Search

Background: Thymoma presents with several autoimmune manifestations and is associated with secondary autoimmune regulator (AIRE) deficiency. Pneumonitis has recently been described as an autoimmune manifestation associated with thymoma presenting with similar clinical, radiographic, histological, and autoantibody features as seen in patients with inherited AIRE deficiency who suffer from Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome. Objectives: To treat two patients with biopsy-proven thymoma-associated pneumonitis with lymphocyte-directed immunomodulation. Methods: Two patients with thymoma were enrolled on IRB-approved protocols at the NIH Clinical Center. We performed history and physical examination; laboratory, radiographic, histologic and pulmonary function evaluations; and measurement of the lung-directed autoantibodies KCNRG and BPIFB1 prior to and at 1- and 6-months following initiation of lymphocyte-directed immunomodulation with azathioprine with or without rituximab. Results: Combination T- and B-lymphocyte-directed immunomodulation resulted in improvement of clinical, functional, and radiographic parameters at 6-month follow-up evaluations in both patients with sustained remission up to 12–36 months following treatment initiation. Conclusion: Lymphocyte-directed immunomodulation remitted autoimmune pneumonitis in two patients with thymoma. [ABSTRACT FROM AUTHOR]

The text introduces the Data Challenge Expo 2019, an annual event sponsored by the American Statistical Association. The challenge involves analyzing a data set from the New York City Housing and Vacancy Survey. Participants were asked to explore various research questions related to housing conditions, rent control, gentrification, immigrant residency, and the costs and benefits of renting versus owning in New York City. The winners of the challenge were announced at the Joint Statistical Meetings in 2019, and their analyses are described in this special issue of Computational Statistics. Supplementary materials, including data sets and code, are available for reproducibility purposes. [Extracted from the article]

Background: Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in metastatic cancers remains unclear. Many patients, especially those without radiologic complete remission, develop progressive disease after ICI discontinuation. Extending DoT with ICI may potentially improve efficacy outcomes but presents major logistical and cost challenges with standard frequency dosing (SFD). Receptor occupancy data supports reduced frequency dosing (RFD) of anti-PD-1 antibodies, which may represent a more practical and economically viable option to extend DoT. Methods: We conducted a retrospective study of patients with metastatic melanoma and Merkel cell carcinoma (MCC), who received ICI at RFD administered every 3 months, after initial disease control at SFD. We evaluated efficacy, safety, and cost-savings of the RFD approach in this cohort. Results: Between 2014 and 2021, 23 patients with advanced melanoma (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT was 1.1 years at SFD and 1.2 years at RFD. The 3 year PFS after start of RFD was 73% in melanoma and 100% in MCC patients, which compare favorably to historical control rates. In the subset of 15 patients who received at least 2 years of therapy, total savings amounted to $1.1 million in drug costs and 384 h saved despite the extended DoT (median 3.4 years), as compared to the calculated cost of 2 years at SFD. Conclusions: ICI administration at RFD can allow extension of treatment duration, while preserving efficacy and reducing logistical and financial burden. RFD approach deserves further exploration in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are approved for the treatment of a variety of cancer types. The doses of these drugs, though approved by the Food and Drug Administration (FDA), have never been optimised, likely leading to significantly higher doses than required for optimal efficacy. Dose optimisation would hypothetically decrease the risk, severity, and duration of immune-related adverse events, as well as provide an opportunity to reduce costs through interventional pharmacoeconomic strategies such as off-label dose reductions or less frequent dosing. We summarise existing evidence for ICI dose optimisation to advocate for the role of interventional pharmacoeconomics. [ABSTRACT FROM AUTHOR]

Introduction: The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC. Methods: We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates. Results: In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5 years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% (n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose (p = 0.55) and mean dose per NAC cycle (p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided (p = 0.72) or mean dose per cycle (p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS (p = 0.45) or OS (p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean dexamethasone dose used. Conclusion: Our findings demonstrate that dexamethasone has no clinically significant impact on pCR, RFS, or OS when given concurrently with NAC in patients with curative TNBC, regardless of diabetic status. [ABSTRACT FROM AUTHOR]

