Validation of the NIH Toolbox in Individuals with Neurologic Disorders.

OBJECTIVE: Individuals with spinal cord injury (SCI), traumatic brain injury (TBI), and stroke experience a variety of neurologically related deficits across multiple domains of function. The NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIHTB) examines motor, sensation, cognition, and emotional functioning. The purpose of this paper is to establish the validity of the NIHTB in individuals with neurologic conditions. METHODS: Community-dwelling individuals with SCI (n = 209), TBI (n = 184), or stroke (n = 211) completed the NIHTB. Relative risks for impaired performance were examined relative to a matched control groups. RESULTS: The largest group differences were observed on the Motor domain and for the Fluid Cognition measures. All groups were at increased risk for motor impairment relative to normative standards and matched controls. Fluid cognitive abilities varied across groups such that individuals with stroke and TBI performed more poorly than individuals with SCI; increased relative risks for impaired fluid cognition were seen for individuals in the stroke and TBI groups, but not for those in the SCI group. All three neurologic groups performed normally on most measures in the Sensation Battery, although TBI participants evidenced increased risk for impaired odor identification and the stroke group showed more vision difficulties. On the Emotion Battery, participants in all three groups showed comparably poor psychological well-being, social satisfaction, and self-efficacy, whereas the TBI group also evidenced slightly increased negative affect. CONCLUSIONS: Data provide support for the validity of the NIHTB in individuals with neurologic conditions.

HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system).

PURPOSE: Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD. METHODS: An EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items. RESULTS: EFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying. CONCLUSION: The HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.

The development of a new computer adaptive test to evaluate chorea in Huntington disease: HDQLIFE Chorea.

PURPOSE: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease associated with motor, behavioral, and cognitive deficits. The hallmark symptom of HD, chorea, is often the focus of HD clinical trials. Unfortunately, there are no self-reported measures of chorea. To address this shortcoming, we developed a new measure of chorea for use in HD, HDQLIFE Chorea. METHODS: Qualitative data and literature reviews were conducted to develop an initial item pool of 141 chorea items. An iterative process, including cognitive interviews, expert review, translatability review, and literacy review, was used to refine this item pool to 64 items. These 64 items were field tested in 507 individuals with prodromal and/or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to identify a unidimensional set of items. Then, an item response theory graded response model (GRM) and differential item functioning analyses were conducted to select the final items for inclusion in this measure. RESULTS: EFA and CFA supported the retention of 34 chorea items. GRM and DIF supported the retention of all of these items in the final measure. GRM calibration data were used to inform the selection of a 6-item, static short form and to program the HDQLIFE Chorea computer adaptive test (CAT). CAT simulation analyses indicated a 0.99 correlation between the CAT scores and the full item bank. CONCLUSIONS: The new HDQLIFE Chorea CAT and corresponding 6-item short form were developed using established rigorous measurement development standards; this is the first self-reported measure developed to evaluate the impact of chorea on HRQOL in HD. This development work indicates that these measures have strong psychometric properties; future work is needed to establish test-retest reliability and responsiveness to change.

HDQLIFE: the development of two new computer adaptive tests for use in Huntington disease, Speech Difficulties, and Swallowing Difficulties.

PURPOSE: Huntington disease (HD) is an autosomal dominant neurodegenerative disease which results in several progressive symptoms, including bulbar dysfunction (i.e., speech and swallowing difficulties). Although difficulties in speech and swallowing in HD have a negative impact on health-related quality of life, no patient-reported outcome measure exists to capture these difficulties that are specific to HD. Thus, we developed a new patient-reported outcome measure for use in the Huntington Disease Health-Related Quality of Life (HDQLIFE) Measurement System that focused on the impact that difficulties with speech and swallowing have on HRQOL in HD. METHODS: Five hundred and seven individuals with prodromal and/or manifest HD completed 47 newly developed items examining speech and swallowing difficulties. Unidimensional item pools were identified using exploratory factor analysis and confirmatory factor analysis (EFA and CFA, respectively). Item response theory (IRT) was used to calibrate the final measures. RESULTS: EFA and CFA identified two separate unidimensional sets of items: Speech Difficulties (27 items) and Swallowing Difficulties (16 items). Items were calibrated separately for these two measures and resulted in item banks that can be administered as computer adaptive tests (CATs) and/or 6-item, static short forms. Reliability of both of these measures was supported through high correlations between the simulated CAT scores and the full item bank. CONCLUSIONS: CATs and 6-item calibrated short forms were developed for HDQLIFE Speech Difficulties and HDQLIFE Swallowing Difficulties. These measures both demonstrate excellent psychometric properties and may have clinical utility in other populations where speech and swallowing difficulties are prevalent.

