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1
Miles, M. "The Pool of Bethesda: Art in British Hospitals." Scottish Medical Journal 36, no. 2 (April 1991): 55–58. http://dx.doi.org/10.1177/003693309103600212.
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Connelly, Angela. "‘A pool of Bethesda’: Manchester‘s First Wesleyan Methodist Central Hall." Bulletin of the John Rylands Library 89, no. 1 (March 2012): 105–25. http://dx.doi.org/10.7227/bjrl.89.1.5.
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Methodist Central Halls were built in most British towns and cities. They were designed not to look like churches in order to appeal to the working classes. Entirely multi-functional, they provided room for concerts, plays, film shows and social work alongside ordinary worship. Some contained shops in order to pay for the future upkeep of the building. The prototype for this programme was provided in Manchester and opened on Oldham Street in 1886. This article offers a first analysis of it as a building type and looks at the wider social and cultural contribution of the building. It continues the narrative by discussing changing use and design during a twentieth century that witnessed the widespread contraction of Methodist congregations.
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Lee, Young Ho. "The Healing at the Pool of Bethesda (Jn 5:1-15)." Journal of Youngsan Theology 17 (December 31, 2009): 331. http://dx.doi.org/10.18804/jyt.2009.12.17.331.
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Verbruggen, Bert, Georges Rivard, Jerome Teitel, Irwin Walker, and Alan Giles. "A Detailed Comparison of the Performance of the Standard versus the Nijmegen Modification of the Bethesda Assay in Detecting Factor VIII:C Inhibitors in the Haemophilia A Population of Canada." Thrombosis and Haemostasis 79, no. 04 (1998): 872–75. http://dx.doi.org/10.1055/s-0037-1615080.
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SummaryThe Bethesda assay is widely used to monitor the development and progress of Factor VIII:C inhibitors. Factor VIII stability in the substrate plasma (normal pool) is compromised by pH shift and reduction in protein concentration. Preliminary study, by Verbruggen and colleagues (8), suggested a reduction in spuriously positive assay results may result from buffering the normal pool plasma substrate with imidazole to pH 7.4 and substituting Factor VIII deficient plasma for imidazole buffer in the control incubation mix. These laboratory findings have now been confirmed by the performance of both the standard and the modified Bethesda assays in parallel on 877 patient samples screened during the Factor VIII:C Inhibitor Surveillance Program instituted following the conversion of all Canadian haemophilia A patients to recombinant Factor VIII. Although this study does not address the question of the clinical significance of spurious positive assays, these laboratory findings do support the conclusions of Verbruggen and the modified assay has recently been endorsed by the Factor VIII/IX Subcommittee of the SSC.
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Baudino, Isabelle. "William Hogarth et la peinture baroque continentale : emprunts, satire et création dans The Pool of Bethesda." XVII-XVIII. Revue de la société d'études anglo-américaines des XVIIe et XVIIIe siècles 54, no. 1 (2002): 81–96. http://dx.doi.org/10.3406/xvii.2002.1640.
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Németh, István. "Between Christian and prophane Iconography: Depictions of the Pool of Bethesda in Netherlandish Art from circa 1400 to 1700." Acta Historiae Artium 44, no. 1 (November 1, 2003): 225–35. http://dx.doi.org/10.1556/ahista.44.2003.1-4.26.
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Miller, Connie H., S. Jean Platt, Thomas Abshire, Doreen Brettler, Paula Brockenstedt, Jorge DiPaola, Gita Massey, et al. "Experience with a Modified Nijmegen-Bethesda Method for Measurement of Inhibitors in Hemophilia Patients: The CDC Inhibitor Surveillance Pilot Project." Blood 110, no. 11 (November 16, 2007): 1156. http://dx.doi.org/10.1182/blood.v110.11.1156.1156.
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Abstract A pilot project of a prospective surveillance system for coagulation factors VIII and IX inhibitors has been initiated at 9 U.S. Hemophilia Treatment Centers (HTCs). More than 500 patients have been enrolled. Risk factor and product exposure data are recorded at each HTC. A blood specimen is collected upon entry, annually, at product switch, or for clinical indication and tested centrally at the CDC, using a modified Nijmegen-Bethesda method. Plasma from specimens collected in 4.5mL evacuated tubes containing 3.2% sodium citrate is shipped overnight on cold packs. Specimens are heated to 56oC for 30 minutes to remove endogenous and infused FVIII and centrifuged. Specimens are initially screened for inhibitor using a single dilution of 3 parts patient plasma to 1 part normal pool plasma buffered with imidazole to pH 7.4 (BNPP). Specimens showing inhibition and those from previously positive patients are tested in multiple dilutions at 1 part patient dilution to 1 part BNPP. Dilution is in naturally FVIII-deficient plasma containing normal von Willebrand factor. After a 2-hour incubation at 37oC, FVIII remaining in the patient mixture is divided by FVIII remaining in a 1:1 mixture of BNPP and FVIII-deficient plasma and expressed as % residual activity (RA). %RA is converted to Nijmegen-Bethesda units (NBU) using a curve with one NBU equal to 50% RA. An inhibitor plasma of known titer is run with each assay as positive control. Split specimens shipped frozen and on cold packs showed a correlation of 0.998. 3:1 and 1:1 mixtures showed a correlation of 0.97. Almost 50% of the first 200 specimens received had measurable FVIII activity. The heating step was introduced to remove FVIII without damaging the antibody. 65 specimens went from >100% RA to a titer of 0–0.2 NBU after heating. Among 538 specimens tested for FVIII inhibitors, 435 (81%) were from patients with no previous history of inhibitor (shown below). 429 (98.6%) were < 0.5 NBU. The 6 specimens (1.4%) with > 0.6 NBU are under investigation as possible seroconversions. Nijmegen-Bethesda Units in Patients with No Previous Inhibitor NBU No. Pts. (%) NBU No. Pts. (%) NBU No. Pts. (%) 0 220 (50.6%) 0.4 3 (0.7%) 0.8 1 (0.2%) 0.1 127 (29.2%) 0.5 0 0.9 0 0.2 59 (13.6%) 0.6 0 1.0–4.0 2 (0.5%) 0.3 20 (4.6%) 0.7 2 (0.5%) 5.0–19.0 1 (0.2%) Among 121 specimens tested for factor IX (FIX) inhibitors, 113 were from patients with no previous history of inhibitor and all had NBU <0.2, using a comparable FIX inhibitor assay. Testing in a central laboratory by uniform methods will facilitate detection of new inhibitors and investigation of risk factors.
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Nutu, Ela. "Angels in America and Semiotic Cocktails of Sex, Bible and Politics." Biblical Interpretation 14, no. 1-2 (2006): 175–86. http://dx.doi.org/10.1163/156851506776145814.
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AbstractThis paper offers a reading of Mike Nichols' television adaptation of Tony Kushner's Angels in America with reference to biblical encounters with angels, whether direct, like those of Jacob and Elijah, or indirect, like that of the sick man by the Bethesda pool (John 5). Kushner's work is complex, and it addresses issues like the human condition, homosexuality, AIDS, race, religion and politics, while emphasising elements of choice and identity. For Kushner, it seems, 'angels' signify an absence rather than a presence of the divine, puzzles rather than answers (many of which refer to sex and gender identities), and turn-of-the-millennium angst. Kushner's 'Prior' character is declared a prophet by the messenger angel while dying of AIDS. Prior's encounter harbours echoes of Elijah's own encounter with an angel of the Lord while struggling with exhaustion and an apparent desire for death (1 Kings 19:1-9). Furthermore, unwilling to accept the role of prophet, Prior wrestles with the angel, and, in a similar vein to Jacob's experience (Gen. 32:22-32), this results in a ladder leading to heaven and a blessing. This paper explores the complex world of signifiers in Angels in America, while paying particular attention to the biblical elements present in the text.
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Sundue, Sharon Braslaw. "Confining the Poor to Ignorance? Eighteenth-Century American Experiments with Charity Education." History of Education Quarterly 47, no. 2 (May 2007): 123–48. http://dx.doi.org/10.1111/j.1748-5959.2007.00086.x.
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In 1738, the English evangelist George Whitefield traveled to the new colony of Georgia intending to establish “a house for fatherless children.” Inspired by both August Hermann Francke, the German Pietist who had great success educating and maintaining poor orphans in Halle, and by charity schools established in Great Britain, Whitefield's orphan house and charity school, named Bethesda, opened its doors early in 1740. For years, Whitefield devoted himself tirelessly to ensuring the success of the Bethesda school, preaching throughout Britain and North America on its behalf. Whitefield's preaching tour on behalf of his beloved Bethesda is well known for its role in catalyzing the religious revivals known collectively as the Great Awakening. The tour also marked an important shift in the history of education in America. News of the establishment of the orphanage at Bethesda coincided with new efforts to school the poor throughout the colonies. Drawing on both the British and German models of charity schooling that were highly influential for Whitefield, eighteenth-century Americans began or increased commitments to charity schooling for poor children. But the European models were not adopted wholesale. Instead, local administrators of the schooling experiments deviated from these models in a striking way. In America, elites offered some children the opportunity for extensive charity instruction, but not necessarily children at the bottom of the social hierarchy. This article will argue that the execution of these charity schooling programs was contingent upon local social conditions, specifically what appears to have been local elites' desire to maintain a certain social order and ensure a continued supply of cheap labor.
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Davies, Phil. "Role of multi-layer foam dressings with Safetac in the prevention of pressure ulcers: a review of the clinical and scientific data." Journal of Wound Care 25, Sup1 (January 1, 2016): S3—S23. http://dx.doi.org/10.12968/jowc.2016.25.sup1.s1.
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Background Despite the implementation of prevention strategies, pressure ulcers (PUs) continue to be a challenging health problem for patients (and their carers), clinicians and health-care providers. One area of growing interest is the use of prophylactic dressings (which were originally designed for the treatment of PUs and other wound types) as a component of standard prevention measures. Over the past few years, a large amount of scientific and clinical data relating to this subject has been published in peer-reviewed journals and presented at international meetings and conferences. A substantial proportion of these data relate to one group of dressings: multi-layer foam dressings with Safetac, which are manufactured by Mölnlycke Health Care (Gothenburg, Sweden). This evidence pool has influenced the experts involved in updating the Clinical Practice Guideline, produced by the National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance, on the prevention and treatment of PUs. The updated Guideline, published in 2014, recommends that, as part of their PU prevention regimens, clinicians should consider applying prophylactic dressings to bony prominences in anatomical areas that are frequently subjected to friction and shear. Aims A literature review was undertaken to identify clinical data from the entire evidence hierarchy, as well as scientific data from laboratory studies, on the use of multi-layer foam dressings with Safetac in the prevention of pressure ulceration. Method The MEDLINE (National Library of Medicine, Bethesda, US) and EMBASE (Elsevier BV, Amsterdam, Netherlands) bibliographic databases were searched. In addition, abstract books and proceedings documents relating to national and international conferences were scanned in order to identify presentations (i.e. oral, e-posters and posters) of relevance to the review. Results Clinical and health economic experts have undertaken numerous studies, including randomised controlled trials, to assess the efficacy and cost-effectiveness of using multi-layer foam dressings with Safetac as a component of standard PU prevention strategies. The results of these studies indicate that the application of multi-layer foam dressings containing Safetac can reduce the occurrence of PUs on anatomical locations such as the sacrum and the heel, and underneath medical devices. Scientists have also developed and used laboratory methods to gain a better understanding of how prophylactic dressings work. The results of these studies indicate that the composition of foam dressings containing Safetac (i.e. their multi-layer structure) sets them apart from other dressings due to their ability to mediate the effects of physical forces (i.e. pressure, friction and shear) and control microclimate, all of which contribute to pressure ulceration. Conclusion The evidence pool clearly indicates that the prophylactic use of multi-layer foam dressings with Safetac as a component of standard prevention measures is beneficial to the clinician, the health-care provider and the patient. It should be noted that the findings outlined in this review may not be transferable to other products as their makeup and components are likely to differ significantly from those of multi-layer foam dressings with Safetac. As the importance of evidence-based practice and the need for cost-effective care continues to grow, clinicians and provider should carefully consider this point when selecting prophylactic dressings for PU prevention.
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Lonky, N. M., D. Lenhoff, and M. Sadeghi. "Poor Cytohistopathological Correlation in a Bethesda System-Based Colposcopic Triage System." Journal of Lower Genital Tract Disease 3, no. 1 (January 1999): 39. http://dx.doi.org/10.1097/00128360-199901000-00020.
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Diaz, Isabelle, Karine Bollore, Chantal Rothschild, Hervé Chambost, Ségolène Claeyssens, Edouard Tuaillon, Priscilla Lapalud, Jean-François Schved, Jean-Pierre Vendrell, and Géraldine Lavigne-Lissalde. "FVIII Specific Memory B Lymphocytes in Hemophilia A with Inhibitors Treated by Immune Tolerance Induction." Blood 114, no. 22 (November 20, 2009): 3162. http://dx.doi.org/10.1182/blood.v114.22.3162.3162.
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Abstract Abstract 3162 Poster Board III-99 Background and objectives Hemophilia A (HA) is a life-threatening hemorrhagic bleeding disorder caused by deficiency of Factor VIII (FVIII). Twenty to thirty percent of HA patients treated by FVIII develop inhibitors. The presence of these inhibitors in high titer (>5 Bethesda Units (BU)/ml) requires modification of the treatment regimen: use of products that by-pass the action of FVIII for haemorrhagic accidents and treatment protocols by immune tolerance induction (ITI) to eradicate inhibitors. The aim of our study was to enumerate and characterize FVIII-specific memory B-cells in peripheral blood by using polyclonal activation of enriched B-cells and an ELISpot assay in hemophilia patients with inhibitors. Methods Two groups of patients were prospectively included. First group included six severe HA patients treated by ITI; three with inhibitors (mean 3.04 ± 0.67 BU/ml; mean 14.6±4.2 years old) while the three others had a past of inhibitors, successfully treated by ITI (<0.6BU/ml; mean 18.6 ±6.3 years old). Second group were six severe HA who never developed inhibitors (mean 19.5±1.7 years old). Circulating FVIII specific memory B-cells were enumerated in each cohort and 13 controls using the ELISpot system as previously described. The results were expressed as the number of FVIII specific Secreting Cells (SCs) (IgG, IgA or IgM)/106 B-cells. Results In the first group,circulating FVIII-specific IgM-SCs were detected in 5 patients (1.07-45/106 B-cells), FVIII-specific IgA-SCs in 6 patients ( 2.9-7.5/106 B-cells).Only in patients with detectable inhibitors, FVIII-specific IgG-SCs (4-5.2/106 B-cells) were detected. In the second group FVIII-specific IgM-SCs (between 5 and 52 per 106 B-cells) were found, one patient had FVIII-specific IgA-SCs (2/106 B-cells). Conclusion We were able to detect FVIII specific memory B-cells. Before the treatment by ITI, the FVIII-specific immune memory seems to be characterized by the presence of circulating FVIII-specific memory B-cells belonging to the three isotype classes whereas FVIII-specific IgG-memory B-cells could not be found after a successful treatment. These results suggest an evolution of the pool of FVIII-specific circulating memory B-cells during the period of ITI. It would be interesting to study the FVIII-specific memory B-cells at the different periods of ITI (before, during and at the end of the protocol).The significance of FVIII specific memory B-cells in HA patients without inhibitor deserve to be study. Disclosures No relevant conflicts of interest to declare.
