Goshen College

The guideline group was selected to be representative of UK-based medical experts. MEDLINE and EMBASE were searched systematically for publications in English, using the keywords: thrombotic thrombocytopenia purpura (TTP), ADAMTS13, plasma exchange (PEX) and relevant key words related to the subsections of this guideline. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH. The guideline was then reviewed by a sounding board of British haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com. The objective of this guideline is to provide healthcare professionals with clear, up-to-date, and practical guidance on the management of TTP and related thrombotic microangiopathies, defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Thrombotic thrombocytopenic purpura (TTP) is rare, with a reported incidence of six cases per million per year in the UK (Scully et al, 2008). It is an important diagnosis to make because the untreated mortality is 90%, which can be reduced with the prompt delivery of plasma exchange (PEX). Early death still occurs: approximately half of the deaths in the regional UK registry occurred within 24 h of presentation, primarily in women (Scully et al, 2008). In the last 15 years there has been a marked increase in the understanding of the pathogenesis of TTP. It is now recognized that congenital and acute acquired TTP are due to a deficiency of von Willebrand factor (VWF) cleaving protein, also known as ADAMTS1, (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 – von Willebrand factor cleaving protein) (Fujikawa et al, 2001; Levy et al, 2001). In the absence of ADAMTS13, ultra large multimers of VWF (ULVWF) released from endothelium are not cleaved appropriately, and cause spontaneous platelet aggregates in conditions of high shear, such as in the microvasculature of the brain, heart and kidneys. Congenital TTP is due to an inherited deficiency of ADAMTS13, but acquired immune TTP is due to the reduction of ADAMTS13 by autoantibodies directed against ADAMTS13 (Furlan et al, 1998a; Tsai & Lian, 1998). Other clinical forms of thrombotic microangiopathy (TMA) occur in the absence of severe deficiency. Diagnosis can be difficult, as there is clinical overlap with haemolytic uraemic syndrome (HUS), autoimmune disease and a spectrum of pregnancy-related problems. Thrombotic thrombocytopenic purpura was originally characterized by a pentad of thrombocytopenia, MAHA, fluctuating neurological signs, renal impairment and fever, often with insidious onset. However, TTP can present without the full pentad; up to 35% of patients do not have neurological signs at presentation and renal abnormalities and fever are not prominent features. The revised diagnostic criteria state that TTP must be considered in the presence of thrombocytopenia and MAHA alone (Galbusera et al, 2006). This can result in an increased referral of other TMAs (Table 1). TTP remains a diagnosis based on clinical history, examination of the patient and the blood film. ADAMTS 13 assays help to confirm the diagnosis and monitor the course of the disease and possible need for additional treatments. Presenting symptoms and signs are summarized in Table 2 and reflect widespread multi organ thromboses. Neurological impairment has multiple presentations including headache, altered personality, reduced cognition, transient ischaemic attacks, fits and fluctuating levels of consciousness including coma; the latter is a poor prognostic sign. Acute renal failure requiring haemodialysis is rare in TTP and more indicative of HUS (Coppo et al, 2006; Scully et al, 2008). Additional ischaemic complications may be seen, such as abdominal pain due to intestinal ischaemia. Consumption of platelets in platelet-rich thrombi results in thrombocytopenia. The median platelet count is typically 10–30 × 109/l at presentation (Dervenoulas et al, 2000; Vesely et al, 2003; Coppo et al, 2006; Tuncer et al, 2007; Scully et al, 2008). Mechanical fragmentation of erythrocytes during flow through partially occluded, high shear small vessels causes a MAHA. Median haemoglobin levels on admission are typically 80–100 g/l, with schistocytes in the film, low haptoglobin levels and raised reticulocyte counts due to haemolysis. The direct Coombs test is negative. The combination of haemolysis and tissue ischaemia produces elevated lactate dehydrogenase (LDH) values. The clotting screen (prothrombin time, activated partial thromboplastin time and fibrinogen) is usually normal. A virology screen pre-treatment is necessary to exclude human immunodeficency virus (HIV) and other viral-associated TTP, and as a baseline prior to plasma exposure. Troponin T levels are raised in 50% of acute idiopathic TTP cases (Hughes et al, 2009), highlighting that cardiac involvement is common. Raised troponin levels are a sinister finding, for coronary artery occlusion is a common mode of early death. The incidence of symptomatic heart failure is increased in patients who have been given a recent platelet transfusion (Gami et al, 2005) (Table 3). Blood must be taken prior to treatment to assess baseline ADAMTS13 activity. Severely reduced ADAMTS13 activity (<5%) ± the presence of an inhibitor or IgG antibodies, confirms the diagnosis (Peyvandi et al, 2004; Coppo et al, 2006; Ferrari et al, 2007; Scully et al, 2007a). Decreased ADAMTS13 activity (<40% but >5%) has been reported in a wide variety of non-TTP conditions such as uraemia, inflammatory states, post-operatively and during pregnancy (Loof et al, 2001; Mannucci et al, 2001; Moore et al, 2001). The specificity of severe ADAMTS13 deficiency (<5%) in distinguishing acute TTP from HUS is 90% (Bianchi et al, 2002; Zheng et al, 2004) ADAMTS13 assays currently available include assays of activity, antigen and neutralizing or non-neutralizing anti-ADAMTS13 autoantibodies. Functional assays measuring ADAMTS13 activity are based on the failure of the patient plasma to degrade VWF multimers or synthetic VWF peptides. Inhibitory autoantibodies can be titrated in vitro using classical mixing studies and non-neutralizing antibodies can be detected by Western blotting or enzyme-linked immunosorbent assays (Peyvandi et al, 2010). 