Safety and Tolerability of Thrombin Inhibition in Scleroderma-Associated Interstitial Lung Disease.

OBJECTIVE: Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) (scleroderma) and the leading cause of scleroderma-related deaths. There exists an unmet need for a new drug therapy for ILD-complicated SSc. Substantial evidence supports an important role for thrombin in the pathogenesis of SSc-associated ILD (hereafter SSc-ILD), and targeting thrombin with a direct thrombin inhibitor could prove to be a novel and effective treatment strategy. As a first step toward designing a clinical trial to test the efficacy of thrombin inhibition in SSc-ILD, we conducted this study to test the safety and tolerability of dabigatran in patients with SSc-ILD. METHODS: We performed a prospective, single-center, open-label treatment trial with the direct thrombin inhibitor, dabigatran, in patients with SSc-ILD. Any patient with a history of gastrointestinal hemorrhage or gastric antral vascular ectasia was excluded. Blood monitoring was performed monthly, and patient-reported outcomes, pulmonary function tests, and skin scores were obtained at baseline and at 3- and 6-month visits. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at baseline and at 6 months for measurement of lung thrombin activity. RESULTS: Of 15 patients with SSc-ILD, 14 completed 6 months of treatment with dabigatran at 75 mg taken orally twice daily. Adverse events were uncommon and usually mild or unrelated to the study medication. No serious adverse event was observed. Dabigatran was well tolerated, and we observed no significant gastrointestinal, pulmonary, or other safety issues or intolerability. BAL fluid thrombin activity decreased or remained stable in 13 of 14 (92.8%) subjects. CONCLUSION: Dabigatran appears to be safe and well tolerated in patients with SSc-ILD. A larger randomized controlled trial to test the efficacy of direct thrombin inhibition with dabigatran can be considered.

Prolonged Microgravity Affects Human Brain Structure and Function.

BACKGROUND AND PURPOSE: Widespread brain structural changes are seen following extended spaceflight missions. The purpose of this study was to investigate whether these structural changes are associated with alterations in motor or cognitive function. MATERIALS AND METHODS: Brain MR imaging scans of National Aeronautics and Space Administration astronauts were retrospectively analyzed to quantify pre- to postflight changes in brain structure. Local structural changes were assessed using the Jacobian determinant. Structural changes were compared with clinical findings and cognitive and motor function. RESULTS: Long-duration spaceflights aboard the International Space Station, but not short-duration Space Shuttle flights, resulted in a significant increase in total ventricular volume (10.7% versus 0%, P < .001, n = 12 versus n = 7). Total ventricular volume change was significantly associated with mission duration (r = 0.72, P = .001, n = 19) but negatively associated with age (r = -0.48, P = .048, n = 19). Long-duration spaceflights resulted in significant crowding of brain parenchyma at the vertex. Pre- to postflight structural changes of the left caudate correlated significantly with poor postural control; and the right primary motor area/midcingulate correlated significantly with a complex motor task completion time. Change in volume of 3 white matter regions significantly correlated with altered reaction times on a cognitive performance task (bilateral optic radiations, splenium of the corpus callosum). In a post hoc finding, astronauts who developed spaceflight-associated neuro-ocular syndrome demonstrated smaller changes in total ventricular volume than those who did not (12.8% versus 6.5%, n = 8 versus n = 4). CONCLUSIONS: While cautious interpretation is appropriate given the small sample size and number of comparisons, these findings suggest that brain structural changes are associated with changes in cognitive and motor test scores and with the development of spaceflight-associated neuro-optic syndrome.

Development of High Signal Intensity within the Globus Pallidus and Dentate Nucleus following Multiple Administrations of Gadobenate Dimeglumine.

