Phenotypic regional functional imaging patterns during memory encoding in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Reliable blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) phenotypic biomarkers of Alzheimer's disease (AD) or mild cognitive impairment (MCI) are likely to emerge only from a systematic, quantitative, and aggregate examination of the functional neuroimaging research literature. METHODS: A series of random-effects activation likelihood estimation (ALE) meta-analyses were conducted on studies of episodic memory encoding operations in AD and MCI samples relative to normal controls. ALE analyses were based on a thorough literature search for all task-based functional neuroimaging studies in AD and MCI published up to January 2010. Analyses covered 16 fMRI studies, which yielded 144 distinct foci for ALE meta-analysis. RESULTS: ALE results indicated several regional task-based BOLD consistencies in MCI and AD patients relative to normal control subjects across the aggregate BOLD functional neuroimaging research literature. Patients with AD and those at significant risk (MCI) showed statistically significant consistent activation differences during episodic memory encoding in the medial temporal lobe, specifically parahippocampal gyrus, as well superior frontal gyrus, precuneus, and cuneus, relative to normal control subjects. CONCLUSIONS: ALE consistencies broadly support the presence of frontal compensatory activity, medial temporal lobe activity alteration, and posterior midline "default mode" hyperactivation during episodic memory encoding attempts in the diseased or prospective predisease condition. Taken together, these robust commonalities may form the foundation for a task-based fMRI phenotype of memory encoding in AD.

Using quality improvement science to implement a multidisciplinary behavioral intervention targeting pediatric inpatient airway clearance.

OBJECTIVE: The objective of this study was to use quality improvement science methodology to develop a multidisciplinary intervention improving occurrence of best-practice airway clearance therapy (ACT) in inpatient adolescents with cystic fibrosis during routine clinical care. METHODS: The model for improvement was used to develop and implement interventions. Primary outcomes were quality of ACT (% ACT meeting criteria for best practice) and quantity of ACT (% of hospital days patients received ACT four times/day). Annotated control charts were used to document the impact of the interventions. RESULTS: Quality of ACT significantly improved from 21% best practice ACT at baseline to 73%. Quantity of ACT significantly improved from 41% days with ACT four times/day at baseline to 64%. CONCLUSIONS: A multidisciplinary, evidence-based intervention was effective for improving occurrence of best-practice ACT. Pediatric psychology can make valuable contributions to improving the quality of care provided in the medical setting.

Coilin methylation regulates nuclear body formation.

Cajal bodies (CBs) are nuclear suborganelles involved in biogenesis of small RNAs. Twin structures, called gems, contain high concentrations of the survival motor neurons (SMN) protein complex. CBs and gems often colocalize, and communication between these subdomains is mediated by coilin, the CB marker. Coilin contains symmetrical dimethylarginines that modulate its affinity for SMN, and, thus, localization of SMN complexes to CBs. Inhibition of methylation or mutation of the coilin RG box dramatically decreases binding of coilin to SMN, resulting in gem formation. Coilin is hypomethylated in cells that display gems, but not in those that primarily contain CBs. Likewise, extracts prepared from cells that display gems are less efficient in methylating coilin and Sm constructs in vitro. These results demonstrate that alterations in protein methylation status can affect nuclear organization.

Neuroanatomical correlates of malingered memory impairment: event-related fMRI of deception on a recognition memory task.

PRIMARY OBJECTIVE: Event-related, functional magnetic resonance imaging (fMRI) data were acquired in healthy participants during purposefully malingered and normal recognition memory performances to evaluate the neural substrates of feigned memory impairment. METHODS AND PROCEDURES: Pairwise, between-condition contrasts of neural activity associated with discrete recognition memory responses were conducted to isolate dissociable neural activity between normal and malingered responding while simultaneously controlling for shared stimulus familiarity and novelty effects. Response timing characteristics were also examined for any association with observed between-condition activity differences. OUTCOMES AND RESULTS: Malingered recognition memory errors, regardless of type, were associated with inferior parietal and superior temporal activity relative to normal performance, while feigned recognition target misses produced additional dorsomedial frontal activation and feigned foil false alarms activated bilateral ventrolateral frontal regions. Malingered response times were associated with activity in the dorsomedial frontal, temporal and inferior parietal regions. Normal memory responses were associated with greater inferior occipitotemporal and dorsomedial parietal activity, suggesting greater reliance upon visual/attentional networks for proper task performance. CONCLUSIONS: The neural substrates subserving feigned recognition memory deficits are influenced by response demand and error type, producing differential activation of cortical regions important to complex visual processing, executive control, response planning and working memory processes.

