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Aim: Understanding barriers and facilitators to pharmacogenomics (PGx) implementation and how to structure a clinical program with the Veterans Health Administration (VA). Materials & methods: Healthcare provider (HCP) survey at 20 VA facilities assessing PGx knowledge/acceptance and qualitative interviews to understand how best to design and sustain a national program. Results: 186 (12% response rate) surveyed believed PGx informs drug efficacy (74.7%) and adverse events (71.0%). Low confidence in knowledge (43.0%) and ability to implement (35.4-43.5%). 23 (60.5% response rate) interviewees supported a nationally program to oversee VA education, consultation and IT resources. Prescribing HCPs should be directing local activities. Conclusion: HCPs recognize PGx value but are not prepared to implement. Healthcare systems should build system-wide programs for implementation education and support.

Mononuclear Fe ions ligated by nitrogen (FeN x ) dispersed on nitrogen-doped carbon (Fe-N-C) serve as active centers for electrocatalytic O 2 reduction and thermocatalytic aerobic oxidations. Despite their promise as replacements for precious metals in a variety of practical applications, such as fuel cells, the discovery of new Fe-N-C catalysts has relied primarily on empirical approaches. In this context, the development of quantitative structure-reactivity relationships and benchmarking of catalysts prepared by different synthetic routes and by different laboratories would be facilitated by the broader adoption of methods to quantify atomically dispersed FeN x active centers. In this study, we develop a kinetic probe reaction method that uses the aerobic oxidation of a model hydroquinone substrate to quantify the density of FeN x centers in Fe-N-C catalysts. The kinetic method is compared with low-temperature Mössbauer spectroscopy, CO pulse chemisorption, and electrochemical reductive stripping of NO derived from NO 2 - on a suite of Fe-N-C catalysts prepared by diverse routes and featuring either the exclusive presence of Fe as FeN x sites or the coexistence of aggregated Fe species in addition to FeN x . The FeN x site densities derived from the kinetic method correlate well with those obtained from CO pulse chemisorption and Mössbauer spectroscopy. The broad survey of Fe-N-C materials also reveals the presence of outliers and challenges associated with each site quantification approach. The kinetic method developed here does not require pretreatments that may alter active-site distributions or specialized equipment beyond reaction vessels and standard analytical instrumentation.

Nonprecious metal heterogeneous catalysts composed of first-row transition metals incorporated into nitrogen-doped carbon matrices (M-N-Cs) have been studied for decades as leading alternatives to Pt for the electrocatalytic O 2 reduction reaction (ORR). More recently, similar M-N-C catalysts have been shown to catalyze the aerobic oxidation of organic molecules. This Focus Review highlights mechanistic similarities and distinctions between these two reaction classes and then surveys the aerobic oxidation reactions catalyzed by M-N-Cs. As the active-site structures and kinetic properties of M-N-C aerobic oxidation catalysts have not been extensively studied, the array of tools and methods used to characterize ORR catalysts are presented with the goal of supporting further advances in the field of aerobic oxidation.

We report a strategy to integrate atomically dispersed iron within a heterogeneous nitrogen-doped carbon (N-C) support, inspired by routes for metalation of molecular macrocyclic iron complexes. The N-C support, derived from pyrolysis of a ZIF-8 metal-organic framework, is metalated via solution-phase reaction with FeCl 2 and tributyl amine, as a Brønsted base, at 150 °C. Fe active sites are characterized by 57 Fe Mössbauer spectroscopy and aberration-corrected scanning transmission electron microscopy. The site density can be increased by selective removal of Zn 2+ ions from the N-C support prior to metalation, resembling the transmetalation strategy commonly employed for the preparation of molecular Fe-macrocycles. The utility of this approach is validated by the higher catalytic rates (per total Fe) of these materials relative to established Fe-N-C catalysts, benchmarked using an aerobic oxidation reaction.

M-N-C catalysts, incorporating non-precious-metal ions (e.g. M = Fe, Co) within a nitrogen-doped carbon support, have been the focus of broad interest for electrochemical O 2 reduction and aerobic oxidation reactions. The present study explores the mechanistic relationship between the O 2 reduction mechanism under electrochemical and chemical conditions. Chemical O 2 reduction is investigated via the aerobic oxidation of a hydroquinone, in which the O-H bonds supply the protons and electrons needed for O 2 reduction to water. Mechanistic studies have been conducted to elucidate whether the M-N-C catalyst couples two independent half-reactions (IHR), similar to electrode-mediated processes, or mediates a direct inner-sphere reaction (ISR) between O 2 and the organic molecule. Kinetic data support the latter ISR pathway. This conclusion is reinforced by rate/potential correlations that reveal significantly different Tafel slopes, implicating different mechanisms for chemical and electrochemical O 2 reduction.