Purpose: Hemorrhagic stroke (HS) is a devastating complication during extracorporeal membrane oxygenation (ECMO) but markers of risk stratification during COVID-19 are unknown. Lactate dehydrogenase (LDH) is a readily available biomarker of cell injury and permeability. We sought to determine whether an elevated LDH before ECMO placement is related to the occurrence of HS during ECMO for COVID-19. Methods: Adult patients with COVID-19 requiring ECMO between March 2020 and February 2022 were included. LDH values prior to ECMO placement were captured. Patients were categorized into high (> 750 U/L) or low (≤ 750 U/L) LDH groups. Multivariable regression modeling was used to determine the association between LDH and HS during ECMO. Results: There were 520 patients that underwent ECMO placement in 17 centers and 384 had an available LDH. Of whom, 122 (32%) had a high LDH. The overall incidence of HS was 10.9%, and patients with high LDH had a higher incidence of HS than those with low LDH level (17% vs 8%, p = 0.007). At 100 days, the probability of a HS was 40% in the high LDH group and 23% in those with a low LDH, p = 0.002. After adjustment for clinical covariates, high LDH remained associated with subsequent HS (aHR: 2.64, 95% CI 1.39–4.92). Findings were similar when restricting to patients supported by venovenous ECMO only. Conclusion: Elevated LDH prior to ECMO cannulation is associated with a higher incidence of HS during device support. LDH can risk stratify cases for impending cerebral bleeding during ECMO. [ABSTRACT FROM AUTHOR]

Aging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the factors within the aged lung that compromise host defense to IAV remain unknown. Using a murine model and human samples, we identified prostaglandin E2 (PGE2), as such a factor. Senescent type II alveolar epithelial cells (AECs) are overproducers of PGE2 within the aged lung. PGE2 impairs the proliferation of alveolar macrophages (AMs), critical cells for defense against respiratory pathogens, via reduction of oxidative phosphorylation and mitophagy. Importantly, blockade of the PGE2 receptor EP2 in aged mice improves AM mitochondrial function, increases AM numbers and enhances survival to IAV infection. In conclusion, our study reveals a key mechanism that compromises host defense to IAV, and possibly other respiratory infections, with aging and suggests potential new therapeutic or preventative avenues to protect against viral respiratory disease in older adults.Ageing has been associated with impaired function of alveolar macrophages and increased susceptibility, mortality and complications as a result of viral infection. Here, the authors show that prostaglandin E2 is one of the factors responsible for impairing immune defences against influenza during ageing. [ABSTRACT FROM AUTHOR]

As pharmaceutical companies seek patent protection for combinations of cancer therapeutics, it is worthwhile to assess what constitutes an 'unexpected result' for the purpose of an appropriate patent and whether randomized, controlled trials of drug combinations have the ability to generate them. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma" published in the journal Cancer Immunology, Immunotherapy. The correction addresses an error in the discussion section of the article, specifically the 6th sentence of the 10th paragraph. The corrected sentence emphasizes the use of tests such as clinical biopsy or ctDNA to identify patients with residual disease who may benefit from extended treatment duration. The correction notice also includes a statement from the publisher, Springer Nature, asserting their neutrality regarding jurisdictional claims and institutional affiliations. [Extracted from the article]

The population pharmacokinetics of atezolizumab demonstrate that the trough concentrations are well above the putative target of 6 µg/ml. Thus, alternative dosing schedules are indeed of interest, focusing on reducing the frequency to allow greater patient convenience and reduced costs. [ABSTRACT FROM AUTHOR]

We investigate whether beliefs about the income distribution are associated with political positions for or against redistribution. Using a novel elicitation method, we assess individuals' beliefs about the shape of the income distribution in the United States. We find that respondents' beliefs approximate the actual distribution on average. However they tend to overestimate the median income and underestimate the level of inequality. Surprisingly we find that beliefs about overall inequality, measured in terms of income dispersion, play only a marginal role in political positions as well as prospects of future wealth. Political preferences, however, are predicted by first, beliefs about the level of income of the poorest members of society, and second, a belief in an open society with equal opportunities for all. Support for redistribution is lower for people who give higher estimates of the income level of the poorest members of society and for people who perceive that opportunities for upward mobility are available. [ABSTRACT FROM AUTHOR]