BACKGROUND AND PURPOSE: Previous studies have evaluated various gadolinium based contrast agents and their association with gadolinium retention, however, there is a discrepancy in the literature concerning the linear agent gadobenate dimeglumine. Our aim was to determine whether an association exists between the administration of gadobenate dimeglumine and the development of intrinsic T1-weighted signal in the dentate nucleus and globus pallidus. MATERIALS AND METHODS: In this single-center, retrospective study, the signal intensity of the globus pallidus, dentate nucleus, thalamus, and middle cerebellar peduncle was measured on unenhanced T1-weighted images in 29 adult patients who had undergone multiple contrast MRIs using exclusively gadobenate dimeglumine (mean, 10.1 ± 3.23 doses; range, 6-18 doses). Two neuroradiologists, blinded to the number of prior gadolinium-based contrast agent administrations, separately placed ROIs within the globi pallidi, thalami, dentate nuclei, and middle cerebellar peduncles on the last MR imaging examinations. The correlations between the globus pallidus:thalamus and the dentate nucleus:middle cerebellar peduncle signal intensity ratios with the number of gadolinium-based contrast agent administrations and cumulative dose were tested with either 1-tailed Pearson or Spearman correlations. A priori, P < .05 was considered statistically significant. RESULTS: Both the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the number of gadolinium-based contrast agent administrations (r = 0.39, P = .017, and r = 0.58, P = .001, respectively). Additionally, the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the cumulative dose of gadobenate dimeglumine (r = 0.48, P = .004, and r = 0.43, P = .009, respectively). Dentate nucleus hyperintensity was qualitatively present on the last MR imaging in 79.3%-86.2% of patients and in all patients who had received >10 doses. CONCLUSIONS: At high cumulative doses (commonly experienced by patients, for example, with neoplastic disease), gadobenate dimeglumine is associated with an increase in the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncles signal intensity ratios.

Diffusional Kurtosis Imaging and Motor Outcome in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Motor impairment is the most common deficit after stroke. Our aim was to evaluate whether diffusional kurtosis imaging can detect corticospinal tract microstructural changes in the acute phase for patients with first-ever ischemic stroke and motor impairment and to assess the correlations between diffusional kurtosis imaging-derived diffusion metrics for the corticospinal tract and motor impairment 3 months poststroke. MATERIALS AND METHODS: We evaluated 17 patients with stroke who underwent brain MR imaging including diffusional kurtosis imaging within 4 days after the onset of symptoms. Neurologic evaluation included the Fugl-Meyer Upper Extremity Motor scale in the acute phase and 3 months poststroke. For the corticospinal tract in the lesioned and contralateral hemispheres, we estimated with diffusional kurtosis imaging both pure diffusion metrics, such as the mean diffusivity and mean kurtosis, and model-dependent quantities, such as the axonal water fraction. We evaluated the correlations between corticospinal tract diffusion metrics and the Fugl-Meyer Upper Extremity Motor scale at 3 months. RESULTS: Among all the diffusion metrics, the largest percentage signal changes of the lesioned hemisphere corticospinal tract were observed with axial kurtosis, with an average 12% increase compared with the contralateral corticospinal tract. The strongest associations between the 3-month Fugl-Meyer Upper Extremity Motor scale score and diffusion metrics were found for the lesioned/contralateral hemisphere corticospinal tract mean kurtosis (ρ = -0.85) and axial kurtosis (ρ = -0.78) ratios. CONCLUSIONS: This study was designed to be one of hypothesis generation. Diffusion metrics related to kurtosis were found to be more sensitive than conventional diffusivity metrics to early poststroke corticospinal tract microstructural changes and may have potential value in the prediction of motor impairment at 3 months.

Pediatric Patients Demonstrate Progressive T1-Weighted Hyperintensity in the Dentate Nucleus following Multiple Doses of Gadolinium-Based Contrast Agent.