Purpose: To implement and optimize a pilot transitions of care model for scheduled chemotherapy admissions in patients with hematologic malignancies at our institution. Methodology: We utilized the plan-do-study-act (PDSA) quality improvement technique to prospectively measure success of interventions related to improving transitions of care processes that occurred in multiple stages including development of standardized operating procedures, electronic medical record documentation, and education to the malignant hematology multidisciplinary group. Chart review was performed retrospectively for at least nine patients per PDSA cycle. Areas of intervention addressed and measured regarding communication between the ambulatory care and acute care settings included: admission purpose, processes related to insurance benefits investigations for specialty medications required in the post-discharge setting, and plan for growth factors, prophylactic antimicrobials, and follow-up. Results and conclusions: We included 28 patients and performed a total of three PDSA cycles demonstrating specific improvements in: communication regarding status of benefits investigations performed for specialty medications prior to admission, resolution of these benefits investigations at various time points, improvement in efficient use of the electronic medical record for chemotherapy orders, and patient instructions for appropriate use of prophylactic antimicrobials. Although improvement was noted initially with prescribing of discharge antiemetics and antimicrobials, regression to baseline was noted with the third PDSA cycle.

Reactions catalyzed within porous inorganic and organic materials and at electrochemical interfaces commonly occur at high coverage and in condensed media, causing turnover rates to depend strongly on interfacial structure and composition, collectively referred to as "solvent effects". Transition state theory treatments define how solvation phenomena enter kinetic rate expressions, and identify two distinct types of solvent effects that originate from molecular clustering and from the solvation of such clusters by extended solvent networks. We review examples from the recent literature that investigate reactions within microporous zeolite catalysts to illustrate these concepts, and provide a critical appraisal of open questions in the field where future research can aid in developing new chemistry and catalyst design principles., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Zeolite reactivity depends on the solvating environments of their micropores and the proximity of their Brønsted acid sites. Turnover rates (per H + ) for methanol and ethanol dehydration increase with the fraction of H + sites sharing six-membered rings of chabazite (CHA) zeolites. Density functional theory (DFT) shows that activation barriers vary widely with the number and arrangement of Al (1-5 per 36 T-site unit cell), but cannot be described solely by Al-Al distance or density. Certain Al distributions yield rigid arrangements of anionic charge that stabilize cationic intermediates and transition states via H-bonding to decrease barriers. This is a key feature of acid catalysis in zeolite solvents, which lack the isotropy of liquid solvents. The sensitivity of polar transition states to specific arrangements of charge in their solvating environments and the ability to position such charges in zeolite lattices with increasing precision herald rich catalytic diversity among zeolites of varying Al arrangement., (© 2020 Wiley-VCH GmbH.)

Aqueous-phase reactions within microporous Brønsted acids occur at active centers comprised of water-reactant-clustered hydronium ions, solvated within extended hydrogen-bonded water networks that tend to stabilize reactive intermediates and transition states differently. The effects of these diverse clustered and networked structures were disentangled here by measuring turnover rates of gas-phase ethanol dehydration to diethyl ether (DEE) on H-form zeolites as water pressure was increased to the point of intrapore condensation, causing protons to become solvated in larger clusters that subsequently become solvated by extended hydrogen-bonded water networks, according to in situ IR spectra. Measured first-order rate constants in ethanol quantify the stability of S N 2 transition states that eliminate DEE relative to (C 2 H 5 OH)(H + )(H 2 O) n clusters of increasing molecularity, whose structures were respectively determined using metadynamics and ab initio molecular dynamics simulations. At low water pressures (2-10 kPa H 2 O), rate inhibition by water (-1 reaction order) reflects the need to displace one water by ethanol in the cluster en route to the DEE-formation transition state, which resides at the periphery of water-ethanol clusters. At higher water pressures (10-75 kPa H 2 O), water-ethanol clusters reach their maximum stable size ((C 2 H 5 OH)(H + )(H 2 O) 4-5 ), and water begins to form extended hydrogen-bonded networks; concomitantly, rate inhibition by water (up to -3 reaction order) becomes stronger than expected from the molecularity of the reaction, reflecting the more extensive disruption of hydrogen bonds at DEE-formation transition states that contain an additional solvated non-polar ethyl group compared to the relevant reactant cluster, as described by non-ideal thermodynamic formalisms of reaction rates. Microporous voids of different hydrophilic binding site density (Beta; varying H + and Si-OH density) and different size and shape (Beta, MFI, TON, CHA, AEI, FAU), influence the relative extents to which intermediates and transition states disrupt their confined water networks, which manifest as different kinetic orders of inhibition at high water pressures. The confinement of water within sub-nanometer spaces influences the structures and dynamics of the complexes and extended networks formed, and in turn their ability to accommodate the evolution in polarity and hydrogen-bonding capacity as reactive intermediates become transition states in Brønsted acid-catalyzed reactions., (This journal is © The Royal Society of Chemistry 2020.)

