In its Sixth Edition, this book has been updated and revised to incorporate new information on technology, economic, and political issues that have impacted the use of fluids to drill and complete ...oil and gas wells. With updated content on completion fluids and reservoir drilling fluids; health, safety and environment; drilling fluid systems and products; new fluid systems and additives from both chemical and engineering perspectives; wellbore stability, adding the new R&D on water-based muds; and equipment and procedures for evaluating drilling fluid performance in light of the advent of digital technology and better manufacturing techniques, this book has been thoroughly updated to meet the drilling and completion engineer's needs.
IMPORTANCE: Emergency medical services (EMS) commonly perform endotracheal intubation (ETI) or insertion of supraglottic airways, such as the laryngeal tube (LT), on patients with out-of-hospital ...cardiac arrest (OHCA). The optimal method for OHCA advanced airway management is unknown. OBJECTIVE: To compare the effectiveness of a strategy of initial LT insertion vs initial ETI in adults with OHCA. DESIGN, SETTING, AND PARTICIPANTS: Multicenter pragmatic cluster-crossover clinical trial involving EMS agencies from the Resuscitation Outcomes Consortium. The trial included 3004 adults with OHCA and anticipated need for advanced airway management who were enrolled from December 1, 2015, to November 4, 2017. The final date of follow-up was November 10, 2017. INTERVENTIONS: Twenty-seven EMS agencies were randomized in 13 clusters to initial airway management strategy with LT (n = 1505 patients) or ETI (n = 1499 patients), with crossover to the alternate strategy at 3- to 5-month intervals. MAIN OUTCOMES AND MEASURES: The primary outcome was 72-hour survival. Secondary outcomes included return of spontaneous circulation, survival to hospital discharge, favorable neurological status at hospital discharge (Modified Rankin Scale score ≤3), and key adverse events. RESULTS: Among 3004 enrolled patients (median interquartile range age, 64 53-76 years, 1829 60.9% men), 3000 were included in the primary analysis. Rates of initial airway success were 90.3% with LT and 51.6% with ETI. Seventy-two hour survival was 18.3% in the LT group vs 15.4% in the ETI group (adjusted difference, 2.9% 95% CI, 0.2%-5.6%; P = .04). Secondary outcomes in the LT group vs ETI group were return of spontaneous circulation (27.9% vs 24.3%; adjusted difference, 3.6% 95% CI, 0.3%-6.8%; P = .03); hospital survival (10.8% vs 8.1%; adjusted difference, 2.7% 95% CI, 0.6%-4.8%; P = .01); and favorable neurological status at discharge (7.1% vs 5.0%; adjusted difference, 2.1% 95% CI, 0.3%-3.8%; P = .02). There were no significant differences in oropharyngeal or hypopharyngeal injury (0.2% vs 0.3%), airway swelling (1.1% vs 1.0%), or pneumonia or pneumonitis (26.1% vs 22.3%). CONCLUSIONS AND RELEVANCE: Among adults with OHCA, a strategy of initial LT insertion was associated with significantly greater 72-hour survival compared with a strategy of initial ETI. These findings suggest that LT insertion may be considered as an initial airway management strategy in patients with OHCA, but limitations of the pragmatic design, practice setting, and ETI performance characteristics suggest that further research is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02419573
Adsorbed molecules can significantly affect the properties of atomically thin materials. Physisorbed water plays a significant role in altering the optoelectronic properties of single‐layer MoS2, one ...such 2D film. Here the distinct quenching effect of adsorbed water on the photoluminescence of single‐layer MoS2 is demonstrated through scanning‐probe and optical microscopy.
The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma ...kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance.
Small cell lung cancer
TP53
mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-type
...TP53
(vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study was not designed to detect overall response rate differences between arms. Of 69 patients enrolled (performance status 0/1, median age 62 years), 55 were treated in stage 1 (18 in arm A, 20 in arm B, and 17 in arm C) and 14 in stage 2 (arm C only), per 2-stage Simon Minimax design. The vaccine was safe, with mostly grade 1/2 toxicities, although 1 arm-B patient experienced grade 3 fatigue and 8 arm-C patients experienced grade 3 toxicities. Positive immune responses were obtained in 20% of arm B (95% confidence interval CI, 5.3–48.6) and 43.3% of arm C (95% CI 23.9–65.1). The ORRs to the second-line chemotherapy (including paclitaxel) were 15.4% (95% CI 2.7–46.3), 16.7% (95% CI 2.9–49.1), and 23.8% (95% CI 9.1–47.5) for arms A, B, and C, with no survival differences between arms. Although our vaccine failed to improve ORRs to the second-line chemotherapy, its safety profile and therapeutic immune potential remain. Combinations with the other immunotherapeutic agents are reasonable options.
Summary
Purpose
LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation ...study evaluated the combination of LY with pemetrexed/carboplatin.
Patients and Methods
Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10–120 mg) plus pemetrexed/carboplatin (500 mg/m
2
and 5–6 AUC, respectively) across 8 dose levels every 21 days. Primary objective was maximum tolerated dose (MTD) determination; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics.
Results
MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥40 mg: grade 2 visual disturbance (
n
= 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (
n
= 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (
n
= 4) and grade 4 neutropenia (
n
= 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer
n
= 3, mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approximately linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY.
Conclusions
The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 weeks plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.
