Functional correlates of cognitive dysfunction in clinically isolated syndromes.

Cognitive dysfunction can be identified in patients with clinically isolated syndromes suggestive of multiple sclerosis using ocular motor testing. This study aimed to identify the functional neural correlates of cognitive dysfunction in patients with clinically isolated syndrome using MRI. Eighteen patients with clinically isolated syndrome and 17 healthy controls were recruited. Subjects underwent standard neurological and neuropsychological testing. Subjects also underwent functional MRI (fMRI) during a cognitive ocular motor task, involving pro-saccade (direct gaze towards target) and anti-saccade (direct gaze away from target) trials. Ocular motor performance variables (averaged response time and error rate) were calculated for each subject. Patients showed a trend towards a greater rate of anti-saccade errors (p = 0.09) compared to controls. Compared to controls, patients exhibited increased activation in the right postcentral, right supramarginal gyrus, and the right parietal operculum during the anti-saccade>pro-saccade contrast. This study demonstrated that changes in functional organisation of cognitive brain networks is associated with subtle cognitive changes in patients with clinically isolated syndrome.

Availability of ulipristal acetate: A secret shopper survey of pharmacies in a metropolitan area on emergency contraception.

OBJECTIVES: To assess levonorgestrel (LNG) and ulipristal acetate (UPA) availability in pharmacies in a metropolitan area. METHODS: A cross-sectional survey was conducted of all identified pharmacies within 25 miles of an urban medical center in Kansas City, KS. We categorized the pharmacies as dedicated commercial (national chains), store-associated (affiliated with a general merchandise or grocery store), or independent. We assessed LNG and UPA availability or time to availability if not currently stocked. RESULTS: We contacted 165 pharmacies. Of the 165 pharmacies, few stocked UPA (12/165, 7%) whereas the majority stocked oral LNG (128/165, 78%). Dedicated commercial pharmacies were more likely to carry UPA than store-associated and independent pharmacies (11/84 [13%] vs. 1/61 [1%] vs. 0/20, respectively; P = 0.016). Most pharmacies that did not stock UPA reported that they could obtain it within 24 hours (94/153, 62%). Dedicated commercial pharmacies were most likely report the ability to obtain UPA in 24 hours (P = 0.016). CONCLUSION: Few pharmacies stock UPA, the most effective form of oral emergency contraception. Enhanced communication between medical providers and pharmacists within current laws and regulations could enhance patient access to UPA.

Assessment of technician barcode scanning verification compared to pharmacist verification.

PURPOSE: This study aims to show the feasibility and sustainability of technician barcode scanning verification as an alternative to pharmacist visual verification of first dose medications in an acute care setting. METHODS: A two-phase, noninferiority, single-center study was conducted to compare the accuracy of technician barcode scanning verification to pharmacist visual verification of pre-packaged first dose medications within a large acute care medical center. In phase 1, a pharmacy technician utilized barcode scanning as a means of verification. These preparations were then re-verified for accuracy by pharmacist visual verification. In phase 2, the verification order was reversed, starting with pharmacist visual verification of first doses, which were subsequently re-verified by a technician utilizing barcode scanning. Accuracy and efficiency (first dose processing time) of each phase was analyzed via error logs and retrospective dose tracking. RESULTS: A total of 12,328 first dose preparations were included in the analysis and showed no difference between technician barcode scanning verification and pharmacist visual verification. Retrospective time study showed a 4-minute decrease in processing time when doses were verified by technician barcode scanning. Based on initial study outcomes, a variance was granted to pilot first dose tech-check-tech by the Wisconsin State Board of Pharmacy. CONCLUSION: This study determined that there is no difference in verification accuracy between technician barcode scanning verification and pharmacist visual verification of first doses in an acute care setting. Through leveraging technology and skill mix, Froedtert Hospital was able to provide the same level of patient safety while decreasing pharmacy processing time, developing our technician workforce, and reallocating pharmacist staff from distributive roles in central pharmacy to decentralized clinical activities.

Middle Cerebellar Peduncle Width-A Novel MRI Biomarker for FXTAS?

