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1.  Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008) 
Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.
doi:10.1038/ki.2008.613
PMCID: PMC3500614  PMID: 19180126
drug-associated TTP; epidemiology; ADAMTS13
2.  A model for teaching bedside detection of glass in wounds 
Emergency Medicine Journal : EMJ  2007;24(6):413-416.
Background
Emergency physicians often manage wounds contaminated with glass. Even when glass is visible on x rays, removal may require real‐time bedside imaging.
Aim
To assess whether novices can be easily trained to accurately detect tiny glass foreign bodies (GFBs) using low‐power portable fluoroscopy.
Methods
21 medical students with no prior experience using fluoroscopy were taught to detect 1 mm GFBs in chicken legs either by training over three separate days or by training on 1 day. Skills were reassessed at 3 months. The number of mean correct responses was compared between groups using analysis of variance (ANOVA) and by examination of 95% CIs.
Results
Examination of CI overlap and ANOVA suggested that asymptotic accuracy was achieved after 15–30 training specimens. The final accuracy was similar between protocols, was comparable to prior accuracy reports of plain film radiography and was maintained in both protocols at the 3 month follow‐up: 10.9 (0.3) and 12.0 (0.8; out of 15).
Conclusions
Novices can easily be taught to detect GFBs using fluoroscopy, with accuracy comparable to that achieved by radiologists using plain films. Further studies are needed to assess doctors' use of the technique in real patients.
doi:10.1136/emj.2007.047340
PMCID: PMC2658276  PMID: 17513538
3.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
Objectives
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
Background
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Methods
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Results
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Conclusions
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
doi:10.1016/j.jacc.2007.04.093
PMCID: PMC3167088  PMID: 17868804
4.  Evaluation of a Potential Clinical Interaction between Ceftriaxone and Calcium▿  
In April 2009, the FDA retracted a warning asserting that ceftriaxone and intravenous calcium products should not be coadministered to any patient to prevent precipitation events leading to end-organ damage. Following that announcement, we sought to evaluate if the retraction was justified. A search of the FDA Adverse Event Reporting System was conducted to identify any ceftriaxone-calcium interactions that resulted in serious adverse drug events. Ceftazidime-calcium was used as a comparator agent. One hundred four events with ceftriaxone-calcium and 99 events with ceftazidime-calcium were identified. Adverse drug events were recorded according to the listed description of drug involvement (primary or secondary suspect) and were interpreted as probable, possible, unlikely, or unrelated. For ceftriaxone-calcium-related adverse events, 7.7% and 20.2% of the events were classified as probable and possible for embolism, respectively. Ceftazidime-calcium resulted in fewer probable embolic events (4%) but more possible embolic events (30.3%). Among cases that considered ceftriaxone or ceftazidime and calcium as the primary or secondary drug, one case was classified as a probable embolic event. That patient received ceftriaxone-calcium and died, although an attribution of causality was not possible. Our analysis suggests a lack of support for the occurrence of ceftriaxone-calcium precipitation events in adults. The results of the current analysis reinforce the revised FDA recommendations suggesting that patients >28 days old may receive ceftriaxone and calcium sequentially and provide a transparent and reproducible methodology for such evaluations.
doi:10.1128/AAC.01111-09
PMCID: PMC2849391  PMID: 20086152
5.  Serial Plasma Voriconazole Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation▿  
Plasma voriconazole concentrations vary considerably between patients receiving standard dosing, and trough voriconazole concentrations are known to affect efficacy and toxicity. Temporal variations in serial plasma voriconazole concentrations through the course of therapy in hematopoietic stem cell transplantation patients has not been carefully described. Paired voriconazole concentrations in 64 patients were studied to determine the predictability of the second concentration based on the first. The difference between the two values was ≤5% in six patients. In 25 patients, the second concentration was higher by a median of 40%. In 33 patients, the subsequent concentration was lower by a median of 59%. For patients with an initial concentration of <2 μg/ml, the correlation between the two values was poor (r = 0.24; P < 0.17). For those with an initial concentration of ≥2 μg/ml, the correlation was good (r = 0.72; P < 0.0001). There was no relationship between the magnitude of the change and the time elapsing between the two measurements. Among the 43 patients who had an initial concentration of ≥1 μg/ml, the two voriconazole measurements were strongly correlated (r = 0.66, P < 0.0001), but only 67% had a voriconazole serum concentration of ≥1 μg/ml on the second measurement. No studied variables were reliable predictors in identifying concentrations above or below 1 or 2 μg/ml. Our data suggest that variations in voriconazole concentrations are unpredictable despite standard dosing, and the acceptability of a concentration on one occasion cannot be extrapolated to future concentrations in the same patient. This suggests that ongoing therapeutic drug monitoring and dose adjustment may be beneficial in patients requiring prolonged voriconazole therapy.