BACKGROUND AND PURPOSE: While there have been recent reports of brain retention of gadolinium following gadolinium-based contrast agent administration in adults, a retrospective series of pediatric patients has not previously been reported, to our knowledge. We investigated the relationship between the number of prior gadolinium-based contrast agent doses and increasing T1 signal in the dentate nucleus on unenhanced T1-weighted MR imaging. We hypothesized that despite differences in pediatric physiology and the smaller gadolinium-based contrast agent doses that pediatric patients are typically administered based on weighted-adjusted dosing, the pediatric brain would also demonstrate dose-dependent increasing T1 signal in the dentate nucleus. MATERIALS AND METHODS: We included children with multiple gadolinium-based contrast agent administrations at our institution. A blinded reader placed ROIs within the dentate nucleus and adjacent cerebellar white matter. To eliminate reader bias, we also performed automated ROI delineation of the dentate nucleus, cerebellar white matter, and pons. Dentate-to-cerebellar white matter and dentate-to pons ratios were compared with the number of gadolinium-based contrast agent administrations. RESULTS: During 20 years at our institution, 280 patients received at least 5 gadolinium-based contrast agent doses, with 1 patient receiving 38 doses. Sixteen patients met the inclusion/exclusion criteria for ROI analysis. Blinded reader dentate-to-cerebellar white matter ratios were significantly associated with gadolinium-based contrast agent doses (rs = 0.77, P = .001). The dentate-to-pons ratio and dentate-to-cerebellar white matter ratios based on automated ROI placement were also significantly correlated with gadolinium-based contrast agent doses (t = 4.98, P < .0001 and t = 2.73, P < .02, respectively). CONCLUSIONS: In pediatric patients, the number of prior gadolinium-based contrast agent doses is significantly correlated with progressive T1-weighted dentate hyperintensity. Definitive confirmation of gadolinium deposition requires tissue analysis. Any potential clinical sequelae of gadolinium retention in the developing brain are unknown. Given this uncertainty, we suggest taking a cautious stance, including the use, in pediatric patients, of higher stability, macrocyclic agents, which in both human and animal studies have been shown to be associated with lower levels of gadolinium deposition, and detailed documentation of dosing. Most important, a patient should not be deprived of a well-indicated contrasted MR examination.

Medication prescribing and monitoring errors in primary care: a report from the Practice Partner Research Network.

INTRODUCTION: Medication errors have been associated with poor patient outcomes and pose significant public health consequences. Establishing medication safety quality indicators is crucial to capturing the pervasiveness of preventable errors and is a fundamental first step in the process of improvement. In this article, a study is presented in which a set of medication prescribing and monitoring quality indicators were developed, and adherence to them was assessed among a group of US primary care practices. METHODS: Twenty Practice Partner Research Network practices in 14 US states with 94 clinicians and 52,246 active adult patients participated in the study. All practices use a common electronic medical record with dosing, interaction and monitoring decision support features. A consensus development process was used to select indicators in the categories of inappropriate treatment, dosing, drug-drug and drug-disease interactions, and monitoring of potential adverse events. Data extracted electronically from practices' electronic medical record were used to assess practice-level adherence with the indicator set as of 1 July 2008. RESULTS: Thirty medication safety indicators were selected. Across all practices, inappropriate treatment, dosing, drug-drug and drug-disease interactions were avoided in 75%, 84%, 98% and 86% of eligible patients, respectively; monitoring of preventable adverse drug events occurred in 75% of patients. There was wide variability in practice adherence with the indicators. DISCUSSION: The consensus development process was successful in selecting a broad set of primary care medication safety quality indicators. Although aggregate adherence was relatively high in this group of practices, opportunities exist to improve potential errors in treatment selection, dosing and monitoring.

The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases.

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

Falls in individuals with incomplete spinal cord injury.

STUDY DESIGN: Mail survey of participants with incomplete spinal cord injury (SCI). OBJECTIVE: To describe the incidence, circumstances, consequences, and perceived contributory factors associated with falls among ambulatory individuals with incomplete SCI. SETTING: Southeast region of the United States. METHODS: A survey instrument was developed largely from existing measures and mailed to individuals with incomplete SCI to collect self-reported information on participant characteristics and fall-related variables. RESULTS: Seventy-five percent of study participants sustained at least one fall over the previous year. Even though most injuries were minor, 18% of fallers sustained a fracture and 45% reported reduced ability to get out into the community and engage in productive activity. Factors perceived to contribute to falls most often were decreased strength in the trunk and lower extremities, loss of balance, and hazards in the environment. CONCLUSIONS: Falls occur frequently and often have significant consequences among ambulatory individuals with SCI. These data may assist rehabilitation professionals to identify those at risk and implement fall prevention strategies. SPONSORSHIP: This project was supported by a grant from the South Carolina Spinal Cord Injury Research Fund Grant # 0703.

Hospital admissions, length of stay, charges, and in-hospital death among patients with systemic sclerosis.