Background: The North Carolina Cancer Hospital at the University of North Carolina Medical Center serves patients with a variety of malignant conditions and discharges more than 130 patients each month. Processes to improve transitions of care prompted implementation of a first-cycle, pharmacist-led chemotherapy consultation service on the inpatient oncology units. This process provides education to improve patient engagement and activation. High patient activation has been associated with better patient outcomes; poor patient activation has been associated with increased health care costs., Objective: To determine the effect of pharmacist-led comprehensive chemotherapy consultation services on adherence to outpatient follow-up appointments within 30 days of discharge., Methods: This was a single-center, retrospective chart review. This study consisted of 2 groups: adult patients who received comprehensive consultation services between April 2017 and September 2017 and a 2:1 historical group of adult control patients randomly selected from a list of patients who received their first cycle of chemotherapy during a hospital admission between April 2014 and April 2017. The primary endpoint was the effect of comprehensive consultation services on adherence to outpatient follow-up appointments within 1 month after discharge., Results: Ninety-six patients were included in this study. The percentage of appointments attended was 98.0% for the intervention group and 92.3% for the control group ( P = 0.0018)., Conclusions: This study demonstrates that pharmacy consultation in the inpatient oncology setting is associated with improved adherence to outpatient appointments within 30 days of discharge. This represents the first published data on pharmacist interventions resulting in improved outpatient appointment adherence., Disclosures: Funding for this study was contributed by the Hematology/Oncology Pharmacy Association (HOPA). This publication was also supported by Grant Number UL1TR002489 from the National Center for Advancing Translational Sciences at the National Institutes of Health. Auten reports fees from PTCE and ASHP/ACCP, unrelated to this study. Clark reports consulting fees from Ellion Benson Research, unrelated to this study. The other authors do not have any conflicts of interest to report. This study was presented as a trainee poster on April 5, 2019, at the HOPA Ahead 15th Annual Conference in Fort Worth, TX.

Ab-initio molecular dynamics simulations and transmission infrared spectroscopy are employed to characterize the structure of water networks in defect-functionalized microporous zeolites. Thermodynamically stable phases of clustered water molecules are localized at some of the defects in zeolite Beta, which include catalytic sites such as framework Lewis acidic Sn atoms in closed and hydrolyzed-open forms, as well as silanol nests. These water clusters compete with ideal gas-like structures at low water densities and pore-filling phases at higher water densities, with the equilibrium phase determined by the water chemical potential. The physical characteristics of these phases are determined by the defect identity, with the local binding and orientation of hydroxyl moieties around the defects playing a central role. The results suggest general principles for how the structure of polar solvents in microporous solid acids is influenced by local defect functionalization, and the thermodynamic stability of the condensed phases surrounding such sites, in turn, implies that the catalysis of Lewis acids will be influenced by local water ordering., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Lenalidomide, bortezomib, and dexamethasone (RVd) has emerged as a preferred induction therapy in multiple myeloma (MM) in the United States. Due to lenalidomide's teratogenic risk, patients and prescribers must comply with a risk evaluation and mitigation strategy (REMS) program. The REMS program limits dispensing to certain third-party specialty pharmacies, whose average prescription fill times are longer than in-house specialty pharmacies. In practice, a delay in procurement of lenalidomide may mean that patients start therapy with only bortezomib and dexamethasone, delaying the start of more effective triplet therapy. The primary objective of this study is to determine if a delay from start of bortezomib and dexamethasone to start of triplet therapy with lenalidomide impacts rate of achievement of very good partial response (VGPR) after four cycles of RVd., Methods: This was a single-center retrospective review of adults with newly diagnosed MM who received RVd induction therapy at University of North Carolina Medical Center between April 2014 and June 2017. Patients who started lenalidomide ≥10 days after bortezomib comprised the "Delay" group, while those who started lenalidomide concurrently with bortezomib or within 1-9 days after bortezomib comprised the "No Delay" group. The primary outcome was VGPR or better response rate after four cycles of RVd., Results: Thirty-eight patients met inclusion criteria. Nine patients (23.7%) experienced any delay in initiation of lenalidomide, with a mean delay of 7.8 days (range 1-18). Four patients (10.5%) experienced a delay ≥10 days. No patients in the Delay group were of reproductive potential, compared to 8.8% in the No Delay group ( p  = 0.54). VGPR or better response rate did not differ between the Delay and No Delay groups (66.7% vs. 58.8%, p  = 0.79). The mean number of lenalidomide prescriptions generated per RVd cycle was 1.35 (range 1-5, SD 0.74)., Conclusions: This study did not demonstrate an effect on clinical response after delays ≥10 days between bortezomib and lenalidomide initiation. No patients in the delay group were females of reproductive potential, which is the primary target for increased safety behind the REMS program.

