Feasibility of a Collaborative, Prospective Interdisciplinary Review and Pharmacy-Based Dispensing Process for Prothrombin Complex Concentrate.

BACKGROUND: Therapeutic options for rapid reversal of vitamin K antagonist therapy include 4-factor prothrombin complex concentrate (PCC4) and fresh frozen plasma (FFP). These agents have unique requirements for preparation, potential adverse effects, and cost-effectiveness considerations. OBJECTIVE: To retrospectively assess whether our process for collaborative prospective review and pharmacy preparation facilitates timely and safe warfarin reversal with PCC4 as compared with FFP and to compare effectiveness and safety of the agents in practice. METHODS: We performed a retrospective, single-center, before and after cohort study of patients requiring warfarin reversal for life-threatening bleeding or urgent invasive procedures over an 18-month period. The primary end point was time from ordering of reversal agent to administration. Secondary end points measured time to therapeutic effect and rates of adverse events. RESULTS: Of 98 patients studied, 72 received FFP, and 26 received PCC4. The median times from ordering to administration of FFP and PCC4 were 69 and 44 minutes, respectively ( P = 0.015). Median time from ordering to end of infusion was significantly shorter for PCC4 compared with FFP (54 vs 151 minutes, respectively; P < 0.0001). In all, 72% of PCC4 patients and 28% of FFP patients achieved the goal international normalized ratio (INR) of ≤1.4 at the first INR check ( P < 0.0001). Adverse reactions occurred in 4% of patients in each group. CONCLUSION: In routine clinical practice incorporating collaborative prospective review and dispensing from the institution's pharmacy, PCC4 was associated with faster administration, a higher rate of INR correction, and similar rates of adverse events compared with FFP.

Arctic grayling (Thymallus arcticus) in saltwater: a response to Blair et al. (2016).

Although not well known, Arctic grayling can move through saline waters and are captured regularly in nearshore coastal waters in Arctic Canada and Alaska with salinities up to 18 ppt. We highlight the implications this has for Blair et al. (2016), a paper recently published in Conservation Physiology.

Thyroid function parameters in normal pregnancies in an iodine sufficient population.

BACKGROUND: The aim of this retrospective observational study was to describe thyroid function parameters (fT3, fT4 and TSH) in the course of normal pregnancies. METHODS: Data were obtained between 2006 and 2007 at the University Hospital in Innsbruck, Austria. The starting point was the identification of women who had had a normal birth as recorded in the birth registry of Tyrol. Thyroid function parameters were determined using methods implemented at the Department of Nuclear Medicine in Innsbruck. RESULTS: The fT3 and fT4 values were normally distributed. Grouping the results by trimester revealed the following values: 4.93 ± 0.59, 4.54 ± 0.48, and 4.27 ± 0.45 pmol/l for fT3; and 15.23 ± 2.43, 13.79 ± 1.99, and 13.32 ± 0.2.01 pmol/l for fT4, respectively. The values corresponding to the 10th-percentile were 3.9 pmol/l for fT3 and 11.3 pmol/l for fT4, respectively. TSH values showed a typical left skewed distribution, thus the mean values were calculated after log transformation of the data. The corresponding mean trimestral values for TSH were 1.46 ± 1.29, 1.68 ± 1.23, and 1.70 ± 2.22 mIU/l, respectively. CONCLUSION: In an iodine sufficient population, thyroid function parameters in normal pregnancies do not differ from those in non-pregnant women. Our previously defined reference range for TSH of 0.3 to 3.5 mIU/l is equally valid for normal pregnancies. GENERAL SIGNIFICANCE: The question of cognition and IQ development of children has been proposed to be associated with thyroid function. The addition of data regarding normal thyroid function during pregnancy will contribute to this research.

Type-specific antiviral antibodies to genital human papillomavirus types in mothers and newborns.

Type-specific antibodies to human papillomaviruses (HPVs) can be detected in most infected adult patients, and they have virus-neutralizing properties. However, there is a dearth of information on the seroprevalence of maternal and neonatal antibodies to HPV capsid antigens. Sera from 104 mothers, their newborns, and 3 twin pregnancies were analyzed by an enzyme-linked immunosorbent assay (ELISA) for the presence of specific IgG, IgM, and IgA antibodies to virus-like particles of HPV-6, -11, -16, -18, and -31. Maternal IgG positivity rates to HPV types 6, 11, 16, 18, and 31 were 23.1%, 2.9%, 8.7%, 5.8%, and 9.6%, respectively. Neonatal rates did not differ significantly, and individual IgG ELISA values of mothers and their infants and all paired twins showed a very high correlation. In contrast, nearly all IgM and IgA individual values in newborns were designated negative, whereas mothers' positivity rates ranged as high as 19.2%. Infants showed no HPV-related lesions at birth or at 4-year follow-up. Seven of 8 tested children lost IgG HPV antibodies in a follow-up examination. Similar anti-HPV IgG seropositivity in mothers and newborns and a lack of neonatal IgA and IgM together with twin and follow-up results indicate that neonatal IgG is not a sign of intrauterine HPV infection but, rather, maternofetal antibody transmission.

Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73 cross-talk in vivo.

PURPOSE: We aimed to determine the clinical role of the p53 family members p53 and p73 in the responsiveness to platinum-based chemotherapy and survival in ovarian cancer, considering their cross-talk and the p53 polymorphism at codon 72. EXPERIMENTAL DESIGN: A detailed analysis of p53 and p73 in a series of 122 ovarian cancers was done. We used a functional yeast-based assay to determine the p53 mutational status. Red yeast colonies, indicating mutant p53, were subsequently sequenced to determine the specific p53 alteration. p53 mutations were divided into two groups according to their previous characterization in the literature: those that efficiently inhibit transcriptionally active TAp73 function and those that do not. A p53 polymorphism at codon 72 was determined in corresponding normal tissue or blood of ovarian cancer patients. Isoform-specific p73 expression analysis using real-time reverse transcription-PCR has previously been done in the majority of ovarian cancers included in this study. In a retrospective chart review, responsiveness to chemotherapy was assessed, and survival data with long follow-up times were collected. RESULTS: Eighty of 122 (65.6%) of ovarian cancers harbored p53 mutations. p53 mutational status was an important determinant of responsiveness to platinum-based chemotherapy in all patients with a residual tumor of <2 cm in diameter after initial surgery (wild-type versus mutant, P = 0.029). In addition, p53 mutational status was a strong prognosticator for recurrence-free and overall survival (P < 0.0001 and P = 0.003, respectively) in univariate analyses. High expression levels of dominant-negative p73 isoforms (DeltaNp73 and DeltaN'p73) significantly correlated with chemotherapeutic failure (P = 0.048) and with worse recurrence-free and overall survival in patients with p53 mutant cancers (P = 0.048 and P = 0.005, respectively). Eight p53 mutations, present in 19 cases, were found that efficiently inhibit TAp73 (i.e., 175H, 220C, 245S, 245D, 248W, 248Q, 266E, and 273H). Patients with p53 mutations that efficiently inhibit TAp73 function had a significantly shorter overall survival than patients with p53 mutations of unknown effect on TAp73 (P = 0.044). The p53 polymorphism at codon 72 had no influence on responsiveness to chemotherapy or survival. CONCLUSION: We provide the first clinical evidence that dominant-negative p73 isoforms contribute to drug resistance in vivo, underscoring the importance of a p53-p73 cross-talk. NH2-terminally truncated p73 isoforms were of significant clinical effect by providing an additional unfavorable factor for response to platinum-based chemotherapy and survival in p53 mutant ovarian cancers.

Polymorphisms of the Nos3 gene and unexplained late intrauterine fetal death.

OBJECTIVE: Genetic polymorphisms associated with vascular diseases have been proposed to be involved in the pathogenesis of late unexplained intrauterine fetal death (IUFD). The Nos3 gene is known to regulate vascular tone via the endothelial nitric oxide synthase/nitric oxide pathway. STUDY DESIGN: In a multicenter case-control study, we evaluated two Nos3 polymorphisms (exon 7 Glu298Asp and a 27bp-repeat in intron 4) in 92 women with IUFD and 92 healthy control women. RESULTS: The investigated Nos3 polymorphisms were not associated with the occurrence of IUFD. In the subgroup of pregnancies affected by IUFD, women with at least one mutant allele of the Nos3 intron 4 polymorphism were diagnosed with IUFD at a significantly earlier gestational age (31.8 [standard deviation (S.D.) = 4.9] weeks versus 34.6 [S.D. = 4.8] weeks, p = 0.02) and showed a significantly reduced birth weight (2113 g [S.D. = 1028] versus 1571 g [S.D. = 568], p = 0.03). CONCLUSION: We are the first to report on Nos3 polymorphisms and IUFD. While not being associated with the incidence of IUFD overall, the intron 4 Nos3 polymorphism might modulate the timing of IUFD in affected pregnancies.

Specific serologic response to genital human papillomavirus types in patients with vulvar precancerous and cancerous lesions.

OBJECTIVE: Antibodies to human papillomavirus are indicative for previous human papillomavirus exposure. Human papillomavirus antibody reactivities to vulvar precancerous lesions were reported poorly, and the role of human papillomavirus in some of these lesions is still unclear. STUDY DESIGN: In a direct enzyme-linked immunosorbent assay, serum samples from 126 healthy control subjects, 97 women with lichen sclerosus with or without squamous hyperplasia, 78 women with vulvar intraepithelial neoplasia, and 16 women with verrucous carcinoma were examined for immunoglobulin G and A antibodies to L1 virus-like particles of genital human papillomavirus types 6, 11, 16, 18, and 31, cutaneous human papillomavirus type 8, bovine papilloma virus, and cottontail rabbit papilloma virus. RESULTS: In lichen sclerosus/squamous hyperplasia with atypia immunoglobulin G and A, antibody positivity rates to high-risk human papillomavirus virus-like particle types 16, 18, and 31 were significantly higher than in the control group and the lichen sclerosus/squamous hyperplasia group without atypia. In patients with vulvar intraepithelial neoplasia I, increased immunoglobulin G antibody prevalences with both high-risk and low-risk human papillomavirus-virus-like particles were detected; whereas in patients with vulvar intraepithelial neoplasia II/III, this was observed only with the human papillomavirus types 16, 18, and 31. When only reactivities with 2 genital human papillomavirus types were compared, percentages of positives to only 1 of these 2 types ranged between 43% and 82%, with regard to all respective positives. CONCLUSION: Our data support the role of high-risk human papillomavirus types, mainly human papillomavirus-16, in the pathogenesis of different vulvar lesions with atypia. Serologically, there are no indications that lichen sclerosus/squamous hyperplasia without atypia is associated with human papillomavirus, but high-risk human papillomavirus in lichen sclerosus/squamous hyperplasia with atypia could play a role in carcinogenesis. High antibody specificity was clearly demonstrated among 5 genital, 1 cutaneous human, and 2 animal papillomavirus types.