Implementation of a Communication Bundle for High-Risk Patients.

BACKGROUND: Interventions that facilitate early identification and management of hospitalized pediatric patients who are at risk for deterioration are associated with decreased mortality. In our large pediatric hospital with a history of success in decreasing unrecognized deterioration, patients at higher risk of deterioration are termed "watchers." Because communication errors often contribute to unrecognized deterioration, clear and timely communication of watcher status to all team members and contingency planning was desired. OBJECTIVES: Increase the percentage of eligible watchers with a complete communication, teamwork, and planning bundle within 2 hours of identification from 28% to 80%. METHODS: Watchers admitted to Hospital Medicine on 2 targeted units were eligible. Stakeholders were educated to facilitate ownership. Daily data analysis enabled real-time failure identification. Automated physician notification provided reminders for timely communication. RESULTS: The percentage of watchers with a complete situation awareness bundle within 2 hours increased from 28% to 81% and was sustained for more than 2 years. There was no change in rates of rapid response team calls or ICU transfers on our intervention units, but these both increased throughout the hospital. Education facilitated modest improvement, with marked improvements and sustainment through use of technology. CONCLUSIONS: A novel bundle that included contingency planning and communication expectations was created to improve situation awareness for watchers. Multidisciplinary engagement and use of automated technology facilitated by an electronic health record helped implement and sustain bundle adherence.

Development of a New Care Model for Hospitalized Children With Medical Complexity.

Children with medical complexity are a rapidly growing inpatient population with frequent, lengthy, and costly hospitalizations. During hospitalization, these patients require care coordination among multiple subspecialties and their outpatient medical homes. At a large freestanding children's hospital, a new inpatient model of care was developed in an effort to consistently provide coordinated, family-centered, and efficient care. In addition to expanding the multidisciplinary team to include a pharmacist, dietician, and social worker, the team redesign included: (1) medication reconciliation rounds, (2) care coordination rounds, and (3) multidisciplinary weekly handoff with outpatient providers. During weekly medication reconciliation rounds, the team pharmacist reviews each patient's current medications with the team. In care coordination rounds, the team collaborates with unit care managers to identify discharge needs and complete discharge tasks. Finally, at the end of the week, the outgoing hospital medicine attending physician hands off patient care to the incoming attending with input from the team's pharmacist, dietician, and social worker. Families and providers noted improvements in care coordination with the new care model. Remaining challenges include balancing resident autonomy and attending supervision, as well as supporting providers in delivering care that can be emotionally challenging. Aspects of this care model could be tested and adapted at other hospitals that care for children with medical complexity. Additionally, future work should study the impact of inpatient complex care models on patient health outcomes and experience.

Neurocognitive functioning and HAART in HIV and hepatitis C virus co-infection.

OBJECTIVES: This study examined the effects of HAART on neurocognitive functioning in persons with hepatitis C virus (HCV) and HIV co-infection. DESIGN: A prospective study examining neurocognitive performance before and after HAART initiation. METHOD: Participant groups included a mono-infected group (45 HIV+/HCV- participants) and a co-infected group (20 HIV+/HCV+ participants). A neuropsychological battery (attention/concentration, psychomotor speed, executive functioning, verbal memory, visual memory, fine motor, and gross motor functioning) was used to evaluate all participants. After 6 months of HAART, 31 HIV+ mono-infected and 13 HCV+/HIV+ co-infected participants were reevaluated. RESULTS: Neurocognitive functioning by domain revealed significantly worse performance in the co-infected group when compared to the monoinfected group on domains of visual memory and fine motor functioning. Assessment of neurocognitive functioning after antiretroviral therapy revealed that the co-infected group was no longer performing worse than the monoinfected group. CONCLUSIONS: The findings of the current study suggest that persons with HCV+/HIV+ co-infection may have greater neurocognitive declines than persons with HIV infection alone. HCV+/HIV+ co-infection may accelerate the progression of HIV related neurocognitive decline.