OBJECTIVE: To investigate population hospitalization rates to community hospitals for systemic sclerosis (SSc, scleroderma) and examine whether age, sex, race, and insurance status independently predict length of stay (LOS), hospital charges, and in-hospital death. METHODS: The 1995 Healthcare Cost and Utilization Project national inpatient sample was used to identify 3,621 SSc hospitalizations. Weighted age, sex, and race-specific frequencies were divided by population estimates to calculate hospitalizations per million people. Regression models were used to model LOS, charges, and in-hospital death with age, sex, race, and insurance serving as the primary independent variables. Covariates included numbers of diagnoses and procedures, whether or not the admission was a transfer from another hospital, and the presence of comorbid conditions. RESULTS: Population hospitalization rates were higher for non-whites compared to whites among those < 65, while rates were higher for whites compared to non-whites for those > or =65 years old. On average, non-whites were at least 10 years younger than whites. The mean LOS was 7.5 days, with whites' average LOS being 10% shorter than non-whites', and patients with public health insurance having approximately 9% longer LOS than those with private insurance. Charges averaged almost US$15,000 per hospitalization (median = $8,441), amounting to $280 million in community hospital charges in the U.S. in 1995. The overall in-hospital death rate was 7.1%. CONCLUSION: These patterns are consistent with a greater burden and increased severity of disease among non-whites under age 65 with Ssc.

Predicted impact of attaining smoking reduction goals on mortality.

The impact of reducing smoking initiation, increasing smoking cessation, and combination approaches on life expectancy, deaths averted, and life-years gained in a birth cohort of 50,000 persons and in the state population (3.6 million) were analyzed. A 60% reduction in initiation of smoking in adolescents would increase life expectancy by 0.42 years. Over the next 100 years, there would be an additional 18,000 years of life for a birth cohort and an additional 675,000 years of life for the state's population. The reduction in mortality, however, would not begin before 35 years, and only 25% of the benefit would occur in the next 70 years. An increase in smoking cessation would have a smaller impact that would occur sooner. Maximum reduction in mortality could be achieved by reducing initiation and increasing cessation at all ages, but a reduction in mortality would not occur for several decades.

System supports for chronic illness care and their relationship to clinical outcomes.

The Chronic Care Model proposes that organizational system changes improve the quality of chronic care. This cross-sectional study explores the relationship between system supports for chronic care and clinical outcomes for two major chronic illnesses: diabetes and cardiovascular disease. Nine community-based primary care practices from the Practice Partner Research Network (PPRNet) are studied using practice group interviews and clinical data from the PPRNet database. As overall system support increases, providers' achievement of recommended care and desirable patient outcomes improves (r = .828, p = .006). Enhanced systems for provider decision support had the strongest positive correlation with clinical outcomes (r = .907, p = .001).

Electrical muscle stimulation as an adjunct to exercise therapy in the treatment of nonacute low back pain: a randomized trial.

A prospective, randomized, double-blind, placebo-controlled clinical trial was performed to investigate the efficacy of electrical muscle stimulation when combined with a therapist-guided, standardized exercise therapy program in the treatment of nonacute low back pain. Eighty patients with low back pain of at least 6 weeks' duration were randomized into the following 2 groups: standardized exercise therapy with functional electrical muscle stimulation or standardized exercise therapy with placebo electrical stimulation. Subjects were evaluated at baseline, 2 months, and 6 months with a standardized back pain questionnaire and objective measurements of lumbar spine function. Exercise therapy was continued for 6 months, but electrical stimulation was discontinued at the 2-month interval. Of the 80 patients initially enrolled, 42 discontinued or withdrew before completing the entire study protocol. At the 2-month follow-up interval, subjects in the treatment group had statistically significantly improved lumbar spine function compared with the control subjects. This effect continued during the last 4 months of the study after electrical stimulation had been discontinued. This suggests that electrical muscle stimulation can be an effective adjunctive treatment modality for nonacute low back pain. The effects of this combined therapy seem to last beyond the duration of electrical stimulation treatment.

Systemic sclerosis: environmental and occupational risk factors.

There is growing concern about the association between systemic sclerosis and certain environmental and occupational risk factors, including exposures to vinyl chloride, adulterated cooking oils, L-tryptophan, silica, silicone breast implants, organic solvents, and other agents such as epoxy resins, pesticides, and hand/arm vibration. This article highlights the current medical research that has examined these associations in scleroderma-like disorders and in systemic sclerosis.