1 The diagnosis of TTP should be treated as a medical emergency (1A). 2 The initial diagnosis of TTP should be made on clinical history, examination and routine laboratory parameters of the patient, including blood film review (1A). 3 In view of the high risk of preventable, early deaths in TTP, treatment with PEX should be initiated as soon as possible, preferably within 4–8 h, regardless of the time of day at presentation, if a patient presents with a MAHA and thrombocytopenia in the absence of any other identifiable clinical cause (1B). 4 Serological tests for HIV, hepatitis B virus and hepatitis C virus, autoantibody screen and when appropriate, a pregnancy test, should be performed at presentation (1A). 5 Pre-treatment samples should be obtained to measure ADAMTS13 activity levels and to detect anti-ADAMTS13 antibodies. Measurement of ADAMTS 13 antigen levels is also useful in congenital TTP cases (1B). Congenital TTP is a rare disorder, with over 100 patients described worldwide, but this is likely to be an underestimate. It has a varied phenotype and can present at any age. As a general rule, those with more severe phenotypes present early: 1 Neonates typically have severe neonatal jaundice. Blood film examination may show schistocytes together with red cell anisocytosis. (Scully et al, 2006a). 2 More frequently, the diagnosis is made later in infancy or childhood (Schiff et al, 2004), typically with thrombocytopenia, MAHA, jaundice and elevated LDH, although some children may only have an isolated thrombocytopenia. Neurological symptoms, such as hemiparesis, hemiplegia or seizures, occur in 35% of cases (Loirat et al, 2006). 3 Patients may present in adulthood. In women, pregnancy is a common precipitant and is associated with a significant neonatal morbidity and mortality (Fujimura et al, 2009). Rarely ‘late-onset phenotype’ cases may not develop symptoms until their 50s and 60s with isolated cerebral events or renal disease ((Fujimura et al, 2011). Asymptomatic male cases have been reported, usually detected because they have affected siblings. Patients with congenital TTP have persistently low levels of ADAMTS13, but they can be asymptomatic until a further precipitating event results in a frank TTP episode. Events include febrile episodes, infections, vaccinations, excess alcohol intake and pregnancy (Furlan et al, 1997, 1998b; Schneppenheim et al, 2003). Congenital TTP has been missed in the past, because the diagnosis has not been considered, or diagnosed as idiopathic thrombocytopenic purpura or ‘atypical’ HUS (Veyradier et al, 2003), illustrating the importance of consideration of the diagnosis, review of the blood film and measurement of ADAMTS13 . The diagnosis of congenital TTP is dependent on detecting ADAMTS13 activity <5%, in the absence of antibodies to ADAMTS13. In the last few years molecular diagnosis has been used to confirm the diagnosis, and either a homozygous or compound heterozygote defect in ADAMTS13 is found. Testing of siblings and other first-degree relatives at risk should be considered. 1 Congenital TTP should be considered in neonates presenting with severe jaundice. Presentation may also occur in childhood or as an adult (1A). 2 The diagnosis of congenital TTP should be considered in children and adults with unexplained thrombocytopenia (1B). 3 The diagnosis of congenital TTP is confirmed by ADAMTS13 activity <5%, absence of antibody and confirmation of homozygous or compound heterozygous defects of the ADAMTS13 gene (1A). Acute idiopathic TTP is the most common form of TTP. It is an autoimmune disease characterized by antibodies, usually IgG, directed against ADAMTS13. The incidence is four to six cases per million of the population per year in the United States (Miller et al, 2004; Terrell et al, 2005) and six cases per million per year in the UK (Scully et al, 2008). Thrombotic thrombocytopenia purpura may be the initial presenting feature of HIV disease or in those with low CD4 counts following non- compliance with antiviral treatment (Ucar et al, 1994; Gervasoni et al, 2002). Remission is dependent upon improving the immune status of the patient, for stopping highly active anti retroviral therapy (HAART) can result in acute TTP relapse (Miller et al, 2005), but continued use of HAART usually prevents further relapses. TTP in HIV-positive individuals may be associated with the presence of severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies. Those with severe ADAMTS13 deficiency (<5%) have fewer acquired immunodeficiency syndrome-related complications and higher CD4+ T cell counts, compared to HIV-TTP with ADAMTS13 levels >5%, who have an increased mortality (Malak et al, 2008). Pregnancy can be the