Cue-induced brain activity changes and relapse in cocaine-dependent patients.

This study used functional magnetic resonance imaging (fMRI) to examine the association between brain activation during exposure to cocaine-related cues and relapse to drug use in cocaine-dependent (CD) patients. We imaged 17 CD subjects during a 2-week in-patient stay. The subjects then entered a 10-week outpatient placebo-controlled, double-blind randomized clinical trial where urine toxicologies were assessed three times weekly to calculate the treatment effectiveness score (TES). Worse TES correlated with BOLD activation in the left precentral, superior temporal, and posterior cingulate cortices (PCC), and right middle temporal and lingual cortices (R>0.65; P<0.005). The left PCC activation also distinguished eight nonrelapsers (TES above mean and completed treatment) from nine relapsers. Cocaine-free urines were significantly greater in the nonrelapsers (92%) than in the relapsers (66%), who also remained in treatment for an average of only 3.2 weeks. Self-reports of craving during fMRI did not differ between nonrelapsers and relapsers and did not correlate with TES. Relapse to cocaine abuse was associated with increased activation in the sensory association cortex, the motor cortex, and PCC while viewing images of cocaine-related cues. These results suggest that relapse to cocaine abuse is associated with increased brain activation to cocaine cues in sensory, motor, and cognitive-emotional processing areas. This physiological activation was a better predictor of relapse than subjective reports of craving, and may be a useful target for treatment development.

Improving Discharge Efficiency in Medically Complex Pediatric Patients.

BACKGROUND AND OBJECTIVE: Children with medical complexity have unique needs when facilitating transitions from hospital to home. Defining readiness for discharge is challenging, and preparation requires coordination of family, education, equipment, and medications. Our multidisciplinary team aimed to increase the percentage of medically complex hospital medicine patients discharged within 2 hours of meeting medical discharge goals from 50% to 80%. METHODS: We used quality improvement methods to identify key drivers and inform interventions. Medical discharge goals were defined on admission for each patient. Interventions included implementation of a complex care inpatient team with electronic admission order set, weekly care coordination rounds, needs assessment tool, and medication pathway. The primary measure, percentage of patients discharged within 2 hours of meeting medical discharge goals, was followed on a run chart. The secondary measures, pre- and post-intervention length of stay and 30-day readmission rate, were compared by using Wilcoxon rank-sum and χ(2) tests, respectively. RESULTS: The percentage of medically complex patients discharged within 2 hours of meeting medical discharge goals improved from 50% to 88% over 17 months and sustained for 6 months. In preintervention-postintervention comparison, median length of stay did not change (3.1 days [interquartile range, 1.8-7.0] vs 2.9 days [interquartile range, 1.7-6.1]; P = .67) and 30-day readmission rate was not impacted (30.7% vs 26.4%; P = .51). CONCLUSIONS: Efficient discharge for medically complex patients requires support of a multidisciplinary team to proactively address discharge needs, ensuring patients are ready for discharge when medical goals are met.

Platelet abnormalities associated with cerebral perfusion defects in cocaine dependence.