Multiple chemotherapy regimens are available for the treatment of metastatic pancreas cancer (mPCA). Choice of regimen is based on the patient's performance status and toxicity profile of the regimen. The objective of this study was to analyze the costs of first-line regimens to further aid in decision-making and develop a platform upon which to assess value. We calculated the monthly cost for individual standard regimens (gemcitabine, gemcitabine/nab-paclitaxel, gemcitabine/erlotinib and FOLFIRINOX) and the overall treatment cost for a course of therapy based on the median progression-free survival achieved in published studies. In addition to cost of drugs, we included administration costs and costs of toxicities (including growth factor support, blood product transfusion and hospitalization for toxicities). Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services. Drug costs were based on Medicare average sale prices (all 2014 US$). The monthly costs for gemcitabine, FOLFIRINOX, gemcitabine/erlotinib and gemcitabine/nab-paclitaxel were $1363, $7234, $8007 and $12,221, respectively. The overall treatment costs for a course of the same regimens based on median PFS were $5043, $46,298, $51,004 and $67,216, respectively. The choice of chemotherapy regimen for mPCA should be based on tolerability and efficacy of the regimen individualized to patient's performance status. Healthcare systems have finite resources; thus, there is increasing emphasis on metrics to define value in health care when outcomes of therapy are similar or produce marked differences in value. These data provide useful financial information to incorporate into the decision-making process. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer diagnosis and cause of cancer-related death in the USA. It accounts for more than one million cases diagnosed each year worldwide. In the past 10 years, new drugs have been approved, but the survival times are still modest. Alternative therapeutic strategies are clearly needed. A large number of tumor antigens and epitopes recognized by cytotoxic T lymphocytes (CTLs) have been identified in CRC. Cancer vaccines, designed to activate immune effectors (T cells and antibodies), to prevent recurrence, or to treat advanced cancers, have demonstrated clinical benefit in melanoma, prostate cancer, and lymphoma. Immunotherapy that targets tumor-associated antigens (TAAs) on cancer cells or tumor stroma is under investigation. This review discusses CRC immune responsiveness, current status of CRC vaccines, challenges, and future directions. New therapeutic modalities hold a promise to improve the patient's clinical outcome. [ABSTRACT FROM AUTHOR]

We review research on revenue models used by online firms who offer digital goods. Such goods are non-rival, have near zero marginal cost of production and distribution, low marginal cost of consumer search, and low transaction costs. Additionally, firms can easily observe and measure consumer behavior. We start by asking what consumers can offer in exchange for digital goods. We suggest that consumers can offer their money, personal information, or time. Firms, in turn, can generate revenue by selling digital content, brokering consumer information, or showing advertising. We discuss the firm's trade-off in choosing between the different revenue streams, such as offering paid content or free content while relying on advertising revenues. We then turn to specific challenges firms face when choosing a revenue model based on either content, information, or advertising. Additionally, we discuss nascent revenue models that combine different revenue streams such as crowdfunding (content and information) or blogs (information and advertising). We conclude with a discussion of opportunities for future research including implications for firms' revenue models from the increasing importance of the mobile Internet. [ABSTRACT FROM AUTHOR]