Purpose To investigate the morphologic features and clinical efficacy of barely visible Pascal (Optimedica Corporation) photocoagulation burns in diabetic macular edema (DME) using Fourier-domain ...optical coherence tomography (FD OCT) and fundus autofluorescence (AF). Design Interventional case series. Methods Retrospective evaluation of 10 eyes with newly diagnosed DME that underwent barely visible Pascal photocoagulation using an array of 10-μm, 10-millisecond photocoagulation burns. FD OCT and camera-based AF was performed at baseline and at 1 hour, 2 weeks, 4 weeks, and 12 weeks after laser. Changes in retinal thickening after laser treatment were measured using retinal thickness maps within the treated sector and the central foveal subfield. Results At 1 hour after treatment, burns were visualized partially with clinical biomicroscopy. AF demonstrated spots lacking autofluorescence that confirmed effective laser uptake within the Pascal arrays. Sequential changes in hyperreflectivity on FD OCT correlated with morphologic alterations seen on AF. Burns became increasingly hyperautofluorescent between 2 and 4 weeks. There were significant reductions in the retinal thickness within treated sectors on FD OCT at 2 weeks (26 ± 32 μm; P = .012) and 3 months after laser (20 ± 21 μm; P = .02) compared with baseline. Clinical biomicroscopic reduction of DME was the most common finding in 80%. Conclusions Barely visible 10-millisecond Pascal laser seems to produce an effect at the level of the inner and outer photoreceptor segments and apical retinal pigment epithelium, with minimal axial and lateral spread of burns. FD OCT confirmed spatial localization of AF signal changes that correlated with laser burn–tissue interactions over 3 months. The technique of lower-fluence barely visible 10-millisecond laser may reduce retinal edema within affected sectors and effectively treat DME with minimization of scar formation.
Diagnosis of infections of public health significance, such as leptospirosis, often present challenges for laboratories. To counter common challenges and ensure quality driven health responses, ...rigorous validation and verification processes are required. Despite such rigor, however, can one be certain laboratory reports are truly reflective of infection, given the risk of rare, but potentially very significant quality oversights? Here we present a real-world scenario where diagnosis of leptospirosis cases was compromised over a 6-year period despite quality measures suggesting a well performing serological assay. A subsequent investigation revealed this was attributed to the programming of an automated microtitration plate analyser, evading detection by both quality control and external quality assurance processes. The quality oversight provides insight into potential limitations in quality processes in multi-targeted serological platforms.
•The E. coli lacZ reversion assay was used to measure mutation frequencies.•Revertant frequencies are higher when there are fewer viable cells per plate.•The increase in revertant frequency shares ...properties with adaptive mutation.•An artifact that mimics mutagenesis may occur after toxic but nonmutagenic treatments.
The lacZ reversion assay in Escherichia coli measures point mutations that occur by specific base substitutions and frameshift mutations. The tester strains cannot use lactose as a carbon source (Lac−), and revertants are easily detected by growth on lactose medium (Lac+). Six strains identify the six possible base substitutions, and five strains measure +G, −G, −CG, +A and −A frameshifts. Strong mutagens give dose-dependent increases in numbers of revertants per plate and revertant frequencies. Testing compounds that are arguably nonmutagens or weakly mutagenic, we often noted statistically significant dose-dependent increases in revertant frequency that were not accompanied by an absolute increase in numbers of revertants. The increase in frequency was wholly ascribable to a declining number of viable cells owing to toxicity. Analysis of the conditions revealed that the frequency of spontaneous revertants is higher when there are fewer viable cells per plate. The phenomenon resembles “adaptive” or “stress” mutagenesis, whereby lactose revertants accumulate in Lac− bacteria under starvation conditions in the absence of catabolite repression. Adaptive mutation is observed after long incubation and might be expected to be irrelevant in a standard assay using 48-h incubation. However, we found that elevated revertant frequencies occur under typical assay conditions when the bacterial lawn is thin, and this can cause increases in revertant frequency that mimic chemical mutagenesis when treatments are toxic but not mutagenic. Responses that resemble chemical mutagenesis were observed in the absence of mutagenic treatment in strains that revert by different frameshift mutations. The magnitude of the artifact is affected by cell density, dilution, culture age, incubation time, catabolite repression and the age and composition of media. Although the specific reversion assay is effective for quickly distinguishing classes of mutations induced by potent mutagens, its utility for discerning effects of weak mutagens may be compromised by the artifact.
After more than 35 years of exposure to Equal Employment Opportunity (EEO) laws, employers in the United States are struggling to understand and effectively deal with the challenges of employee ...rights and needs in the workplace. The workplace of the early 21st century is a much more diverse and dynamic environment than that visualized by legislative crafters of EEO laws. Though religion was addressed in the original laws, the primary focus was accommodation for religious observances outside the workplace. However, technology, global competition, downsizing, and reengineering have created a workforce of employees seeking value, support, and meaning in their lives that finds expression not only at home but also on the job. This search for religious and spiritual meaning in the workplace is a departure from the more traditional business mentality of "power, profit, and takeovers, where religion was something saved for the Sabbath day." Greater spiritual and religious accommodation has become a source for achieving that meaning and support. Legal interpretations have historically required that employees requesting religious accommodation meet certain tests relative to the sincerity and meaningfulness of their belief. The practice of spirituality through meditation, visioning, or spiritual contemplation has become increasingly prevalent in the United States work environment and has remained less controversial and less subject to regulation as an employee rights issue than formal religion. Those practicing formal religion want the same opportunities and rights provided to employees who practice spirituality. This article investigates the current state of religious and spiritual practice in business organizations and discusses the impact of employment law on such activity. We offer a broad and inclusive interpretation of religious and spiritual belief relevant to the workplace and provide a framework of analysis in addressing accommodation concerns.
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