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Danilovic, Debora L. S., Erika U. Lima, Regina B. Domingues, Lenine G. Brandão, Ana O. Hoff, and Suemi Marui. "Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma." European Journal of Endocrinology 170, no. 4 (April 2014): 619–25. http://dx.doi.org/10.1530/eje-13-0944.
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ObjectiveThe p.V600E BRAF and RAS mutations are found in 30–80% of differentiated thyroid carcinoma (DTC). BRAF mutation has been associated with poor prognosis. This study investigated the role of molecular studies in preoperative diagnosis of DTC and the association of p.V600E mutation with prognostic factors.DesignProspective study.MethodsA total of 202 patients with cytological diagnosis of Bethesda III–VI underwent preoperative molecular studies and subsequent thyroidectomy. p.V600E and RAS mutations were studied in the cytology smears, using real-time PCR genotyping technique. The BRAF mutation (BRAF+ or BRAF−) was correlated with histological and clinical findings.ResultsMolecular study of 172 nodules with Bethesda III–V cytology improved negative predictive value and accuracy of Bethesda III and IV diagnosis. BRAF mutation was present in 65% of 94 DTC and p.Q61R NRAS in one. Except for age, BRAF+ and BRAF− did not differ in sex, tumor size, histological subtype, multifocality, vascular invasion, extrathyroidal extension, or prognostic staging. Among papillary carcinomas, lymph node (LN) metastasis was diagnosed in 23% BRAF+ and 37% BRAF−. Distant metastasis occurred in four BRAF−. Recurrent or persistent disease was more frequent in BRAF− (26.7 vs 3.3% BRAF+, P=0.002) along follow-up of 29.8±10 months. BRAF+ patients without LN metastasis by pre-operative evaluation submitted to thyroidectomy with central neck dissection (CND) had more frequent LN metastasis (45 vs 5% no CND, P=0.002), but no difference in clinical outcome was observed.ConclusionsPre-operative identification of BRAF mutation improved cytological diagnosis of DTC, but it was not associated with poor prognostic factors. Prophylactic CND did not guarantee better outcome in BRAF+ patients.
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van Helden, Pauline M. W., Paul H. P. Kaijen, H. Marijke van den Berg, and Jan Voorberg. "Factor VIII-Specific Memory B-Cells in Patients with Hemophilia A." Blood 108, no. 11 (November 16, 2006): 1020. http://dx.doi.org/10.1182/blood.v108.11.1020.1020.
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Abstract The quick anamnestic antibody response seen after recurrent exposure to antigen involves memory B- cells that, helped by T-cells, undergo rigid proliferation and subsequent differentiation into antibody producing cells. The presence of a pool of memory B-cells allows for a rapid response to antigens which quickly eliminates incoming pathogens. In the context of immune responses to therapeutic agents such as blood coagulation factor VIII (FVIII), antigenic re-stimulation of specific memory B-cells is undesirable. In approximately 25% of hemophilia A patients replacement therapy is hampered by inhibitory antibodies that bind to FVIII. Currently, the FVIII-specific memory B-cell compartment in patients with hemophilia A has remained poorly characterized. We have developed a protocol that allows for identification and quantification of circulating memory B-cells in patients with hemophilia A. CD19+ B-cells were sorted on a layer of irradiated EL4B5 thymoma cells expressing CD40L in the presence of the supernatant of mitogen-stimulated T-cells. These experimental conditions, that mimic the interaction of B-cells with an activating helper CD4+ T-cell, induce proliferation of memory B-cells and allow them to differentiate into antibody secreting cells (ASC) in an antigen-independent manner. After 9–10 days of culture, total IgG and FVIII-specific IgG was determined by ELISA and number of ASC was determined by ELISpot. We analyzed blood samples of five multi-transfused patients (>50 FVIII administrations) who never experienced any inhibitor episode, five patients who experienced inhibitory antibodies in the past but were successfully treated with immune tolerance induction and 6 patients with an inhibitor at the time of blood sampling. The ELISA set-up appeared to be more sensitive than ELISpot showing ASC producing anti-FVIII antibodies varying from 0.2–50 ng/ml. In contrast, ELISpot analysis only allowed for detection of B-cell clones producing over ~4 ng/ml of FVIII-specific IgG. Frequencies of FVIII-specific memory B-cells varied from 0–0.027% of total number of circulating peripheral B-cells. The relative amount of circulating memory B-cells did not correspond to inhibitor titers as measured in a Bethesda assay. The highest frequencies were observed in patients suffering from anamnestic response to FVIII suggesting the importance of antigenic stimulation for maintenance of memory B-cell levels. This is further supported by the low frequency that was observed in a high-titer inhibitor patient who had not been treated with FVIII for several months prior to blood sampling. Surprisingly, we detected FVIII-specific memory B-cells in two multi-transfused patients who did not experience any inhibitor episode in the past. These B-cells were present in a low frequency however and developed into ASC producing only limited amounts of anti-FVIII antibodies. These observations suggest that peripheral blood memory B-cells can develop in the absence of clinically relevant inhibitors.
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Gill, Joan Cox, Michelle A. Stapleton, Nancy Kern, Karen Stephany, and Megan Gavin. "Detection of Inhibitor Development in Hemophilia A Patients From the Time of First Exposure to Factor VIII: Performance of An ELISA-Based Factor VIII Antibody Screening Assay." Blood 114, no. 22 (November 20, 2009): 3482. http://dx.doi.org/10.1182/blood.v114.22.3482.3482.
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Abstract Abstract 3482 Poster Board III-419 About 25% of patients with severe hemophilia A develop neutralizing antibodies to factor VIII (FVIII), termed inhibitors, within a median of eleven exposure days to factor VIII containing therapeutic replacement products. Effective monitoring of inhibitor development in young hemophilic children is hampered by their frequently difficult venous access and their limitations on blood sample size, often making it a challenge to obtain samples suitable to carry out standard PTT based Bethesda assays. We evaluated the performance of the Factor VIII Antibody Screen (GTI Diagnostics, Waukesha, WI), an ELISA-based assay to detect FVIII antibodies in a cohort of hemophilia A patients as they were first exposed to FVIII replacement therapy for treatment of hemorrhages. FVIII antibodies were detected in the assay by incubation of duplicate patient samples and controls in microtiter wells coated with recombinant FVIII. After washing, bound FVIII antibody was detected with alkaline phosphatase conjugated goat anti-human IgG, and a colorimetric endpoint (optical density [OD] read at 405or 410 nm by spectrophotometry) determined in an ELISA plate-reader after incubation with p-nitrophenyl phosphate. Samples were considered positive if the average of the sample ODs was higher than the positive controls or negative if the average of the sample ODs was lower than the negative controls. Thirty consecutively identified patients with severe hemophilia A, who were enrolled in a longitudinal inhibitor study, and had samples of serum or plasma banked from the time of their first exposures to FVIII-containing therapeutic products were included. Patients were followed a median of 15.5 years (range 2 – 23 years). Nineteen (63%) of the patients never developed clinical or laboratory evidence of inhibitor development during follow-up. Eleven of the thirty (37%) developed an inhibitor during follow-up; one of these occurred in a 5 year-old after more than 650 exposure days to factor VIII concentrate. There were no differences in the time-to-first-exposure or pattern of hemorrhages in the two groups with the exception that all post-circumcision hemorrhages (N=6) occurred in the non-inhibitor group. In the non-inhibitor group, banked samples were selected corresponding to 0, 5, 10 and >50 factor VIII exposure-days; none of these samples had a positive result in the FVIII antibody screen ELISA. In the 11 inhibitor patients, banked samples were selected that corresponded with the earliest available sample, a sample obtained prior to the first positive Bethesda assay, the first Bethesda positive sample, a sample obtained at the initiation of immune tolerance induction (ITI), the peak Bethesda titer sample, the first negative Bethesda titer sample during ITI, and the most recent sample. All eleven of those who developed an inhibitor underwent successful immune-tolerance therapy with high dose (100 units/kg/day) factor VIII infusions. All Bethesda positive samples were positive by the FVIII antibody screen ELISA with one exception, a sample from one of the inhibitor patients just prior to development of a recurrent inhibitor. There were 5 Bethesda assay negative/FVIII antibody screen ELISA positive samples in the inhibitor patients; each of these samples had been obtained during ITI at 24-48 hours post factor VIII concentrate infusions, and were concordant with lower than expected factor VIII recoveries. We conclude that the ELISA-based FVIII antibody screen is sensitive and specific for the detection of factor VIII antibodies in patients with hemophilia A who develop inhibitors. Because it can be carried out with small serum as well as plasma samples, it provides a convenient method to obtain results in small patients with poor venous access, although quantification of the antibody titer in positive samples would require additional sample to carry out a PTT-based Bethesda assay. Unlike the Bethesda assay, this ELISA-based assay was able to detect antibodies in transfused patients undergoing ITI without the need for a prolonged washout period. Prospective studies to determine the utility and cost-effectiveness of this method are warranted. Disclosures: Gill: GTI Diagnositcs: Consultancy. Stapleton:GTI Diagnostics: Employment. Kern:GTI Diagnostics: Employment.
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Seheult, Jansen N., Laynalee Cardel, Julie I. Tange, Aneel Ashrani, William L. Nichols, Nahla Heikal, and Dong Chen. "An In Silico Exploration of the Factors That Affect the Precision of the Bethesda Assay." American Journal of Clinical Pathology 154, no. 5 (July 20, 2020): 671–82. http://dx.doi.org/10.1093/ajcp/aqaa085.
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Abstract Objectives Despite more than 40 years of experience performing the Bethesda assay (BA), poor intra- and interlaboratory precision remains the biggest laboratory challenge to date. Methods The BA procedure was modeled using stochastic simulation techniques to determine the precision of the BA up to dilutions of 1:4,096, to estimate the minimum significant relative change at various inhibitor titers, and to understand the laboratory procedural variables that could significantly affect the performance of the BA at high dilutions. Results Selecting the lowest dilution tube with a residual activity closest to 25% for calculating the reported Bethesda titer (BT), using a factor activity assay with a coefficient of variation less than or equal to 7.5% in the range of 15% to 50% factor activity level, performing the factor activity measurement in replicates, and minimizing pipette volumetric error resulted in the lowest imprecision in the reported BT. The factor neutralization kinetics of the inhibitor appear to have little impact on the precision of the assay if the incubation time is greater than 90 minutes. Conclusions This in silico model will assist future laboratory efforts in standardizing the quantification of specific coagulation factor inhibitors and improving the precision of the reported results.
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Koch, Noam, Liat Applebaum, Haggi Mazeh, Lilach Katz, and Rena Pollack. "Interobserver Variability in Ultrasound Reporting - Tertiary Hospital Radiologists Do Better." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A863. http://dx.doi.org/10.1210/jendso/bvab048.1762.
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Abstract Introduction: Thyroid Imaging Reporting and Data System (TI-RADS) was developed to provide a standardized risk-stratification system for patients with thyroid nodules. Single-center studies have demonstrated an acceptable level of interobserver agreement in applying TI-RADS in clinical practice, however data regarding consistency among different centers is limited. In Israel, thyroid nodules are initially evaluated by ultrasound performed by radiologists at the health maintenance organization (HMO) and then patients are referred to tertiary hospitals for ultrasound-guided fine needle aspiration (FNA) biopsy when indicated. Objective: To evaluate the interobserver concordance in TI-RADS classification system reporting between the HMO and a tertiary hospital. Methods: We performed a retrospective analysis of the sonographic features of 370 thyroid nodules TI-RADS category 2 or higher, from 350 patients evaluated by ultrasound at the HMO and at Hadassah Medical Center from January 1, 2018 to December 31, 2019. The primary outcome was concordance between the TI-RADS classification at the HMO compared to the hospital. Additional endpoints included correlation of TI-RADS to the Bethesda category following FNA, and correlation of TI-RADS with malignancy on final pathology. Results: Of 370 nodules, only 73 (19.8%) demonstrated concordance between the HMO and the hospital. The level of agreement was poor, with 277 (74.8%) nodules demonstrating higher TI-RADS at the HMO compared to the hospital, and 20 (5.4%) with lower TI-RADS at the HMO compared to the hospital (p<0.001, weighted Kappa = 0.120). Of the nodules referred to the hospital, 241 (65.1%) were selected for FNA. A strong correlation between the hospital TI-RADS and Bethesda category was demonstrated (p<0.001). Furthermore, 60 (16.2%) nodules were surgically removed. A strong correlation was identified between the hospital TI-RADS and malignancy on final pathology (p<0.001), yet there was no correlation with the TI-RADS of the HMO (p=0.346). Conclusions: There is poor concordance between TI-RADS classification on ultrasound performed in the HMO compared to a tertiary hospital. In patients who underwent FNA and eventually surgery, the hospital TI-RADS strongly correlated with Bethesda category and final risk of malignancy. Standardization of thyroid ultrasound terminology and dedicated training in thyroid imaging are needed to improve the interobserver concordance in clinical practice.
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Doubi, Aseel, Nuha S. Alrayes, Abdulaziz K. Alqubaisi, and Saleh F. Al-Dhahri. "The value of repeating fine-needle aspiration for thyroid nodules." Annals of Saudi Medicine 41, no. 1 (January 2021): 36–42. http://dx.doi.org/10.5144/0256-4947.2021.36.
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BACKGROUND: Fine-needle aspiration (FNA) is an invaluable technique used in the evaluation of thyroid nodules. OBJECTIVES: Evaluate the concordance of results for consecutive FNA readings. DESIGN: Retrospective, descriptive. SETTINGS: Two tertiary care centers. METHODS: Demographics were collected along with every FNA result and final pathology results for all patients (aged 9-90 years old) who underwent thyroid surgery from 2010 to 2017. The Bethesda system was used for cytology. Agreement levels were calculated and compared with final pathology. SAMPLE SIZE: Of 1237 initially included, 1134 had at least one FNA performed with results available for review. RESULTS: For the 1134 patients, demographic and clinical data were collection and a comparison was made between the three FNA results; the highest agreement was between FNA 2 and 3 (53.6%); however, the kappa value was consistently low for all comparisons, indicating a poor level of agreement overall. Also, the risk of malignancy was higher in this study than in the 2017 Bethesda system for reporting thyroid cytopathology in FNA cytology categories I and II. CONCLUSION: Repeating FNA biopsies yield different results every time; hence, there is a low level of agreement. The clinical decision should therefore include other important risk factors. Prospective studies could help shed more light on this topic. LIMITATIONS: Retrospective design. CONFLICT OF INTEREST: None.