BACKGROUND: This study assessed whether reduced regional cerebral blood flow (rCBF; hypoperfusion) in cocaine-dependent (CD) patients is associated with platelet abnormalities and whether these platelet abnormalities predict improvement in hypoperfusion after 1 month of abstinence. METHODS: We correlated platelet number and aggregation with rCBF hypoperfusion in 54 CD patients at baseline and after a month of abstinence while taking either 325 mg aspirin or placebo. We measured rCBF by (SPECT) with (Tc-HMPAO). Platelet aggregation to adenosine diphosphate was compared at baseline and after treatment. RESULTS: At baseline the number of hypoperfused voxels positively correlated with higher platelet aggregation, and five brain regions (bilateral frontal, right insula, right cingulate, left temporal lobes) showed significantly more hypoperfusion in the high than low platelet aggregation group. After abstinence, hypoperfusion significantly improved regardless of treatment assignment, and greater platelet aggregation at baseline predicted greater improvement in hypoperfusion. After abstinence, only the cingulate continued to show more hypoperfusion in the high- than low-aggregation group. CONCLUSIONS: Because platelet function was related to hypoperfusion primarily in the distribution of the middle cerebral artery, where CD patients most commonly have strokes, more potent antiplatelet agents than aspirin might be effective.

Perfusion abnormalities and decision making in cocaine dependence.

BACKGROUND: Previous studies have shown that cocaine abusers have cerebral perfusion deficits that may diminish cognitive functioning. This study examined whether cocaine-dependent patients have perfusion abnormalities associated with poor decision-making ability as measured by the Iowa Gambling Task (IGT). METHODS: Seventeen abstinent cocaine-dependent patients were administered the IGT after completion of resting 99mTc-HMPAO single-photon emission computed tomography (SPECT). RESULTS: Better IGT performance was negatively correlated with perfusion within the anterior cingulate gyrus, middle frontal gyrus, medial frontal gyrus, and superior frontal gyrus. The time to complete card selections was positively correlated with the severity of impairment. CONCLUSIONS: Resting hyperperfusion in brain regions previously implicated in decision making and response inhibition was associated with worse IGT scores. Impaired performance was related to a greater amount of time taken for card selections, suggesting that reduced ability was due to cognitive factors other than an impulsive response pattern.

Neuroimaging in human immunodeficiency virus infection.

Human immunodeficiency virus (HIV) is associated with central nervous system (CNS) changes that may affect cerebral blood flow (CBF), metabolism, structure, and diffusion. Each of the available neuroimaging techniques offers unique insight into the neural mechanisms underlying HIV, as well as a potential means of monitoring disease progression and treatment response. The purpose of the article is to provide a review of experimental studies evaluating changes related to HIV with imaging techniques, including single-photon emission computed tomography (SPECT), positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and perfusion MRI (pMRI).

Gender-specific vulnerability for rCBF abnormalities among cocaine abusers.

Fifty abstinent cocaine-dependent patients and 20 healthy controls were evaluated with 99mTc-HMPAO SPECT to examine gender differences in perfusion. Group contrasts with statistical parametric mapping revealed male and female patients exhibited not only different regions, but different types of perfusion abnormality, including decreased perfusion in the anterior cingulate/frontal regions among cocaine-dependent men, and increased perfusion in the posterior cingulate of cocaine-dependent women. The findings suggested that cocaine-dependent men have perfusion deficits previously associated with cocaine withdrawal and impaired response inhibition, whereas, cocaine-dependent women demonstrated perfusion abnormalities consistent with heightened stress responsivity and worse treatment outcome. The possibility of different neural mechanisms underlying relapse in men and women, and the implications for utilizing specialized treatments are discussed.

Aspirin or amiloride for cerebral perfusion defects in cocaine dependence.

Cocaine dependent (CD) patients have regional cerebral blood flow (rCBF) deficits that may be related to occlusion of blood vessels by vasoconstriction and abnormal platelet aggregation. This study determined whether aspirin, which reverses platelet aggregation, or amiloride, a vasodilator, significantly reversed this rCBF hypoperfusion. This 1-month randomized trial compared clusters of voxels with significant hypoperfusion in recently abstinent CD patients after aspirin (325 mg daily), amiloride (10 mg daily) or placebo treatment. Forty-nine primary CD patients and 18 non-drug abusing controls were compared using single photon emission computed tomography (SPECT) neuroimaging with 99mTc-hexamethyl-propyleneamine-oxime and statistical parametric mapping (SPM). Platelet aggregation to adenosine diphosphate (ADP) was examined after treatment to determine whether rCBF improvement was related to decreased platelet aggregation. Following treatment, areas of hypoperfusion were improved with amiloride, unchanged with aspirin, and worsened with placebo in comparison to baseline levels. Platelet aggregation after ADP showed no significant change during the month, but reduced rCBF significantly improved after 1-month treatment with amiloride compared with placebo and cocaine abstinence alone.

