Clinically significant psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, and the mediating influence of executive functioning.

OBJECTIVES: To clarify the neuropsychiatric phenotype of fragile X-associated tremor/ataxia syndrome (FXTAS), and assess the extent to which it is mediated by the dysexecutive syndrome that is a major feature of the disorder. METHODS: We examined the prevalence of clinically meaningful psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, in comparison with men with a normal allele. Measures included the Neuropsychiatric Inventory (NPI), Symptom Checklist-90-R (SCL-90-R), and the Behavioral Dyscontrol Scale, a measure of executive functioning. Between-group differences were evaluated using logistic regression, followed by a mediation analysis with ordinary least squares regression to assess the contribution of dysexecutive syndrome to the observed psychiatric domains. RESULTS: Men with FXTAS showed higher rates of clinically significant symptoms overall and in specific domains: somatization, obsessive compulsive, depression, anxiety, psychoticism, agitation/aggression, apathy/indifference, irritability, and nighttime behavior problems. Post hoc analyses suggested that findings of psychoticism among men with FXTAS may be associated with participants' accurate acknowledgment of cognitive and physical dysfunction, rather than reflecting psychosis. Asymptomatic carriers showed no evidence of clinically significant psychiatric symptoms, but when all carriers were compared with men having a normal FMR1 allele, executive function deficits were found to mediate scores in several domains on both NPI and SCL-90-R. CONCLUSIONS: Building on prior research, the results provide evidence that the psychiatric phenotype for men includes clinically meaningful depression, hostility, and irritability, in association with behavioral and attentional disinhibition. It is likely that these problems reflect the effects of impaired executive functioning.

White matter disease and cognitive impairment in FMR1 premutation carriers.

OBJECTIVE: This cross-sectional, observational study examined the role of white matter involvement in the cognitive impairment of individuals with the fragile X mental retardation 1 (FMR1) premutation. METHODS: Eight asymptomatic premutation carriers, 5 participants with fragile X tremor/ataxia syndrome (FXTAS), and 7 noncarrier controls were studied. The mean age of the asymptomatic premutation carriers, participants with FXTAS, and noncarrier controls was 60, 71, and 67 years, respectively. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) were used to examine the middle cerebellar peduncles (MCP) and the genu and splenium of the corpus callosum in relation to executive function and processing speed. MRS measures were N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine, and fractional anisotropy (FA) was used for DTI. Executive function was assessed with the Behavioral Dyscontrol Scale and the Controlled Oral Word Association Test (COWAT), and processing speed with the Symbol Digit Modalities Test. RESULTS: Among all 13 FMR1 premutation carriers, significant correlations were found between N-acetyl aspartate/creatine and choline/creatine in the MCP and COWAT scores, and between FA in the genu and performance on the Behavioral Dyscontrol Scale, COWAT, and Symbol Digit Modalities Test; a correlation was also found between FA in the splenium and COWAT performance. In all regions studied, participants with FXTAS had the lowest mean FA. CONCLUSION: Microstructural white matter disease as determined by MRS and DTI correlated with executive dysfunction and slowed processing speed in these FMR1 premutation carriers. Neuroimaging abnormalities in the genu and MCP suggest that disruption of white matter within frontocerebellar networks has an important role in the cognitive impairment associated with the FMR1 premutation.

Ethical conduct of palliative care research: enhancing communication between investigators and institutional review boards.

Palliative care has faced moral and ethical challenges when conducting research involving human subjects. There are currently no resources to guide institutional review boards (IRBs) in applying standard ethical principles and terms-in a specific way-to palliative care research. Using as a case study a recently completed multisite palliative care clinical trial, this article provides guidance and recommendations for both IRBs and palliative care investigators to facilitate communication and attain the goal of conducting ethical palliative care research and protecting study participants while advancing the science. Beyond identifying current challenges faced by palliative care researchers and IRBs reviewing palliative care research, this article suggests steps that the palliative care research community can take to establish a scientifically sound, stable, productive, and well-functioning relationship between palliative care investigators and the ethical bodies that oversee their work.

Strategies to support recruitment of patients with life-limiting illness for research: the Palliative Care Research Cooperative Group.