The first historically documented pandemic caused by Yersinia pestis began as the Justinianic Plague in 541 within the Roman Empire and continued as the so-called First Pandemic until 750. Although paleogenomic studies have previously identified the causative agent as Y. pestis , little is known about the bacterium's spread, diversity, and genetic history over the course of the pandemic. To elucidate the microevolution of the bacterium during this time period, we screened human remains from 21 sites in Austria, Britain, Germany, France, and Spain for Y. pestis DNA and reconstructed eight genomes. We present a methodological approach assessing single-nucleotide polymorphisms (SNPs) in ancient bacterial genomes, facilitating qualitative analyses of low coverage genomes from a metagenomic background. Phylogenetic analysis on the eight reconstructed genomes reveals the existence of previously undocumented Y. pestis diversity during the sixth to eighth centuries, and provides evidence for the presence of multiple distinct Y. pestis strains in Europe. We offer genetic evidence for the presence of the Justinianic Plague in the British Isles, previously only hypothesized from ambiguous documentary accounts, as well as the parallel occurrence of multiple derived strains in central and southern France, Spain, and southern Germany. Four of the reported strains form a polytomy similar to others seen across the Y. pestis phylogeny, associated with the Second and Third Pandemics. We identified a deletion of a 45-kb genomic region in the most recent First Pandemic strains affecting two virulence factors, intriguingly overlapping with a deletion found in 17th- to 18th-century genomes of the Second Pandemic., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Healthcare systems and policy makers worldwide are demonstrating interest in shared decision making, which requires patient activation. Patient activation can be measured using a validated tool called the patient activation measure-10. First cycle comprehensive chemotherapy consultation services (3CS) is provided by an oncology pharmacy team member during a patient encounter at the beginning of the patient's treatment for cancer., Methods: This was a single center, prospective, non-randomized, observational clinical study in patients with cancer who required a new chemotherapy plan. A baseline patient activation measure-10 survey was administered and a pharmacy team member met with the patient to complete the first cycle 3CS encounter. Within two business days of that encounter, a second patient activation measure-10 survey was administered, and thus, patients served as their own control., Results: Forty-nine patients who met the inclusion criteria were enrolled, of which 36 completed the study. Mean patient activation measure-10 scores measured at baseline and two business days after the 3CS encounter were significantly different (68.5 ± SD 14.7 vs. 75.0 ± SD 14.3, p = 0.001). This difference persisted when evaluated by gender (female: 70.0 ± SD 14.8 vs. 81.6 ± SD 10.5, p = 0.001; male: 66.1 ± SD 14.8 vs. 70.8 ± SD 14.7, p = 0.022)., Conclusion: This study demonstrates that cancer patients had significantly increased patient activation scores after engagement in a 3CS encounter provided by an oncology pharmacy team. Further studies are needed to verify these data in a larger population, different healthcare settings, and to evaluate for patients who have solid tumor malignancies.