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe neurodegenerative movement disorder affecting over 40% of male and 16% of female FMR1 premutation carriers over the age of 50. However, there is a lack of prognostic biomarkers to aid early diagnosis and treatment planning. Therefore, this study aimed to assess the utility of the Magnetic Resonance Parkinson Index (MRPI) as a potential MRI biomarker for FXTAS. The four measurements required for the MRPI were assessed in 45 male premutation carriers at risk of developing FXTAS (Mean age = 59.54 years), 53 male patients with FXTAS (Mean age = 66.16 years) and 61 male controls (Mean age = 60.75 years), of which 73 participants had follow-up visits on average 1.96 years later. Middle cerebellar peduncle (MCP) width as well as midbrain and pons cross-sectional area were reduced in patients with FXTAS compared to both premutation carriers without FXTAS and controls. While these measurements were not found to change over time in the three-group analysis, age was an important predictor of midbrain cross-sectional area and pons/midbrain ratio. MCP width was initially reduced in a subset of premutation carriers who developed FXTAS symptoms between their initial and follow-up visits, which also decreased between visits, compared to age-matched premutation carriers who did not show any FXTAS symptom development over time. Therefore, while the MPRI may not be a useful biomarker for FXTAS, decreased MCP width may be one of the first notable signs of FXTAS, and therefore the first biomarker with the potential to identify those most at risk for the disorder.

Long term verbal memory recall deficits in fragile X premutation females.

Carriers of a FMR1 premutation allele (between 55 and 199 CGG repeats) are at risk of developing a wide range of medical, psychiatric and cognitive disorders, including executive dysfunction. These cognitive deficits are often less severe for female premutation carriers compared to male premutation carriers, albeit similar in nature. However, it remains unclear whether female premutation carriers who exhibit executive dysfunction also report verbal learning and memory deficits like those of their male counterparts. Here we employed the CVLT to assess verbal learning and memory function in 19 female premutation carriers, contrasting performance with 19 age- and IQ-matched controls. Group comparisons revealed similar performance during the learning and short delay recall phases of the CVLT. However, after a long delay period, female premutation carriers remembered fewer words for both free and cued recall trials, but not during recognition trials. These findings are consistent with reports for male premutation carriers, and suggest that aspects of long term memory may be adversely affect in a subgroup of premutation carriers with signs of executive dysfunction.

White matter microstructure, cognition, and molecular markers in fragile X premutation females.

OBJECTIVE: To examine the interrelationships between fragile X mental retardation 1 (FMR1) mRNA and the FMR1 exon 1/intron 1 boundary methylation, white matter microstructure, and executive function, in women with a FMR1 premutation expansion (PM; 55-199 CGG repeats) and controls (CGG < 44). METHODS: Twenty women with PM without fragile X-associated tremor/ataxia syndrome (FXTAS) and 20 control women between 22 and 54 years of age completed this study. FMR1 mRNA and methylation levels for 9 CpG sites within the FMR1 exon 1/intron 1 boundary from peripheral blood samples were analyzed. To measure white matter microstructure, diffusion-weighted imaging was used, from which fractional anisotropy (FA) and mean diffusivity (MD) values from anatomic regions within the corpus callosum and cerebellar peduncles were extracted. Executive function was assessed across a range of tasks. RESULTS: No differences were revealed in white matter microstructure between women with PM and controls. However, we reveal that for women with PM (but not controls), higher FMR1 mRNA correlated with lower MD values within the middle cerebellar peduncle and Paced Auditory Serial Addition Test scores, higher methylation of the FMR1 exon 1/intron 1 boundary correlated with lower MD within the inferior and middle cerebellar peduncles and longer prosaccade latencies, and higher FA values within the corpus callosum and cerebellar peduncle regions corresponded to superior executive function. CONCLUSIONS: We provide evidence linking white matter microstructure to executive dysfunction and elevated FMR1 mRNA and FMR1 exon 1/intron 1 boundary methylation in women with PM without FXTAS. This suggests that the FXTAS phenotype may not be distinct but may form part of a spectrum of PM involvement.

Disassociation between brain activation and executive function in fragile X premutation females.