initiating event for approximately 5–25% of TTP cases (Ridolfi & Bell, 1981; Vesely et al, 2004; Scully et al, 2008), which are late onset adult congenital TTP or acute idiopathic TTP. Differentiating TTP from the more common pregnancy-related TMAs, such as pre-eclampsia, syndrome elevated low and HUS is difficult, if TTP presents (Table Thrombosis in the in untreated TTP and results in death and is a continued risk of relapse during with levels of ADAMTS13 have a risk of relapse et al, 2003; Scully et al, to be for of TTP cases et al, 2003; Scully et al, 2008). can cause an disorder, typically in TTP is recognized in with with an incidence of per patients but has been described with and there is there is a et al, 2009). et al, Vesely et al, 2003; et al, 2004; Scully et al, 2008), et al, and used to hepatitis C et al, 2007; et al, 2007; et al, have been associated with TTP. are of acquired TTP associated with such as the and therapy (Scully et al, 2008). such as and can cause HUS but not TTP. 1 associated with of TTP include and which should be to relapse in patients with a of TTP 2 with TTP should be microangiopathy is a MAHA and thrombocytopenia that It may reflect associated with infections, such as A and disease has important from TTP, absence of ADAMTS13 rare neurological a poor to PEX and of of et al, Thrombotic microangiopathy in with a variety of & 2001). Presentation may be either at an early of or associated with ADAMTS13 activity is not reduced in patients et al, 2001). haemolytic anaemia has been reported in with acute a of of ADAMTS13 activity was only reduced and not with the of TTP or patients were treated with PEX and et al, 2009). associated typically with is treated with which in some cases renal not typically associated with but may be associated with symptoms, to TTP, should be treated with PEX et al, 2011). The factor HUS and TTP is the presence of renal in the of defects in HUS is defined & and use of the in cases et al, et al, but may also have a in severe et al, 2011). A of the treatment is in preferably with is the of treatment and has reduced mortality from over 90% to It of and ADAMTS13. in of PEX to early mortality et al, PEX remains the treatment of large plasma are if there is to be a in PEX has been to be to plasma at the of the treatment and at and and et al, The of PEX and the of to is highly but is in TTP (Coppo et al, 2006). has not been In the plasma exchange was performed on the 3 by exchange et al, More such as may be in cases if there is such as neurological or cardiac The of an PEX has been to as other are often initiated or et al, 2008). should for a of 2 defined as platelet count of has not been to relapse & 1998). is at as as plasma et al, et al, The UK of the use of plasma in TTP patients to the risk of and immune (Scully et al, plasma reduced levels of but an increased thrombotic has not been reported in cases where with low molecular and low was used the platelet count was × 109/l (Scully et al, ADAMTS13 activity is present in in and et al, In the is the plasma for use in in those to the risk of et al, has been associated with increased of PEX and in TTP et al, 2001; et al, 2008). A using compared to and et al, 2006). such as and to be more prior to the use of plasma (Scully et al, 1 PEX should be with using plasma in and (1B). 2 The of exchange can be reduced to when the clinical and laboratory test results are 3 in and or of PEX should be considered in cases 4 PEX should for a of 2 platelet count has been × and then or of ADAMTS13 are not treatment of plasma or the use of a factor ADAMTS13, such as et al, which has a small and can be given in the or of has been used with reported although there is of ADAMTS13 in such to ADAMTS 13 have not been detected following the use of that ADAMTS13 has a of only (Furlan et al, et al, 2004), the clinical of of plasma or are such that are only to a platelet and haemoglobin the of treatment on the therapy to the platelet count and at of and other The who have a platelet count most of the time, only 1 plasma or should be used to congenital TTP 2 for congenital TTP should be to the phenotype (1A). Diagnosis of TTP is if In any with a and as to the diagnosis that and can present in the PEX should be considered. TTP in the PEX may of pregnancy with delivery of a et al, et al, et al, Scully et al, is the treatment of for although delivery not of TTP. Pre-treatment ADAMTS13 assays congenital and acquired TTP from other In and syndrome ADAMTS13 activity is reduced but antibodies to ADAMTS13 are not found. with an with in and is with artery should be used to assess if there is and to assess blood alone may be in with congenital TTP. However, at delivery PEX may be to levels of ADAMTS13. The of plasma during pregnancy is In acquired TTP, is to relapse in A reduction in ADAMTS13 activity at the of pregnancy may therapy to during has been used in pregnancy in autoimmune and et al, 2011). 1 a be by a non-TTP pregnancy-related then the diagnosis of TTP must be considered and PEX should be 2 with congenital TTP should a and ADAMTS13 pregnancy and the (1A). 3 with an with a in is in with TTP (1A). 4 In with acquired TTP, ADAMTS13 activity should be pregnancy to help the need for therapy and (1B). 5 is for and women of should be of pregnancy and In those with severe ADAMTS13 there is in ADAMTS13 activity, as the CD4 count and HIV treatment with HAART and further therapy is for with or which do not cause a significant increase in complications et al, 2011). HAART should be given PEX to for time for 1 a patient with TTP is found to have HIV then should be and an HIV should be in management (1A). 