Chemotherapy order review by pharmacists requires careful attention to many details, and serious consequences can occur if errors are made. Other high-risk industries have long used checklists to improve accuracy and reduce the risk of errors. Despite the recent expansion of checklist use in other areas of medicine, there is currently no published evidence that checklists are being widely used by pharmacists in the evaluation of chemotherapy orders. This article explains a flexible checklist called PRONTO (Patient, Regimen, Organ Function, Numbers, Toxicity, Order Verification) that has been successfully used by pharmacists in variety of practice settings in two academic centers in North Carolina. Proposed benefits of using a checklist in order review include standardization of review for better communication between collaborating pharmacists, a training tool for new or cross-training pharmacists, and an educational tool for students.

Lewis acid sites in zeolites catalyze aqueous-phase sugar isomerization at higher turnover rates when confined within hydrophobic rather than within hydrophilic micropores; however, relative contributions of competitive water adsorption at active sites and preferential stabilization of isomerization transition states have remained unclear. Here, we employ a suite of experimental and theoretical techniques to elucidate the effects of coadsorbed water on glucose isomerization reaction coordinate free energy landscapes. Transmission IR spectra provide evidence that water forms extended hydrogen-bonding networks within hydrophilic but not hydrophobic micropores of Beta zeolites. Aqueous-phase glucose isomerization turnover rates measured on Ti-Beta zeolites transition from first-order to zero-order dependence on glucose thermodynamic activity, as Lewis acidic Ti sites transition from water-covered to glucose-covered, consistent with intermediates identified from modulation excitation spectroscopy during in situ attenuated total reflectance IR experiments. First-order and zero-order isomerization rate constants are systematically higher (by 3-12×, 368-383 K) when Ti sites are confined within hydrophobic micropores. Apparent activation enthalpies and entropies reveal that glucose and water competitive adsorption at Ti sites depend weakly on confining environment polarity, while Gibbs free energies of hydride-shift isomerization transition states are lower when confined within hydrophobic micropores. DFT calculations suggest that interactions between intraporous water and isomerization transition states increase effective transition state sizes through second-shell solvation spheres, reducing primary solvation sphere flexibility. These findings clarify the effects of hydrophobic pockets on the stability of coadsorbed water and isomerization transition states and suggest design strategies that modify micropore polarity to influence turnover rates in liquid water.

Background: Pharmacy practice models that foster pharmacists' accountability for medication-related outcomes are imperative for the profession. Comprehensive medication management (CMM) is an opportunity to advance patient care., Objective: The objective of this study was to evaluate the impact of a CMM practice model in the acute care setting on organizational, patient, and financial outcomes., Methods: Three adult service lines focused on at-risk patients identified using internal risk stratification methodology were implemented. Core CMM elements included medication reconciliation, differentiated clinical pharmacy services, inpatient MTM consultations, discharge services, and documentation. Mixed methods compared the effect of the CMM model before and after implementation. Historical patients served as comparative controls in an observational design. Pharmacists completed a 60-minute interview regarding their experiences. Qualitative data were analyzed using thematic coding to characterize perception of the model., Results: Three pharmacists implemented the model on cardiology, hematology/oncology, and surgery transplant services and provided services to 75 patients during the study. A total of 145 medication-related problems were identified and resolved. CMM was associated with a nonsignificant reduction of 8.8% in 30-day hospital readmission rates ( P = 0.64) and a 24.9% reduction in 30-day hospital utilization ( P = 0.41) as well as a significant reduction of 86.5% in emergency department visits ( P = 0.02). Patients receiving discharge prescriptions from our outpatient pharmacies increased by 21.4%, resulting in an 11.3% increase in discharge prescription capture and additional revenue of $5780. Themes identified from qualitative interviews included CMM structure, challenges, value, and resources., Conclusion: This study demonstrated successful implementation of a CMM model that positively affected organizational, patient, and financial outcomes.