doi:10.1128/AAC.01316-08
PMCID: PMC2681520  PMID: 19223632
6.  Hepatotoxicity Associated with Long-versus Short-Course HIV-Prophylactic Nevirapine Use 
Background and objective
The antiretroviral nevirapine can cause severe hepatotoxicity when used ‘off-label’ for preventing mother-to-child HIV transmission (PMTCT), newborn post-exposure prophylaxis and for pre- and post-exposure prophylaxis among non-HIV-infected individuals. We describe the incidence of hepatotoxicity with short- versus long-course nevirapine-containing regimens in these groups.
Methods
We reviewed hepatotoxicity cases among non-HIV-infected individuals and HIV-infected pregnant women and their offspring receiving short- (≤4 days) versus long-course (≥5 days) nevirapine prophylaxis. Sources included adverse event reports from pharmaceutical manufacturers and the US FDA, reports from peer-reviewed journals/scientific meetings and the Research on Adverse Drug events And Reports (RADAR) project. Hepatotoxicity was scored using the AIDS Clinical Trial Group criteria.
Results
Toxicity data for 8216 patients treated with nevirapine-containing regimens were reviewed. Among 402 non-HIV-infected individuals receiving short- (n = 251) or long-course (n = 151) nevirapine, rates of grade 1–2 hepatotoxicity were 1.99%versus 5.30%, respectively, and rates of grade 3–4 hepatotoxicity were 0.00% versus 13.25%, respectively (p < 0.001 for both comparisons). Among 4740 HIV-infected pregnant women receiving short- (n = 3031) versus long-course (n = 1709) nevirapine, rates of grade 1–2 hepatotoxicity were 0.62% and 7.04%, respectively, and rates of grade 3–4 hepatotoxicity were 0.23% versus 4.39%, respectively (p < 0.001 for both comparisons). The rates of grade 3–4 hepatotoxicity among 3074 neonates of nevirapine-exposed HIV-infected pregnant women were 0.8% for those receiving short-course (n = 2801) versus 1.1%for those receiving long-course (n = 273) therapy (p < 0.72).
Conclusions
Therapy duration appears to significantly predict nevirapine hepatotoxicity. Short-course nevirapine for HIV prophylaxis is associated with fewer hepatotoxic reactions for non-HIV-infected individuals or pregnant HIV-infected women and their offspring, but administration of prophylactic nevirapine for ≥2 weeks appears to be associated with high rates of hepatotoxicity among non-HIV-infected individuals and HIV-infected pregnant mothers. When full highly active antiretroviral therapy (HAART) regimens are not available, single-dose nevirapine plus short-course nucleoside reverse transcriptase inhibitors to decrease the development of HIV viral resistance is an essential therapeutic option for PMTCT and these data support the safety of single-dose nevirapine in this setting.
PMCID: PMC2768573  PMID: 19236121
7.  The Roles of Low Literacy and Social Support in Predicting the Preventability of Hospital Admission 
BACKGROUND
Prior studies found higher hospitalization rates among patients with low literacy, but did not determine the preventability of these admissions or consider other determinants of hospitalization, such as social support. This study evaluated whether low literacy was a predictor for preventability of hospitalization when considered in the context of social support, sociodemographics, health status, and risk behaviors.
METHODS
A convenience sample of 400 patients, admitted to general medicine wards in a university-affiliated Veterans Affairs hospital between August 1, 2001 and April 1, 2003, completed a face-to-face interview to assess literacy, sociodemographics, social support, health status, and risk behaviors. Two Board-certified Internists independently assessed preventability of hospitalization and determined the primary preventable cause through blinded medical chart reviews.
RESULTS
Neither low literacy (
CONCLUSIONS
While low literacy was not predictive of admission preventability, the formal assessment of alcohol binge drinking, social support for medical care, social network size, and prior outpatient utilization may enhance our ability to predict the preventability of hospitalizations and develop targeted interventions.
doi:10.1111/j.1525-1497.2005.00300.x
PMCID: PMC1484663  PMID: 16336616
health literacy; social support; hospital medicine; veterans; preventable admission
Journal of Clinical Microbiology  2005;43(1):462-463.