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Morini, Nori, Lauro Bucchi, Carlo Naldoni, Patrizia Schincaglia, Nadia Capacci, Vilma Fantozzi, and Gianfranco Buzzi. "Effects of the Bethesda System on the Rate of Unsatisfactory Pap Smears in Spontaneous Cervical Screening." Tumori Journal 82, no. 5 (September 1996): 437–40. http://dx.doi.org/10.1177/030089169608200504.
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Aims In 1990, The Bethesda System (TBS) was introduced into spontaneous cervical screening practice in Ravenna, Italy. Negative/benign reports with the recommendation for early repeat smears (RERS) due to some limitation in sample adequacy were considered no longer acceptable. A monitoring program for the rate of unsatisfactory smears (UNS) was implemented. The aim of the present study was to evaluate the effects of such changes in the screening procedure. Methods The frequency of UNS in 1990 was compared with that of UNS+RERS in 1988 (assumed as a baseline year) by the calculation of the standardized rate ratio with the 95% confidence interval (CI). The trend in the standardized rate of UNS from 1990 to 1994 was evaluated by the calculation of the average annual variation with the 95% CI. Results The immediate effect of TBS (1990:1988 comparison) was a significant increase in the rate of UNS attributable to scant cellularity, poor fixation and thick areas (rate ratio, 2.35; 95% CI, 2.18 to 2.53) and to the absence of endocervical component (1.45; 95% CI, 1.30 to 1.60). The rate of UNS attributable to the presence of cytolysis, inflammation, blood and foreign material decreased by about 6 times (0.16; 95% CI, 0.13 to 0.19). The midterm effect of TBS (trend from 1990 to 1994) was a decrease in the total rate of UNS by an average of 2.3% per year. The downward trend was significant for smears showing scant cellularity, poor fixation and thick areas (-1.5% per year) and the absence of endocervical component (-0.7% per year). UNS attributable to the presence of cytolysis, inflammation, blood and foreign material stabilized. Conclusions TBS led to a substantial change in the type of information provided by the cytology report (Immediate effect). The monitoring program according to TBS led to a reduction in UNS attributable to sample taker (midterm effect).
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Mantovani, Lorenzo G., Matteo Rota, Paolo Cortesi, Katharina Steinitz, Armin Reininger, and Alessandro Gringeri. "Meta-Analysis on Incidence of Inhibitors in 1,945 Previously Untreated Patients Treated with Recombinant Factor VIII Products: Is There a Difference?" Blood 126, no. 23 (December 3, 2015): 289. http://dx.doi.org/10.1182/blood.v126.23.289.289.
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Abstract Introduction. Recent large cohort studies have shown data on inhibitor incidence in previously untreated patients (PUPs) with hemophilia A treated with recombinant factor VIII concentrates (rFVIII), which disputed previous reports or clinical trials. Aim of this meta-analysis was to assess the risk of inhibitor development in this patient population in order to clarify the relationship between the rFVIII product used and the development of FVIII inhibitors. Methods. We carried out a systematic literature search in electronic databases (Medline through PubMed, EMBASE) for studies published from 1 January 1988 to 31 January 2015. We aimed to identify clinical studies (both prospective and retrospective) investigating the relationship between rFVIII product used and the development of FVIII inhibitors in PUPs and minimally treated patients (MTPs), with less than 5 previous exposure days, with severe (FVIII<1%) and moderate (FVIII1-5%) hemophilia. We conducted the systematic review in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. The primary outcome measure of this meta-analysis was the development of clinically relevant inhibitory antibodies, while the secondary outcome measure was the development of a high-titer inhibitor, which was defined as a peak titer of at least 5 Bethesda units per millimeter (BU/mL) up to the 75th exposure day. We computed pooled meta-analytic estimates according to the rFVIII product used by using the inverse-variance method, assuming a fixed, or a random-effects model if significant between-studies heterogeneity was present. Heterogeneity was measured using Cochrane Q statistics and Higgins I-squared statistics, i.e. the ratio of true heterogeneity between studies compared to the total observed variation. Results. We identified 717 papers through database searches (538 from PubMed; 181 from EMBASE), of which 662 papers were excluded for the following reasons: duplicates (n=49); title and/or abstract not relevant for the endpoint of this study (n=231); review articles (n=131); letter to the editor (n=33); case-reports (n=98); animal studies (n=40); and others (n=80). Fifty-five (55) full-text papers were retrieved for detailed evaluation, plus eight additional papers identified through review of reference lists of the retrieved articles. Of these, 47 articles were excluded after full-text evaluation (incompleteness of data, multiple publications on the same cohort); sixteen (16) studies were included in the final meta-analysis. The pooled estimate of all inhibitors (571 inhibitors out of 1,945 PUPs/MTPs), including high titer (>5 BU/mL) and low titer (≤ 5 BU/mL), in the overall population considered was 0.27 (95% CI: 0.23-0.31) with significant heterogeneity (I-squared: 68.9%, p<0.01). Considering only inhibitors in PUPs with severe hemophilia (353 inhibitors out of 1,223 PUPs), the pooled estimate of all inhibitors was 0.27 (95% CI: 0.23-0.32) with significant heterogeneity (I-squared: 64.9%, p<0.01). The heterogeneity observed was due to differences of inhibitor incidence among studies for the same product used. Pooled inhibitor incidence estimates among products used ranged from 0.23 to 0.42 with overlapping confidence intervals, in the absence of heterogeneity (p=0.28). Similar patterns were observed in subpopulations of patients with high titer inhibitors or low titer inhibitors. Only few studies reported inhibitor hazard ratios with the different products used, adjusted to slightly different potential risk factors (Gouw et al, 2007, Gouw et al, 2013, Calvez et al, 2014, Collins et al, 2014). Meta-analysis of these studies showed PUPs/MTPs treated with Antihemophilic Factor (Recombinant) (Advate, Baxalta US Inc., Westlake Village, CA 91362) had a pooled inhibitor hazard ratio estimate of 0.63 (95% CI 0.48-0.83) as compared to Antihemophilic Factor (Recombinant) (Kogenate FS, Bayer HealthCare LLC, Whippany, NJ 07981). The pool estimates of other products used and tested were not significantly different. Conclusions. The incidence of inhibitors in PUPs/MTPs included in this meta-analysis was 27%. Although significant heterogeneity among studies was observed, no significant differences among products were found. Differences between products used were found only by considering hazard ratios in which potential risk factors were considered. Disclosures Mantovani: Baxalta Innovation GmbH: Consultancy. Rota:Baxalta Innovations GmbH: Consultancy. Cortesi:Baxalta Innovations GmbH: Consultancy. Steinitz:Baxalta Innovations GmbH: Employment. Reininger:Baxalta Innovations GmbH: Employment. Gringeri:Baxalta Innovations GmbH: Employment.
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Albert, Helen. "Pushing the boundaries of life itself." Biochemist 39, no. 6 (December 1, 2017): 34–39. http://dx.doi.org/10.1042/bio03906034.
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The ability of some organisms to live in extreme environments has always fascinated us. While more complex species such as mammals can live in very cold or hot surroundings, microorganisms definitely take the crown when it comes to being able to survive the most extreme conditions. These extremophiles are very resilient and can survive conditions that would kill other organisms in seconds. Indeed, some researchers believe that life may have begun with such organisms living deep under the ocean on hydrothermal vents. Helen Albert talks to Professor Rania Siam from The American University in Cairo, Egypt, about her research on microbes living near highly salty underwater ‘brine pools’ in the Red Sea. Helen also discusses the remarkable bacterium Deinococcus radiodurans, which is able to withstand high levels of radiation and desiccation, with Professor Michael Daly from the Uniformed Services University in Bethesda in the USA.
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Francis, Frincy, Sheeba E. Johnsunderraj, Divya K. Y, Divya Raghavan, Atiya Al-Furgani, Lily P. Bera, and Aniamma Abraham. "Ergonomic Stressors Among Pregnant Healthcare Workers." Sultan Qaboos University Medical Journal [SQUMJ] 21, no. 2 (June 21, 2021): e172-181. http://dx.doi.org/10.18295/squmj.2021.21.02.004.
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Workplace environment can have a considerable impact on the physical, psychological and maternal health of pregnant healthcare workers. This article aimed to summarise the impact of work-related ergonomic stressors on pregnancy outcomes for healthcare workers, along with potential interventions to resolve these stressors. A narrative review analysis using the Pearl Growing Strategy was conducted between February 2019 and June 2020 to identify English-language articles published between 2000 and 2020. A total of 89 studies were identified from the SCOPUS (Elsevier, Amsterdam, Netherlands), MEDLINE® (National Library of Medicine, Bethesda, Maryland, USA) databases and Google Scholar (Google LLC, Menlo Park, California, USA). The results indicated that poor work-related ergonomics had detrimental effects on pregnancy outcomes, resulting in spontaneous abortions, preterm delivery, low birth weight babies and infertility. Policymakers and employers should conduct ergonomic assessments and implement appropriate practices to ensure the safety of pregnant healthcare workers.
Keywords: Healthcare Workers; Physical Ergonomics; Pregnancy Outcomes; Occupational Health; Occupational Exposure.
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Livnat, Tami, Amy Dunn, Shirley Azar- Avivi, Courtney Cox, Einat Avishai, Shannon L. Meeks, and Gili Kenet. "Beyond the Bethesda Assay- Towards Individualized Interpretation of Inhibitor Patients' FVIII Brand Specific Profiles." Blood 124, no. 21 (December 6, 2014): 2841. http://dx.doi.org/10.1182/blood.v124.21.2841.2841.
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Abstract Background: Patients with hemophilia A (HA) and inhibitory antibodies are typically treated with bypassing agents if the inhibitor titer is >5 Bethesda units (BU). However, some patients with elevated inhibitor titers are treated with FVIII therapy in conjunction with immune tolerance regimens or in combination with bypassing agents. The Bethesda assay detects the inhibitory capacity for FVIII neutralization after 2 hours' incubation of patient's plasma mixed with pooled normal plasma (PNP). Nonetheless the inhibitory titer does not express the kinetic behavior of the inhibitor throughout the 2 hours of incubation. Furthermore, standard plasma derived FVIII is used for the Bethesda assay, whereas many patients are currently treated with recombinant FVIII products. Patients with severe HA who develop inhibitors typically have a polyclonal response. In vitro responses to monoclonal specific anti- epitope antibodies showed that group A anti-A2 antibodies ( high titer, type I antibodies) rapidly and completely inhibit FVIII and are not affected by the presence of Von Willebrand factor (VWF). In contrast, many anti- C1 and C2 antibodies compete with VWF for binding to FVIII. As patients' response to various FVIII sources (eg: with/ without VWF) may be affected by their unique B cell epitope profile, personalized individually tailored FVIII brand specific therapy may be considered. Aims : We aimed to define our inhibitor patients' individual response to various FVIII sources by assessing the kinetics of FVIII inhibition and by patients' FVIII epitope specificity. Methods: Plasma was obtained from HA patients with inhibitors. FVIII neutralization profile was determined against PNP, recombinant full length FVIII (rFVIII= Kogenate- FS, Bayer), plasma derived Von Willebrand containing FVIII (pdFVIII = Optivate, BPL) and correlated to the inhibitory (BU) titer. To test FVIII neutralization profile, patients' platelet poor plasma was either incubated with PNP or spiked with 2U/ml rFVIII/pdFVIII and sequential measurements of residual FVIII activity was recorded over 120 minutes. FVIII activity was measured by one stage aPTT assay. All inhibitor assays were performed on the same sample simultaneously. Results were compared to the standard Bethesda assay. Domain-specific anti-FVIII antibody mapping was carried out by direct ELISA using purified single human domain hybrid FVIII protein. Patient plasma was serially diluted down the ELISA plate. Domain predominance was determined by comparison of resultant ELISA curves. In addition the presence of anti-A2 group A antibodies in the polyclonal patient plasma was assessed by competition ELISA. Results: Our patient cohort was heterogeneous, consisting of patients aged 3-70 years with inhibitor titers of 0.5-131 BU. No obvious correlation was found between kinetic profiles and the inhibitory BU titer. For each patient, variability of inhibitor activity against different FVIII sources was noted. In individual patients, discrepant inhibitory kinetics were identified when commercial FVIII (rFVIII or pd-FVIII) was added, compared to PNP, utilized for standard determination of inhibitory titer in BU/ml. Among patients with similar BU titer, different FVIII neutralization profile was noted. Furthermore, the source of FVIII yielded individual neutralization curves that did not correlate with the common gold standard of inhibitory (BU) titer (Figure). Correlation between patients' epitopes and their neutralization profile was difficult to assess as in most patients no single predominant inhibitory epitope could be defined. However, in patients with C2 predominance antibodies improved neutralization was detected with pd -FVIII as compared to rFVIII source. High titer patient plasmas that contained anti-A2 group A antibodies inhibited FVIII completely at the first time point regardless of the VWF content of the FVIII source. Conclusion: The Bethesda assay neither predicts inhibitory kinetics nor defines patients' response to various FVIII sources. Our combination of assays may identify the best potential FVIII source for treatment of patients with inhibitory antibodies. We suggest that FVIII source dependent neutralization kinetics and epitope mapping may be applied as additional tools for future individual therapy tailoring. Larger sample sizes and repeated samples over time will be required to validate these results. Figure 1 Figure 1. Disclosures Dunn: CSL Behring,: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfiser: Membership on an entity's Board of Directors or advisory committees. Meeks:Grifols: Membership on an entity's Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Baxter: Membership on an entity's Board of Directors or advisory committees. Kenet:BPL: Research Funding; Opko Biologics (Prolor Biotech): Consultancy, Research Funding; Novonordisk: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Baxter: Research Funding.
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Koen, Tracie M., Dina R. Mody, Miriam Scheiber-Pacht, Todd Fairley, and Michael J. Thrall. "Limiting the Use of Atypical/Inconclusive as a Category in Nongynecologic Cytology Specimens." Archives of Pathology & Laboratory Medicine 134, no. 7 (July 1, 2010): 1016–19. http://dx.doi.org/10.5858/2009-0357-oa.1.