College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban.

OBJECTIVE: To review the role of the laboratory in monitoring therapy with low-molecular-weight heparin, danaparoid, hirudin, and argatroban, as reflected in the medical literature and the consensus opinion of recognized experts in the field. DATA SOURCES: Review of the medical literature and current clinical practice by a panel of 6 international experts in the field of anticoagulant therapy. DATA EXTRACTION AND SYNTHESIS: The experts made an extensive review of the published literature and prepared a draft manuscript, which included preliminary recommendations. The draft manuscript was circulated to participants in the College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy prior to the conference. The manuscript and recommendations were then presented at the Conference for discussion. Recommendations were accepted if a consensus of the 26 experts attending the Conference was reached. The results of the discussion were used to revise the manuscript into its final form. CONCLUSIONS: This report reviews the mechanism of action and potential uses of these newer anticoagulant agents. General guidelines for monitoring these agents and 9 specific recommendations for laboratory monitoring of low-molecular-weight heparin and danaparoid are provided, along with citation of the appropriate supporting literature. Issues for which a consensus was not reached at the Conference are also discussed.

A non-thrombocytopenic bleeding disorder due to an IgG4-kappa anti-GPIIb/IIIa autoantibody.

Autoantibodies in chronic immune thrombocytopenic purpura occasionally interfere with platelet function. We describe a patient with a normal platelet count who had clinically significant mucosal bleeding, a prolonged bleeding time and abnormal platelet aggregation. The patient had high titres of an IgG4 kappa autoantibody, directed to a cation-dependent epitope on platelet glycoprotein IIb/IIIa, which blocked the binding of fibrinogen and fibronectin to this complex. Corticosteroid treatment resulted in clinical improvement and a marked drop in autoantibody concentration. The lack of thrombocytopenia in this patient, despite high autoantibody levels, is best explained by the poor recognition of IgG4 antibodies by phagocytic cells.

Acute promyelocytic leukaemia in the all trans retinoic acid era.

Bleeding diathesis is a common complication of acute promyelocyctic leukaemia (APL). Multiple haemostatic defects are found in most patients with APL, which often worsen following cytoreductive chemotherapy. Besides thrombocytopenia, most patients develop disseminated intravascular coagulation, systemic fibrinolysis or both. A major aim in treating haemostatic defects of APL is to prevent death or disability from bleeding until chemotherapy clears the malignant promyelocytes from the blood and bone marrow. The therapeutic options are discussed in this review and practical guidelines for treatment are outlined.

Prospective comparison of infrainguinal bypass grafting in patients with and without antiphospholipid antibodies.

PURPOSE: The antiphospholipid antibodies (APL)-anticardiolipin antibodies (ACL) and lupus anticoagulant (LA)-are widely believed to be associated with decreased lower extremity bypass graft patency rates. To date, no prospective cohort study has confirmed this assumption. A prospective comparison of the result of infrainguinal revascularization procedures performed since 1990 in patients with and without APL forms the basis of this report. METHODS: Patients who underwent elective infrainguinal bypass procedures from 1990 to 1994 were evaluated for hypercoagulable states (ACL, LA, protein C, protein S, and antithrombin III). Patient data were prospectively entered in a computerized vascular registry, and postoperative follow-up was maintained for life. Graft patency, limb salvage, and patient survival rates were calculated by life-table methods. RESULTS: Three hundred twenty-seven lower extremity bypass grafting procedures were performed in 262 patients. APLs were present in 83 patients (32%); 70 patients (84%) had ACLs only, 11 patients (13%) had LA only, and two patients (3%) had both ACLs and LA. There was no significant difference between APL-positive and APL-negative patients with respect to demographics, associated medical conditions, indication for operations, and type of procedures performed. More patients who had APLs had warfarin treatment after surgery (43% vs 24%, p = 0.002). Life table 4-year primary patency rates showed minimal difference (APL-positive, 43%; APL-negative, 59%; p = 0.087), and no significant difference was noted in assisted primary patency rates (APL positive, 72%; APL negative, 73%; p = NS), limb salvage rates (APL positive, 79%; APL negative, 88%; p = NS), and patient survival rates (APL positive, 67%; APL negative, 66%; p = NS). CONCLUSIONS: APLs were found in a surprising one third of the patients who underwent leg bypass grafting procedures. The majority of APLs identified were ACLs (87%). There was minimal difference in graft primary patency rates, and no difference in assisted primary patency, limb salvage, and survival rates between patients with and without APLs who underwent leg bypass grafting procedures. The extreme morbidity rate associated with APLs in previous reports is not confirmed by this prospective study. APLs should not be regarded as a contraindication to indicated leg bypass grafting procedures.