Historically, most clinical microbiology laboratories report that 80 to 90% of enterococci are Enterococcus faecalis, whereas E. faecium accounts for 5 to 10% of isolates. At our medical center from 1993 to 2002, we evaluated the percentages of E. faecium among all enterococcal isolates and the percentages of E. faecium isolates that were vancomycin resistant. Over this 10-year period, the percentage of enterococci that were identified as E. faecium increased from 12.7 to 22.2% (P < 0.001) and the proportion of E. faecium that was vancomycin resistant increased from 28.9 to 72.4% (P < 0.001). Both the percentage of E. faecium among the enterococci and the proportion of vancomycin-resistant E. faecium increased significantly over this 10-year period.
doi:10.1128/JCM.43.1.462-463.2005
PMCID: PMC540171  PMID: 15635016
OBJECTIVE
To determine whether older age continues to influence patterns of care and in-hospital mortality for hospitalized persons with HIV-related Pneumocustis carinii pneumonia (PCP), as determined in our prior study from the 1980s.
DESIGN
Retrospective chart review.
PATIENTS/SETTING
Patients (1,861) with HIV-related PCP at 78 hospitals in 8 cities from 1995 to 1997.
MEASUREMENTS
Medical record notation of possible HIV infection; alveolar-arterial oxygen gradient; CD4 lymphocyte count; presence or absence of wasting; timely use of anti-PCP medications; in-hospital mortality.
MAIN RESULTS
Compared to younger patients, patients ≥50 years of age were less likely to have HIV mentioned in their progress notes (70% vs 82%, P < .001), have mild or moderately severe PCP cases at admission (89% vs 96%, P < .002), receive anti-PCP medications within the first 2 days of hospitalization (86% vs 93%, P <.002), and survive hospitalization (82% vs 90%, P < .003). However, age was not a significant predicator of mortality after adjustment for severity of PCP and timeliness of therapy.
CONCLUSIONS
While inpatient PCP mortality has improved by 50% in the past decade, 2-fold age-related mortality differences persist. As in the 1980s, these differences are associated with lower rates of recognition of HIV, increased severity of illenss at admission, and delays in initiation of PCP-specific treatments among older individuals—factors suggestive of delayed recognition of HIV infection, pneumonia, and PCP, respectively. Continued vigilance for the possibility of HIV and HIV-related PCP among persons ≥50 years of age who present with new pulmonary symptoms should be encouraged.
doi:10.1046/j.1525-1497.2001.016009583.x
PMCID: PMC1495267  PMID: 11556938
HIV; Pneumocystis carinii pneumonia; age; quality of care; outcomes
OBJECTIVE
To define the prevalence and detection rates of mental disorders among high utilizers as compared with typical utilizers, and to examine the effect of case-mix adjustment on these parameters.
DESIGN
Cross-sectional study.
SETTING
General internal medicine outpatient clinic associated with an urban, academic medical center.
PATIENTS
From patients attending a general medicine clinic, 304 were selected randomly in three utilization groups, defined by number of clinic visits: (1) high utilizers; (2) case-mix adjusted high utilizers; and (3) typical utilizers (control patients).
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
The presence of any mental disorder was ascertained by the PRIME-MD screening instrument. Chart review on all patients was performed to ascertain mental disorders detected by primary care physicians. The prevalence of mood disorders was markedly higher in high utilizers (29%) than in adjusted high utilizers (15%) or controls (10%) (p < .001). Anxiety disorders were slightly, but not statistically, more prevalent in the group adjusted for case mix (16%) than in other high utilizers (12%) or controls (9%). Alcoholism was significantly more prevalent in controls (12%) than in adjusted (6%) or other high utilizers (3%) (p < .03). The discrepancy in detection rates between PRIME-MD and chart review for any mental disorder was less for high utilizers (37% vs 31%) as compared with adjusted high utilizers (31% vs 11%) or controls (24% vs 8%).
CONCLUSIONS
Mood disorders are associated with a high overall burden of illness, while anxiety disorders are more predominant among outliers after case-mix adjustment. Detection rates differ substantially by utilization pattern. Screening efforts can be more appropriately targeted with knowledge of these patterns.
doi:10.1046/j.1525-1497.1999.07238.x
PMCID: PMC1496609  PMID: 10417600
mental disorders; high utilizers; depression; anxiety; case-mix adjustment; PRIME-MD

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