2 TTP should be considered in an HIV-positive with a MAHA and thrombocytopenia (1A). 3 PEX in with HAART or should be as soon as the diagnosis of TTP is made (1B). 3 HAART should be given PEX therapy to time for (1A). 4 HAART should be continued to further relapse (1B). 5 In TTP, be considered is difficult, as stopping or to such as may has been with in a review was associated with an increased mortality et al, is of use of et al, et al, exchange has et al, The treatment of the is the of 1 PEX is not in the management of and (1A). 2 In associated further treatment for the should be considered (1A). are used in combination with PEX in the initial treatment of acute immune TTP. have to be associated with an patient and usually have et al, 2010). there is a combination of PEX and is to PEX 1 for – adult or high 1 should be considered (1B). studies have that is and in immune TTP, when patients to to PEX and and in acute idiopathic TTP et al, Scully et al, 2007a). has been used for 4 Patients in anti-ADAMTS13 IgG antibody levels and increased ADAMTS13 activity (Scully et al, 2007a). The risk of relapse to be reduced with use et al, 2007; Scully et al, 2011). PEX should be for at 4 h a & 2006; Scully et al, 2007a). more may during PEX et al, 2010). is of increased risk with in TTP A recent UK has in using as a therapy at presentation of TTP (Scully et al, 2011). 1 In acute idiopathic TTP with which are associated with a high should be considered on in with PEX and (1B). 2 Patients with or TTP should be (1B). A was used in patient with TTP et al, but further occurred of In a clinical of PEX with either or initial occurred in subsequently on and there was a relapse stopping of of the patients a relapse in the compared with of the patients a with an increase in ADAMTS13 activity and in antibodies to ADAMTS13 et al, In patients with renal is an but may and may be considered as therapy in patients with acute or acquired TTP the and of other used for and such as and use is associated with severe and has been in small of patients et al, et al, 2005), are not as of a clinical The mortality of in acute TTP was reported to be approximately In a of patients for acute and the was et al, et al, may be considered in the of TTP but has The TTP patients to PEX and with and without and et al, was in or and a of early death in the 15 in the group et al, 1 The clinical of in TTP is but they are (1B). 2 may be given during platelet count × cell transfusion and are during active haemolysis. It has been that transfusion in the is using a transfusion of this was not to those with cardiac disease et al, as cardiac is a feature of TTP, a higher haemoglobin may be in those with of cardiac involvement and acute haemolysis. to the risk of precipitating further thrombotic platelet are there is The risk of has been in acute TTP but is likely to be increased due to and acute routine should be given the platelet count has to × 109/l et al, 2003). B should be considered in TTP, a platelet of × 109/l has been but studies of are in the of continued PEX with 1 cell transfusion should be to clinical need if there is cardiac involvement (1A). 2 is during active haemolysis (1A). 3 are in TTP there is (1A). 4 with is platelet count has × (1B). is a of patients who present with TTP who subsequently show a or to PEX ± disease was defined as thrombocytopenia or a of PEX is not a of disease activity. have disease as of clinical symptoms or thrombocytopenia of PEX with the of or and the of further have some et al, et al, & & 2004; et al, 2008). is the of in disease (Scully et al, 2007a). of PEX and of can be considered in TTP (1B). is defined as an of acute TTP more and in of cases et al, & & The that over a of patients relapse et al, Patients with ADAMTS13 activity or an anti-ADAMTS13 antibody in a increase in relapse over 1 year (Peyvandi et al, 2008). In a further if ADAMTS13 was in relapse occurred in but if ADAMTS13 activity was only et al, The use of in an acute and the incidence of relapse (Scully et al, 2011). to patients should be the risk and the symptoms and signs of In patients who have TTP and where a reduction of ADAMTS 13 activity from levels to is therapy has been with of ADAMTS 13 activity (Scully et al, et al, 2009). Patients up with ADAMTS 13 1 PEX therapy are the of in disease (1B). 2 Patients should be symptoms, signs and risk of relapse with and (1A). 3 In patients with a reduction of ADAMTS 13 activity to <5%, therapy with can be considered (1B). uraemic syndrome is characterized by MAHA, thrombocytopenia and acute renal It associated with and cardiac and diagnostic overlap with TTP can It is important to HUS and TTP because the and management are (Table The is to et al, and et al, for further guidance in children and TTP and other TMAs The is to that haematologists, and are of the need to acute TTP as a medical emergency to early The of and in the should to in the the and in is to be and at the time of to the the British Society for Haematology the any for the of . In the British Society for Haematology the for the diagnosis and management of thrombotic et al, 2003). have revised based on available and for syndrome et al, and HUS et al, are now have been UK for review of 1 and for review of Table The Haemostasis has an from