The debate over genetically modified (GM) crops has raged in Europe since 1996, but had barely risen above a whisper in the USA until recent labeling debates raised public attention. This article will explain GM crops and traits discuss safety assessment provide a view on safety from authoritative organizations discuss selected issues of current debate, and provide the author's perspective as to why the public debate has drifted so far from scientific reality. The economic and environmental benefits of GM crops are beyond scope, but references are provided. GM food and feed undergo comprehensive assessments using recognized approaches to assure they are as safe as the conventional congener. Issues of food safety and nutrition, unrelated to the GM process, may arise when GM foods display novel components or composition. Unanticipated genetic effects in GM crops appear to be limited in contrast to existing variations among conventional varieties resulting from breeding, mutation, and natural mobile genetic elements. Allergenic potential is assessed when selecting genes for introduction into GM crops and remains a theoretical risk to date. Emerging weed and insect resistance is not unique to GM technology and will require the use of integrated pest management/best practices for pest control. Gene flow from GM crops to wild relatives is limited by existing biological barriers but can at time be a relevant consideration in gene selection and planting practices. Insect-resistant GM crops have significantly reduced use of chemical insecticides and appear to have reduced the incidence of pesticide poisoning in areas where small scale farming and hand application are common. Changes in herbicide patterns are more complex and are evolving over time in response to weed resistance management needs. Recent public debate is driven by a combination of unfounded allegations about the technology and purveyors, pseudoscience, and attempts to apply a strict precautionary principle. [ABSTRACT FROM AUTHOR]

As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses that involve multiple immune and non-immune cell types and that vary depending on the cell activation state and tissue context. This ageing-associated basal inflammation, particularly in humans, is thought to be induced by several factors, including the reactivation of latent viral infections and the release of endogenous damage-associated ligands of pattern recognition receptors (PRRs). Innate immune cell functions that are required to respond to pathogens or vaccines, such as cell migration and PRR signalling, are also impaired in aged individuals. This immune dysregulation may affect conditions associated with chronic inflammation, such as atherosclerosis and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The way a choice is presented influences what a decision-maker chooses. This paper outlines the tools available to choice architects, that is anyone who present people with choices. We divide these tools into two categories: those used in structuring the choice task and those used in describing the choice options. Tools for structuring the choice task address the idea of what to present to decision-makers, and tools for describing the choice options address the idea of how to present it. We discuss implementation issues in using choice architecture tools, including individual differences and errors in evaluation of choice outcomes. Finally, this paper presents a few applications that illustrate the positive effect choice architecture can have on real-world decisions. [ABSTRACT FROM AUTHOR]

lthough our understanding of the immunological mechanisms of transplant tolerance induction has greatly improved, how the innate immune system impacts transplant tolerance has only been recently appreciated. In this review, the involvement of the innate immune receptors, Toll-like receptors (TLRs), in both experimental models of acute allograft rejection and transplant tolerance induction in addition to clinical studies of organ transplantation are described. Several inflammatory cytokines, including IL-6, TNF-α, and type I interferons, which are induced by TLRs and other activators of innate immunity, prevent transplant tolerance induction. Their induction may be provoked by environmental exposures, such as viral or bacterial infections. Further investigation as to the innate inflammatory basis that controls the balance between immune acceptance and allograft rejection may lead us closer to the elusive goal of transplant tolerance acquisition. [ABSTRACT FROM AUTHOR]

While great strides have been made in the management of heart failure syndromes, acute refractory cardiogenic shock carries a dismal prognosis. Initial treatment with inotropes and balloon counterpulsation can restore hemodynamics, but many patients deteriorate and succumb to multisystem organ failure if timely mechanical circulatory support is not established. Institution of support is intended as a life-saving measure where the final treatment strategy remains uncertain. This scenario is referred to as 'bridge to decision.' Notably, most of these patients present to community hospitals, where advanced mechanical support technologies are scarce or nonexistent. Delays in referral to a tertiary center contribute to the bleak outcomes. Herein, we review the initial management of acute heart failure and refractory cardiogenic shock, profile the typical patient, delineate current options for mechanical support in patients with acute refractory cardiogenic shock, and propose suggestions for the establishment of a seamless transfer process of these ill patients to tertiary centers. [ABSTRACT FROM AUTHOR]

Does it pay to pay online panel members? A three-wave longitudinal experiment was conducted with an online panel to examine whether per person payments, paid through an online intermediary, influence response and retention rates. In the payment condition, participants were promised payment for participation at each wave, whereas control participants were not offered any payment. The promise of a payment had a negative effect on response in Wave 1, but a positive effect on response in Wave 2. Payment had no significant effect on retention. Completing a given wave was an indicator for responding to a subsequent invitation. [ABSTRACT FROM AUTHOR]

Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88−/− and Tlr4−/−Tlr2−/− mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell–specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell–surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-κB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury. [ABSTRACT FROM AUTHOR]

This paper presents a direction for narrative ethics based on ethical ideas found in the works of Michel Foucault. Narrative ethics is understood here at the meta-level of cultural discourse to see how the moral subject is constituted by the discursive practices that structure the contemporary debate on reproductive technologies. At this level it becomes meta-narrative-ethics. After a theoretical discussion, this paper uses two literary narratives representing the polarized views in the debate to show how the moral subject may be compelled to relate to its self. Ethics is redefined as Foucauldian rapport à soi, and ethical analysis, at this meta-level, shows how the moral self is intimately connected to cultural discourse. [ABSTRACT FROM AUTHOR]

Opinion. Discusses the biology of mathematics, highlighting the causes of mathematical ability. Actions of Alain Connes as a results of the absoluteness and universality of mathematics and its comparative independence of cultural influences; Use of the functioning structures of the central nervous system in explaining the views that mathematics shared by the whole species; Three canonical activities related with the visual system. INSET: Seeing the idea, by Jean Pedersen.

Feulgen-DNA contents and chromosome lengths and projected areas were measured in salivary gland nuclei from Drosophila prepupae which had developed at 25° or 15° C. Nuclei from a given prepupa fell into 3 to 5 DNA classes corresponding to different levels of polyteny. The 15° nuclei tended to fall into higher classes than those from 25°-reared animals, and their chromosomes were, on average, about 50% wider. Chromosomes within a given DNA class did not differ significantly in mean area, length or width between the temperature groups, and slight apparent differences in mean DNA content were attributable to systematic microdensitometric errors associated with differences in the spreading behaviour of the nuclei. On cytological examination, chromosomes from the two temperature groups differed mainly in width and stain intensity, but some other differences in appearance could not be accounted for by levels of polyteny. The mean length of the chromosome complement was about 400 μm. From one polytenic level to the next the chromosomes increased by about 10% in length, 40% in width and 17% in mean absorbance. The DNA content approximately doubled; small apparent deviations from the 1∶2 ratio could have been due to microdensitometric error or to underreplication of heterochromatin. [ABSTRACT FROM AUTHOR]

The financial impact of an extensive duration of adjuvant immunotherapy is severe. The clinical and biological rationale for this extensive duration is unclear. This study aims to understand the biologic and clinical rationale for the duration of treatment in designing adjuvant trials and to assess the economic impact of different treatment durations in adjuvant therapy. We searched http://www.clinicaltrials.gov for adjuvant immunotherapy clinical trials. Based on our inclusion and exclusion criteria, we identified 47 trials targeting PD-1, PD-L1, and CTLA-4. We examined the duration of these trials and performed a US based budget impact analysis of three representative trials based on various data sources. Most current adjuvant immunotherapy trials provide treatment for 1 year. Our budget impact analyses estimate that the cost per patient of 1 year treatment with nivolumab for melanoma is $165,000 while the cost of 3 years treatment with ipilimumab for melanoma is more than $1,850,000 assuming full duration of treatment. The annual cost for adjuvant treatment with nivolumab for melanoma is approximately $1.15 billion for the entire target population in the United States assuming full uptake. The necessary duration of adjuvant immunotherapy is unknown. The rationale for duration in current trials is not clear and may be longer than necessary. Non-inferiority trials testing shorter duration of therapies should be conducted. Appropriate mechanisms to fund such trials should be sought out by healthcare payers. [ABSTRACT FROM AUTHOR]

A correction to the article "The role of subjective beliefs in preferences for redistribution" that was published online on March 29, 2016 is presented.

Discusses the function of mathematics in understanding biological phenomena. Role of genetics and molecular chemistry in explaining biological complexity in terms of interacting molecules; Contribution of x-ray diffraction and nuclear magnetic resonance in determining molecular structure; Factors necessary in understanding the function of biological systems.

Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances--damage-associated molecular patterns (DAMPs)--that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients. [ABSTRACT FROM AUTHOR]