Executive dysfunction has been demonstrated among premutation (PM) carriers (55-199 CGG repeats) of the Fragile X mental retardation 1 (FMR1) gene. Further, alterations to neural activation patterns have been reported during memory and comparison based functional magnetic resonance imaging (fMRI) tasks in these carriers. For the first time, the relationships between fMRI neural activation during an interleaved ocular motor prosaccade/antisaccade paradigm, and concurrent task performance (saccade measures of latency, accuracy and error rate) in PM females were examined. Although no differences were found in whole brain activation patterns, regions of interest (ROI) analyses revealed reduced activation in the right ventrolateral prefrontal cortex (VLPFC) during antisaccade trials for PM females. Further, a series of divergent and group specific relationships were found between ROI activation and saccade measures. Specifically, for control females, activation within the right VLPFC and supramarginal gyrus correlated negatively with antisaccade latencies, while for PM females, activation within these regions was found to negatively correlate with antisaccade accuracy and error rate (right VLPFC only). For control females, activation within frontal and supplementary eye fields and bilateral intraparietal sulci correlated with prosaccade latency and accuracy; however, no significant prosaccade correlations were found for PM females. This exploratory study extends previous reports of altered prefrontal neural engagement in PM carriers, and clearly demonstrates dissociation between control and PM females in the transformation of neural activation into overt measures of executive dysfunction. Hum Brain Mapp 38:1056-1067, 2017. © 2016 Wiley Periodicals, Inc.

Implementation of cystic fibrosis clinical pathways improved physician adherence to care guidelines.

INTRODUCTION: There is significant variability in clinical outcomes, including growth and lung function, between the various cystic fibrosis (CF) centers. No specific or unique therapeutic practices have been identified to account for these differences. However, more uniform care within centers was associated with better outcomes. The objective of this study was to implement clinical pathways for diagnosis and treatment of nutritional failure and lung inflammation in order to achieve better health care provider adherence to center-specific, agreed-on practices. METHODS: Agreed-on clinical pathway treatment plans for both nutrition and lower airway inflammation were implemented on January 1, 2010. The primary outcome measure was to evaluate if patients' diagnoses and treatments were consistent with the agreed-on clinical pathways. RESULTS: The proportion of clinic visits from baseline to 18 months post-intervention where the provider completely followed nutrition clinical pathway increased from 57.72% to 79.49% (P = 0.049) and the proportion for lower airway inflammation clinical pathway increased from 65.85% to 86.32% (P = 0.035). The use of nutritional diagnosis and documentation of associated clinical pathway in the clinical plan increased from 16.26% to 61.54% and 56.10% to 94.87%, respectively. Similarly, diagnosis of lower airway inflammation and documentation related to their treatment plans increased from 1.63% to 43.59% and 30.08% to 87.18%, respectively. CONCLUSION: Implementation of clinical pathways for nutrition and lower airway inflammation issues resulted in more uniform care of CF patients. Having objective criteria for diagnoses and agreed-on treatment plans for each of those diagnoses allowed for monitoring and individual feedback. Increases in utilization of correct diagnoses and discussion of specific therapeutic interventions in the clinic notes were associated with increased adherence to clinical pathways. Pediatr Pulmonol. 2017;52:175-181. © 2016 Wiley Periodicals, Inc.

Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The disorder is characterized by kinetic tremor and cerebellar ataxia, shows age-dependent penetrance, and occurs more frequently in men. This paper summarizes the key emerging issues in FXTAS as presented at the Second International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2015. The topics discussed include phenotype-genotype relationships, neurobehavioral function, and updates on FXTAS genetics and imaging.

Executive Dysfunction in Female FMR1 Premutation Carriers.

There is now growing evidence of cognitive weakness in female premutation carriers (between 55 and 199 CGG repeats) of the fragile X mental retardation gene, including impairments associated with executive function. While an age-related decline in assessments of executive function has been found for male premutation carriers, few studies have explored whether female carriers show a similar trajectory with age. A total of 20 female premutation carriers and 21 age- and IQ-matched healthy controls completed a battery of tasks assessing executive function tasks, including the behavioural dyscontrol scale (BDS), symbol digit modalities test (SDMT), paced auditory serial addition test (PASAT), Haylings sentence completion test and the digit span task (forward and backward). Performance was compared between premutation carriers and healthy controls, and the association between task performance and age was also ascertained. Compared to controls, female premutation carriers had significant impairment on the BDS, SDMT, PASAT, and Haylings sentence completion task, all of which rely on quick, or timed, responses. Further analyses revealed no significant association between age and task performance for either premutation carriers or controls. This study demonstrates that a cohort of female premutation carriers have deficits on a range of tasks of executive function that require the rapid temporal resolution of responses. We propose that the understanding of the phenotype of premutation carriers will be advanced through use of such measures.