Relationship of factors affecting age of onset of independent ambulation.

Despite the standard available pediatric developmental scales and popular lore that girls walk at an earlier age than boys, no large-scale evaluation of the age of onset of independent ambulation has been previously published. The purpose of this study was the prospective epidemiologic evaluation of a large heterogeneous group of normal children to determine the effect of gender, race, birth order, and socioeconomic status on the age of onset of independent ambulation. The study cohort consisted of 986 children (575 male, 471 female). A multivariable analysis of covariance model was used to examine the effects of race, gender, income, and birth order on age at ambulation. After controlling for the other variables in the model, race was the only statistically significant predictor of age at ambulation (p < 0.0001), with black children walking at a younger age (10.9 +/- 2.1 months) than white children (11.6 +/- 2.3 months). Overall, the independent variables included in the model were only able to explain 2.5% of the variance of age at ambulation.

Bone marrow transplantation versus periodic prophylactic blood transfusion in sickle cell patients at high risk of ischemic stroke: a decision analysis.

Measurement of cerebral blood velocity (CBV) by transcranial Doppler has been used to identify patients with sickle cell disease (SCD) who are at high risk of ischemic stroke. This study examines outcomes of bone marrow transplantation (BMT) and periodic blood transfusion (PBT) as a basis for making treatment recommendations for patients who have elevated CBV and no other indications for BMT. Decision analysis was used to compare the number of quality-adjusted life years (QALYs) experienced by a population of patients with SCD at high risk for stroke who were treated with PBT or BMT. Markov models were constructed to represent the clinical course of patients with SCD who were treated with PBT or BMT. Medical literature and expert opinion provided risks of stroke and death for different disease states, estimates of transition probabilities from one clinical state to another, and quality of life. An intention-to-treat analysis and an analysis of treatment received were both performed on hypothetical cohorts of 100 000 patients. Patients with SCD who were managed with a strategy of intending to provide BMT could expect 16.0 QALYs, compared with 15.7 QALYs for a strategy of intending to provide PBT; however, the variation around these estimates was large. In the treatment received analysis, patients compliant with PBT therapy and iron chelation could expect the best outcomes (19.2 QALYs). From a policy perspective, neither BMT nor PBT can be considered the "best" treatment for children with SCD who have abnormal CBV. Abnormal CBV should not be the only criterion for selecting patients with sickle cell for BMT.

Pleural fluid pH as a predictor of survival for patients with malignant pleural effusions.

STUDY OBJECTIVES: To assess the accuracy of pleural fluid (PF) pH in predicting duration of survival of patients with malignant pleural effusions. DESIGN: Analysis of patient-level data from nine sources retrieved from a MEDLINE search and correspondence with primary investigators. STUDY SELECTION: Published and unpublished studies that report PF pH values and duration of survival of patients with malignant pleural effusions. DATA COLLECTION AND ANALYSIS: Primary investigators supplied patient-level data (n = 417), which was examined by receiver operating characteristic (ROC) analysis, logistic regression, and survival time modeling to determine the utility of PF pH for predicting survival compared with other clinical factors. The primary investigations were graded for study design. MEASUREMENTS AND RESULTS: Median survival (n = 417) was 4.0 months: PF pH (p < 0.0039) was an independent predictor of survival duration. A PF pH test threshold < or = 7.28 had the highest accuracy for identifying poor 1-, 2-, and 3-month survivals. The predictive accuracies of PF pH (area under the ROC curve range, 0.571 to 0.662) and a PF pH-high-risk tumor (lung, soft tissues, renal, ovary, gastrointestinal, prostate, and oropharynx) model (odds ratio range, 2.91 to 6.67), however, were modest for predicting 1-, 2-, and 3-month survival. Only 54.4% and 62.7% of patients identified by PF pH < or = 7.28 or the PF pH-high-risk tumor model to die within 3 months were correctly classified. Weaknesses of the primary data were identified. CONCLUSIONS: PF pH has insufficient predictive accuracy for selecting patients for pleurodesis on the basis of estimated survival.