Solvent additives such as diiodooctane (DIO) are becoming ubiquitous in processing high performance organic photovoltaic (OPV) active layers. Here, we investigate the effects of DIO on the long-term stability of the active layer by studying the photodegradation under ambient white light illumination of the polymer PTB7-Th in pure polymer thin films and in blend films with PC71BM. Using X-ray fluorescence, we directly detect iodine in the active layer films, indicating the presence of residual DIO after casting from solution. Additionally, we show that this residual DIO dramatically decreases the photostability of the active layer. Structural changes in the films upon illumination are probed with grazing-incidence wide-angle X-ray scattering (GIWAXS). FTIR spectroscopy is used to monitor chemical changes in the polymer structure during irradiation in the presence of DIO. Furthermore, we demonstrate that film treatment either with high vacuum (10–8 Torr) for 60 min or with a high-temperature thermal anneal at 175 °C for 30 min removes residual DIO from the film and delays photodegradation. Therefore, when processing polymer solar cells with DIO-containing solutions, it is imperative to remove any trace amounts of DIO from deposited films.

There is growing evidence that people who are transgender and gender diverse (TGD) are impacted by disparities across a variety of cardiovascular risk factors compared with their peers who are cisgender. Prior literature has characterized disparities in cardiovascular morbidity and mortality as a result of a higher prevalence of health risk behaviors. Mounting research has revealed that cardiovascular risk factors at the individual level likely do not fully account for increased risk in cardiovascular health disparities among people who are TGD. Excess cardiovascular morbidity and mortality is hypothesized to be driven in part by psychosocial stressors across the lifespan at multiple levels, including structural violence (eg, discrimination, affordable housing, access to health care). This American Heart Association scientific statement reviews the existing literature on the cardiovascular health of people who are TGD. When applicable, the effects of gender-affirming hormone use on individual cardiovascular risk factors are also reviewed. Informed by a conceptual model building on minority stress theory, this statement identifies research gaps and provides suggestions for improving cardiovascular research and clinical care for people who are TGD, including the role of resilience-promoting factors. Advancing the cardiovascular health of people who are TGD requires a multifaceted approach that integrates best practices into research, health promotion, and cardiovascular care for this understudied population.

A substantial body of epidemiological and experimental evidence suggests that serum uric acid is an important, independent risk factor for cardiovascular and renal disease especially in patients with hypertension, heart failure, or diabetes. Elevated serum uric acid is highly predictive of mortality in patients with heart failure or coronary artery disease and of cardiovascular events in patients with diabetes. Further, patients with hypertension and hyperuricemia have a 3- to 5-fold increased risk of experiencing coronary artery disease or cerebrovascular disease compared with patients with normal uric acid levels. Although the mechanisms by which uric acid may play a pathogenetic role in cardiovascular disease is unclear, hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation. Xanthine oxidase inhibitors (e.g., allopurinol) or a variety of uricosuric agents (e.g., probenecid, sulfinpyrazone, benzbromarone, and benziodarone) can lower elevated uric acid levels but it is unknown whether these agents reversibly impact cardiovascular outcomes. However, the findings of the recent LIFE study in patients with hypertension and left ventricular hypertrophy suggest the possibility that a treatment-induced decrease in serum uric acid may indeed attenuate cardiovascular risk. LIFE showed that approximately 29% (14% to 107%, p = 0.004) of the treatment benefit of a losartan-based versus atenolol-based therapy on the primary composite endpoint (death, myocardial infarction, or stroke) may be ascribed to differences in achieved serum uric acid levels. Overall, serum uric acid may be a powerful tool to help stratify risk for cardiovascular disease. At the very least, it should be carefully considered when evaluating overall cardiovascular risk.

