Predictors for atrial fibrillation detection after cryptogenic stroke: Results from CRYSTAL AF.

OBJECTIVE: We assessed predictors of atrial fibrillation (AF) in cryptogenic stroke (CS) or transient ischemic attack (TIA) patients who received an insertable cardiac monitor (ICM). METHODS: We studied patients with CS/TIA who were randomized to ICM within the CRYSTAL AF study. We assessed whether age, sex, race, body mass index, type and severity of index ischemic event, CHADS2 score, PR interval, and presence of diabetes, hypertension, congestive heart failure, or patent foramen ovale and premature atrial contractions predicted AF development within the initial 12 and 36 months of follow-up using Cox proportional hazards models. RESULTS: Among 221 patients randomized to ICM (age 61.6 ± 11.4 years, 64% male), AF episodes were detected in 29 patients within 12 months and 42 patients at 36 months. Significant univariate predictors of AF at 12 months included age (hazard ratio [HR] per decade 2.0 [95% confidence interval 1.4-2.8], p = 0.002), CHADS2 score (HR 1.9 per one point [1.3-2.8], p = 0.008), PR interval (HR 1.3 per 10 milliseconds [1.2-1.4], p < 0.0001), premature atrial contractions (HR 3.9 for >123 vs 0 [1.3-12.0], p = 0.009 across quartiles), and diabetes (HR 2.3 [1.0-5.2], p < 0.05). In multivariate analysis, age (HR per decade 1.9 [1.3-2.8], p = 0.0009) and PR interval (HR 1.3 [1.2-1.4], p < 0.0001) remained significant and together yielded an area under the receiver operating characteristic curve of 0.78 (0.70-0.85). The same predictors were found at 36 months. CONCLUSION: Increasing age and a prolonged PR interval at enrollment were independently associated with an increased AF incidence in CS patients. However, they offered only moderate predictive ability in determining which CS patients had AF detected by the ICM.

Examining the safety of dental treatment in pregnant women.

BACKGROUND: Although clinicians generally consider it safe to provide dental care for pregnant women, supporting clinical trial evidence is lacking. This study compares safety outcomes from a trial in which pregnant women received scaling and root planing and other dental treatments. METHODS: The authors randomly assigned 823 women with periodontitis to receive scaling and root planing, either at 13 to 21 weeks' gestation or up to three months after delivery. They evaluated all subjects for essential dental treatment (EDT) needs, defined as the presence of moderate-to-severe caries or fractured or abscessed teeth; 351 women received complete EDT at 13 to 21 weeks' gestation. The authors used Fisher exact test and a propensity-score adjustment to compare rates of serious adverse events, spontaneous abortions/stillbirths, fetal/congenital anomalies and preterm deliveries (<37 weeks' gestation) between groups, according to the provision of periodontal treatment and EDT. RESULTS: Rates of adverse outcomes did not differ significantly (P> .05) between women who received EDT and those who did not require this treatment, or between groups that received both EDT and periodontal treatment, either EDT or periodontal treatment alone, or no treatment. Use of topical or local anesthetics during root planing also was not associated with an increased risk of experiencing adverse outcomes. CONCLUSIONS: EDT in pregnant women at 13 to 21 weeks' gestation was not associated with an increased risk of experiencing serious medical adverse events or adverse pregnancy outcomes. Data from larger studies and from groups with other treatment needs are needed to confirm the safety of dental care in pregnant women. CLINICAL IMPLICATIONS: This study provides evidence that EDT and use of topical and local anesthetics are safe in pregnant women at 13 to 21 weeks' gestation.

Cystatin C is not superior to creatinine-based models in estimating glomerular filtration rate in former kidney donors.

