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Providing optimal care for patients with thrombotic thrombocytopenic purpura (TTP) is challenging because of multiple involved specialties, knowledge gaps, and a high rate of disease relapse. A thrombotic microangiopathy (TMA) Team and TTP Pathway could improve outcomes. To assess if a structured TTP Pathway, supported by a TMA Team, improved TTP care by reducing TTP relapse and TTP-related death (TTP-RRD) at a rural Appalachian medical center. Prospective cohort quality improvement project using the DMAIC quality improvement framework (Define, Measure, Analyze, Improve, Control) to develop a TMA Team and TTP Pathway. Pathway care included standardized use of therapeutic plasma exchange (TPE), rituximab, caplacizumab, as well as improved coordination between medical services, and regular outpatient biochemical TTP surveillance. Outcomes were determined by retrospective chart review for patients with acute TTP treated with usual care (N = 16 episodes) and the TTP Pathway (N = 16 episodes). All patients had acquired TTP. TTP-RRD at 90 days was reduced from 69% with usual care to 6% with Pathway care (95% CI 0.35 to 0.90, P = 0.0004), a relative risk reduction of 91%; TTP relapse alone at 90 days was reduced from 62% to 0% (95% CI 0.36 to 0.88, P = 0.0002) with Pathway care. The number needed to treat to prevent TTP-RRD was 1.59 at 90 days. Over the project duration usual care demonstrated a hazard ratio for TTP-RRD of 12.58 compared to Pathway care. With the intervention, the duration of TPE was increased (median 6 vs 12 sessions, P < 0.05), as was use of rituximab (31.3% vs 93.8%, 95% CI -0.36 to -0.88, P = 0.003), and caplacizumab (6.3% vs 62.5%, 95% CI -0.027 to -0.81, P = 0.001). All Pathway patients underwent biochemical surveillance, and 31% had pre-emptive rituximab to reduce possibility of clinical relapse. A structured TTP Pathway significantly reduces morbidity and aligns care with modern clinical guidelines. The TMA Team is a valuable institutional resource to improve outcomes.

In the United States and Latin America, candidates for national and state-level office frequently must win primary elections in order to advance to the general election. We model policy and valence issues for office-seeking candidates facing such two-stage elections. We determine a Nash equilibrium for the candidates' optimal strategies, and we find that holding a primary is likely to increase a party's chances of winning the general election, particularly in situations where valence issues that involve the candidates' campaigning skills and that are not known prior to the campaign are more salient than policy issues. Furthermore, we find that primary elections are especially likely to benefit parties that expect to be underdogs in the general election. Our conclusions are directly relevant to U.S. politics and by extension to the strategic decisions that many Latin American parties currently confront, about whether it is strategically desirable to hold primaries.

Introduction: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. Methods: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011–2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. Results: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. Conclusions: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.

A unidimensional spatial model of multiparty parliamentary elections under proportional representation is presented, in which parties project that the median parliamentary party will implement its policy position. The parties are assumed to be uncertain about the electoral impact of valence issues relating to party elites’ images of competence, integrity and charisma. The assumptions of the model, highlighting the importance of the median party in parliament, are consistent with empirical work by McDonald and Budge. Under them, the existence of a Nash equilibrium under quite general concavity conditions is proved and it is shown that parties will moderate their positions when their valence images deteriorate. Computations of party equilibria are reported. The model and its implications for policy-seeking parties with results on vote-seeking parties can be contrasted with that recently reported by Schofield and Sened.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation syndrome characterized by uncontrolled immune cell activation. Timely diagnosis is important, since early treatment can improve survival rates. However, completing all assessments needed to reach ≥5 positive criteria out of the 8 HLH-2004 criteria can be time consuming and may delay timely initiation of treatment. Hence, we applied a data-driven approach to identify a minimal parameter set for early decision-making towards the initiation of HLH-specific treatment. We retrospectively evaluated 165 patients from five Dutch tertiary hospitals with suspected HLH. Sixteen pHLH (median age 0.5 years) and 70 sHLH patients (median age 8.7 years) were identified using the HLH-2004 criteria. Clustering analysis and multi-receiver operator characteristics were used to identify parameters distinctive of HLH. The presence of either increased ferritin, cytopenia in ≥2 lineages, or splenomegaly distinguished HLH from non-HLH cases with a negative predictive value of 100%. A minimal parameter set consisting of 2 major criteria (phagocytosis and splenomegaly) and 3 minor criteria (cytopenia, increased ferritin, and increased triglycerides/low fibrinogen) predicted HLH with 95% (88–99) sensitivity and 94% (86–98) specificity. This finding was replicated in an independent retrospective validation cohort of 109 US patients (n = 109). By dividing a subset of the HLH-2004 criteria into major and minor criteria, this strategy uses the evaluation of less than 5 criteria to quickly identify patients with HLH. When confirmed in a prospective setting, this approach could be of value for timely diagnosis and treatment of HLH.