CONTEXT: The Palliative Care Research Cooperative Group (PCRC) is the first clinical trials cooperative for palliative care in the U.S. OBJECTIVES: To describe barriers and strategies for recruitment during the inaugural PCRC clinical trial. METHODS: The parent study was a multisite randomized controlled trial enrolling adults with life expectancy anticipated to be one to six months, randomized to discontinue statins (intervention) vs. to continue on statins (control). To study recruitment best practices, we conducted semistructured interviews with 18 site principal investigators (PIs) and clinical research coordinators (CRCs) and reviewed recruitment rates. Interviews covered three topics: 1) successful strategies for recruitment, 2) barriers to recruitment, and 3) optimal roles of the PI and CRC. RESULTS: All eligible site PIs and CRCs completed interviews and provided data on statin protocol recruitment. The parent study completed recruitment of 381 patients. Site enrollment ranged from 1 to 109 participants, with an average of 25 enrolled per site. Five major barriers included difficulty locating eligible patients, severity of illness, family and provider protectiveness, seeking patients in multiple settings, and lack of resources for recruitment activities. Five effective recruitment strategies included systematic screening of patient lists, thoughtful messaging to make research relevant, flexible protocols to accommodate patients' needs, support from clinical champions, and the additional resources of a trials cooperative group. CONCLUSION: The recruitment experience from the multisite PCRC yields new insights into methods for effective recruitment to palliative care clinical trials. These results will inform training materials for the PCRC and may assist other investigators in the field.

Achieving palliative care research efficiency through defining and benchmarking performance metrics.

PURPOSE OF REVIEW: Research efficiency is gaining increasing attention in the research enterprise, including palliative care research. The importance of generating meaningful findings and translating these scientific advances to improved patient care creates urgency in the field to address well documented system inefficiencies. The Palliative Care Research Cooperative Group (PCRC) provides useful examples for ensuring research efficiency in palliative care. RECENT FINDINGS: Literature on maximizing research efficiency focuses on the importance of clearly delineated process maps, working instructions, and standard operating procedures in creating synchronicity in expectations across research sites. Examples from the PCRC support these objectives and suggest that early creation and employment of performance metrics aligned with these processes are essential to generate clear expectations and identify benchmarks. These benchmarks are critical in effective monitoring and ultimately the generation of high-quality findings that are translatable to clinical populations. Prioritization of measurable goals and tasks to ensure that activities align with programmatic aims is critical. SUMMARY: Examples from the PCRC affirm and expand the existing literature on research efficiency, providing a palliative care focus. Operating procedures, performance metrics, prioritization, and monitoring for success should all be informed by and inform the process map to achieve maximum research efficiency.

Functional status of men with the fragile X premutation, with and without the tremor/ataxia syndrome (FXTAS).

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in some premutation carriers of the fragile X mental retardation 1 (FMR1) gene, is a neurodegenerative disorder characterized by action tremor, gait ataxia, and impaired executive cognitive functioning. OBJECTIVE: To evaluate the nature and severity of functional limitations among male carriers of the fragile X premutation, both with and without FXTAS. METHODS: Forty-two subjects with FXTAS and 24 asymptomatic premutation carriers were compared to 32 control subjects on measures of physical functioning, activities of daily living (ADLs; e.g. eating, bathing), and instrumental activities of daily living (IADLs; e.g. shopping, managing medications). Ordinary least squares regression, controlling for age, education, medical comorbidity, and pain, was used to examine group differences in physical and functional performance. RESULTS: Men with FXTAS performed significantly worse than control subjects on all dependent measures, showing greater limitations in physical functioning, as well as ADL and IADL performance (p < 0.05). Subsequent analyses suggested that physical and functional impairments among men with FXTAS result largely from deficits in motor and executive functioning and that CGG repeat length is associated with functional impairment. Asymptomatic carriers of the fragile X premutation performed similarly to control subjects on all measures. CONCLUSIONS: This study provides the first comprehensive evaluation of functional status among male premutation carriers. Although carriers without FXTAS performed similarly to control subjects, men with FXTAS showed evidence of significant physical and functional impairment, which appears to result largely from motor and executive deficits characteristic of the syndrome.

The primary cognitive deficit among males with fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation trinucleotide repeat expansion in the fragile X mental retardation 1 gene. Symptoms include gait ataxia, action tremor, and cognitive impairment. The objectives of the study were to clarify the nature of the dysexecutive syndrome observed in FXTAS and to assess the contribution of executive impairment to deficits in nonexecutive cognitive functions. Compared to controls, men with FXTAS demonstrated significant executive impairment, which was found to mediate group differences in most other cognitive abilities. Asymptomatic premutation carriers performed similarly to controls on all but two measures of executive functioning. These findings suggest that the impairment of nonexecutive cognitive skills in FXTAS is in large part secondary to executive dysfunction.

Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder.

The slow pace of interactive video telemedicine adoption: the perspective of telemedicine program administrators on physician participation.

We conducted semistructured interviews with telemedicine program administrators as part of a national survey of physicians and managers regarding attitudes toward, and knowledge of, telemedicine. Telemedicine administrators were interviewed regarding factors affecting physician adoption of interactive video (IAV) telemedicine. The seven networks with which these managers were affiliated represented "traditional" telemedicine programs, primarily providing specialty teleconsultation via IAV. These programs were located in different geographic regions, and included both consulting and referring sites. We include data only for well-established networks for which multiple administrators responded. Data were analyzed using standard qualitative research methods. We conclude that reimbursement issues are important determinants of the rate of adoption, but that by themselves they do not fully account for the slow diffusion of IAV telemedicine. Likewise, appeals to physicians as rational decision-makers are necessary but insufficient means of increasing the volume of telemedicine within a network. Telemedicine networks and administrators that have been effective in persuading physicians to practice telemedicine or to refer patients demonstrate an emphasis on aggressive recruitment of physicians who will be involved actively in one or the other role. Most efforts to encourage physicians to adopt telemedicine, however, have focused on the supply of specialists, rather than stimulating demand among primary care providers who have patients to refer. Habit was identified as an important, albeit overlooked, factor explaining physician adoption of telemedicine.

Specialist physicians' knowledge and beliefs about telemedicine: a comparison of users and nonusers of the technology.

Telemedicine as a technology has been available for nearly 50 years, but its diffusion has been slower than many had anticipated. Even efforts to reimburse providers for interactive video (IAV) telemedicine services have had a limited effect on rates of participation. The resulting low volume of services provided (and consequent paucity of research subjects) makes the phenomenon difficult to study. This paper, part of a larger study that also explores telemedicine utilization from the perspectives of referring primary care physicians and telemedicine system administrators, reports the results of a survey of specialist and subspecialist physicians who are users and nonusers of telemedicine. The survey examined self-assessed knowledge and beliefs about telemedicine among users and nonusers, examining also the demographic characteristics of both groups. Statistically significant differences were found in attitudes toward telemedicine between users and nonusers, but in many respects the views of the two groups were rather similar. Physicians who used telemedicine were aware of the limitations of the technology, but also recognized its potential as a means of providing consultation. Demographic differences did not explain the differences in the knowledge and beliefs of user and nonuser consultant physicians, although some of the differences may be explained by other aspects of the professional environment.

Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently identified phenotype associated with trinucleotide repeat expansions in the premutation range of the fragile X mental retardation 1 (FMR1) gene. In addition to progressive gait ataxia, action tremor, peripheral neuropathy, and parkinsonism, FXTAS involves impaired cognition. Our preliminary research suggests that executive cognitive functioning (ECF) is especially affected. In this study, a brief neuropsychological exam was administered to 33 men with FXTAS and 27 healthy controls. Compared with controls, individuals with FXTAS showed statistically significant impairments on measures from the Wechsler Adult Intelligence Scale, third edition (WAIS-III; verbal IQ, performance [nonverbal] IQ, verbal comprehension, perceptual organization, and processing speed). FXTAS subjects scored significantly lower on three of four measures of ECF and on two tests of information processing speed. The results provide evidence that FXTAS involves impairment of general intellectual functioning, with marked impairment of executive cognitive abilities. The pattern of cognitive performance is somewhat similar to that observed in the frontal variant of frontotemporal dementia and several of the spinocerebellar ataxias, but differs from the deficits observed in dementia of the Alzheimer type.

Alternatives to randomized controlled trials in telemedicine.

Research designs other than true experiments may be useful in the evaluation of telemedicine. Potential methods include those that do not rely on randomization and tight control of the intervention, and analysis of existing administrative and clinical databases. Quasi-experimental designs may also be useful, especially when conducted in association with careful statistical methods that allow the investigator to control for certain differences between groups. Databases, such as those maintained by the Centers for Medicare and Medicaid Services, contain information on both outcomes and claims, as well as disease/procedure registries and electronic health records. This may provide a potential tool for understanding the effects of telemedicine on access to care in conjunction with costs and quality. These different approaches have advantages and disadvantages, but may be useful in telemedicine, where the conduct of randomized controlled trials is generally very expensive and frequently not feasible.