Purpose: The outcomes of a patient-centered layered learning practice model (LLPM) in which the clinical specialist acted as the attending pharmacist and managed a pharmacy team to provide direct patient care were evaluated., Methods: Two 30-day evaluations were conducted on the acute care malignant hematology and medical oncology services of the University of North Carolina Medical Center in 2011. The primary objective of this study was to design an LLPM that used a team to expand the pharmacist care services offered. The primary outcome was the frequency of pharmacy team encounters at discharge (medication reconciliation and counseling), termed the discharge capture rate., Results: During the study months, 42 and 78 malignant hematology and medical oncology patients were eligible for study inclusion, respectively. The overall discharge capture rate was 51%. Sixty-one patients received discharge medication reconciliation services during patient counseling. Patients included in the malignant hematology group received a mean of 11 prescriptions at discharge, compared with 9.83 in the medical oncology group. Means of 1.26 and 2.1 medication-related problems per patient were identified in the malignant hematology and medical oncology studies, respectively, during discharge medication reconciliation. The overall mean face time spent per patient was 21.3 minutes., Conclusion: Patients in malignant hematology and medical oncology services were counseled and provided discharge medication reconciliation by a pharmacy student or resident whose activities were managed and reviewed by an attending pharmacist using an LLPM, resulting in an improvement in all clinical outcomes and measures., (Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Objective. To explore use of pharmacy learners as a means to expand pharmacy services in a layered learning practice model (LLPM), to examine whether an LLPM environment precludes achievement of knowledge-based learning objectives, and to explore learner perception of the experience. Design. An acute care oncology pharmacy practice experience was redesigned to support the LLPM. Specifically, the redesign focused on micro discussion, standardized feedback (eg, rubrics), and cooperative learning to enhance educational gain through performing clinical activities. Assessment. Posttest scores evaluating knowledge-based learning objectives increased in mean percentage compared to pretest values. Learners viewed the newly designed practice experience positively with respect to perceived knowledge attainment, improved clinical time management skills, contributions to patient care, and development of clinical and self-management skills. A fifth theme among students, comfort with learning, was also noted. Conclusion. Layered learning in an oncology practice experience was well-received by pharmacy learners. Data suggest a practice experience in the LLPM environment does not preclude achieving knowledge-based learning objectives and supports further studies of the LLPM.

Bleomycin-induced pulmonary toxicity can have a significant impact on patient outcomes. However, no guidelines for ideal screening and monitoring are available. This paper reviews the literature to identify the best way to monitor and reduce patient risk for bleomycin pulmonary toxicity. We have created evidence-based guidelines to help healthcare professionals identify patient risk factors and provide appropriate assessment and monitoring for patients receiving bleomycin therapy., (© The Author(s) 2015.)

The mental health of aging men is an understudied social issue. Although it is widely accepted that meaningful family relationships are associated with fewer depressive symptoms and greater positive affect, scholars have largely overlooked relationships between grandfathers and grandchildren as being beneficial to men's mental health. This study investigates the differences in the depressive symptoms and positive affect of 351 grandfathers. Using a cluster analytic technique, participants were categorized as involved, passive, and disengaged based on their frequency of contact, level of commitment, and participation in activities with grandchildren. Comparative analyses indicate that involved grandfathers had fewer depressive symptoms than disengaged grandfathers. Involved grandfathers had significantly higher scores on positive affect than disengaged grandfathers, and passive grandfathers had significantly higher scores on positive affect than disengaged grandfathers. This study provides evidence that grandfather-grandchild relationships influence aging men's mental health. Implications for practitioners working with aging men are discussed.

Abnormal uterine bleeding in women with a blood dyscrasia, such as leukemia, or who experience thrombocytopenia secondary to myelosuppressive chemotherapy is a clinical condition associated with significant morbidity. Consequently, effective management is necessary to prevent adverse outcomes. Prevention of menorrhagia, defined as heavy regular menstrual cycles with more than 80 ml of blood loss/cycle or a cycle duration longer than 7 days, in this patient population is the goal of therapy. Gonadotropin-releasing hormone analogs (e.g., leuprolide) are promising therapies that have been shown to decrease vaginal bleeding during periods of thrombocytopenia and to have minimal adverse effects other than those associated with gonadal inhibition. In patients who experience menorrhagia despite preventive therapies, or in patients who have thrombocytopenia and menorrhagia at diagnosis, treatment is indicated. For these women, treatment options may include platelet transfusions, antifibrinolytic therapy (e.g., tranexamic acid), continuous high-dose oral contraceptives, cyclic progestins, or other therapies for more refractory patients such as danazol, desmopressin, and recombinant factor VIIa. Hormonal therapies are often the mainstay of therapy in women with menorrhagia secondary to thrombocytopenia, but data for these agents are sparse. The most robust data for the treatment of menorrhagia are for tranexamic acid. Most women receiving tranexamic acid in randomized trials experienced meaningful reductions in menstrual bleeding, and this translated into improved quality of life; however, these trials were not performed in patients with cancer. Further clinical trials are warranted to evaluate both preventive and therapeutic agents for menorrhagia in premenopausal women with cancer who are receiving myelosuppressive chemotherapy.

Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

TNFAIP3 encodes the ubiquitin-modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). To further localize the risk variant(s), we performed a meta-analysis using genetic data available from two Caucasian case-control datasets (1453 total cases, 3381 total control subjects) and 713 SLE trio families. The best result was found at rs5029939 (P=1.67 x 10(-14), odds ratio=2.09, 95% confidence interval 1.68-2.60). We then imputed single nucleotide polymorphisms (SNPs) from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 control subjects. Imputation identified 11 SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a twofold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene.

Objective: To evaluate the use of rituximab in the clinical management of steroid-refractory chronic graft-versus-host disease (GVHD)., Data Sources: Literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1990-September 2008), both indexed and nonindexed citations, using the terms rituximab, graft-versus-host disease, monoclonal antibodies, and CD20. In addition, reference citations from the publications identified were reviewed., Study Selection and Data Extraction: All articles discussing rituximab as a therapeutic option in the treatment of GVHD that were published in English and enrolled human study participants were evaluated., Data Synthesis: Rituximab is a genetically engineered chimeric murine monoclonal antibody that binds to the CD20 differentiation antigen found on B-lymphocytes. GVHD is the leading cause of procedural-related morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Chronic GVHD (cGVHD) occurs in up to 70% of individuals undergoing HSCT, and approximately 40% of those patients are refractory to conventional T-lymphocyte-directed therapies. Limited treatments are available for individuals with steroid-refractory cGVHD. Rituximab therapy in individuals with extensive cGVHD has demonstrated clinical efficacy with manageable toxicities in retrospective and prospective studies., Conclusions: Available data suggest that rituximab is a treatment option for patients with extensive steroid-refractory cGVHD. Rituximab may be particularly effective for individuals with steroid-refractory cGVHD manifesting as thrombocytopenia or with sclerodermatous, cutaneous, and rheumatologic involvement.

One hundred Hampshire x Duroc cross-bred pigs and 100 Nebraska Index line pigs were infected with porcine reproductive and respiratory syndrome virus (PRRSV) and evaluated for resistance and susceptibility. Controls (100/line) were uninfected littermates to infected pigs. Viremia (V), BW change (WTDelta), and rectal temperature at 0, 4, 7, and 14 d postinfection were recorded. Lung, bronchial lymph node (BLN), and blood tissue were collected at necropsy (14 d postinfection). Infected pigs were classified as low or high responders to PRRSV based on the first principal component from principal component analyses of all variables. Low responders to PRRSV (low PRRSV burden) and their uninfected littermates were assigned to the low (L) class. High responders to PRRSV (high PRRSV burden) and their uninfected littermates were assigned to the high (H) class. Infected pigs in the L class had large WTDelta, low V, and few lung lesions; H-class pigs had small WTDelta, high V, and many lung lesions. Ribonucleic acid was extracted from lung and BLN tissue of the 7 highest and 7 lowest responders per line and from each of their control littermates. A control reference design was used, and cDNA from each reference sample tissue was prepared from pooled RNA extracted from 2 control pigs from each line whose infected littermates had a principal component value of 0. Design variables in data analyses were line (Index vs. Hampshire x Duroc), class (H vs. L), treatment (infected vs. uninfected controls), and slide/pig as error. Oligo differential expression was based on P < 0.01 occurring in both lung and BLN. Line and treatment effects were significant for 38 and 541 oligos, respectively, in both lung and BLN. Line x class interaction existed for expression of thymosin beta-4, DEAD box RNA helicase 3, acetyl-cholinesterase, and Homo sapiens X (inactive)-specific transcript in both tissues. Treatment x class existed for expression of CCAAT/enhancer-binding delta protein, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, thioredoxin-interacting protein, major facilitator superfamily domain containing 1, and unknown sequences SS00012040 and SS00012343. Line x treatment and line x treatment x class interactions were not significant. Possible important genetic associations for fine-mapping candidate genes related to response to PRRSV and determining causative alleles were revealed.