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Abstract Context.—Atypical has served as a descriptive term in cytology since the birth of the specialty by Dr Papanicolaou. This indeterminate diagnosis often results in repeat biopsies or additional tissue sampling and a needless delay in patient care if used inappropriately. Because of the definitional ambiguity of this term and the associated physician frustration, we have made a concerted effort at Methodist Hospital since 1995 to minimize the use of atypical as a diagnostic category. Objective.—To evaluate whether the dissolution of the atypical category has increased our cytologic-histologic discordance rate to more than the published reference range. Design.—From March 3, 2006, through December 31, 2008, all nongynecologic cases with atypical/indeterminate listed as the general diagnostic category were identified and retrieved from our laboratory data files. We then assessed the cytologic-histologic correlation rate during the corresponding time frame. Results.—A total of 48 atypical cases (0.2%) from 19 347 nongynecologic specimens were identified. Of the atypical cases, 52% (25 of 48) had intradepartmental consultation, 58% (28 of 48) had additional preparations examined, and 29% (14 of 48) documented limitations because of poor preservation. Our cytologic-histologic discrepancy rate for the period was 5.5% (214 of 3912 cases), with 89.3% (191 of 214 cases) resulting from sampling issues. On review of the small percentage of cytologic interpretative discrepancies, only one case was unhampered by less than 10% tumor cellularity or poor preservation. Conclusions.—Not using atypical as a diagnostic category, unless defined by Bethesda guidelines, has not affected our cytologic-histologic correlation rate.
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Wolff, Hans, Joseph A. Politch, Adriana Martinez, Florina Haimovici, Joseph A. Hill, and Deborah J. Anderson. "Leukocytospermia is associated with poor semen quality**Supported by the Fearing Research Laboratory Endowment and grants AI25305, HD23775 and CA42738 from the National Institutes of Health, Bethesda, MD." Fertility and Sterility 53, no. 3 (March 1990): 528–36. http://dx.doi.org/10.1016/s0015-0282(16)53352-4.
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Dobbelstein, Christiane, Georgios Leandros Moschovakis, and Andreas Tiede. "Reduced-intensity, risk factor–stratified immunosuppression for acquired hemophilia A: single-center observational study." Annals of Hematology 99, no. 9 (July 3, 2020): 2105–12. http://dx.doi.org/10.1007/s00277-020-04150-y.
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Abstract Immunosuppressive therapy (IST) is administered to patients with acquired hemophilia A (AHA) to eradicate autoantibodies against coagulation factor VIII (FVIII). Data from registries previously demonstrated that IST is often complicated by adverse events, in particular infections. This pilot study was set out to assess the feasibility of reduced-intensity, risk factor–stratified IST. We followed a single-center consecutive cohort of twenty-five patients with AHA receiving IST according to a new institutional treatment standard. Based on results from a previous study, GTH-AH 01/2020, patients were stratified into “poor risk” (FVIII < 1 IU/dl or inhibitor ≥ 20 Bethesda units (BU)/ml) or “good risk” (FVIII ≥ 1 IU/dl and inhibitor < 20 BU/ml). Outcomes were compared between the current cohort and the GTH registry as a historic control (n = 102). Baseline characteristics of the cohort were not different from the historic control. Partial remission, defined as FVIII recovered to > 50 IU/dl, was achieved by 68% of patients after a median time of 112 days, which was lower and significantly later than in the historic control (hazard ratio: 1.8, 95% confidence interval 1.2–2.8). Complete remission, overall survival, and frequency of fatal infections were not different. Grade 3 and 4 infections were more frequent. The impact of risk factors that was observed in the historic cohort was no longer apparent, as partial and complete remission and overall survival were similar in “good risk” and “poor risk” patients. In conclusion, reduced-intensity, risk factor–stratified IST is feasible in AHA but did not decrease the risk of infections and mortality in this cohort.
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Barloese, M., N. Lund, A. Petersen, M. Rasmussen, P. Jennum, and R. Jensen. "Sleep and chronobiology in cluster headache." Cephalalgia 35, no. 11 (January 8, 2015): 969–78. http://dx.doi.org/10.1177/0333102414564892.
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Background and aim M.R. present address: PAIN, National Institutes of Health, Bethesda, MD, USA Cluster headache (CH) is the headache disorder with the strongest chronobiological traits. The severe attacks of pain occur with diurnal and annual rhythmicity but the precise rhythm and involvement of potential zeitgebers is unknown. Patients complain of poor sleep quality yet this has never been studied. We investigated triggers, rhythms, sleep quality and chronotypes in CH. Methods Patients and controls completed questionnaires and structured interviews composed of new and previously validated parts including the Pittsburgh Sleep Quality Index (PSQI) and Morningness-Eveningness Questionnaire (MEQ). Patients were characterized by a CH index, a unified measure of headache burden. Results A total of 275 CH patients and 145 matched controls were included. The most common trigger was sleep (80%) and a relationship between clusters and daylight was identified. Of the patients, 82.2% reported diurnal and 56% annual rhythmicity. Patients reported impaired sleep quality (PSQI) ( p < 0.0001) and an inverse relationship between time passed since last attack and sleep quality was identified ( p < 0.0001). The CH index was positively related to the PSQI ( p < 0.0001). Conclusion Diurnally, CH exhibits a relationship with night-time and annually with daylight hours. Patients’ sleep quality is reduced compared with controls. Results suggest a complex relationship as sleep quality improves between clusters, but remains pathological.
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Escuriola-Ettingshausen, Carmen, Vladimir Vdovin, Nadezhda Zozulya, Olga Plyushch, Wolfhart Kreuz, and Bruce A. Schwartz. "ITI with a VWF-Stabilised FVIII Concentrate in Haemophilia A Patients with Inhibitors and a Poor Prognosis for ITI Success: Progress Report on octanate® in the Observational ObsITI Study,." Blood 118, no. 21 (November 18, 2011): 3310. http://dx.doi.org/10.1182/blood.v118.21.3310.3310.
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Abstract Abstract 3310 FVIII inhibitors that neutralise FVIII efficacy are the most serious complication of FVIII replacement therapy in patients with haemophilia A (HA) and can be overcome with high-dose FVIII (Bonn protocol) during immune tolerance induction (ITI) therapy. The ongoing investigator-initiated Observational Immune Tolerance Induction (ObsITI) study systematically documents the tolerisation process, retrospectively and prospectively, in patients with HA and inhibitors, including those with a poor prognosis for ITI success. Here we report interim data on Octanate®, a human plasma-derived, von Willebrand factor-stabilised FVIII product. Data were analysed for a subgroup of 18 prospective patients who received octanate® as the sole FVIII replacement therapy for a treatment/follow-up period of 36 months. ITI success was determined by fulfilment of three stringent criteria: (I) inhibitor titre < 0.6 Bethesda Units, (II) incremental in vivo recovery ≥ 80% of 1.5% per IU/kg body weight reference and (III) FVIII half-life ≥ 7 hours. According to the criteria fulfilled, patients achieved the following: partial response (I), partial success (I, II), complete success (I, II, III) or failure. Following complete success, patients received prophylaxis with octanate® every second day. Of 18 patients, with at least one risk factor for a poor ITI outcome, 14 patients (77.8%) achieved complete success; 2 patients (11.1%) had partial response and 2 patients (11.1%) failed the ITI. Cox regression analysis of time to achievement of treatment outcome, suggested that both commencing ITI at ≤ 7 years of age and having had no prior ITI attempt appear to be positive prognostic factors for earlier ITI success in this population. Despite the stringent success criteria, complete or partial ITI success was achieved in 77.8 % of the patients. Treatment with octanate® administered according to the Bonn protocol is safe and effective in the induction of immune tolerance, even in patients with a poor-prognosis for ITI success. Disclosures: Schwartz: Octapharma usa: Employment.
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Rakhe, Swapnil, Sheryl Bowley, John E. Murphy, and Debra D. Pittman. "A Neutralizing Monoclonal Antibody (PF-06741086) Against Tissue Factor Pathway Inhibitor in Combination with Activated Prothrombin Complex Concentrate Increases Hemostasis in Inhibitor Hemophilia Plasmas without Excessive Thrombin Generation." Blood 132, Supplement 1 (November 29, 2018): 3779. http://dx.doi.org/10.1182/blood-2018-99-119831.
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Abstract Hemophilia A and B are hereditary bleeding disorders caused by intrinsic coagulation pathway deficiencies of Factor VIII or Factor IX, respectively. Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor that negatively regulates thrombin generation within the extrinsic pathway of coagulation. PF-06741086 is a fully human monoclonal antibody which binds the Kunitz-2 domain and neutralizes the inhibitory activity of human tissue factor pathway inhibitor and is currently under development as a potential prophylactic treatment to prevent bleeding episodes in hemophilia A and hemophilia B patients with and without inhibitors. Activated prothrombin complex concentrate (aPCC) is used as bypass treatment for the resolution of bleeding in some hemophilia patients with inhibitors. Hemophilia inhibitor patients receiving PF-06741086 have a possibility to also receive treatment with aPCC. The aim of the current study was to assess the potential additive effect of PF-06741086 with aPCC added in vitro to Hemophilia A and B inhibitor plasmas using a thrombin generation assay (TGA). Thrombin generation in the presence of 1 pM tissue factor and 4 µM phospholipid, was measured using the calibrated automated thrombogram (CAT) system in citrated platelet poor hemophilia A inhibitor (88-160 Bethesda Units) donor plasma or hemophilia B inhibitor (FIX immune-depleted and spiked with FIX neutralizing antibody, 14 Bethesda Units) plasma following the addition of PF-06741086 or aPCC (FEIBA) either alone or in combination. All donors had less than 1% coagulation factor activity. Non-hemophilic plasma from healthy donors alone or spiked in vitro with 16 µg/mL of PF-06741086 was also included in the analysis. Non-hemophilic plasma would have the full complement of coagulation factors. Dose-dependent increases in peak thrombin were observed with the addition of aPCC alone or PF-06741086 alone to the hemophilia plasmas. For combination studies, the aPCC concentration of 1 Unit/mL was selected to correspond to plasma levels that could be achieved clinically post-dosing. The concentration of PF-06741086 at 16µg/mL in these studies was chosen to approximate the Cmax concentration following a single 300 mg subcutaneous dose. Both PF-06741086 (16 µg/mL) and aPCC (1 Unit/mL) decreased the lag time in hemophilia plasma, however, there was not an additive decrease in the lag time with the combination of PF-06741086 and aPCC. The addition of PF-06741086 in combination with aPCC to hemophilia plasma resulted in an increase in thrombin generation including a higher peak thrombin concentration compared to the addition of either alone, but was within the range reported in studies for non-hemophilic normal plasma. To summarize, the addition of aPCC (1 Unit/mL) in combination with PF-06741086 (16µg/mL) in vitro resulted in increased thrombin generation in hemophilia A and hemophilia B inhibitor plasmas without inducing excessive coagulation. Disclosures Rakhe: Pfizer: Employment. Bowley:Pfizer: Employment. Murphy:Pfizer: Employment. Pittman:Pfizer: Employment.
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Vodopivec, Danica M., Niyoti Reddy, and Stephanie L. Lee. "A Subtype of Papillary Thyroid Carcinoma Bone Metastasis With Excellent Response to RAI-Therapy." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A880. http://dx.doi.org/10.1210/jendso/bvab048.1797.
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Abstract Introduction: Bone metastases from differentiated thyroid cancer are generally resistant to radioactive iodine (RAI) therapy and are associated with poor prognosis, except for RAI-avid bone metastases with no structural correlate on imaging studies. Case: A 59 y/o woman presented for the evaluation of non-toxic multinodular goiter. Thyroid US showed a 2.7 cm nodule meeting FNAB criteria and no suspicious cervical lymph nodes. Cytology reported a Bethesda IV category with ThyroSeq V3 positive for chromosomal copy number alterations and a high Na+/I− symporter (NIS) expression (27%) with an ~ 60% probability of cancer. The patient underwent left lobectomy with isthmusectomy without neck dissection. Surgical pathology showed a 3.5 cm papillary thyroid carcinoma with extensive angioinvasion (≥4 vessels), negative margins, no ETE, and did not contain a BRAF V600E mutation. Completion thyroidectomy, in anticipation of RAI treatment, showed no additional tumor. Post-operative Tg after 6 weeks was unexpectedly high at 69 ng/mL (negative Tg Ab, TSH 5.7 uIU/ml) which prompted a rhTSH I-123 RAI WBS with SPECT/ CT and a diagnostic chest CT to uncover possible distant metastases. There was RAI uptake in the thyroid bed and right anterolateral 9thrib without a CT correlate (no osteolytic lesion) but with a signal abnormality on MRI. She was categorized as T2NxM1, 8th Edition AJCC Stage IVB, and ATA high risk. She was treated with 148.3 mCi I-131. Unfortunately, 6 months later the Tg was elevated and rising (Tg 38.4 ng/mL, negative Tg Ab, TSH 0.05 uIU/ml). A second diagnostic I-123 WBS with SPECT/ CT showed a new recurrence in the neck but no uptake in the rib lesion on planar images or other distant sites. Because of the unusually high Tg without any RAI-avid metastatic disease, an 18-FDG PET/CT was ordered to search for non-RAI avid disease. This showed disease confined to the neck and increased sclerosis of the rib lesion without increased FDG-uptake consistent with treated disease status post-RAI. There were no other distant hypermetabolic lesions. The left thyroid bed lesion was biopsied and consistent with Bethesda VI cytology and she will soon undergo left central neck dissection with tumor resection. Discussion: RAI-avid bone metastases without structural correlate on high-resolution imaging are a subtype of bone metastases located in the marrow. They do not present as the typical lytic lesions from cortical destruction. They often resolve following RAI treatment, do not cause skeletal-related complications, and do not significantly affect prognosis. The combination of high NIS expression and increased vascularity in the bone marrow (as opposed to the protected microenvironment in the bone cortex) makes them vulnerable to RAI treatment. Recognition of this subset of bone lesions may prevent overtreatment with high doses of RAI treatment and avoid the use of bisphosphonates or external beam radiation.
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Setiawan, Christianus Heru, Zullies Ikawati, and Abdul Gofir. "THE CORRELATION OF TRANEXAMIC ACID USED AS ANTIFIBRINOLYTIC THERAPY TO GLASGOW COMA SCALE FOR THE FIRST 7 DAYS IN HAEMORRHAGIC STROKE PATIENTS." Asian Journal of Pharmaceutical and Clinical Research 10, no. 14 (May 1, 2017): 94. http://dx.doi.org/10.22159/ajpcr.2017.v10s2.19498.