An interleukin-6 gene promoter polymorphism and unexplained late intrauterine fetal death: a multicenter study.

OBJECTIVE: Interleukin-6 (IL-6)-mediated inflammatory processes have been proposed to be involved in the pathogenesis of pregnancy-associated complications such as late unexplained intrauterine fetal death (IUFD). Therefore we determined whether a common guanine/cytosine polymorphism at position -174 of the promoter of the IL-6 gene (IL6) known to affect in vivo protein activity can serve as candidate gene for this condition. METHODS: In a multicenter case-control study, we evaluated the IL6 promoter polymorphism by pyrosequencing in 92 women with IUFD. Ninety-four healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD served as the control group. RESULTS: No significant association was found between the presence of at least one mutant allele of the IL6 promoter polymorphism (P = .2; odds ratio = 1.5 [95% confidence interval, 0.8-2.7]) and the incidence of IUFD. In women with IUFD, the presence of at least one mutant allele of the IL6 promoter polymorphism did not influence timing of fetal death (33.9 [5.1] gestational weeks vs 34.1 [4.9] gestational weeks, P = .8) or birth weight (2055 [1119] g vs 1963 [992] g, P = .7). CONCLUSION: To our knowledge, we are the first to report on a common polymorphism of the IL6 promoter gene in women with late IUFD. The investigated IL6 promoter polymorphism can not be seen as candidate gene for IUFD in Caucasian women.

Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study.

OBJECTIVE: We determined whether gene polymorphisms associated with thrombophilia and vascular disease as etiologic factors were involved in the pathogenesis of pregnancy-associated complications. METHODS: We conducted a multicenter case-control study in which we studied 94 women with late unexplained intrauterine fetal death (IUFD) and 94 healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD. We obtained blood samples from all subjects and analyzed their DNA for 12 common polymorphisms of thrombophilic and vascular genes (factor V Leiden, factor V H1299R, prothrombin G20210A, factor XIII V34L, MTHFR C677T, MTHFR A1298C, beta-fibrinogen-455 G to A, PAI-1 4G/5G, GPIIIa L33P, HFE C282Y, apolipoprotein B R3500Q, and apolipoprotein E2/E3/E4). RESULTS: We found no significant association between any of the polymorphisms investigated and IUFD. Subgroup analyses involving various combinations of polymorphisms and in which gestational age and fetal weight were corrected for also showed no significant results. CONCLUSIONS: Our data represent the largest study to date with respect to thrombophilic and vascular gene polymorphisms in IUFD. In accordance with others, we challenge the importance of thrombophilic and vascular gene polymorphisms in the pathogenesis of this condition.

Antibodies to human papillomavirus 16 L1 virus-like particles as an independent prognostic marker in cervical cancer.

OBJECTIVE: Infection with high-risk human papillomavirus (HPV) types such as HPV-16 is a major risk factor for the development of cervical cancer. HPV-16 capsid antibodies are detectable in approximately 50% of patients with HPV-16 DNA-positive cervical cancer. We investigated the prognostic significance of HPV capsid antibodies for survival in patients with cervical cancer in comparison with conventional clinicopathologic features such as staging, histologic grading, histology, age, and treatment modality. STUDY DESIGN: Serum samples from 68 patients with cervical cancer and 65 healthy female control subjects were analyzed by enzyme-linked immunosorbent assay for HPV-specific immunoglobulin G (IgG) antibodies to baculovirus expressed HPV-6, HPV-11, HPV-16, and HPV-18 L1 virus-like particles (VLPs). RESULTS: HPV-16 L1 IgG antibodies were detectable in 6 of 65 (9%) of the control subjects and in 19 of 68 (28%) of the patients with cervical cancer (P =.007). In the subgroup of patients with HPV-16 DNA-positive cervical cancer (comprising 50% of the investigated samples), HPV-16 L1 antibodies were detected in 40%. HPV-16 L1 seropositivity was in univariate and multivariate analysis in addition to International Federation of Gynecology and Obstetrics stage, the only independent positive prognostic factor for overall survival (P =.01). CONCLUSION: Antibodies to HPV-16 L1 were found to be an independent prognostic factor for overall survival in patients with cervical cancer. Thus, HPV-16 infection may be involved not only in oncogenesis but also in tumor development and behavior.