BACKGROUND: The long-term renal consequences of kidney donation need to be accurately quantitated. Cystatin C is a freely filtered glycoprotein that may not have the limitations of creatinine as a measure of glomerular filtration rate (GFR). Whether cystatin C is superior to creatinine-based estimates of GFR in those who have donated a kidney in the past has not been tested. METHODS: We assessed the performance of seven cystatin C and two creatinine-based GFR prediction equations in 187 former kidney donors against iohexol GFR for measuring GFR. We calculated bias, precision, and relative accuracy of these models. RESULTS: The majority of former donors had a GFR >60 mL/min/1.73 m(2). All cystatin C models, except the Rule model, overestimated GFR (range 5.3-31.4 mL/min/1.73 m(2)). Among the cystatin C models, the Hoek and Rule formulas were least biased at 5.3 and -3.8 mL/min/1.73 m(2), most precise at 0.41, and were within 30% of iohexol GFR, 89.3 and 96% of the time, respectively. The Modification of Diet in Renal Disease (MDRD) formula underestimated GFR by 7.2 mL/min/1.73 m(2), was most precise (R(2)=0.47) and fell within 30% of measured GFR at the highest frequency of 96%. When all models were given a rank based on their performance in the bias, precision and accuracy domains, the MDRD model was clearly superior. CONCLUSION: The MDRD equation is superior to cystatin C-based equations for estimating GFR in former kidney donors. Creatinine measurement is cheaper and the MDRD GFR is given out by most laboratories and therefore it should be the preferred model in this population.

Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy.

Mucopolysaccharidosis type I (MPS-I or Hurler syndrome) is an inherited deficiency of the lysosomal glycosaminoglycan (GAG)-degrading enzyme alpha-l-iduronidase (IDUA) in which GAG accumulation causes progressive multi-system dysfunction and death. Early allogeneic hematopoietic stem cell transplantation (HSCT) ameliorates clinical features and extends life but is not available to all patients, and inadequately corrects its most devastating features including mental retardation and skeletal deformities. To test novel therapies, we characterized an immunodeficient MPS-I mouse model less likely to develop immune reactions to transplanted human or gene-corrected cells or secreted IDUA. In the liver, spleen, heart, lung, kidney and brain of NOD/SCID/MPS-I mice IDUA was undetectable, and reduced to half in heterozygotes. MPS-I mice developed marked GAG accumulation (3-38-fold) in these organs. Neuropathological examination showed GM(3) ganglioside accumulation in the striatum, cerebral peduncles, cerebellum and ventral brainstem of MPS-I mice. Urinary GAG excretion (6.5-fold higher in MPS-I mice) provided a non-invasive and reliable method suitable for serially following the biochemical efficacy of therapeutic interventions. We identified and validated using rigorous biostatistical methods, a highly reproducible method for evaluating sensorimotor function and motor skills development. This Rotarod test revealed marked abnormalities in sensorimotor integration involving the cerebellum, striatum, proprioceptive pathways, motor cortex, and in acquisition of motor coordination. NOD/SCID/MPS-I mice exhibit many of the clinical, skeletal, pathological and behavioral abnormalities of human MPS-I, and provide an extremely suitable animal model for assessing the systemic and neurological effects of human stem cell transplantation and gene therapeutic approaches, using the above techniques to measure efficacy.

Financial implications of refugee malaria: the impact of pre-departure presumptive treatment with anti-malarial drugs.

This study is a cost-benefits analysis of the recommendations of the Centers for Disease Control and Prevention for presumptive anti-malarial treatment among departing West African refugees. We conducted a retrospective chart review of symptomatic, blood smear-positive cases of malaria seen in Minneapolis, Minnesota, from 1996 through 2005. Billing charges of U.S. care were compared with estimates of implementation costs for overseas treatment. Fifty-eight symptomatic malaria infections occurred among West African refugees. After overseas pre-departure presumptive treatment, symptomatic malaria in arriving refugees decreased from 8.2% to 0%. The pre-departure number needed to treat to prevent one case of symptomatic malaria is 13.9 (95% confidence interval = 9.8-24). The average U.S. billing charge for each malaria case is $1,730. Overseas implementation costs for presumptive treatment are estimated to be between $141 and $346 to prevent one U.S. malaria case. Overseas presumptive pre-departure anti-malarial therapy prevents clinical malaria in refugees and results in cost-benefits when the malaria prevalence is > 1%. Overseas presumptive therapy has greater cost-benefits than U.S. based screening and treatment strategies.