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Objective: Treatment of haemorrhagic stroke using tranexamic acid is still used in some hospitals, to prevent the occurrence of the complication called rebleeding. Rebleeding is an important cause of bad outcomes that result loss of consciousness and even death. The administration of the antifibrinolytic tranexamic acid in patients with haemorrhagic stroke can reduce the occurrence of rebleeding but it also can increase poor outcome caused by cerebral ischemia that can worsen the patient's condition.Methods: This study used observational study design, cohort, prospective, and multicenter. The purpose of this study was to determine the effectiveness of the use of tranexamic acid in patients with haemorrhagic stroke. Statistical testing is done by analyzing the Glasgow Coma Scale (GCS) score on day 1st, day 3rd, and day 7th between the treatment groups haemorrhagic stroke patients who received tranexamic acid therapy as antifibrinolytic therapy in Bethesda Hospital for 23 patients compared with a control group of patients haemorrhagic stroke who did not receive therapy as tranexamic acid antifibrinolytic therapy in the Dr. Sardjito Hospital for 23 patients.Results: The statistical analysis of the independent t-test showed that there was no significant difference between the average GCS score of day 1st (P=262), day 3rd (P=0.293), and day 7th (P=0.648) between treatment group and control group. The statistical analysis of the Mann-Whitney showed that there was not significant difference comparing the difference between the pre and post GCS score at treatment group and control group (P=0.158).Conclusion: Administration of tranexamic acid in patients with haemorrhagic stroke (treatment group) gives the same clinical response compared to the patients who did not receive tranexamic acid therapy (control group) based on assessment of the Glasgow Coma Scale (GCS) score.
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Rahman, Mohammed Mustafizur, Shabnam Imam, Mst Sayedatun Nessa, Joyosree Saha, Farhana Islam, and Abu Khalid Muhammad Maruf Raza. "Pap smear in women with leucorrhea : Experience in a tertiary medical college hospital of Bangladesh." Northern International Medical College Journal 9, no. 1 (March 12, 2018): 252–54. http://dx.doi.org/10.3329/nimcj.v9i1.35921.
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Background : Poor genital hygiene has been responsible for high prevalence of excessive vaginal discharge. Leucorrhoea is the clinical evidence of infection and can be treated satisfactorily whenever diagnosed. Occurrence of various cervical epithelial lesion associated with discharge can be easily prevented if detected early. Majority of the patients with various cervical epithelial lesion attending in the hospital present with varying degree of vaginal discharge and cytological cellular aberrations in the cervical epithelium.Objective : The aim of the present study is to observe the various patterns of cervical epithelial lesions in cytopathology and associated infections in patients with Leucorrhoea.Methodology : This observational study was done over a period of ten months in Popular Medical college hospitals of Bangladesh. A total of 230 cases were included in the study with women of age range 15-45 years, complaining of leucorrhoea. After a thorough vaginal examination Pap smears were taken and immediately fixed in absolute alcohol and stained according to the papanicolaous technique. The cytopathological changes observed in the cervical smears were graded according to the Bethesda system for reporting cervical cytology.Results : Out of 230 cases the cytological patterns were found Normal in 4 (1.7%), Inflammatory 204 (88.3%), Low grade squamous intraepithelial (LSIL)10 (4.8%), High grade squamous intraepithelial (HSIL) 6(2.6%), Atypical squamous cells of undetermined significance (ASCUS) 6 (2.6%) and the distribution of different types of pathogens detected were Trichomonas 33 (70.62%), Candida albicans 19 (40.66%).Conclusion : In this study significant numbers of Leucorrhoea patients were detected with cervical squamous intraepithelial lesions (SIL) in which LSIL (Low grade squamous intraepithelial) was higher. Associated infections were Trichomonas and Candida albicans. Therefore cytological screening for early detection of cervical squamous intraepithelial lesion is essential routine medical examination for Leucorrhoea patients in gynaecological practice.Northern International Medical College Journal Vol.9(1) July 2017: 252-254
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Yu, Feng-xia, Min-xia Hu, Han-xue Zhao, Li-juan Niu, Xue-yu Rong, Wei-hua Li, Qiang Zhu, Jian-ming Ying, and Ning Lyu. "Precise Detection of Gene Mutations in Fine-Needle Aspiration Specimens of the Papillary Thyroid Microcarcinoma Using Next-Generation Sequencing." International Journal of Endocrinology 2019 (February 19, 2019): 1–7. http://dx.doi.org/10.1155/2019/4723958.
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Purpose. To assess the feasibility of next-generation sequencing (NGS) to detect mutations in BRAF, RAS, TERT promoter, and TP53 genes in ultrasound-guided fine-needle aspiration (FNA) biopsy samples of the papillary thyroid microcarcinoma (PTMC). Methods. A total of 135 FNA samples out of 135 patients with suspected PTMC were submitted for mutation testing using NGS. NGS was successfully performed in 114 specimens, while the remaining 21 samples were excluded due to insufficient amount/poor quality of DNA and sequencing failure. Of those 114 samples, 72 who were confirmed as having PTMC by postoperative histopathology were enrolled in our study, and the other 42 who had a follow-up with ultrasound were excluded. Mutations of genes including BRAF, NRAS, HRAS, KRAS, TERT promoter, and TP53 were evaluated using NGS. The associations of gene mutations and clinicopathological characteristics of PTMC were analyzed. Results. BRAF mutation was observed in 59 (81.94%) of 72 specimens. This mutation detected in BRAF was p.V600E (c.1799T>A) in exon 15 of all 59 specimens. NRAS mutation was identified in 1 (1.39%) specimen classified as Bethesda III and pathologically confirmed as a follicular variant PTMC. There were no mutations found in TERT promoter or TP53. The tumor with a maximum diameter (Dmax) larger than 5 mm was shown to be significantly correlated with the BRAF mutation in a multivariate analysis (OR 5.52, 95% CI 1.51-26.42, P=0.033). But the BRAF mutation was not found to be significantly associated with the gender or age of patients with PTMC (P>0.05). Conclusions. This study demonstrated that gene mutations in FNA specimens of PTMC could be successfully analyzed with a higher sensitivity using NGS compared to conventional methods for mutation detection. BRAF mutation of p.V600E was statistically associated with PTMC with a Dmax larger than 5 mm.
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Marginean, Esmeralda Celia, and Barbara Melosky. "Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part I—Colorectal Cancer: Microsatellite Instability, Testing, and Clinical Implications." Archives of Pathology & Laboratory Medicine 142, no. 1 (November 16, 2017): 17–25. http://dx.doi.org/10.5858/arpa.2017-0040-ra.
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Context.— Colorectal cancer (CRC) represents the third most-common cancer in developed countries and is a leading cause of cancer deaths worldwide. Two recognized pathways contribute to CRC development: a more-common chromosomal instability pathway and, in 15% of cases, a deficient mismatch repair or microsatellite instability–high (MSI-H) pathway. The MSI-H CRC can be associated with somatic or germline mutations. Microsatellite status has been recognized as a prognostic and predictive biomarker. Objectives.— To summarize the molecular pathways of CRC, with an emphasis on the MSI (mismatch repair) pathway; the recommended MSI testing algorithms and interpretation; and the prognostic and predictive role of MSI-H status in personalized treatment, including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy. Data Sources.— A PubMed (US National Library of Medicine, Bethesda, Maryland) review was performed for articles pertaining to CRC, MSI and mismatch repair systems, molecular classification, immune response, programmed death receptor-1/programmed death ligand-1, and immunotherapy. Conclusions.— Although the TNM classification of malignant tumor stage remains the key determinant of CRC prognosis and treatment, there are considerable stage-independent, interindividual differences in clinical outcome and therapy response by patients. In addition, MSI-H status has an important role in CRC management and can be reliably detected by molecular and immunohistochemistry techniques and genetic testing. Efforts must be made to identify whether MSI-H CRC is germline or sporadic to ensure appropriate treatment, accurate prognosis, and risk assessment for relatives. Microsatellite status has been recognized as a good prognostic indicator and is predictive of a poor response to 5-fluorouracil–based chemotherapy and a good response to programmed death ligand-1 inhibitor pembrolizumab in metastatic/refractory MSI-H CRC.
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Lange, R., S. Lippa, T. Brickell, P. Yeh, and L. French. "B-58 Post-traumatic Stress Symptoms Are Associated with Worse Neuropsychological Functioning, but not Diffusion Tensor Imaging Findings, in Military Service Members Following Mild Traumatic Brain Injury." Archives of Clinical Neuropsychology 34, no. 6 (July 25, 2019): 1004. http://dx.doi.org/10.1093/arclin/acz034.141.
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Abstract Objective The purpose of this study was to examine neurobehavioral and neurocognitive functioning, and white matter integrity (using Diffusion Tensor Imaging [DTI]), in service members with versus without PTSD following mild traumatic brain injury (MTBI). Method Participants were 101 U.S. military service members who had sustained an uncomplicated MTBI (n = 80) or an injury without TBI (i.e., Injured Control [IC], n = 21) prospectively enrolled from the Walter Reed National Military Medical Center (Bethesda, Maryland). Participants completed a battery of neuropsychological tests, as well as DTI of the brain, on average 4-years post-injury. Measures of FA, MD, AD, and RD were generated for 18 regions of interest [ROIs]. Participants in the MTBI group were divided into two sub-groups based on DSM-IV-TR diagnostic criteria for PTSD: MTBI/PTSD-Present (n = 22) and MTBI/PTSD-Absent (n = 58). Results The MTBI/PTSD-Present group reported a significantly higher number of postconcussion symptoms, had higher scores on the majority of MMPI-2-RF scales, and had worse scores on the vast majority of cognitive domains (i.e., Attention, Processing Speed, Immediate Memory, Delayed Memory, Executive Functioning, Visuospatial Ability) compared to both the MTBI/PTSD-Absent group (all p’s < .05) and IC/PTSD-Absent group (all p’s < .05). For the DTI variables, there were no significant group differences for all DTI measures in all regions of the brain, with the exception of a handful of measures (i.e., right cingulum–cingulate gyrus, and bilaterally in the corticospinal tract). Conclusion These results provide support for a (a) strong relationship between PTSD and poor neurobehavioral and neurocognitive outcome following MTBI, and (b) weak relationship between PTSD and white matter integrity following MTBI.
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Purt, Boonkit, Timothy Ducey, Sean Sykes, Joseph F. Pasternak, Denise S. Ryan, Rose K. Sia, and Marcus H. Colyer. "Comparison of Simulation-Based versus Cadaveric-Tissue-Based Ocular Trauma Training on Novice Ophthalmologists: Repair of Corneal Laceration Model." Journal of Academic Ophthalmology 13, no. 01 (January 2021): e57-e65. http://dx.doi.org/10.1055/s-0041-1725093.
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Abstract Purpose The aim of this study was to evaluate whether the simulated tissue models may be used in place of animal-based model for corneal laceration repair for surgical skills acquisition. Design Prospective randomized controlled trial. Participants Seventy-nine military and civilian 2nd- and 3rd-year ophthalmology residents and 16 staff ophthalmologists participating in the Tri-Service Ocular Trauma Skills Laboratory at the Uniformed Services University (Bethesda, MD). Methods Resident ophthalmologists underwent preliminary evaluation of their ability to close a 5-mm linear, full-thickness corneal laceration involving the visual axis. They then were randomized to undergo 90 to 120 minutes of either simulator-based (SIM) or swine cadaveric-tissue-based (CADAVER) corneal laceration repair. The same evaluation was performed post training. On a more limited basis, the study was repeated for attending ophthalmologists to act as a pilot for future analysis and test efficacy for “refresher” training. Main Outcome Measures Successful wound closure with secondary outcomes of suture length, tension, depth, and orientation, as graded by attending ophthalmologists. Results No significant difference in CADAVER versus SIM groups in the primary outcome of watertight wound closure of the corneal laceration. CADAVER group performed better than SIM group for certain metrics (suture depth, p = 0.009; length, p = 0.003; and tension, p = 0.043) that are associated with poor wound closure and increased amount of induced corneal astigmatism. For attending ophthalmologists, six of the eight in each group (SIM and CADAVER) retained or improved their skills. Conclusions For resident ophthalmologists, SIM training is sufficient for achieving the primary outcome of watertight wound closure. However, CADAVER training is superior for wound metrics for the ideal closure. For attending ophthalmologists, SIM training may be useful for retention of skills.
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Ellsworth, Patrick, Sheh-Li Chen, Nigel S. Key, Raj S. Kasthuri, Micah J. Mooberry, and Alice D. Ma. "Recombinant Porcine FVIII in Acquired Hemophilia: Decreased Product Usage When Used Upfront, Non-Utility of Baseline Porcine Bethesda Titer, and Confirmation of Dosing Algorithm." Blood 132, Supplement 1 (November 29, 2018): 2474. http://dx.doi.org/10.1182/blood-2018-99-118839.
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Abstract Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired autoantibodies to endogenous Factor VIII (FVIII) decrease FVIII activity. AHA can lead to serious bleeding, with effective treatment requiring both immunosuppressive therapy (IST) and bypassing agents such as recombinant activated Factor VII (rFVIIa) or activated prothrombin complex concentrates (APCC). Disadvantages to bypassing agents include the inability to monitor response with standard lab assays, inconsistent hemostatic efficacy, and thrombosis (Astermark et al. 2007). Recombinant porcine FVIII (rpFVIII) ), by virtue of its incomplete homology in the A2 and C2 domains of the FVIII molecule, has decreased reactivity with anti-human FVIII (hFVIII) inhibitors (Mulliez et al. 2014), enabling its use in AHA. It also has the advantage of laboratory monitoring of FVIII activity levels and hemostatic efficacy after failure of bypassing agents (Trautmann-Grill et al. 2018). Between July 2015 and April 2018, 14 patients with AHA were treated with rpFVIII at the University of North Carolina. Data from our cohort show that the initial anti-porcine Bethesda titer (pBIA) does not reliably predict the clinical response to rpFVIII treatment and is not correlated with the anti-human Bethesda titer (hBIA). We also present data showing lower total rpFVIII use for initial bleed resolution when rpVIII is used up front, as compared to use as rescue therapy. Lastly, we validated our dosing algorithm which uses much lower than FDA-recommended doses with 10 more patients than in our previously reported patient series (Martin et al. 2016). Methods We analyzed clinical, pharmacy, and laboratory data from 14 patients treated with rpFVIII at the University of North Carolina for AHA from July 2015 to April 2018. All patients were initially treated according to our previously established dosing algorithm (Fig. 3). Investigational review board approval was obtained for our data collection and analysis. Results Of our 14 patients, 11 had a pBIA drawn prior to receiving rpFVIII, with 9/11 having a detectable porcine inhibitor, and only 2 of these showing no clinical response to rpFVIII infusion. There was no correlation between initial pBIA and FVIII response to rpFVIII infusion (Figs 1a-c). Only 2 patients lost their FVIII response and needed subsequent bypass agent use. One had a peak pBIA of 212 BU, and the other had a pBIA of 7, though 3 other patients who developed high titer pBIA did not lose their response. pBIA and hBIA showed poor correlation (r = 0.4, P = 0.2). 2/11 patients with available values had pBIA of <0.4, but had high titer hBIA. 13/14 patients achieved excellent resolution of their presenting bleed at much lower than FDA-recommended doses (see Fig 1c and Table 1). In 12/14 patients, the inhibitor resolved after IST. rpFVIII was given as up front therapy in 6/14 patients (i.e., preceded by < 24 hours of bypassing agent), and they required less cumulative rpFVIII for resolution of the presenting bleed compared to the 8 patients given rpFVIII as rescue therapy (up front mean dose = 400 U/kg, rescue mean dose = 663 U/kg, P=0.06, see Fig 2). Conclusion Our data validate our previously established dosing algorithm, providing hemostatic efficacy at lower than FDA-approved doses, and allowing for rapid and standardized dosing adjustments based on laboratory and clinical response without delaying initial treatment. As the initial pBIA does not reliably predict response to rpFVIII, and is not correlated with the hBIA, our practice has been to initiate rpFVIII therapy without waiting for results of the pBIA. The pBIA can be useful in case of repeat bleeding events, though not in a predictable manner. Our data also suggest lower dose requirements when used up front, rather than as rescue therapy, which can also allow pharmacy cost savings. Disclosures Key: UniQure BV: Research Funding. Ma:CSL: Consultancy; Shire: Honoraria, Research Funding; Novo Nordisk: Consultancy; CVS: Honoraria.
