring with proportions of different nucleotypes. We hypothesized that (1) AMF respond rapidly to a change of environment (plant host) through changes in the frequency of nucleotypes; (2) genotypically novel offspring exhibit different genetic responses to environmental change than the parent; and (3) genotypically novel offspring exhibit a wide range of phenotypic plasticity to a change of environment. We subjected AMF parents and offspring to a host shift. We observed rapid and large genotypic changes in all AMF lines that were not random. Genotypic and phenotypic responses were different among offspring and their parents. Even though growing vegetatively, AMF offspring display a broad range of genotypic and phenotypic changes in response to host shift. We conclude that AMF have the ability to rapidly produce variable progeny, increasing their probability to produce offspring with different fitness than their parents and, consequently, their potential adaptability to new environmental conditions. Such genotypic and phenotypic flexibility could be a fast alternative to sexual reproduction and is likely to be a key to the ecological success of AMF.

Brain volumetric correlates of autism spectrum disorder symptoms in attention deficit/hyperactivity disorder.

Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children's Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners' ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.

Choosy moral punishers.

The punishment of social misconduct is a powerful mechanism for stabilizing high levels of cooperation among unrelated individuals. It is regularly assumed that humans have a universal disposition to punish social norm violators, which is sometimes labelled "universal structure of human morality" or "pure aversion to social betrayal". Here we present evidence that, contrary to this hypothesis, the propensity to punish a moral norm violator varies among participants with different career trajectories. In anonymous real-life conditions, future teachers punished a talented but immoral young violinist: they voted against her in an important music competition when they had been informed of her previous blatant misconduct toward fellow violin students. In contrast, future police officers and high school students did not punish. This variation among socio-professional categories indicates that the punishment of norm violators is not entirely explained by an aversion to social betrayal. We suggest that context specificity plays an important role in normative behaviour; people seem inclined to enforce social norms only in situations that are familiar, relevant for their social category, and possibly strategically advantageous.

Reduced hippocampal volume in healthy young ApoE4 carriers: an MRI study.

The E4 allele of the ApoE gene has consistently been shown to be related to an increased risk of Alzheimer's disease (AD). The E4 allele is also associated with functional and structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess volumes of deep grey matter structures of 22 healthy younger ApoE4 carriers and 22 non-carriers (20-38 years). Volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen, thalamus and brain stem were calculated by FMRIB's Integrated Registration and Segmentation Tool (FIRST) algorithm. A significant drop in volume was found in the right hippocampus of ApoE4 carriers (ApoE4+) relative to non-carriers (ApoE4-), while there was a borderline significant decrease in the volume of the left hippocampus of ApoE4 carriers. The volumes of no other structures were found to be significantly affected by genotype. Atrophy has been found to be a sensitive marker of neurodegenerative changes, and our results show that within a healthy young population, the presence of the ApoE4+ carrier gene leads to volume reduction in a structure that is vitally important for memory formation. Our results suggest that the hippocampus may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age. Although volume reductions were noted bilaterally in the hippocampus, atrophy was more pronounced in the right hippocampus. This finding relates to previous work which has noted a compensatory increase in right hemisphere activity in ApoE4 carriers in response to preclinical declines in memory function. Possession of the ApoE4 allele may lead to greater predilection for right hemisphere atrophy even in healthy young subjects in their twenties.

Sexual dimorphism in healthy aging and mild cognitive impairment: a DTI study.

Previous PET and MRI studies have indicated that the degree to which pathology translates into clinical symptoms is strongly dependent on sex with women more likely to express pathology as a diagnosis of AD, whereas men are more resistant to clinical symptoms in the face of the same degree of pathology. Here we use DTI to investigate the difference between male and female white matter tracts in healthy older participants (24 women, 16 men) and participants with mild cognitive impairment (21 women, 12 men). Differences between control and MCI participants were found in fractional anisotropy (FA), radial diffusion (DR), axial diffusion (DA) and mean diffusion (MD). A significant main effect of sex was also reported for FA, MD and DR indices, with male control and male MCI participants having significantly more microstructural damage than their female counterparts. There was no sex by diagnosis interaction. Male MCIs also had significantly less normalised grey matter (GM) volume than female MCIs. However, in terms of absolute brain volume, male controls had significantly more brain volume than female controls. Normalised GM and WM volumes were found to decrease significantly with age with no age by sex interaction. Overall, these data suggest that the same degree of cognitive impairment is associated with greater structural damage in men compared with women.

Using support vector machines with multiple indices of diffusion for automated classification of mild cognitive impairment.

Few studies have looked at the potential of using diffusion tensor imaging (DTI) in conjunction with machine learning algorithms in order to automate the classification of healthy older subjects and subjects with mild cognitive impairment (MCI). Here we apply DTI to 40 healthy older subjects and 33 MCI subjects in order to derive values for multiple indices of diffusion within the white matter voxels of each subject. DTI measures were then used together with support vector machines (SVMs) to classify control and MCI subjects. Greater than 90% sensitivity and specificity was achieved using this method, demonstrating the potential of a joint DTI and SVM pipeline for fast, objective classification of healthy older and MCI subjects. Such tools may be useful for large scale drug trials in Alzheimer's disease where the early identification of subjects with MCI is critical.