Adherence-inhibitory intestinal immunoglobulin a antibody response in baboons elicited by use of a synthetic intranasal lectin-based amebiasis subunit vaccine.

We designed an amebiasis subunit vaccine that is constructed by using four peptide epitopes of the galactose-inhibitable lectin heavy subunit that were recognized by intestinal secretory immunoglobulin A (IgA) antibodies from immune human subjects. These epitopes are contained in the region encompassing amino acids 758 to 1134 of the lectin heavy subunit, designated LC3. Baboons (Papio anubis) are natural hosts for Entamoeba histolytica; naturally infected baboons raised in captivity possess serum IgA antibodies to the same four LC3 epitopes as humans. Uninfected, seronegative baboons received four intranasal immunizations at 7-day intervals with the synthetic peptide vaccine (400, 800, or 1,600 mug per nostril) with cholera toxin (20 mug) as the adjuvant. As determined by an enzyme-linked immunosorbent assay (ELISA), each dose of the peptide vaccine elicited antipeptide serum IgA and IgG and intestinal IgA antibody responses in all six immunized baboons by day 28, 7 days after the last immunization (P, <0.01 for each dose compared to the cholera toxin control). The peptide vaccine elicited serum IgG and intestinal IgA antibodies that recognized purified recombinant LC3 protein (P, <0.008 and 0.02, respectively) and native lectin protein (P < 0.01). In addition, an indirect immunofluorescence assay with whole trophozoites (P < 0.01) and Western blot analysis confirmed that serum IgG antibodies from vaccinated baboons recognized native lectin protein on the surfaces of axenic E. histolytica trophozoites or from solubilized amebae. All four synthetic peptides were immunogenic; the vaccine elicited dose- and time-dependent responses, as determined by ELISA optical density readings indicating the production of serum and intestinal antibodies (P, <0.02 for antipeptide and antilectin antibodies). As a positive control, intranasal immunization with purified recombinant LC3 protein with cholera toxin as the adjuvant elicited a serum anti-LC3 IgA and IgG antibody response (P, 0.05 and <0.0001, respectively); however, no intestinal anti-LC3 IgA antibody response was observed (P = 0.4). Of interest, serum IgA and IgG antibodies elicited by the recombinant LC3 vaccine did not recognize any of the four putatively protective LC3 peptide epitopes. Both serum and fecal antibodies elicited by the peptide vaccine exhibited neutralizing activity, as determined by their dose-dependent inhibition of the galactose-specific adherence of E. histolytica trophozoites to Chinese hamster ovary cells in vitro (P, <0.001 for each group of antibodies compared to the control). In summary, a lectin-based intranasal polylysine-linked synthetic peptide vaccine was effective in eliciting an adherence-inhibitory, intestinal antilectin IgA antibody response in baboons. Future studies with the baboon model will determine vaccine efficacy against asymptomatic E. histolytica intestinal infection.

Effects of Accreditation Council for Graduate Medical Education work hour restrictions on medical student experience.

BACKGROUND: Residents have a major role in teaching students, yet little has been written about the effects of resident work hour restrictions on medical student education. OBJECTIVE: Our objective was to determine the effects of resident work hour restrictions on medical student education. DESIGN: We compared student responses pre work hour restrictions with those completed post work hour restrictions. PARTICIPANTS: Students on required Internal Medicine, Surgery, and Pediatric clerkships at the University of Minnesota. MEASUREMENTS: Two thousand eight hundred twenty-five student responses on end-of-clerkship surveys. RESULTS: Students reported 1.6 more hours per week of teaching by residents (95%CI 0.8-2.6) in the post work hours era. Students' ratings of the overall quality of their teaching on the ward did not change appreciably, 0.05 points' decline on a 5-point scale (P = .05). Like the residents, students worked fewer hours per week (avg. 1.5 hours less, 95%CI 0.4-2.6). There was no change in quality or quantity of attending teaching, students' relationships with their patients, or the overall value of the clerkships. CONCLUSIONS: Whereas resident duty hour restrictions at our institution have had minimal effect on students' ratings of the overall teaching quality, they do report being taught more by their residents. This may be a factor of decreased resident fatigue or an increased sense of well-being; but more study is needed to clarify the causes of our observations.

