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Vasopressor medications for circulatory shock have historically been administered through central venous catheters due to concern for extravasation injury when given peripherally. However, recent studies have demonstrated the safety of peripheral administration of vasopressor medications at lower doses and for a limited duration. Peripheral use of vasopressors is appealing to both patients and providers, as obtaining central access is an invasive procedure associated with the risk of pneumothorax, bleeding, and infection. Furthermore, waiting to initiate these medications until central access is obtained can lead to delays in care. Conversely, valid concerns remain regarding the risk of tissue extravasation associated with peripheral vasopressors, which can be life and limb threatening. We discuss the guidelines and data for optimal dose, duration, intravenous line (IV) size, IV location, and nursing IV site monitoring for peripheral vasopressors. We then explore adverse events associated with peripheral vasopressors. Finally, we describe how this practice change may impact hospital medicine providers.

We sought to identify factors affecting physicians' cognition and clinical behavior when evaluating patients that may need fluid therapy., Background: Proponents of dynamic fluid responsiveness testing advocate measuring cardiac output or stroke volume after a maneuver to prove that further fluids will increase cardiac output. However, surveys suggest that fluid therapy in clinical practice is often given without prior responsiveness testing., Design: Thematic analysis of face-to-face structured interviews., Setting: ICUs and medical-surgical wards in acute care hospitals., Subjects: Intensivists and hospitalist physicians., Interventions: None., Measurements and Main Results: We conducted 43 interviews with experienced physicians in 19 hospitals. Hospitalized patients with hypotension, tachycardia, oliguria, or elevated serum lactate are commonly seen by physicians who weigh the risks and benefits of more fluid therapy. Encounters are often with unfamiliar patients and evaluation and decisions are completed quickly without involving other physicians. Dynamic testing for fluid responsiveness is used much less often than static methods and fluid boluses are often ordered with no testing at all. This approach is rationalized by factors that discourage dynamic testing: unavailability of equipment, time to obtain test results, or lack of expertise in obtaining valid data. Two mental calculations are particularly influential: physicians' estimate of the base rate of fluid responsiveness (determined by physical examination, chart review, and previous responses to fluid boluses) and physicians' perception of patient harm if 500 or 1,000 mL fluid boluses are ordered. When the perception of harm is low, physicians use heuristics that rationalize skipping dynamic testing., Limitations: Geographic limitation to hospitals in Minnesota, United States., Conclusions: If dynamic responsiveness testing is to be used more often in routine clinical practice, physicians must be more convinced of the benefits of dynamic testing, that they can obtain valid results quickly and believe that even small fluid boluses harm their patients., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background. Variability in outpatient specialty clinic schedules contributes to numerous adverse effects including chaotic clinic settings, provider burnout, increased patient waiting times, and inefficient use of resources. This research measures the benefit of balancing provider schedules in an outpatient specialty clinic. Design. We developed a constrained optimization model to minimize the variability in provider schedules in an outpatient specialty clinic. Schedule variability was defined as the variance in the number of providers scheduled for clinic during each hour the clinic is open. We compared the variance in the number of providers scheduled per hour resulting from the constrained optimization schedule with the actual schedule for three reference scenarios used in practice at M Health Fairview's Clinics and Surgery Center as a case study. Results. Compared to the actual schedules, use of constrained optimization modeling reduced the variance in the number of providers scheduled per hour by 92% (1.70-0.14), 88% (1.98-0.24), and 94% (1.98-0.12). When compared with the reference scenarios, the total, and per provider, assigned clinic hours remained the same. Use of constrained optimization modeling also reduced the maximum number of providers scheduled during each of the actual schedules for each of the reference scenarios. The constrained optimization schedules utilized 100% of the available clinic time compared to the reference scenario schedules where providers were scheduled during 87%, 92%, and 82% of the open clinic time, respectively. Limitations. The scheduling model's use requires a centralized provider scheduling process in the clinic. Conclusions. Constrained optimization can help balance provider schedules in outpatient specialty clinics, thereby reducing the risk of negative effects associated with highly variable clinic settings., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Current management of childhood leukemia is tailored based on disease risk determined by clinical features at presentation. Whether properties of the host immune response impact disease risk and outcome is not known. Here, we combine mass cytometry, single cell genomics, and functional studies to characterize the BM immune environment in children with B cell acute lymphoblastic leukemia and acute myelogenous leukemia at presentation. T cells in leukemia marrow demonstrate evidence of chronic immune activation and exhaustion/dysfunction, with attrition of naive T cells and TCF1+ stem-like memory T cells and accumulation of terminally differentiated effector T cells. Marrow-infiltrating NK cells also exhibit evidence of dysfunction, particularly in myeloid leukemia. Properties of immune cells identified distinct immune phenotype-based clusters correlating with disease risk in acute lymphoblastic leukemia. High-risk immune signatures were associated with expression of stem-like genes on tumor cells. These data provide a comprehensive assessment of the immune landscape of childhood leukemias and identify targets potentially amenable to therapeutic intervention. These studies also suggest that properties of the host response with depletion of naive T cells and accumulation of terminal-effector T cells may contribute to the biologic basis of disease risk. Properties of immune microenvironment identified here may also impact optimal application of immune therapies, including T cell-redirection approaches in childhood leukemia.