Examining the effect of cerebral perfusion abnormality magnitude on cognitive performance in recently abstinent chronic cocaine abusers.

BACKGROUND AND PURPOSE: Cerebral perfusion abnormalities and neuropsychological impairment are common sequelae of chronic cocaine abuse. While perfusion abnormalities have been shown to relate to cognitive deficits in this substance abuse population, the relationship between cognitive performance and the magnitude of perfusion abnormality has yet to be fully determined. METHODS: Thirty-seven abstinent cocaine abusers and 13 normal controls were administered resting 99m-Tc-HMPAO single photon emission computed tomography (SPECT) scans followed by a neuropsychological assessment battery tapping executive skills, attention, memory, and motor performance. Statistical parametric mapping (SPM99) techniques were used to analyze the SPECT data to detect significant regional perfusion abnormalities in the cocaine group relative to normal controls, and resulting abnormal SPECT counts were employed for comparison with the assessment measures to examine the relationship between cocaine-induced perfusion abnormalities and cognitive performance. RESULTS: SPECT data analysis revealed significant regional perfusion abnormalities in the cocaine abuse sample relative to controls and significant differences in neuropsychological functioning on measures of executive functioning, complex attention, memory, and manual dexterity. For chronic cocaine abusers, however, within-group comparisons of the magnitude of abnormal perfusion and neuropsychological performance were largely nonsignificant, with the exception of complex attention and motor speed. CONCLUSIONS: Perfusion abnormalities and neuropsychological impairments readily distinguished cocaine abusers from normal controls. However, when the magnitude of cocaine-induced perfusion abnormalities is examined in relation to cognitive performance, motor speed and complex attention appear to be the best behaviorial indicants of the severity of perfusion dysfunction within this substance abuse population.

Using quality improvement to optimise paediatric discharge efficiency.

BACKGROUND: Bed capacity management is a critical issue facing hospital administrators, and inefficient discharges impact patient flow throughout the hospital. National recommendations include a focus on providing care that is timely and efficient, but a lack of standardised discharge criteria at our institution contributed to unpredictable discharge timing and lengthy delays. Our objective was to increase the percentage of Hospital Medicine patients discharged within 2 h of meeting criteria from 42% to 80%. METHODS: A multidisciplinary team collaborated to develop medically appropriate discharge criteria for 11 common inpatient diagnoses. Discharge criteria were embedded into electronic medical record (EMR) order sets at admission and could be modified throughout a patient's stay. Nurses placed an EMR time-stamp to signal when patients met all discharge goals. Strategies to improve discharge timeliness emphasised completion of discharge tasks prior to meeting criteria. Interventions focused on buy-in from key team members, pharmacy process redesign, subspecialty consult timeliness and feedback to frontline staff. A P statistical process control chart assessed the impact of interventions over time. Length of stay (LOS) and readmission rates before and after implementation of process measures were compared using the Wilcoxon rank-sum test. RESULTS: The percentage of patients discharged within 2 h significantly improved from 42% to 80% within 18 months. Patients studied had a decrease in median overall LOS (from 1.56 to 1.44 days; p=0.01), without an increase in readmission rates (4.60% to 4.21%; p=0.24). The 12-month rolling average census for the study units increased from 36.4 to 42.9, representing an 18% increase in occupancy. CONCLUSIONS: Through standardising discharge goals and implementation of high-reliability interventions, we reduced LOS without increasing readmission rates.

Improving situation awareness to reduce unrecognized clinical deterioration and serious safety events.