Invasive line placement in critically ill patients: do hemostatic defects matter?

BACKGROUND: Blood components are often given prophylactically before the placement of invasive lines in patients with coagulation defects. Little, however, is known about the epidemiology of defects in these patients. The purpose of this study is to ascertain what proportion of intensive care patients who receive invasive lines have hemostatic defects, what actions are taken by physicians to correct these abnormalities before invasive line insertion, and what the incidence is of bleeding complications after invasive line placement. STUDY DESIGN AND METHODS: Charts were retrospectively reviewed for 490 intensive care patients in whom 938 arterial, pulmonary artery, and central venous lines were placed. RESULTS: At least one defect in hemostasis was documented for 388 patients (41%) before line placement, with 253 (27%) of these patients evidencing severe abnormalities. Seventeen percent of patients had no preprocedure laboratory evaluation. Trauma patients showed the highest numbers of abnormalities in hemostatic testing, but medical patients had more-severe defects. The occurrence of isolated abnormal laboratory values did not predict bleeding, but a score derived from a consideration of multiple defects did. Correction of the abnormalities was attempted in 37 percent of patients with hemostatic defects. Sixteen patients had bleeding complications, but only two had complications that were life-threatening. None of the complications were fatal. CONCLUSION: Invasive lines are used frequently in patients with hemostatic defects, often without any attempt to correct the abnormalities. Nevertheless, rates of hemorrhage are low and appear to be closely related to the level of experience of the physician rather than to defects in hemostasis. These findings suggest that the use of blood components for preprocedure correction of hemostatic defects is not necessary, except in those patients who have the most severe hemostatic abnormalities.

Aspirin therapy for cardiovascular disease.

Aspirin is a widely used and effective antithrombotic agent. Recent studies suggest that aspirin's anti-inflammatory effects are mediated via inhibition of an inducible isoform of cyclooxygenase in inflammatory cells (COX-2) and through blockade of the nuclear transcription factor, NF-kappa B. The optimal dose of aspirin for most clinical situations is 75 to 325 mg/d, but debate continues as to whether higher doses are needed to prevent cerebral ischemia. Aspirin is very effective for inhibition of platelet-mediated thrombosis at sites of vascular injury but does not reduce restenosis after coronary angioplasty or carotid endarterectomy, nor does it prevent a first stroke. Combined therapy with warfarin and aspirin has been shown to limit systemic embolic in high-risk patients with artificial heart valves, but at the cost of increased bleeding. A new aspirin derivative is currently being developed that appears to stimulate platelet nitric oxide release, inhibit thrombin-induced platelet aggregation, and lower gastric toxicity.

Molecular detection of a common mutation in coagulation factor V causing thrombosis via hereditary resistance to activated protein C.

More than half of all patients with familial or recurring venous thrombosis have hereditary resistance to activated protein C (HRAPC) as the result of specific missense mutation in the gene for coagulation factor V. Because the mutant factor Va (with an Arg to Gln substitution at codon 506) cannot be cleaved and inactivated by activated protein C, carriers of this mutation are at significantly increased risk of venous thrombosis. We have recently introduced a direct polymerase chain reaction (PCR)-based clinical diagnostic test for the factor V codon 506 mutation based on the destruction of an Mnl I restriction site by the causative nucleotide substitution. To assess the accuracy of this PCR-based assay, we compared a functional clotting time test for HRAPC with the direct mutation test. Of 47 patients dually tested, only five had discrepant values for the functional test versus the DNA test. Either of these two complementary assays is useful for the accurate diagnosis of HRAPC. The DNA-based test is, however, specifically recommended for evaluation of anticoagulated patients or patients with borderline functional tests and confirmation of genotype in HRAPC families. In an additional analysis of 287 normal individuals, we found an extremely high prevalence of the mutated codon 506 allele-- approximately 4% in each of two different populations. The absence of disease in the majority of heterozygous carriers suggests that symptomatic thrombosis requires the simultaneous presence of both a mutated factor V protein and additional synergistic factors.