BACKGROUNDPD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited.METHODSWe analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigen-presenting cells.RESULTSIn contrast to anti-PD-1 therapy, anti-PD-L1 therapy led to a distinct inflammatory signature in CD14+ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion.CONCLUSIONThese data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1-based combination therapies.TRIAL REGISTRATIONNCT02784483.FUNDINGThis work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).

There is widespread concern regarding the high price of innovative medicines and their impact on the sustainability of healthcare systems. However, the debate rarely accounts for the evolution of prices over the lifetime of the medicine and the impact of competitive forces. This article uses the experience of hepatitis C (HCV), during the years 2010-2017 to examine the impact of in-class competition and implications for policies that enable competition. To study the HCV market, we focused on European countries and applied a two-step approach involving a comprehensive literature review and an analysis of monthly sales data in US$ across seven European countries from July 2011 until July 2017. We find that competition to address the unmet medical need has led to significant treatment improvements to the benefit of patients, payers and the wider healthcare system and society. Competitive launches have led to innovative agreements, lowering the cost per treatment and improving patient access to treatment. For innovators, intense competition does not only impact the price set and their market share but in many cases shortens the economic life of the product to only a fraction of the patented period. This has an impact on future research decisions, focusing efforts on areas where unmet need is greatest. Sustainable innovation requires a well-balanced policy framework that provides the appropriate incentives and encourages competition., (Copyright © 2019. Published by Elsevier B.V.)

Preneoplastic lesions carry many of the antigenic targets found in cancer cells but often exhibit prolonged dormancy. Understanding how the host response to premalignancy is maintained and altered during malignant transformation is needed to prevent cancer. In order to understand the immune microenvironment in precursor monoclonal gammopathy of undetermined significance (MGUS) and myeloma, we analyzed bone marrow immune cells from 12 healthy donors and 26 MGUS/myeloma patients by mass cytometry and concurrently profiled transcriptomes of 42,606 single immune cells from these bone marrows. Compared to age-matched healthy donors, memory T cells from both MGUS and myeloma patients exhibit greater terminal-effector differentiation. However, memory T cells in MGUS show greater enrichment of stem-like TCF1/7hi cells. Clusters of T cells with stem-like and tissue-residence genes were also found to be enriched in MGUS by single-cell transcriptome analysis. Early changes in both NK and myeloid cells were also observed in MGUS. Enrichment of stem-like T cells correlated with a distinct genomic profile of myeloid cells and levels of Dickkopf-1 in bone-marrow plasma. These data describe the landscape of changes in both innate and adaptive immunity in premalignancy and suggest that attrition of the bone-marrow-resident T cell compartment due to loss of stem-like cells may underlie loss of immune surveillance in myeloma.

[This corrects the article DOI: 10.18632/oncotarget.1108.].

Background: Hyperactivation of STAT3 via constitutive phosphorylation of tyrosine 705 (Y705) is common in most human cancers, including head and neck squamous carcinoma (HNSCC). STAT3 is rarely mutated in cancer and the (epi)genetic alterations that lead to STAT3 activation are incompletely understood. Here we used an unbiased approach to identify genomic and epigenomic changes associated with pSTAT3(Y705) expression using data generated by The Cancer Genome Atlas (TCGA)., Methods and Findings: Mutation, mRNA expression, promoter methylation, and copy number alteration data were extracted from TCGA and examined in the context of pSTAT3(Y705) protein expression. mRNA expression levels of 1279 genes were found to be associated with pSTAT3(705) expression. Association of pSTAT3(Y705) expression with caspase-8 mRNA expression was validated by immunoblot analysis in HNSCC cells. Mutation, promoter hypermethylation, and copy number alteration of any gene were not significantly associated with increased pSTAT3(Y705) protein expression., Conclusions: These cumulative results suggest that unbiased approaches may be useful in identifying the molecular underpinnings of oncogenic signaling, including STAT3 activation, in HNSCC. Larger datasets will likely be necessary to elucidate signaling consequences of infrequent alterations., Competing Interests: The authors have declared that no competing interests exist.

Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA-wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.