More than 1.2 million percutaneous coronary interventions are performed annually in the United States, with only an estimated 33% performed in women, despite the established benefits of percutaneous coronary intervention and adjunctive pharmacotherapy in reducing fatal and nonfatal ischemic complications in acute myocardial infarction and high-risk acute coronary syndromes. This statement reviews sex-specific data on the safety and efficacy of contemporary interventional therapies in women.

In the early fifteenth century, English poets responded to a changed climate of patronage, instituted by Henry IV and successor monarchs, by inventing a new tradition of public and elite poetry. Following Chaucer and others, Hoccleve and Lydgate brought to English verse a style and subject matter writing about their King, nation, and themselves, and their innovations influenced a continuous line of poets running through and beyond Wyatt. A crucial aspect of this tradition is its development of ideas and practices associated with the role of poet laureate. Robert J. Meyer-Lee examines the nature and significance of this tradition as it developed from the fourteenth century to Tudor times, tracing its evolution from one author to the next. This study illuminates the relationships between poets and political power and makes plain the tremendous impact this verse has had on the shape of English literary culture.

TFClass (http://tfclass.bioinf.med.uni-goettingen.de/) provides a comprehensive classification of human transcription factors based on their DNA-binding domains. Transcription factors constitute a large functional family of proteins directly regulating the activity of genes. Most of them are sequence-specific DNA-binding proteins, thus reading out the information encoded in cis-regulatory DNA elements of promoters, enhancers and other regulatory regions of a genome. TFClass is a database that classifies human transcription factors by a six-level classification schema, four of which are abstractions according to different criteria, while the fifth level represents TF genes and the sixth individual gene products. Altogether, nine superclasses have been identified, comprising 40 classes and 111 families. Counted by genes, 1558 human TFs have been classified so far or >2900 different TFs when including their isoforms generated by alternative splicing or protein processing events. With this classification, we hope to provide a basis for deciphering protein-DNA recognition codes; moreover, it can be used for constructing expanded transcriptional networks by inferring additional TF-target gene relations.

Journal Article Religious Movements in Contemporary America edited by Irving I. Zaretsky and Mark P. Leone. Princeton University Press, 1974, xxxvi + 837 pp. $25.00 Get access Calvin Redekop Calvin Redekop Goshen College Search for other works by this author on: Oxford Academic Google Scholar Sociology of Religion, Volume 36, Issue 3, Fall 1975, Pages 282–283, https://doi.org/10.2307/3710376 Published: 01 October 1975

BACKGROUND: Treatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres Sirtex Medical, Lake Forest, IL) were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment. METHODS: Liver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers. RESULTS: Of the 40 patients, 5 had hepatocellular cancer (HCC), and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma). All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks). Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc) and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4). Average administered activity was 1.2 GBq (0.4 to 2.4 GBq). Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy). Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy). None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 %) had transient and 7 patients (17.5 %) had persistent LFT abnormalities. There were 27 (67.5%) responders (complete response, partial response, and stable disease). Tumor response correlated with higher tumor flow ratio as measured by Tc-99m MAA imaging. CONCLUSION: Doses up to 99.5 Gy to uninvolved liver are tolerated with no clinical venoocclusive disease or liver failure. The lowest tumor dose producing a detectable response is 40.1 Gy. The utilization of MAA-based imaging techniques to determine tumor and liver blood flow for clinical treatment planning and the calculation of administered activity may improve clinical outcomes.

Adolescents have unique health considerations as they transition from parent-managed healthcare to personal responsibility for health behavior. One question to consider is the goodness-of-fit of available theoretical models for explaining and predicting adolescent health-promoting behavior. This integrative review explored Pender's health promotion model in relation to adolescent health. Specifically, this review summarizes the components of Pender's model and the supporting theoretical underpinnings based in the social cognitive theory. Research literature related to the health promotion model and various aspects of teen health is explored. Recommendations for further research and theory development are discussed.