Antiphospholipid antibodies in vascular surgery patients. A cross-sectional study.

BACKGROUND: Autoantibodies to phospholipid (aPL) have been associated with vascular thromboses in cerebral, coronary, and peripheral venous and arterial sites. To date, no large cross-sectional study has examined the incidence of occurrence of aPL in patients with peripheral arterial disease. METHODS: A cross-sectional study was performed with patients admitted for vascular surgery procedures to treat peripheral arterial disease for 23 months between January 1, 1990 and November 1, 1991. Consecutive patients were evaluated for the presence of aPL. Medical records for each patient were reviewed in detail, and historic, operative, and postoperative parameters were tabulated for relationship to the presence of aPL. RESULTS: Two hundred thirty-four patients underwent complete testing for aPL. All patients were receiving chronic aspirin therapy. This represented 86% of admissions. Antiphospholipid antibodies were detected in 60 patients (26%). No differences in age, sex, operation performed, or postoperative outcome were found between patients with and without aPL. However, patients with aPL were 1.8 times more likely to have undergone previous lower extremity (LE) vascular surgery than patients without aPL (95% confidence interval = 1.0 - 3.6, p = 0.047). Patients with aPL and previous LE vascular surgery were 5.6 times more likely to have had occlusion of that procedure than patients without aPL (95% confidence interval = 1.9 - 16.8, p = 0.03). The occluded previous LE procedures had a shorter duration of patency before occlusion in patients with aPL than in those without (mean duration of patency 17 months vs. 50 months, p < 0.003). Patients with occluded previous LE procedures and aPL were 4 times more likely to be female (95% C.I. = 1.4 - 11.3, p = 0.018). CONCLUSIONS: The incidence of aPL in vascular surgery patients is substantial. Vascular surgery patients with aPL are more likely to have failure of previous LE bypass procedures and to be female and the bypass failure occurs significantly more rapidly than in patients without aPL. Based on these data, testing of vascular surgery patients for aPL and investigation of alternative antithrombotic treatment regimens in patients with aPL appears warranted.

Antiphospholipid antibodies and thrombosis.

Antiphospholipid antibodies (eg, anticardiolipin antibodies or the lupus anticoagulant) are a fascinating set of autoantibodies that have been linked to venous and arterial thrombosis, immune-mediated thrombocytopenia, and recurrent pregnancy loss. This review high-lights recent advances in the immunology of antiphospholipid antibodies and their target antigens, potential mechanisms of thrombosis and thrombocytopenia, and new methods for laboratory identification of these antibodies. Clinical syndromes associated with antiphospholipid antibodies are also covered, including ischemic neurological disorders, cardiac lesions, venous thromboembolism, and pregnancy loss. In each instance, recommendations for therapy are discussed.

Effects of dietary fat content, saturated fatty acids, and fish oil on eicosanoid production and hemostatic parameters in normal men.

Populations that consume a diet rich in marine lipids have been reported to have a lower risk of coronary heart disease. However, some Western population groups with a high fish consumption continue to suffer elevated rates of coronary heart disease. Many of these individuals consume a diet rich in saturated fats in addition to the fish. To examine these possible dietary interactions we fed six healthy men diets that contained two levels of saturated fat (5% and 19% of energy). During 3-week periods the study subjects were given diets with a low-(25% of energy) and high-(39% of energy) fat content with and without inclusion of n-3 polyunsaturated or monounsaturated fatty acids (2% of energy). The effects of the n-3 fatty acids on the principal plasma lipid fractions were similar regardless of the saturated fat intake. Platelet function, as measured by the skin bleeding time, was inhibited when n-3 fatty acids were added to the low saturated-fat diet. In vivo thromboxane A2 production as assessed by urinary metabolites also declined (p < 0.01) during supplementation with n-3 fatty acids to a low-fat diet. Prostacyclin production were reduced on a low-fat diet compared to a high-fat diet regardless of supplementation with n-3 fatty acids. N-3 fatty acids stimulated the synthesis of modest amounts of thromboxane A3 and prostacyclin I3, on both the low and high saturated-fat diets. These studies showed that the effects of eicosapentaenoic and docosahexaenoic acids on platelet and vascular function and eicosanoid production are modulated by the content of saturated fatty acids in the diet.(ABSTRACT TRUNCATED AT 250 WORDS)