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Heisel Kurth, Margaret A., Beverly Christie, Vicky Hanneman, Joni Osip, Kristen Appert, Christopher L. Moertel, Jan Watterson, and Maha Hag-Alshiekh. "Immune Tolerance Utilizing Intermediate Purity Factor VIII Concentrate in Hemophilia A Patients with High Factor VIII Titers." Blood 104, no. 11 (November 16, 2004): 3099. http://dx.doi.org/10.1182/blood.v104.11.3099.3099.
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Abstract Immune tolerance therapy (ITT) is a treatment that is used to eliminate factor VIII inhibitors associated with hemophilia A. However, standard ITT is not successful in approximately 20% of patients. In those who do not attain tolerance, the length of treatment with resultant cost of factor concentrate and family stress are major concerns. Utilization of intermediate purity products (IPP) has been suggested as a means to increase the success rate of ITT, shorten the duration of ITT, and decrease the quantity of factor concentrate used. We retrospectively analyzed outcomes for 8 patients who received IPP as part of an ITT regimen from 1993–2004. Four patients were switched from recombinant/monoclonal factor VIII to IPP during ITT because of poor response to initial therapy (Table 1). Four others were started on IPP at the initiation of ITT because they had already failed ITT or past history indicated a likelihood of failing standard ITT (Table 2). Tolerance was defined as having a Bethesda titer of <1 BU/ml, > 66% recovery of factor VIII, and/or a half-life of 6 hours or greater. In the first group, all four patients attained tolerance. In these patients the switch to IPP resulted in a faster drop in inhibitor titer than had been previously achieved. In the second group, one patient attained tolerance rapidly; one achieved partial tolerance and uses prophylactic IPP. A third patient is currently undergoing ITT and is responding well. The fourth patient has failed to achieve tolerance. These four patients had adverse risk factors that made them poor candidates for conventional ITT. Of the 6 patients who have achieved partial or complete tolerance, 4 have been switched back to recombinant factor VIII and have maintained tolerance. However, two patients have been maintained on IPP because attempts to switch to recombinant factor VIII resulted in a rise in their inhibitor titers. If tolerance can be achieved with IPP it can result in major cost savings for these patients. At our institution the cost of IPP is about 50–66% of the cost of recombinant factor VIII. These data are presented as further evidence that choice of factor may influence ITT success and that a subset of patients may benefit from an IPP regimen for ITT. Table 1: Recombinant/Monoclonal Use; Patients Switched to IPP ID Age at Inhibitor Dx (yrs) Peak Inhibitor (BU) Age at Start of ITT (yrs) Inhibitor at ITT Start (BU) Age at Switch to IPP (yrs) Reason for Switch Time to Tolerization 001 6.8 34 9.8 2 10.0 Poor response to ITT 12 months 002 8.2 100 11.8 1 12.1 Poor response to ITT by brother (001) 6 months 005 5.2 124 6.3 9 6.5–7.0 /8.2-present Poor response to initial therapy / inability to sustain tolerization 36 months 007 3.9 270 3.9 13 4.1 Poor response to ITT and bleeding complications 16 months Table 2: Patients Started on IPP Initially ID Age at Inhibitor Dx (yrs) Peak Inhibitor (BU) Age at Start of ITT (yrs) Inhibitor at ITT Start (BU) Time to Partial Tolerization Time to Tolerization 003 4.0 4833 21.4 6 Did not achieve NA 004 1.2 1000 12.4 10–20 29 months NA 006 1.3 600 12.4 0–1 6 months 8 months 008 0.8 277 5.8 1.1 6 months NA
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Mwanda, W. O., J. Orem, P. Fu, C. Banura, J. Kakembo, A. Ness, J. Johnson, J. Black, E. Katongole-Mbidde, and S. Remick. "Dose-modified oral chemotherapy for AIDS-related non-Hodgkin’s lymphoma (AR-NHL) in East Africa." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7564. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7564.
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7564 Background: Dose-modified chemotherapy for AR-NHL in the pre-HAART era has been shown to be equally efficacious and less myelotoxic [N Engl J Med 1997;336:1641 (mBACOD); J Clin Oncol 2001;19:2171 (mCHOP)]. In resource-constrained settings, intravenous chemotherapy and supportive care of the AIDS/cancer patient are challenging (J Natl Cancer Inst 2002;94:718). Methods: We embarked on a pilot feasibility trial of dose-modified oral chemotherapy [lomustine 50 mg/m2 D1 (C1 only); VP-16 100 mg/m2 D1–3; and cyclophosphamide/procarbazine 50 mg/m2 each D22–26 at 6-week intervals (1 cycle) for 2 cycles] in HIV-infected patients with biopsy-proven AR-NHL in East Africa. Results: A total of 52 pts (23 Uganda; 29 Kenya) were registered to study. The majority of pts were female (56%) with median age 39 yrs (range 18–64); poor PS (2 or 3) - 62%; high grade lymphoma (65%); advanced stage (III or IV) - 67%; and B symptoms (79%). At study entry median CD4 count was 207/μL and HIV-1 viral load 98,857 copies/ml. Nineteen pts (37%) had access to ARV. A total of 74.5 cycles of therapy were administered to 49 pts (median 2; range 0.5–2). The regimen was well tolerated. There were 4 episodes of febrile neutropenia and 3 treatment-related deaths (6% mortality rate). Overall objective response rate is 67% (CR/uCR 49%); median survival 8.2 months (range <1.0 to 52.5+ mos.); and 22 patients remain alive as of 10/7/05. Conclusions: Dose-modified oral chemotherapy is efficacious, has comparable outcome to that in the US in pre-HAART era, an acceptable safety profile, and is pragmatic in the resource-limited setting. Further investigation of the oral regimen vs. mCHOP is warranted. [Supported in part by NIH grants: CA83528, AI36219, CA70081, and TW00011. Bristol-Myers Squibb and Sigma Tau Pharmaceuticals provided the chemotherapy drugs for this trial.] (J. Black, PhD, formerly DCTD, NCI, Bethesda, MD, USA). No significant financial relationships to disclose.
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Tie, J., O. M. Sieber, P. Gibbs, L. Lipton, R. N. Jorissen, R. Langland, S. Kosmider, D. McKay, K. B. Nolop, and J. Desai. "Selecting subjects for a therapeutic target in colorectal cancer (CRC): Using a clinical database to enrich for patients harboring the BRAFV600E mutation." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 11003. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11003.
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11003 Introduction: The BRAFV600E mutation (BRAF) causes constitutive activation of the RAS-induced MAPK pathway and is found in 10% of colon cancers. B-RAF inhibitors are in early clinical development, but their development in CRC will be challenging unless subsets of patients (pts) with higher rates of BRAF can be defined. The mutation rate in rectal tumors, the concordance between primary and metastases, and the prognostic/predictive significance of BRAF are current gaps in knowledge. Methods: 481 primary tumors and 80 matched primary-metastasis (prim-met) pairs were analysed from a pre-defined cohort of pts with CRC based on age (≥ 70 vs < 70 years), gender, tumor site (right-R, left-L and rectum), stage (A to C vs D) and ≥ 2 years follow-up. BRAF was assessed by routine sequencing of exon 15 and by a mutant-specific PCR assay. KRAS (KRAS-codon 12 and 13) and MSI (Bethesda markers) status were also examined. Results: Overall prevalence of BRAF was 11%. BRAF (see table ) was independently associated with increasing age, female gender and R-sided cancer, but not with stage. Mutations were rare in rectal cancers. BRAF was associated with inferior overall survival in stage D pts (log-rank, p = 0.0003; HR 0.38, 95% CI, 0.10–0.51). Survival analysis will be further stratified by treatment received. No difference in outcome was seen in preliminary analysis of earlier stage cancers. Mutation frequencies in the prim-met pairs were 38% (30/80) and 1.3% (1/80) for KRAS and BRAF, respectively. Overall concordance was 88% (70/80) for KRAS and 100% (80/80) for BRAF status. Conclusions: The development of selective B-Raf inhibitors in CRC is potentially more attractive due to the ability to define patient subsets with a higher prevalence of BRAF mutations. Analysis of the primary tumor reliably predicts the status of metastatic disease in the same patient. The association between BRAFand poor outcome will need to be considered when interpreting the result of studies targeting this mutation. [Table: see text] [Table: see text]
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Hartmann, Johannes, Anja Schmidt, Marko Beilfuss, Diana Stichel, Christine Heller, Dirk Schwabe, Thomas Klingebiel, Nadia P. Ewing, and Christoph Koenigs. "Correlations of Plasma Cytokine Levels and Anti-FVIII Antibodies during Immune Tolerance Induction." Blood 132, Supplement 1 (November 29, 2018): 2471. http://dx.doi.org/10.1182/blood-2018-99-110588.
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Abstract Introduction The development of neutralizing anti-FVIII antibodies (inhibitors) with reduced or absent activity of substituted factor VIII (FVIII) remains the most serious complication of hemophilia A therapy (Kempton, 2014). Frequent and high doses of FVIII with or without bypassing products can reestablish immune tolerance in 60-70% of patients. Polymorphism in immune response genes including IL-10 and TNFa were identified as risk factors for inhibitor development (Astermark, 2006). Cross-sectional studies showed different cytokine profiles in patients with hemophilia, especially in those with history of an inhibitor (Oliveira, 2013). In this study cytokine profiles were monitored longitudinally during immune tolerance induction (ITI). Methods 107 plasma samples from 18 patients were collected during the RES.I.S.T Experienced and Naive trial, which included patients with a poor prognosis for ITI success (Gringeri, 2007). We quantified 14 cytokines in each sample by using a Human High Sensitivity T-Cell Discovery Array 14-Plex (Eve Technologies Corp, Calgary, AB, Canada). ELISA based FVIII antibody assays were used for anti-FVIII IgG detection. FVIII inhibitor titers (Bethesda assay, BU) were measured and available for the analysis. The cut-off for a positive inhibitor was >0,6 BU mL-1. Bethesda titers (BUpos) between 0,6 - <5,0 were considered as low titer (BUlow), whereas BU ≥5 as high titer (BUhigh). Statistical analyses were performed using GraphPad Prism 7. Mann-Whitney U tests and Spearman correlation tests considered significant when P value <0.05. Results Plasma levels of TNFa (P=0,014) and IL-8 (P=0,048) were positively correlated with FVIII inhibitor titers. Negative correlation was found in levels of IL-10 (P=0,041), IL-12 (P=0,038) and IL-1B (P=0,026). When cytokine levels of plasma samples with detectable and undetectable FVIII inhibitor titers were compared, significant higher plasma levels of TNFa (median: 11,56pg/ml, 8,11pg/ml; P=0,016) and lower levels of IL-12 (median: 4,29 pg/ml, 6,25 pg/ml; P=0,047) and IL-23 (median: 1016 pg/ml, 1353 pg/ml; P=0,049) were measured in samples with detectable FVIII inhibitor (BUpos). Furthermore, TNFa levels were higher in BUlow (median: 10,83 pg/ml; P=0,047) as well as in BUhigh samples (median: 11,75 pg/ml; P=0,019), compared to BUneg (median: 8,11 pg/ml). Cytokine concentrations of IL-1B (median: 2,64 pg/ml, 3,77 pg/ml; P=0,023), IL-2 (median: 2,44 pg/ml, 2,97pg/ml; P=0,043) and IL-17 (median: 15,79 pg/ml, 19,42 pg/ml; P=0,036) were significantly lower in BUhigh plasma samples compared to BUneg. Additionally, plasma level of IL-10 correlated negatively with levels of anti-FVIII IgG (P=0.045). Conclusion This is the first study of cytokine measurement in a longitudinal setting as well as during ITI in patients with hemophilia. FVIII inhibitors and anti-FVIII IgG antibodies were correlated to IL-10 and TNFa levels - of note, polymorphisms in the genes of these cytokines are a known risk factor for inhibitor development. Furthermore, IL-12, IL-17 and IL-23 levels were higher in samples with loss of FVIII Inhibitors. In addition to prediction of inhibitor development, cytokine profiles might serve as prognostic factors for ITI success and considering the emerging evidence of the IL-17-IL-23 immune axis in autoimmunity might also be promising therapeutic approaches for higher ITI success rates. Disclosures Ewing: Genentech: Honoraria; Shire: Honoraria; Bayer: Honoraria; Grifols: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Hema Biologics: Honoraria; Biogen: Research Funding. Koenigs:Jansen: Research Funding; Gilead: Research Funding; Biotest: Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Intersero: Research Funding; CSL Behring: Consultancy, Research Funding; EU (IMI, FP7): Research Funding; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding; Novo Nordisk: Consultancy, Speakers Bureau; Bioverativ: Consultancy; Roche/Chugai: Consultancy.
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de Almeida, Maria Moitinho, and Johan von Schreeb. "Human Stampedes: An Updated Review of Current Literature." Prehospital and Disaster Medicine 34, no. 1 (November 27, 2018): 82–88. http://dx.doi.org/10.1017/s1049023x18001073.