OsCERK1 is a rice receptor-like kinase that mediates the signal of a fungal cell wall component, chitin, by coordinating with a lysin motif (LysM)-containing protein CEBiP. To further elucidate the function of OsCERK1 in the defense response, we disrupted OsCERK1 using an Agrobacterium-mediated gene targeting system based on homologous recombination. In OsCERK1-disrupted lines, the generation of hydrogen peroxide and the alteration of gene expression in response to a chitin oligomer were completely abolished. The OsCERK1-disrupted lines also showed lowered responsiveness to a bacterial cell wall component, peptidoglycan. Yeast two-hybrid analysis indicated that OsCERK1 interacts with the LysM-containing proteins LYP4 and LYP6, which are known to participate in the peptidoglycan response in rice. Observation of the infection behavior of rice blast fungus (Magnaporthe oryzae) revealed that disruption of OsCERK1 led to increased hyphal growth in leaf sheath cells. Green fluorescent protein-tagged OsCERK1 was localized around the primary infection hyphae. These results demonstrate that OsCERK1 is indispensable for chitin perception and participates in innate immunity in rice, and also mediates the peptidoglycan response. It is also suggested that OsCERK1 mediates the signaling pathways of both fungal and bacterial molecular patterns by interacting with different LysM-containing receptor-like proteins.

Despite the importance of fire and herbivory in structuring savanna systems, few replicated experiments have examined the interactive effects of herbivory and fire on plant dynamics. In addition, the effects of fire on associated ant-tree mutualisms have been largely unexplored. We carried out small controlled burns in each of 18 herbivore treatment plots of the Kenya Long-term Exclosure Experiment (KLEE), where experimentally excluding elephants has resulted in 42% greater tree densities. The KLEE design includes six different herbivore treatments that allowed us to examine how different combinations of megaherbivore wildlife, mesoherbivore wildlife, and cattle affect fire temperatures and subsequent loss of ant symbionts from Acacia trees. Before burning, we quantified herbaceous fuel loads and plant community composition. We tagged all trees, measured their height and basal diameter, and identified the resident ant species on each. We recorded weather conditions during the burns and used ceramic tiles painted with fire-sensitive paints to estimate fire temperatures at different heights and in different microsites (under vs. between trees). Across all treatments, fire temperatures were highest at 0-50 cm off the ground and hotter in the grass under trees than in the grassy areas between trees. Plots with more trees burned hotter than plots with fewer trees, perhaps because of greater fine woody debris. Plots grazed by wildlife and by cattle prior to burning had lower herbaceous fuel loads and experienced lower burn temperatures than ungrazed plots. Many trees lost their ant colonies during the burns. Ant survivorship differed by ant species and at the plot level was positively associated with previous herbivory (and lower fire temperatures). Across all treatments, ant colonies on taller trees were more likely to survive, but even some of the tallest trees lost their ant colonies. Our study marks a significant step in understanding the mechanisms that underlie the interactions between fire and herbivory in savanna ecosystems.

Summary We suggest that trauma contributes to the development and persistence of conduct problems, and should be addressed. Eye movement desensitization and reprocessing (EMDR) was selected as a promising trauma treatment. Twenty-nine boys with conduct problems in residential or day treatment were randomized into standard care or standard care plus 3 trauma-focused EMDR sessions. The EMDR group showed large and significant reduction of memory-related distress, as well as trends towards reduction of post-traumatic symptoms. The EMDR group also showed large and significant reduction ofproblem behaviors by 2-month follow-up, whereas the control group showed only slight improvement. These findings provide support for EMDR's use as a trauma treatment for boys ages 10-16, as well as support for the hypothesis that effective trauma treatment can lead to reduced conduct problems in this population. Key Words: TraumaPTSDadolescenttherapyoppositional defiant disorderconduct disorderantisocial

The difference in lattice parameters between germanium crystals of natural isotopic composition and an isotopically enriched crystal of $^{74}\mathrm{Ge}$ was calculated and measured by using a double-beam triple-axis x-ray spectrometer. The measured relative fractional difference was (-6.3\ifmmode\pm\else\textpm\fi{}0.3)\ifmmode\times\else\texttimes\fi{}${10}^{\mathrm{\ensuremath{-}}6}$ and (-14.9\ifmmode\pm\else\textpm\fi{}0.3)\ifmmode\times\else\texttimes\fi{}${10}^{\mathrm{\ensuremath{-}}6}$ at room and liquid-nitrogen temperatures, respectively. The corresponding calculated values are -6\ifmmode\times\else\texttimes\fi{}${10}^{\mathrm{\ensuremath{-}}6}$ and -12\ifmmode\times\else\texttimes\fi{}${10}^{\mathrm{\ensuremath{-}}6}$. The agreement is very good, given uncertainties in the values of physical constants used for the theoretical calculations.