Development of an in vitro colonization model to investigate Staphylococcus aureus interactions with airway epithelia.

Staphylococcus aureus is a bacterial pathogen responsible for a wide range of diseases and is also a human commensal colonizing the upper respiratory tract. Strains belonging to the clonal complex group CC30 are associated with colonization, although the colonization state itself is not clearly defined. In this work, we developed a co-culture model with S. aureus colonizing the apical surface of polarized human airway epithelial cells. The S. aureus are grown at the air-liquid interface to allow an in-depth evaluation of a simulated colonization state. Exposure to wild-type, S. aureus bacteria or conditioned media killed airway epithelial cells within 1 day, while mutant S. aureus strains lacking alpha-toxin (hla) persisted on viable cells for at least 2 days. Recent S. aureus CC30 isolates are natural hla mutants, and we observed that these strains displayed reduced toxicity toward airway epithelial cells. Quantitative real-time polymerase chain reaction of known virulence factors showed the expression profile of S. aureus grown in co-culture correlates with results from previous human colonization studies. Microarray analysis indicated significant shifts in S. aureus physiology in the co-culture model toward lipid and amino acid metabolism. The development of the in vitro colonization model will enable further study of specific S. aureus interactions with the host epithelia.

Delineation of the working memory profile in female FMR1 premutation carriers: the effect of cognitive load on ocular motor responses.

Fragile X mental retardation 1 (FMR1) premutation carriers (PM-carriers) are characterised as having mid-sized expansions of between 55 and 200 CGG repeats in the 5' untranslated region of the FMR1 gene. While there is evidence of executive dysfunction in PM-carriers, few studies have explicitly explored working memory capabilities in female PM-carriers. 14 female PM-carriers and 13 age- and IQ-matched healthy controls completed an ocular motor n-back working memory paradigm. This task examined working memory ability and the effect of measured increases in cognitive load. Female PM-carriers were found to have attenuated working memory capabilities. Increasing the cognitive load did not elicit the expected reciprocal increase in the task errors for female PM-carriers, as it did in controls. However female PM-carriers took longer to respond than controls, regardless of the cognitive load. Further, FMR1 mRNA levels were found to significantly predict PM-carrier response time. Although preliminary, these findings provide further evidence of executive dysfunction, specifically disruption to working memory processes, which were found to be associated with increases in FMR1 mRNA expression in female PM-carriers. With future validation, ocular motor paradigms such as the n-back paradigm will be critical to the development of behavioural biomarkers for identification of PM-carrier cognitive-affective phenotypes.

Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: through eye movements.

There is evidence which demonstrates that a subset of males with a premutation CGG repeat expansion (between 55 and 200 repeats) of the fragile X mental retardation 1 gene exhibit subtle deficits of executive function that progressively deteriorate with increasing age and CGG repeat length. However, it remains unclear whether similar deficits, which may indicate the onset of more severe degeneration, are evident in female PM-carriers. In the present study we explore whether female PM-carriers exhibit deficits of executive function which parallel those of male PM-carriers. Fourteen female fragile X premutation carriers without fragile X-associated tremor/ataxia syndrome and fourteen age, sex, and IQ matched controls underwent ocular motor and neuropsychological tests of select executive processes, specifically of response inhibition and working memory. Group comparisons revealed poorer inhibitory control for female premutation carriers on ocular motor tasks, in addition to demonstrating some difficulties in behaviour self-regulation, when compared to controls. A negative correlation between CGG repeat length and antisaccade error rates for premutation carriers was also found. Our preliminary findings indicate that impaired inhibitory control may represent a phenotype characteristic which may be a sensitive risk biomarker within this female fragile X premutation population.