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AbstractHuman stampedes are a major cause of mortality in mass gatherings, but they have received limited scientific attention. While the number of publications has increased, there is no recent review of new study results. This study compiles and reviews available literature on stampedes, their prevention, preparedness, and response.A search for peer-reviewed and grey literature in PubMed (National Center for Biotechnology Information, National Institutes of Health; Bethesda, Maryland USA), Google Scholar (Google Inc.; Mountain View, California USA), Web of Science (Thomson Reuters; New York, New York USA), the World Health Organization Library Database (WHOLIS; World Health Organization; Geneva, Switzerland), and ReliefWeb (UN Office for the Coordination of Humanitarian Affairs; Geneva, Switzerland) was conducted, and papers were selected according to pre-defined eligibility criteria. Included items were read and results were compiled and summarized. A total of 64 publications were included, of which, 34 were published between 2013-2016. The most studied events were Germany’s Love Parade stampede in 2010 (Duisburg, Germany; n = 6) and the United Kingdom (UK) Hillsborough Stadium stampede in 1989 (Sheffield, England; n = 4). Conflicting definitions of human stampedes were found. The common belief that they result from an irrational and panicking crowd has progressively been replaced by studies suggesting that successive systemic failures are main underlying causes. There is a lack of systematic reporting, making news reports often the only source available. Prevention measures are mainly related to crowd management and venue design, but their effectiveness has not been studied. Drills are recommended in the preparedness phase to improve coordination and communication. Delay in decisions, poor triage, or loss of medical records are common problems in the response, which may worsen the outcome.Stampedes are complex phenomenon that remain incompletely understood, hampering formulation of evidence-based strategies for their prevention and management. Documentation comes mostly from high-profile events and findings are difficult to extrapolate to other settings. More research from different disciplines is warranted to address these gaps in order to prevent and mitigate future events. A start would be to decide on a common definition of stampedes.Moitinho de AlmeidaM,von SchreebJ.Human stampedes: an updated review of current literature.Prehosp Disaster Med.2019;34(1):82–88.
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López-Damián, E. P., T. Fiordelisio, M. A. Lammoglia, M. Alarcón, M. Asprón, and C. S. Galina. "155 CHARACTERIZATION OF LIPID DROPLETS IN BOS INDICUS AND BOS TAURUS EMBRYOS." Reproduction, Fertility and Development 25, no. 1 (2013): 226. http://dx.doi.org/10.1071/rdv25n1ab155.
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Accurate evaluation of bovine embryos for assessing developmental stage and quality is critical to the success of any embryo transfer program. However, this evaluation process has been reported to be highly subjective in Bos indicus (BI) and can vary as much as 23% compared with that of Bos taurus (BT). These differences in assessment may be related to the quantity of lipid droplets (LD) within the embryo, which has been shown to have a negative effect in cryopreserving embryos. The aim of the present study was to characterize the number and size of LD in different developmental stages of fresh embryos from BI and BT and to compare LD across the three different embryo quality grades (1 = excellent or good, 2 = fair, and 3 = poor). Nonsurgical embryo collection was performed 7 days post-insemination in 10 BI and 10 BT females. Forty-eight embryos were evaluated for stage and grade using stereoscopic microscopy, processed for transmission electron microscopy, and stained with Nile red. Digitalized images were analyzed with ImageJ (National Institutes of Health, Bethesda, MD, USA), contour of lipid droplets were designed, and values of perimeter, area, and fluorescence intensity were assessed. Nonparametric statistical analysis (Mann–Whitney) was utilized. There was no difference in LD number for BT or BI for morulae and blastocyst; however, BI morulae presented larger LD compared with blastocyst stage embryos (286 µm2 v. 223 µm2; P < 0.05). Likewise, BI TF cells had more LD compared with inner cell mass (ICM) cells (48 v. 36; P < 0.05). BT TF cells exhibited larger LD compared with ICM cells (149 µm2 v. 128 µm2; P < 0.05), while BI embryos exhibited a larger area of LD in the ICM compared with the TF (591 µm2 v. 472 µm2; P < 0.05). In all embryos, BI contained more lipid droplets than BT (78 v. 49; P < 0.05). Across all quality grades (good, fair, and poor) there was no difference in the number of LD in BT embryos; however, BI grade-3 embryos presented more LD than grade-1 (36 v. 25). BT embryos LD were larger than BI LD (907 µm2 v. 625 µm2; P < 0.05). Fluorescence images showed higher arbitrary units of fluorescence (auf) for LD in BI. Compared with BT embryos (386 auf v. 280 auf; P < 0.05). These results suggest that BI embryos contain more and smaller LD than BT embryos and the LD described for BI embryo quality grade 1 are larger than those of quality grades 2 and 3, and even though the number of LD in morulae and blastocyst stage embryos are not different LD size is reduced as development occurs. Research funding provided by UNAM-DGAPA-PAPIIT IN200810.
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Bortolin, Michelangelo, Ilaria Morelli, Amalia Voskanyan;, Nina R. Joyce, and Gregory R. Ciottone. "Earthquake-Related Orthopedic Injuries in Adult Population: A Systematic Review." Prehospital and Disaster Medicine 32, no. 2 (January 30, 2017): 201–8. http://dx.doi.org/10.1017/s1049023x16001515.
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AbstractIntroductionEarthquake-related trauma results in crush injuries and bony- and soft-tissue trauma. There are no systematic reviews analyzing the typical injury patterns and treatments in “Mega-Mass-Casualty” earthquakes. The characterization of an injury pattern specific to disaster type, be it natural or manmade, is imperative to build an effective disaster preparedness and response system.MethodsThe systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A comprehensive search strategy was developed to identify all publications relating to earthquakes and the orthopedic treatment in adult patients. The following databases were searched: PubMed (Medline; US National Library of Medicine, National Institutes of Health; Bethesda, Maryland USA), Ovid (Ovid Technologies; New York, New York USA), Web of Science (Thomson Reuters; New York, New York USA), and The Cochrane Library (The Cochrane Collaboration; Oxford, United Kingdom).ResultsThe searches identified 4,704 articles: 4,445 after duplicates were removed. The papers were screened for title and abstract and 65 out of those were selected for full-text analysis. The quality of data does not permit a standard-of-care (SOC) to be defined. Scarcity and poor quality of the data collected also may suggest a low level of accountability of the activity of the international hospital teams. Qualitatively, it is possible to define that there are more open fractures during daytime hours than at night. Excluding data about open and closed fractures, for all types of injuries, the results underline that the higher the impact of the earthquake, as measured by Richter Magnitude Scale (RMS), the higher is the number of injuries.DiscussionRegarding orthopedic injuries during earthquakes, special attention must be paid to the management of the lower limbs most frequently injured. Spinal cord involvement following spine fractures is an important issue: this underlines how a neurosurgeon on a disaster team could be an important asset during the response. Conservative treatment for fractures, when possible, should be encouraged in a disaster setting. Regarding amputation, it is important to underline how the response and the quality of health care delivered is different from one team to another. This study shows how important it is to improve, and to require, the accountability of international disaster teams in terms of type and quality of health care delivered, and to standardize the data collection.BortolinM, MorelliI, VoskanyanA, JoyceNR, CiottoneGR. Earthquake-related orthopedic injuries in adult population: a systematic review. Prehosp Disaster Med. 2017;32(2):201–208.
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Scheinberg, Phillip, Olga Nunez, Colin O. Wu, and Neal S. Young. "Treatment of Severe Aplastic Anemia with Combined Immunosuppression: Antithymocyte Globulin (ATG), Cyclosporine A (CSA), and Mycophenolate Mofetil (MMF)." Blood 106, no. 11 (November 16, 2005): 3758. http://dx.doi.org/10.1182/blood.v106.11.3758.3758.
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Abstract Severe aplastic anemia can be successfully treated with immunosuppressive therapies (IST) or hematopoietic stem cell transplantation (HSCT). Response rates with horse anti-thymocyte globulin (ATG) plus cyclosporine (CsA) are about 60–70%, and robust responders have excellent long term survival (Rosenfeld, Follmann et al. 2003). Relapse require reinstitution of IST and does not negatively affect survival. We introduced a third immunosuppressive agent to standard horse ATG/CsA, mycophenolate mofetil, in an attempt to improve response rate, survival and to decrease the relapse rate and clonal evolutions to myelodysplasia or leukemia. MMF blocks the proliferation of active lymphocytes by the inhibition of the enzyme inosine monophosphate dehydrogenase, an important step in purine and therefore DNA synthesis. MMF immunosuppression is due to direct inhibition of T cell proliferation and therefore, would be anticipated to favor the induction of tolerance by selective depletion of active lymphocytes. MMF has been employed as a “kidney-sparing” adjunct to CSA in renal and other solid organ transplantations, post-HSCT, and in certain autoimmune diseases with a favorable toxicity profile. A total of 104 consecutive patients with SAA were treated with horse ATG/CsA/MMF from May 1999 to June 2003 at the Warren Grant Magnuson Clinical Center at the National Institutes of Health in Bethesda, MD. Response was defined by blood counts no longer satisfying criteria for severe AA. The overall response rate at 6 months was 62%, with 24 (37% of responders) patients relapsing at a median of 389 days from ATG. Fifteen relapses occurred after CsA was discontinued at 6 months but before 18 months, while patients were still on MMF. Nine patients showed evidence of clonal evolution following ATG, five responders and 4 nonresponders. The median survival among responders was not reached and among nonresponders was 1,759 days. There was no difference in overall survival among patients who relapsed and those who did not relapse. Over half of the relapses occurred during MMF administration (15 of 24), suggesting that this drug is not active in preventing relapses among responders. Evolution to clonal disorders did not change with the intensification of immunosuppression with MMF. Despite a strong theoretical rationale for its use, MMF did not result in improvement in response or relapse rates, and it cannot be routinely recommended as a CsA-sparing agent in responders with poor tolerability to CsA.
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Modhia, Falgun, Mohammad O. Khalil, Ankur D. Mody, Sarah Johnston, and Daniel Zhao. "Effect of Socioeconomic Factors on Survival in Veterans with Acute Myeloid Leukemia (AML)." Blood 132, Supplement 1 (November 29, 2018): 5917. http://dx.doi.org/10.1182/blood-2018-99-114967.
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Abstract Background: There is limited information about socioeconomic factors effect on survival in veterans with acute myeloid leukemia (AML). Some studies suggested higher risk of leukemia mortality among veterans who were smokers [1, 2, 3, 4]. Few studies investigated socioeconomic factors like insurance status, care at private or academic center, marital status and median household income effect on outcomes in adults with AML [5, 6, 7]. Methods: Medical records of AML patients at the Oklahoma City VAHCS between 2010 and 2017 were reviewed. Information collected included home distance from treatment center (≤ 40 miles vs > 40 miles), marital status at diagnosis, tobacco use in the 3 months preceding diagnosis, history of alcohol abuse, level of college education (college education vs less than college education). Fisher-exact test was used for differences in survival rates. Kaplan-Meier analysis was used to estimate the survival and log-rank test to determine differences among groups. Results: Total number of Veterans were 28. Fifteen patients (56%) had poor risk disease, 8 (30%) had intermediate risk disease, and 4 (15%) had good risk disease. Median survival for the whole group was 9.3 months. Patients with poor and intermediate risk cytogenetic/molecular status had median survival of 5.5 and 37.7 months, respectively (p=0.0066). There was insufficient number of deaths in the good risk group at the time of this analysis. Median survival for veterans with history of alcohol abuse vs none was 66 vs 7 months (p= 0.15). Median survival for veterans who had some college education vs less than college education was 26.1 vs 6.9, (p=0.14). Median survival for veterans with history of tobacco use within 3 months of diagnosis vs others was 6.9 vs 26.1 (p= 0.11). Median survival for veterans who were married at diagnosis vs non married was 14 vs 7.89 (p=0.29). Median survival for veterans who lived > 40 miles from treatment center vs ≤ 40 miles was 7.43 vs 37.7 months (p=0.5). Conclusions: In our retrospective single institute study, poor risk cytogenetic/molecular risk group was associated with inferior survival. While there appeared to be a trend towards worse survival in association with lower education, smoking, non-married status, and longer distance from treatment center, none of these factors had a statistically significant effect. Larger studies are needed to confirm such observations. References: 1. Austin H, Cole P. Cigarette smoking and leukemia. Journal of chronic diseases. 1986; 39: 417-421. 2. Kahn HA. The Dorn study of smoking and mortality among US veterans: Report on 8.5 years of observation. Bethesda, MD: US Department health, Education and Welfare, 1966; 1-125. 3. Rogot E, Murray JL. Smoking and causes of death among US veterans. 16 years of observation. Public Health Rep. 1980; 95: 213-222. 4. McLaughlin JK, Hrubec Z et al. Cigarette smoking and leukemia. J Natl Cancer Inst 1990; 81: 1262-1263. 5. Luciano Costa, Uma Borate et al. Non Biological factors affecting survival in Younger patients with acute myeloid leukemia. Blood 2014; 124:1273; 6. Gaurav Goyal, Lata Nawal et al. Impact of socioeconomic, demographic and health system factors on therapy in Acute myeloid leukemia. Blood 2015; 126: 3316; 7. Lene Sofie Granfeldt et al, Effects of Education and income on treatment and outcome in patients with AML in tax supported health care system: A national population based cohort study. J Clin Oncol Nov 2017; 35: 3678-3687. Disclosures No relevant conflicts of interest to declare.
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Ravandi, Farhad, Hagop M. Kantarjian, Trishna Goswami, Fujun Wang, and Ramy Ibrahim. "Design Of a Phase 1/2 Study Of Moxetumomab Pasudotox In Adult Patients With Relapsed and/Or Refractory Acute Lymphoblastic Leukemia (ALL)." Blood 122, no. 21 (November 15, 2013): 5021. http://dx.doi.org/10.1182/blood.v122.21.5021.5021.
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Abstract Background Adult ALL encompasses a heterogeneous group of lymphoid malignancies. Long-term survival in adults is currently only 35% to 45%; the predominant reason for this is disease recurrence. Current outcomes of salvage chemotherapy for ALL are poor, with complete response rates of 20% to 30% depending on prior therapy and duration of first remission. Older patients with ALL who relapse have a very poor prognosis and very limited options. Thus, adults with relapsed/refractory ALL are a population with significant unmet needs, requiring effective salvage therapies that maintain durable remissions. CD22 is expressed on most B-lineage ALL blasts; thus, it is an ideal target for eliminating leukemic cells. Moxetumomab pasudotox (MP) is a recombinant immunoconjugate composed of an anti-CD22 immunoglobulin variable domain genetically fused to a truncated form of Pseudomonasexotoxin, PE38. MP has been clinically tested and showed antitumor activity in other B-cell malignancies including relapsed hairy cell leukemia (Kreitman RJ, et al. J Clin Onc. 2012;30:1822-28) and pediatric ALL (Shah NN, et al. 2nd International Workshop on the Biology, Prevention, and Treatment of Relapse After HSCT Program and Abstract Book; Bethesda, MD. 2012. P-49). Study Design This is a single-arm, open-label, phase 1/2, single-institution study of MP in relapsed and/or refractory adult patients with ALL. The phase 1 portion will determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the regimen. The phase 2 portion will evaluate the clinical activity of the regimen as well as the tolerability and safety profile. The primary endpoints of the phase 1 are MTD and DLTs. In the phase 2, the primary endpoints are overall response, including complete remission (CR), CR without recovery of counts, and partial remission; the secondary endpoints are event-free survival (time from enrollment to relapse or death, or the last known follow-up) and overall survival at 2 years. MP will be administered intravenously over 30 minutes. The phase 1 will start with a 30 µg/kg dose every other day x 6 doses in a 21-day cycle; it will use a standard 3+3 dose escalation. Additional dose regimens may be investigated. The phase 2 starting dose will be the MTD from phase 1. Dosing will be discontinued upon disease progression, development of unacceptable toxicity, recommendation for alternate therapy, or patient noncompliance. Minimal residual disease at multiple time points and immunogenicity will be assessed. Enrollment will include a maximum of 60 patients. Conclusion This study will provide new insights into the treatment of adults with relapsed/refractory ALL as well as expand upon the clinical activity of MP previously demonstrated in B-cell malignancies. This study is sponsored by MD Anderson Cancer Center. Collaborator: MedImmune. ClinicalTrials.gov Identifier: NCT01891981 Disclosures: Ravandi: MedImmune: Research Funding. Kantarjian:MedImmune: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Bristol Myers-Squibb: Research Funding; Ariad: Research Funding. Goswami:MedImmune: Employment. Wang:MedImmune: Employment. Ibrahim:MedImmune: Employment.