The c-Myc (Myc) oncoprotein is a high-value therapeutic target given that it is deregulated in multiple types of cancer. However, potent small molecule inhibitors of Myc have been difficult to identify, particularly those whose mechanism relies on blocking the association between Myc and its obligate heterodimerization partner, Max. We have recently reported a structure-activity relationship study of one such small molecule, 10074-G5, and generated an analog, JY-3-094, with significantly improved ability to prevent or disrupt the association between recombinant Myc and Max proteins. However, JY-3094 penetrates cells poorly. Here, we show that esterification of a critical para-carboxylic acid function of JY-3-094 by various blocking groups significantly improves cellular uptake although it impairs the ability to disrupt Myc-Max association in vitro. These pro-drugs are highly concentrated within cells where JY-3-094 is then generated by the action of esterases. However, the pro-drugs are also variably susceptible to extracellular esterases, which can deplete extracellular reservoirs. Furthermore, while JY-3-094 is retained by cells for long periods of time, much of it is compartmentalized within the cytoplasm in a form that appears to be less available to interact with Myc. Our results suggest that persistently high extracellular levels of pro-drug, without excessive susceptibility to extracellular esterases, are critical to establishing and maintaining intracellular levels of JY-3-094 that are sufficient to provide for long-term inhibition of Myc-Max association. Analogs of JY-3-094 appear to represent promising small molecule Myc inhibitors that warrant further optimization.

Background: Confusion exists when dosing heparin using a weight-based nomogram in the obese population. At 2 affiliated community teaching hospitals, we compared the activated partial thromboplastin time (aPTT) values in morbidly obese and nonmorbidly obese patients using a standardized nomogram and determined factors associated with achieving a supratherapeutic aPTT value., Methods: This was a retrospective study that included patients who had received intravenous heparin according to a standardized weight-based nomogram for >or=12 hours. The exclusion criteria were age <18 years, pregnancy, and insufficient data. Patients were stratified into morbidly obese (body mass index [BMI] >or=40 kg/m(2)) and nonmorbidly obese (BMI <40 kg/m(2)) groups. The aPTT values were compared and predictors for a supratherapeutic aPTT values were identified., Results: A total of 101 patients were included in the study. Greater aPTT values were noted at 6 hours (155 +/- 37 versus 135 +/- 44, P = .020) and 12 hours (141 +/- 45 versus 117 +/- 45, P = .012) for patients with morbid obesity than for those without it, respectively. Increasing BMI (odds ratio = 1.06, 95% confidence interval 1.02-1.1; P = .003) and age (odds ratio 1.05, 95% confidence interval 1.02-.09; P = .001] were independent predictors of supratherapeutic aPTT values., Conclusion: Heparin dosing with a weight-based nomogram will yield greater aPTT values in morbidly obese patients. Consideration of BMI and age can help identify those patients at risk of supratherapeutic aPTTs. Alternative strategies, such as a dose cap should be considered in patients with morbid obesity.

Purpose: To determine if encasing gold weights in a porous alloplastic material would improve their longevity in situ., Methods: Gold weights used for passive eyelid reanimation in patients with paralytic lagophthalmos were wrapped in either expanded polytetrafluoroethylene (E-PTFE) or porous polyurethane (PPU) to allow cellular infiltration and ingrowth and increase the blood supply to the site of the implant. A total of 14 implants, six encased in E-PTFE, six encased in PPU, and two with no casings (controls), were tested for biocompatibility and stability in rabbit eyelids for 10 months., Results: Two of the PPU-encased gold weights showed some anterior extrusion, one at 3 months and one at 5 months after implantation. All of the E-PTFE-encased gold weights and both control weights were well tolerated for the entire study period. Histology of the alloplastic casings and surrounding tissues showed good tissue compatibility and cellular ingrowth for both alloplastic materials., Conclusions: Encasing the weights in a biocompatible alloplastic material, such as E-PTFE, may decrease micromovement and improve attachment to the eyelid tissue, as well as increase blood supply to the area, thereby reducing the rates of the major complications--infection and extrusion--associated with these implants.

The role of murine IL-1 beta in vitro and in vivo has not been defined. We describe here the production of neutralizing and immunoprecipitating mAb and polyclonal antibodies specific for murine IL-1 beta and their application to a characterization of the murine IL-1 beta protein. Immunization of either hamsters or rabbits with the recombinant mature form of murine IL-1 beta emulsified in CFA elicited antisera and hamster mAb that only recognized denatured IL-1 beta. In contrast, immunization with rIL-1 beta adsorbed to alum resulted in the generation of neutralizing and immunoprecipitating rabbit and hamster antisera and hamster mAb. All of the mAb recognize both the pro-form of IL-1 beta and the mature bioactive form produced by cultures of murine peritoneal macrophages. Using these antibodies, we demonstrate that approximately half of the IL-1 activity present in supernatants of LPS-treated cultured mouse macrophages is composed of IL-1 beta. Additionally, IL-1 beta as well as IL-1 alpha can be detected in the plasma of LPS-treated mice. These studies, therefore, demonstrate the production of IL-1 beta both in vitro and in vivo.