BACKGROUND AND OBJECTIVE: Failure to recognize and treat clinical deterioration remains a source of serious preventable harm for hospitalized patients. We designed a system to identify, mitigate, and escalate patient risk by using principles of high-reliability organizations. We hypothesized that our novel care system would decrease transfers determined to be unrecognized situation awareness failures events (UNSAFE). These were defined as any transfer from an acute care floor to an ICU where the patient received intubation, inotropes, or ≥ 3 fluid boluses in first hour after arrival or before transfer. METHODS: The setting for our observational time series study was a quaternary care children's hospital. Before initiating tests of change, 2 investigators reviewed recent serious safety events (SSEs) and floor-to-ICU transfers. Collectively, 5 risk factors were associated with each event: family concerns, high-risk therapies, presence of an elevated early warning score, watcher/clinician gut feeling, and communication concerns. Using the model for improvement, an intervention was developed and tested to reliably and proactively identify patient risk and mitigate that risk through unit-based huddles. A 3-times daily inpatient huddle was added to ensure risks were escalated and addressed. Later, a "robust" and explicit plan for at-risk patients was developed and spread. RESULTS: The rate of UNSAFE transfers per 10,000 non-ICU inpatient days was significantly reduced from 4.4 to 2.4 over the study period. The days between inpatient SSEs also increased significantly. CONCLUSIONS: A reliable system to identify, mitigate, and escalate risk was associated with a near 50% reduction in UNSAFE transfers and SSEs.

Prospective evaluation of a pediatric inpatient early warning scoring system.

PURPOSE: The present study evaluated the use of the Pediatric Early Warning Score (PEWS) for detecting clinical deterioration among hospitalized children. DESIGN/METHODS: A prospective, descriptive study design was used. The tool was used to score 2,979 patients admitted to a single medical unit of a pediatric hospital over a 12-month period. RESULTS: PEWS discriminated between children who required transfer to the pediatric intensive care unit and those who did not require transfer (area under the curve = 0.89, 95% CI = 0.84-0.94, p < .001). IMPLICATIONS: The PEWS tool was found to be a reliable and valid scoring system to identify children at risk for clinical deterioration.

Targeting SMN to Cajal bodies and nuclear gems during neuritogenesis.

Neurite outgrowth is a central feature of neuronal differentiation. PC12 cells are a good model system for studying the peripheral nervous system and the outgrowth of neurites. In addition to the dramatic changes observed in the cytoplasm, neuronal differentiation is also accompanied by striking changes in nuclear morphology. The large and sustained increase in nuclear transcription during neuronal differentiation requires synthesis of a large number of factors involved in pre-mRNA processing. We show that the number and composition of the nuclear subdomains called Cajal bodies and gems changes during the course of N-ras-induced neuritogenesis in the PC12-derived cell line UR61. The Cajal bodies found in undifferentiated cells are largely devoid of the survival of motor neurons (SMN) protein product. As cells shift to a differentiated state, SMN is not only globally upregulated, but is progressively recruited to Cajal bodies. Additional SMN foci (also known as Gemini bodies, gems) can also be detected. Using dual-immunogold labeling electron microscopy and mouse embryonic fibroblasts lacking the coilin protein, we show that gems clearly represent a distinct category of nuclear body.

Modification of Sm small nuclear RNAs occurs in the nucleoplasmic Cajal body following import from the cytoplasm.

Biogenesis of functional spliceosomal small nuclear RNAs (snRNAs) includes the post-transcriptional covalent modification of numerous internal nucleotides. We have recently demonstrated that synthesis of 2'-O-methylated nucleotides and pseudouridines in the RNA polymerase II-synthesized Sm snRNAs is directed by sequence-specific guide RNAs. Here, we provide evidence supporting the notion that modification of Sm snRNAs occurs in nucleoplasmic Cajal bodies (CBs), where modification guide RNAs accumulate. We show that short fragments of Sm snRNAs are correctly and efficiently modified when targeted to CBs, but not when these same fragments are targeted to the nucleolus. We also demonstrate that internal modification of the U2 snRNA occurs exclusively after nuclear import of the newly assembled Sm snRNP from the cytoplasm. Finally, we show that p80 coilin, the CB marker protein, is not required for snRNA modification. In coilin knockout cells, Sm snRNAs and their modification guide RNAs colocalize in residual CBs, which do not stockpile fibrillarin and fail to recruit the U3 small nucleolar RNA.