Urinary beta2-microglobulin is associated with acute renal allograft rejection.

BACKGROUND: Identifying urinary biomarkers associated with acute rejection (AR) of kidney allografts could improve recipient care by allowing AR to be diagnosed noninvasively and treated earlier. We attempted to identify novel biomarkers associated with AR by analyzing urinary proteins by using matrix-associated laser desorption ionization time-of-flight mass spectroscopy (MALDI-TOF MS). METHODS: Using MALDI-TOF MS, we analyzed urine samples from 30 renal allograft recipients with biopsy-proven AR, 15 allograft recipients without AR, preoperative samples from 29 kidney donors, and 10 subjects with proteinuric native kidney disease. RESULTS: In samples obtained at the time of AR, we identified a protein peak at 11.7 kd that correlated strongly with AR. In regard to its predictive power for AR, this protein peak showed sensitivity of 83.3%, specificity of 80%, positive predictive value of 89%, and negative predictive value of 70.6%, suggesting that this protein is highly associated with AR. We identified this peak as being beta2-microglobulin. This was validated by using enzyme-linked immunosorbent assay, which documented the presence of high urinary beta2-microglobulin levels in subjects with AR. CONCLUSION: Beta2-microglobulin could be a strong biomarker for AR if used in conjunction with other biomarkers, producing an AR-specific urinary protein signature. This possibility must be confirmed in a larger cohort of kidney transplant recipients.

Immunoglobulin M-to-immunoglobulin G anti-human leukocyte antigen class II antibody switching in cardiac transplant recipients is associated with an increased risk of cellular rejection and coronary artery disease.

BACKGROUND: Activation of T cells induces immunoglobulin (Ig)M-to-IgG B-cell isotype switching via costimulatory regulatory pathways. Because rejection of transplanted organs is preceded by alloantigen-dependent T-cell activation, we investigated whether B-cell isotype switching could predict acute cellular rejection and the subsequent development of transplantation-related coronary artery disease (TCAD) in cardiac transplant recipients. METHODS AND RESULTS: Among 267 nonsensitized heart transplant recipients, switching from IgM to IgG anti-human leukocyte antigens (HLA) antibodies directed against class II but not against class I antigens was associated with a shorter duration to high-grade rejection, defined as International Society for Heart and Lung Transplantation grade 3A or higher (P<0.001), a higher cumulative rejection frequency (P=0.002), accelerated development of TCAD (P=0.04), and decreased late survival (P=0.03). Conversely, the persistence of IgM anti-HLA antibodies against class II but not against class I antigens for >30 days and the lack of IgG isotype switching were associated with protection against both acute rejection (P=0.02) and TCAD (P=0.05). Alloisotype switching coincided with T-cell activation, as evidenced by increased serum levels of soluble CD40 ligand costimulatory molecules. Finally, a case-control study showed that reduction of cardiac allograft rejection by mycophenolic acid was accompanied by reduced CD40 ligand serum levels and the prevention of IgM-to-IgG anti-HLA class II antibody switching. CONCLUSIONS: T-cell-dependent B-cell isotype switching and the consequent production of IgG anti-HLA class II antibodies are strongly correlated with acute cellular rejection, a high incidence of recurrent rejections, TCAD, and poor long-term survival. Detecting this isotype switch is a clinically useful surrogate marker for in vivo T-cell activation and may provide a noninvasive approach for monitoring the efficacy of T-cell targeted immunosuppressive therapy in heart transplant recipients.