Journal Article Him/Her/Self: Sex Roles in Modern America. By Peter Gabriel Filene. (New York: Harcourt Brace Jovanovich, 1975. xiv + 351 pp. Appendix, notes, essay on research, and index. $10.00.) Get access Shirley Hershey Showalter Shirley Hershey Showalter Goshen College Search for other works by this author on: Oxford Academic Google Scholar Journal of American History, Volume 65, Issue 2, September 1978, Page 516, https://doi.org/10.2307/1894179 Published: 01 September 1978

Do survey designers bias respondents' answers on attitude/opinion questionnaires through the organization of their survey items? We hypothesize that respondents often employ an anchoring and adjusting strategy in which their response to an initial survey item provides a cognitive anchor from which they insufficiently adjust in answering the subsequent item. Three experiments indicate that respondents often anchor and insufficiently adjust in certain situations. Ultimately, this tendency can affect reliability estimates of scales and the resultant correlations with other measures. In organizing their surveys, researchers may wish to combat this bias by intermixing items designed for different but related constructs.

Stunting affects one-in-five children globally and is associated with greater infectious morbidity, mortality and neurodevelopmental deficits. Recent evidence suggests that the early-life gut microbiome affects child growth through immune, metabolic and endocrine pathways. Using whole metagenomic sequencing, we map the assembly of the gut microbiome in 335 children from rural Zimbabwe from 1-18 months of age who were enrolled in the Sanitation, Hygiene, Infant Nutrition Efficacy Trial (SHINE; NCT01824940), a randomized trial of improved water, sanitation and hygiene (WASH) and infant and young child feeding (IYCF). Here, we show that the early-life gut microbiome undergoes programmed assembly that is unresponsive to the randomized interventions intended to improve linear growth. However, maternal HIV infection is associated with over-diversification and over-maturity of the early-life gut microbiome in their uninfected children, in addition to reduced abundance of Bifidobacterium species. Using machine learning models (XGBoost), we show that taxonomic microbiome features are poorly predictive of child growth, however functional metagenomic features, particularly B-vitamin and nucleotide biosynthesis pathways, moderately predict both attained linear and ponderal growth and growth velocity. New approaches targeting the gut microbiome in early childhood may complement efforts to combat child undernutrition.

The radical-pair mechanism is one of two distinct mechanisms used to explain the navigation of birds in geomagnetic fields, however little research has been done to explore the role of quantum entanglement in this mechanism. In this paper we study the lifetime of radical-pair entanglement corresponding to the magnitude and direction of magnetic fields to show that the entanglement lasts long enough in birds to be used for navigation. We also find that the birds appear to not be able to orient themselves directly based on radical-pair entanglement due to a lack of orientation sensitivity of the entanglement in the geomagnetic field. To explore the entanglement mechanism further, we propose a model in which the hyperfine interactions are replaced by local magnetic fields of similar strength. The entanglement of the radical pair in this model lasts longer and displays an angular sensitivity in weak magnetic fields, both of which are not present in previous models.

From 2000 through 2005, hospitalizations with resistant infections (methicillin-resistant Staphylococcus aureus, Clostridium difficile-associated disease, vancomycin-resistant enterococcus, Pseudomonas aeruginosa, and Candida infection) nearly doubled, from 499,702 to 947,393. Regional variations noted in the aggregate and by individual infection may help clarify modifiable risk factors driving these infections.

BACKGROUND: Preterm birth and low birth weight (LBW) affect one in ten and one in seven livebirths, respectively, primarily in low-income and middle-income countries (LMIC) and are major predictors of poor child health outcomes. However, both have been recalcitrant to public health intervention. The maternal intestinal microbiome may undergo substantial changes during pregnancy and may influence fetal and neonatal health in LMIC populations. METHODS: Within a subgroup of 207 mothers and infants enrolled in the SHINE trial in rural Zimbabwe, we performed shotgun metagenomics on 351 fecal specimens provided during pregnancy and at 1-month post-partum to investigate the relationship between the pregnancy gut microbiome and infant gestational age, birth weight, 1-month length-, and weight-for-age z-scores using extreme gradient boosting machines. FINDINGS: Pregnancy gut microbiome taxa and metabolic functions predicted birth weight and WAZ at 1 month more accurately than gestational age and LAZ. Blastoscystis sp, Brachyspira sp and Treponeme carriage were high compared to Western populations. Resistant starch-degraders were important predictors of birth outcomes. Microbiome capacity for environmental sensing, vitamin B metabolism, and signalling predicted increased infant birth weight and neonatal growth; while functions involved in biofilm formation in response to nutrient starvation predicted reduced birth weight and growth. INTERPRETATION: The pregnancy gut microbiome in rural Zimbabwe is characterized by resistant starch-degraders and may be an important metabolic target to improve birth weight. FUNDING: Bill and Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Agency for Development and Cooperation, US National Institutes of Health, and UNICEF.