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Belletrutti, Mark J., Roxanne Seiferman-Nelson, and Bonny Granfield. "A Case Series Evaluating the Use of a Von Willebrand Factor/Factor VIII Concentrate (Wilate®) for Immune Tolerance Induction (ITI) in Children with Severe Factor VIII Deficiency." Blood 124, no. 21 (December 6, 2014): 5050. http://dx.doi.org/10.1182/blood.v124.21.5050.5050.
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Abstract Introduction: Development of circulating anti-factor VIII antibodies (inhbitors) is the most serious and challenging complication in the treatment of hemophilia A. Up to 38% of hemophilia patients develop inhibitors with recombinant FVIII (rFVIII) products (Gouw et al. N Engl J Med. 2013; 368:231-239). The presence of inhibitors leads to an increased risk of bleeding, poor physical functioning and quality of life (Benson et al., Eur. J. Haematol. 2012; 88:371-379). Immune tolerance induction (ITI) is the most common method for eliminating inhibitors, historically performed with high dose, and prolonged treatment with plasma-derived (pd), or recombinant FVIII (rFVIII) concentrates. Although ITI for the eradication of inhibitors has become standard of care for hemophilia patients the therapeutic superiority of a particular product type (rFVIII vs. pd-FVIII) has not yet been conclusively demonstrated. In accordance with its role in stabilizing FVIII, the presence of von Willebrand factor (VWF) in pd-FVIII concentrates has been shown to improve the outcome of ITI. Wilate® (Octapharma) is a high-purity human plasma derived complex containing two proteins (VWF and FVIII) in a 1:1 ratio. The aim of this study was to determine the effectiveness of Wilate for primary ITI therapy for six patients with severe hemophilia A. Patients and Methods: The case history for six pediatric hemophilia A patients prior to and during primary Wilate ITI was reviewed. For 5/6 patients, inhibitors developed during rFVIII factor replacement therapy. For the sixth patient, inhibitors were detected at the time of hemophilia diagnosis. ITI began once patients achieved an inhibitor titer of less than 10 BU/mL. The ITI dosing regimen ranged from 50-60 IU/Kg of Wilate three times per week to 200 IU/Kg once daily. Inhibitor titers were measured regularly, prior to and during ITI using the Nijmegen-Bethesda assay. The number of port-a-cath infections and bleeding episodes were also monitored. ITI success was defined as: an undetectable inhibitor level (<0.6 BU/mL), FVIII plasma recovery ≥ 66% of predicted, and FVIII half-life ≥6 hours. Results: Wilate ITI was well tolerated in all patients, with no product-related adverse events. All patients had a port-a-cath device inserted for Wilate injections. Two port-a-cath infections occurred during ITI. Five of six patients had poor prognostic factors for ITI outcome. These poor prognostic factors included a high-risk FVIII gene mutation, historical peak inhibitor titer greater than 50 BU/mL, age of ITI onset greater than 6 years, and ITI onset more than 12 months from inhibitor development. The frequency of these poor prognostic factors varied amongst the patients: 1 patient had 4, 1 patient had 2, and 3 patients presented with 1 poor prognostic factor. Despite the presence of these high-risk factors, Wilate was successful at reducing the inhibitor titers to undetectable levels in all patients. Furthermore, inhibitor titers have remained low or undetectable without significant spikes for the duration of treatment. Patient plasma recovery and FVIII half-life results have also indicated that patients are progressing towards successful ITI. Importantly, for 6/6 patients (including 3 patients who had previously been treated with Anti-Inhibitor Coagulant Complex (FEIBA) prophylaxis therapy) - Wilate therapy was successful at reducing the number of bleeding episodes allowing for the cessation of FEIBA prophylaxis. Since commencing Wilate ITI, 6/6 patients have not reported any major bleeding episodes. The improved clinical outcome was perceived by the patients as an improved well-being, and quality of life. Conclusion: Wilate ITI was found to be well tolerated, safe, and successful at reducing inhibitor levels to below the detectable range for six severe hemophilia A patients. Patients experienced no treatment related adverse events, had a low rate of port-a-cath infections, and did not present with any major bleeding episodes while on Wilate ITI. In light of the 3-5 fold increase in overall treatment costs of immune tolerance induction, careful consideration should be given to choice of product (rFVIII versus pd-FVIII) – especially for patients at high-risk of failure. (Dimichele et al. Haemophilia 2004: 10 Suppl 4;140-145). The present data suggest that Wilate, a pd-FVIII product, is effective in managing patients with inhibitors. Disclosures Belletrutti: Baxter Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring Canada: Honoraria.
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Riaz, Muhammad Kashif, Saulius Girnius, and Joseph Edward Palascak. "Recombinant Porcine Factor VIII, Obi-1, Successfully Controlled Gastrointestinal Bleeding in a Patient with Acquired Hemophilia A." Blood 126, no. 23 (December 3, 2015): 4676. http://dx.doi.org/10.1182/blood.v126.23.4676.4676.
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Abstract Introduction: Acquired hemophilia A (AHA) is a rare, life-threatening bleeding diathesis categorized by low levels of Factor VIII (FVIII) due to an acquired auto-antibody against FVIII. Treatment for AHA requires both control of the bleeding and eradication of the inhibitor. Recombinant activated factor VII (rFVIIa) maybe used to control the bleeding, but with only mixed results in controlling gastrointestinal bleeding (GIB). rFVIIa is associated with thrombosis risk and lack of ability to monitor. The recombinant porcine FVIII (rpFVIII), OBI-1, recently obtained regulatory approval based on the results of Phase 2/3 trial, but the patients in this cohort did not have GIBs. Here we present a patient with AHA admitted with a GIB and successfully treated with OBI-1. Case: A 69 year old African American female with T1N0M0 infiltrative ductal carcinoma of the left breast and Stage IVA Squamous cell carcinoma of the cervix, treated in 1997 and 2007 respectively, presented to the emergency department with two days of painless bright red blood per rectum. She was orthostatic (supine: HR 79, BP 112/77 and standing: HR 111, BP 100/72) with hemoglobin (Hb) of 5.7gms/dl. An EGD demonstrated a bleeding vessel and multiple arteriovenous malformations (AVM) in the gastric body that were secured with clipping. Over the next 5 days EGD was repeated twice and multiple endoclips were placed in an attempt to achieve hemostasis. She subsequently underwent angiography to identify a target vessel for embolization, but one could not be found. On hospital day 11, hematology was consulted for a prolonged aPTT (113.8 seconds) and inadequate correction with mixing studies (63.7 seconds). FVIII level was <1% with factor VIII inhibitor titer of 245 Bethesda Units/ml (BU). Prior to starting OBI-1, she received 9 units of packed red blood cells and 2 units of fresh frozen plasma. OBI-1 was started at 200u/kg q4h for first 2 days and then decreased to q8h, with cessation of bleeding within 24 hours. Upon completion of the bolus of OBI-1, her FVIII level was 14%, then 38% at 8 hours, 48% at 16 hours and 62% at 24 hours. Rituximab (375mg/m2 weekly) and corticosteroids (prednisone 1mg/kg daily x7 days) were given in an attempt to eliminate the inhibitor. She remained stable for 6 days but subsequently developed abdominal pain. A CT of the abdomen revealed free air prompting emergent surgical intervention. She had internal hernia in the pelvis, ischemic small bowel and perforated jejunum requiring extensive resection. During this time she remained on rpFVIII (200u/kg q8h) with FVIII pre-infusion levels ranging from 2% - 14% and post-infusion levels from 80% to 217% and had only 25ml estimated blood loss during surgery. Unfortunately, 1 day after surgery she developed multi-organ failure and expired on hospital day 19. Discussion: OBI-1 is a glycosylated, B-domain deleted recombinant porcine factor VIII that retains the ability to interact with Factor IXa and activate Factor X, but it is less inhibited by auto-antibodies to human FVIII. For FVIII inhibitor titers >5 BU, an inhibitor bypassing agent is usually necessary because human FVIII products are not able to overcome the inhibitor. Given the high FVIII inhibitor titers in this patient, administration of rFVIIa or OBI-1 was necessary. Our own institutional experience of treating GIBs in patients with AHA had poor outcomes. The efficacy of rFVIIa in treating GIB is inconclusive, with response rate ranging from 53% to 71%. However, rFVIIa is associated with a risk of thrombosis approaching 9.4%, especially in older patients and those with vasculopathy, a common demographic in AHA. Unlike rFVIIa, OBI-1 allows close monitoring of FVIII and in the aforementioned Phase 2/3 trial, there were no thrombotic complications or serious adverse events. We were successful in controlling the bleeding within 24 hours with OBI-1 and were able to achieve therapeutic levels of FVIII despite high Bethesda titers. Unfortunately, our patient died from an ischemic bowel and perforated jejunum that was likely related to hernia or repeated instrumentation in an attempt to stop the bleeding prior to the diagnosis of AHA. Conclusion: OBI-1 appears to effectively and rapidly overcome a high titer FVIII inhibitor and control bleeding in a patient with AHA and GIB. While this is a promising therapy, additional study is necessary to determine safety, efficacy, and cost-effectiveness. Disclosures No relevant conflicts of interest to declare.
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Letowska, Magdalena Katarzyna, Krystyna Zawilska, Anna Klukowska, Krzysztof Chojnowski, Joanna Zdziarska, Ewa Stefanska-Windyga, and Jerzy Windyga. "Immune Tolerance Induction (ITI) in Paediatric and Adult Patients with Haemophilia a (HA) and High-Titre (HT) Factor VIII (FVIII) Inhibitor - Real Life Data." Blood 134, Supplement_1 (November 13, 2019): 4942. http://dx.doi.org/10.1182/blood-2019-122422.
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Introduction: In Poland, the principles for the management of rare bleeding disorders as well as financing of medication are regulated by the National Program for the Management of Haemophilia and Related Bleeding Disorders. One objective of the Program for 2012-2018 was to include the financing of ITI for all haemophilia patients with inhibitor. The qualification for ITI was performed by a physician from a Haemophilia Treatment Centre (HTC). Goal: the aim of the study is/was prospective assessment of the efficacy of ITI in real life setting. Patients and Methods: The study comprised 30 patients with severe and one with moderate HA and HT FVIII inhibitors. Factor VIII activity (FVIII:C) was measured by one-stage clotting assay and Factor VIII inhibitors by a modified Nijmegen-Bethesda assay and expressed in Bethesda Units/ml (BU/ml). Cut-off level for positive inhibitor was ≥0.5BU/ml. The following data was collected: historical peak inhibitor titre (HPT), pre-ITI titre (measured 1 month prior to ITI), peak titre recorded during the course of ITI, time between inhibitor detection and ITI start, and ITI duration. During ITI course blood samples were collected every 4 weeks. Treatment regimen with dosing and type of FVIII concentrate was at the discretion of the physician in each HTC. ITI success was defined as inhibitor titre below 0.5 BU/ml with FVIII half-life ≥6h and FVIII recovery ≥66% of normal. Partial response to ITI was defined as clinical response to FVIII therapy with no anamnestic response despite the presence of FVIII inhibitor or FVIII half-life <6h and FVIII recovery <66% of normal. Results: 31 patients with HA and inhibitor were divided into two groups: Group 1 comprised 12 adults with severe HA, median age 36 years (mean 40.1±15.1 and Group 2 included 19 boys, (<18 years) (18 with severe, one with moderate HA), median age 8 years (mean 8.1±4.3) The median (mean) duration time between inhibitor detection and ITI start was 108 months (102±91) in Group 1 and 10 months (9±10) in Group 2. The median (mean) HPT before ITI was 68 BU/ml (156±193) and 50 BU/ml (126±242) in Group 1 and 2, respectively. ITI is still ongoing in one patient (Group 1) and in 3 boys (Group 2); these 4 patients were excluded from outcome analysis. Two adult patients (16,6%) of Group 1 and 2 boys (10,5%) of group 2 discontinued ITI therapy for a variety of reasons such as death (one patient), poor compliance or loss to follow-up; those patients were however included in the outcome analysis. The median (mean) duration of ITI was 24 months (30.8±31.7) (1-120) in Group 1 and 28 months (33.4±21.4) (6-84) in Group 2. The median (mean) peak titre during ITI was 40 BU/ml (225.7±185.7) in Group 1 and 85 (160±171.7) in Group 2. Immune tolerance to FVIII (success) was achieved in 3/11 adult (27.3%) and in 6/16 paediatric patients (37.5%). Median HPT, median time between inhibitor detection and ITI start, median peak inhibitor titre during ITI and median duration of ITI in patients who achieved immune tolerance were 380 BU/ml, 120 months, 8 BU/ml, 33 months in Group 1 and 22.5 BU/ml, 9.5 months, 205 BU/ml, 25 months in Group 2, respectively. No partial response to ITI was observed in our patients. The most common initial ITI regimen in both groups was 100 IU/kg/d of FVIII (50 - 200 IU/kg/d). In 28/31 (90.3%) patients only plasma derived FVIII concentrates were used which contained various amounts of von Willebrand factor. In two patients recombinant FVIII was administered. Recombinant, plasma derived and EHL FVIII concentrates were used in the case of one boy. In two patients immunosuppressive therapy (prednisone or rituximab) was concomitantly applied. Conclusions: it is our belief that the presented real-life data reflects i) the challenge of ITI therapy in clinical practice and ii) wide variety of approaches to ITI strategy in individual haemophilia treatment centres. Disclosures Windyga: Octapharma: Honoraria, Research Funding; Rigel Pharmaceuticals: Honoraria, Research Funding; Ferring Pharmaceuticals: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Werfen: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Baxalta/Shire (a Takeda company): Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Siemens: Honoraria, Research Funding; Sobi: Honoraria, Research Funding.