The polyamines spermidine and spermine and their diamine precursor putrescine are essential for mammalian cell growth and viability, and strategies are sought for reducing polyamine levels in order to inhibit cancer growth. Several structural analogues of the polyamines have been found to decrease natural polyamine levels and inhibit cell growth, probably by stimulating normal feedback mechanisms. In the present study, a large selection of spermine analogues has been tested for their effectiveness in inducing the production of antizyme, a key protein in feedback inhibition of putrescine synthesis and cellular polyamine uptake. Bisethylnorspermine, bisethylhomospermine, 1,19-bis-(ethylamino)-5,10,15-triazanonadecane, longer oligoamine constructs and many conformationally constrained analogues of these compounds were found to stimulate antizyme synthesis to different levels in rat liver HTC cells, with some producing far more antizyme than the natural polyamine spermine. Uptake of the tested compounds was found to be dependent on, and limited by, the polyamine transport system, for which all these have approximately equal affinity. These analogues differed in their ability to inhibit HTC cell growth during 3 days of exposure, and this ability correlated with their antizyme-inducing potential. This is the first direct evidence that antizyme is induced by several polyamine analogues. Selection of analogues with this potential may be an effective strategy for maximizing polyamine deprivation and growth inhibition.

All cases of endometrial adenocarcinoma treated at the Geisinger Medical Center from January 1970 to June 1980 were retrospectively reviewed in an attempt to elucidate the clinical and pathologic profiles of the various histologic subtypes. Complete clinical and pathologic data was available in 418 cases of stage I endometrial adenocarcinoma. The frequency of the histologic subtypes were adenocarcinoma 66%, adenoacanthoma 16%, adenosquamous 5%, papillary 8%, clear cell 3%, and secretory 2%. Absolute 5-year survival was adenocarcinoma 88%, adenoacanthoma 91%, adenosquamous 62%, papillary 63% (P less than 0.01), clear cell 43% (P less than 0.001), and secretory 89%. When comparing the clinical and pathologic profile of the various histologic subtypes, adenosquamous (52%, P less than 0.001) and clear cell (43%, P less than 0.05) were associated with the highest percentage of grade 3 differentiation. Adenosquamous (38%, P less than 0.05) and clear cell (36%) also had the highest percentage of deep myometrial invasion. Papillary subtype (46%, P less than 0.05) was associated with the highest percentage of nulliparity. There was no difference among the subtypes when comparing menopausal status, exogenous estrogen, obesity, hypertension, diabetes, or uterine size. In summary, (1) adenocarcinoma and adenoacanthoma are the most frequent subtypes; (2) adenosquamous, papillary, and clear cell have decreased 5-year survival; (3) the decreased 5-year survival in adenosquamous and clear cell subtypes appears to be associated with increased grade 3 differentiation and deep myometrial invasion while the poor prognosis associated with papillary subtype was not related to grade or myometrial invasion.

All cases of endometrial adenocarcinoma from January 1970 to December 1980 treated at the Geisinger Medical Center were reviewed retrospectively. One hundred eighty-eight cases of stage I grade 2 adenocarcinoma of favorable histologic subtype (adenocarcinoma, adenoacanthoma) and limited myometrial invasion (less than one-third of the myometrium) were identified. Surgery and adjuvant radiotherapy was used in 136 cases, and 52 cases were treated with surgery alone. There was no statistically significant difference between the two groups in menopausal status, parity, exogenous estrogen, obesity, hypertension, diabetes, or uterine size. Five-year survival for the surgery and radiotherapy group was 94% (128 of 136), and the recurrence rate was 2.2% (three of 136). The five-year survival for the surgery-alone group was 98% (51 of 52), and the recurrence rate was 1.9% (one of 52). There was no statistically significant difference in five-year survival or recurrence between the two groups. This study suggests that surgery alone is adequate treatment for stage I grade 2 adenocarcinoma of favorable histologic subtype and limited myometrial invasion. This study also shows a possible benefit in the combined use of histologic subtype, grade, and myometrial invasion as prognostic indicators and as guides for adjuvant radiotherapy.

Three hundred tubal specimens obtained at laparoscopic coagulation and resection of the tube for sterilization done in the years 1973 and 1974 were studied. Twenty-three percent of the specimens were not identifiable as of tubal origin, and there was a lack of precision in the diagnosis in 17% of the specimens. Because of the comparable results for sterilization by well-performed coagulation alone and of coagulation with resection of a segment of tube, we feel that resection, with its assocaited hazards, is unnecessary.