The complement system alternative pathway (AP) can be activated excessively in inflammatory diseases, particularly when there is defective complement regulation. For instance, deficiency in complement regulators CD55 and CD59, leads to paroxysmal nocturnal hemoglobinuria (PNH), whereas Factor H mutations predispose to atypical hemolytic uremic syndrome (aHUS), both causing severe thrombohemolysis. Despite eculizumab being the treatment for these diseases, benefits vary considerably among patients. Understanding the molecular mechanisms involved in complement regulation is essential for developing new treatments. Properdin, the positive AP regulator, is essential for complement amplification by stabilizing enzymatic convertases. In this study, the role of properdin in red blood cell (RBC) lysis and endothelial cell opsonization in these AP-mediated diseases was addressed by developing assays using PNH patient RBCs and human primary endothelial cells, where the effects of inhibiting properdin, using novel monoclonal antibodies (MoAbs) that we generated and characterized, were compared to other complement inhibitors. In models of PNH, properdin inhibition prevented hemolysis of patient PNH type II and III RBCs more than inhibition of Factor B, C3, and C5 (>17-fold, or >81-fold, or >12-fold lower molar IC values, respectively). When tested in an aHUS hemolysis model, the anti-properdin MoAbs had 11-fold, and 86-fold lower molar IC values than inhibition of Factor B, or C3, respectively ( < 0.0001). When comparing target/inhibitor ratios in all hemolysis assays, inhibiting properdin was at least as efficient as the other complement inhibitors in most cases. In addition, using endothelial cell assays, the data indicate a critical novel role for properdin in promoting complement activation on human endothelial cells exposed to heme (a hemolysis by-product) and rH19-20 (to inhibit Factor H cell-surface protection), as occurs in aHUS. Inhibition of properdin or C3 in this system significantly reduced C3 fragment deposition by 75%. Altogether, the data indicate properdin is key in promoting RBC lysis and complement activation on human endothelial cells, contributing to the understanding of PNH and aHUS pathogenesis. Further studies to determine therapeutic values of inhibiting properdin in complement-mediated diseases, in particular those that are characterized by AP dysregulation, are warranted.

Artificial Intelligence (AI) has reached memory studies in earnest. This partly reflects the hype around recent developments in generative AI (genAI), machine learning, and large language models (LLMs). But how can memory studies scholars handle this hype? Focusing on genAI applications, in particular so-called ‘chatbots’ (transformer-based instruction-tuned text generators), this commentary highlights five areas of critique that can help memory scholars to critically interrogate AI’s implications for their field. These are: (1) historical critiques that complicate AI’s common historical narrative and historicize genAI; (2) technical critiques that highlight how genAI applications are designed and function; (3) praxis critiques that centre on how people use genAI; (4) geopolitical critiques that recognize how international power dynamics shape the uneven global distribution of genAI and its consequences; and (5) environmental critiques that foreground genAI’s ecological impact. For each area, we highlight debates and themes that we argue should be central to the ongoing study of genAI and memory. We do this from an interdisciplinary perspective that combines our knowledge of digital sociology, media studies, literary and cultural studies, cognitive psychology, and communication and computer science. We conclude with a methodological provocation and by reflecting on our own role in the hype we are seeking to dispel.

The development of successful coastal adaptation strategies for both the built and natural environments requires combining scenarios of climate change and socio-economic conditions, and risk assessment. Such planning needs to consider the adaptation costs and residual damages over time that may occur given a range of possible storm conditions for any given sea level rise scenario. Using the metric of the expected value of annual adaptation costs and residual damages, or another metric that can be related to the elevation of flooding, a simplified method to carry this out is presented. The approach relies upon developing damage-flooding depth probability exceedance curves for various scenarios over a given planning period and determining the areas under the curves. While the approach does have limitations, it is less complex to implement than using Monte Carlo simulation approaches and may be more intuitive to decision makers. A case study in Maine, USA is carried out to illustrate the method.

Plurality-based elections between two major parties or candidates sometimes feature small, centrist, third parties. We modify the standard two-party spatial model of policy-seeking parties to incorporate a centrist third party, and we show that the presence of such a party—even if it has no chance of winning—motivates the major parties to propose policies that are much more divergent than without the third party. We derive explicit formulas for party locations at a three-party equilibrium and provide necessary and sufficient conditions for existence of that equilibrium. We show that, over time, the major parties can be expected to shift their policies in the same direction relative to each other but in the opposite direction relative to the minor party. The predictions of this model are compared with estimates of party policy locations during appropriate periods in postwar Britain.

We present a unified model of turnout and vote choice that incorporates two distinct motivations for citizens to abstain from voting: alienation from the candidates, and indifference between the candidates. Empirically, we find that alienation and indifference each motivated significant amounts of voter abstention in the 1980-1988 U.S. presidential elections. Using model-based computer simulations-which permit us to manipulate factors affecting turnout-we show that distinguishing between alienation and indifference illuminates three controversies in elections research. First, we find that abstention because of either alienation or indifference benefited Republican candidates, but only very modestly. Second, presidential elections involving attractive candidates motivate higher turnout, but only to the extent that abstention stems from alienation rather than from indifference. Third, paradoxically, citizens' individual-level tendencies to abstain because of alienation are strongly affected by their evaluations of the candidates' policies, whereas aggregate turnout rates do not depend significantly on the candidates' policy platforms.